|
1
|
Zhao L, Cui Z, Ouyang J, Qu H, Gao Z. Childhood triglyceride-glucose index and pre-hypertension in adulthood: a prospective cohort study. Front Endocrinol (Lausanne) 2025; 16:1489325. [PMID: 40297176 PMCID: PMC12034547 DOI: 10.3389/fendo.2025.1489325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 03/24/2025] [Indexed: 04/30/2025] Open
Abstract
Background The triglyceride-glucose (TyG) index serves as a surrogate marker for insulin resistance. Multiple studies have demonstrated a positive correlation between the TyG index and blood pressure, indicating that a high TyG index is related to a greater risk of developing pre-hypertension (pre-HTN) and hypertension (HTN). However, the relationship between changes in the TyG index during childhood and pre-HTN in adulthood requires further clarification. Methods The present prospective study utilized data from the Bogalusa Heart Study, a long-term follow-up study. Data on triglycerides (TG), fasting glucose (Fg), and low-density lipoprotein cholesterol (LDL-C) were collected from cross-sectional examinations of participants during childhood. Blood pressure (BP) in early adulthood was categorized into normotensive and pre-HTN groups. Logistic regression was employed to evaluate the relationship between the TyG index in childhood and pre-HTN in adulthood. Results A total of 1,222 participants were included in the study, of whom 258 presented with pre-HTN in adulthood. Significant differences were observed in baseline TyG index, body mass index (BMI), and high-density lipoprotein cholesterol (HDL-C) between the two groups. In both unadjusted logistic regression (Odds Ratio (OR):1.8, 95% CI: 1.4, 2.5, P < 0.001) and simple adjustment (OR: 1.7, 95% CI: 1.2, 2.3, P = 0.003), childhood TyG index were significantly associated with pre-HTN in adulthood. However, this significant relationship disappeared after full adjustment (OR: 1.2, 95% CI: 0.8, 1.9, P = 0.373) which extended Model 1 by including adjustments for baseline BMI, baseline HDL-C, baseline LDL-C, smoking status, drinking status, use of antihypertensive medication and family history of HTN.Stratified analysis in Model 2 showed that gender and race significantly affected the relationship between TyG index and BP. In the male population, elevated TyG index levels increased the probability of pre-HTN, whereas no such relationship was found in female (Male: OR: 1.9, 95% CI: 1.1, 3.5, P = 0.029; Female: OR: 0.8, 95% CI: 0.4, 1.4, P = 0.447; P for interaction = 0.037). Similarly, in American Caucasians, TyG was positively associated with the risk of pre-HTN, but this relationship was not observed in African American (American Caucasian: OR: 1.7, 95% CI: 1.0, 2.9, P = 0.035; African American: OR: 0.5, 95% CI: 0.2, 1.1, P = 0.087; P for interaction = 0.007). Conclusions In males and Caucasians, elevated TyG index during childhood can increase the risk of pre-HTN in adulthood. Monitoring the TyG index may help in screening individuals at higher risk of pre-HTN.
Collapse
Affiliation(s)
- Lingli Zhao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhijie Cui
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiahui Ouyang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hua Qu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Zhuye Gao
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| |
Collapse
|
|
2
|
Nadeau KJ, Arslanian SA, Bacha F, Caprio S, Chao LC, Farrell R, Hughan KS, Rayas M, Tung M, Cross K, El Ghormli L. Insulin clearance at randomisation and in response to treatment in youth with type 2 diabetes: a secondary analysis of the TODAY randomised clinical trial. Diabetologia 2025; 68:676-687. [PMID: 39706874 DOI: 10.1007/s00125-024-06327-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Accepted: 09/26/2024] [Indexed: 12/23/2024]
Abstract
AIMS/HYPOTHESIS Insulin resistance and compensatory hyperinsulinaemia are core features leading to beta cell failure in youth-onset type 2 diabetes. Insulin clearance (IC) is also a key regulator of insulin concentrations, but few data exist on IC in youth-onset type 2 diabetes. In a secondary analysis of our Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) randomised clinical trial, we investigated potential sex-, race-, ethnicity- and treatment-related differences in IC in youth-onset type 2 diabetes and aimed to identify metabolic phenotypes associated with IC at baseline and in response to metformin, metformin plus a lifestyle intervention, and metformin plus rosiglitazone. METHODS A total of 640 youth aged 10-18 years with type 2 diabetes underwent fasting blood tests, anthropometric measurements, dual-energy x-ray absorptiometry to estimate subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) mass, and OGTTs longitudinally over 5 years. IC was calculated from the fasting C-peptide:insulin ratio (fasting IC) and 2 h OGTT C-peptide incremental AUC (iAUC):insulin iAUC ratio (2 h IC). Linear mixed models were used to assess covariate effects on the mean of IC over repeated time points. RESULTS Baseline fasting IC (×10-2 nmol/pmol) was significantly lower in female participants than male participants (median [IQR] 0.72 [0.57-0.93] vs 0.79 [0.63-1.00], respectively; p=0.04) and in non-Hispanic Black participants than Hispanic and non-Hispanic White participants (median [IQR] 0.64 [0.51-0.81] vs 0.78 [0.64-1.00] vs 0.84 [0.68-1.01], respectively; p<0.0001). Similar results were observed for 2 h IC. Lower IC most strongly correlated with higher weight over time (% change [95% CI] in IC per 5 kg increase: fasting IC -1.52 [-2.05, -0.99]; 2 h IC -3.46 [-4.05, -2.86]). Lower IC also correlated with other markers of adiposity (higher BMI and SAT mass), and markers of insulin sensitivity (higher waist:height ratio, VAT mass, VAT:SAT mass ratio, triacylglycerol concentrations, triacylglycerol:HDL-cholesterol ratio, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] concentrations, and systolic and diastolic BP, and lower HDL-cholesterol and total and high molecular weight adiponectin concentrations) over time. Beta cell function as determined from OGTTs, not insulin sensitivity or IC, was predictive of persistently elevated blood glucose levels. IC was higher with metformin+rosiglitazone than metformin alone (p=0.03 for fasting IC; p=0.02 for 2 h IC) and metformin+lifestyle (2 h IC, p=0.005), but not after adjusting for adiponectin (p value not significant for all). CONCLUSIONS/INTERPRETATION In youth with type 2 diabetes, low IC is correlated with female sex, non-Hispanic Black race and ethnicity, and markers of adiposity and insulin resistance, but not with beta cell function. Along with insulin sensitivity and adiponectin, IC increased in response to rosiglitazone treatment. These findings suggest that, in youth-onset type 2 diabetes, low IC is a compensatory response to changes in insulin sensitivity and/or adiponectin concentrations and is not a mediator of beta cell function. TRIAL REGISTRATION ClinicalTrials.gov NCT00081328 DATA AVAILABILITY: Data from the TODAY study (V4; https://doi.org/10.58020/2w6w-pv88 ) reported here are available on request from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research ( https://repository.niddk.nih.gov/ ).
Collapse
Affiliation(s)
| | - Silva A Arslanian
- UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
| | - Sonia Caprio
- Pediatric Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Lily C Chao
- Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Ryan Farrell
- University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital, Cleveland, OH, USA
| | - Kara S Hughan
- UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Maria Rayas
- University of Texas Health Science Center San Antonio, San Antonio, TX, USA
| | - Melinda Tung
- The Biostatistics Center, George Washington University, Rockville, MD, USA
| | - Kaitlyn Cross
- The Biostatistics Center, George Washington University, Rockville, MD, USA
| | - Laure El Ghormli
- The Biostatistics Center, George Washington University, Rockville, MD, USA.
| |
Collapse
|
|
3
|
Abstract
Insulin action is impaired in type 2 diabetes. The functions of the hormone are an integrated product of insulin secretion from pancreatic β-cells and insulin clearance by receptor-mediated endocytosis and degradation, mostly in liver (hepatocytes) and, to a lower extent, in extrahepatic peripheral tissues. Substantial evidence indicates that genetic or acquired abnormalities of insulin secretion or action predispose to type 2 diabetes. In recent years, along with the discovery of the molecular foundation of receptor-mediated insulin clearance, such as through the membrane glycoprotein CEACAM1, a consensus has begun to emerge that reduction of insulin clearance contributes to the disease process. In this review, we consider the evidence suggesting a pathogenic role for reduced insulin clearance in insulin resistance, obesity, hepatic steatosis, and type 2 diabetes.
Collapse
Affiliation(s)
- Sonia M Najjar
- Department of Biomedical Sciences and the Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA;
| | - Sonia Caprio
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology-National Research Council, Pisa, Italy
| |
Collapse
|
|
4
|
Najjar SM, Abdolahipour R, Ghadieh HE, Jahromi MS, Najjar JA, Abuamreh BAM, Zaidi S, Kumarasamy S, Muturi HT. Regulation of Insulin Clearance by Non-Esterified Fatty Acids. Biomedicines 2022; 10:biomedicines10081899. [PMID: 36009446 PMCID: PMC9405499 DOI: 10.3390/biomedicines10081899] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022] Open
Abstract
Insulin stores lipid in adipocytes and prevents lipolysis and the release of non-esterified fatty acids (NEFA). Excessive release of NEFA during sustained energy supply and increase in abdominal adiposity trigger systemic insulin resistance, including in the liver, a major site of insulin clearance. This causes a reduction in insulin clearance as a compensatory mechanism to insulin resistance in obesity. On the other hand, reduced insulin clearance in the liver can cause chronic hyperinsulinemia, followed by downregulation of insulin receptor and insulin resistance. Delineating the cause–effect relationship between reduced insulin clearance and insulin resistance has been complicated by the fact that insulin action and clearance are mechanistically linked to insulin binding to its receptors. This review discusses how NEFA mobilization contributes to the reciprocal relationship between insulin resistance and reduced hepatic insulin clearance, and how this may be implicated in the pathogenesis of non-alcoholic fatty liver disease.
Collapse
Affiliation(s)
- Sonia M. Najjar
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Correspondence: ; Tel.: +1-740-593-2376; Fax: +1-740-593-2320
| | - Raziyeh Abdolahipour
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Hilda E. Ghadieh
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Balamand P.O. Box 100, Lebanon
| | - Marziyeh Salehi Jahromi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - John A. Najjar
- Department of Internal Medicine, College of Medicine, University of Toledo, Toledo, OH 43606, USA
| | - Basil A. M. Abuamreh
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Sobia Zaidi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Sivarajan Kumarasamy
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| | - Harrison T. Muturi
- Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
- Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA
| |
Collapse
|
|
5
|
Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models. Clin Pharmacokinet 2022; 61:1251-1270. [PMID: 35699913 PMCID: PMC9439993 DOI: 10.1007/s40262-022-01132-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 11/24/2022]
Abstract
Background Obesity is associated with physiological changes that can affect drug pharmacokinetics. Obese individuals are underrepresented in clinical trials, leading to a lack of evidence-based dosing recommendations for many drugs. Physiologically based pharmacokinetic (PBPK) modelling can overcome this limitation but necessitates a detailed description of the population characteristics under investigation. Objective The purpose of this study was to develop and verify a repository of the current anatomical, physiological, and biological data of obese individuals, including population variability, to inform a PBPK framework. Methods A systematic literature search was performed to collate anatomical, physiological, and biological parameters for obese individuals. Multiple regression analyses were used to derive mathematical equations describing the continuous effect of body mass index (BMI) within the range 18.5–60 kg/m2 on system parameters. Results In total, 209 studies were included in the database. The literature reported mostly BMI-related changes in organ weight, whereas data on blood flow and biological parameters (i.e. enzyme abundance) were sparse, and hence physiologically plausible assumptions were made when needed. The developed obese population was implemented in Matlab® and the predicted system parameters obtained from 1000 virtual individuals were in agreement with observed data from an independent validation obese population. Our analysis indicates that a threefold increase in BMI, from 20 to 60 kg/m2, leads to an increase in cardiac output (50%), liver weight (100%), kidney weight (60%), both the kidney and liver absolute blood flows (50%), and in total adipose blood flow (160%). Conclusion The developed repository provides an updated description of a population with a BMI from 18.5 to 60 kg/m2 using continuous physiological changes and their variability for each system parameter. It is a tool that can be implemented in PBPK models to simulate drug pharmacokinetics in obese individuals.
Collapse
Affiliation(s)
- Mattia Berton
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. .,University of Basel, Basel, Switzerland.
| | - Sara Bettonte
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | | | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| |
Collapse
|
|
6
|
Koh HCE, Cao C, Mittendorfer B. Insulin Clearance in Obesity and Type 2 Diabetes. Int J Mol Sci 2022; 23:596. [PMID: 35054781 PMCID: PMC8776220 DOI: 10.3390/ijms23020596] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/02/2022] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.
Collapse
Affiliation(s)
| | | | - Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8031-14-0002, St. Louis, MO 63110, USA; (H.-C.E.K.); (C.C.)
| |
Collapse
|
|
7
|
Lamprinou A, Willmann C, Machann J, Schick F, Eckstein SS, Dalla Man C, Visentin R, Birkenfeld AL, Peter A, Stefan N, Häring HU, Fritsche A, Heni M, Wagner R. Determinants of hepatic insulin clearance - Results from a Mendelian Randomization study. Metabolism 2021; 119:154776. [PMID: 33862045 DOI: 10.1016/j.metabol.2021.154776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 04/07/2021] [Accepted: 04/08/2021] [Indexed: 11/22/2022]
Abstract
AIMS/HYPOTHESIS Besides insulin resistance, type 2 diabetes associates with decreased hepatic insulin clearance (HIC). We now tested for causal relationship of HIC to liver fat accumulation or features of the metabolic syndrome. METHODS HIC was derived from oral glucose tolerance tests with the "Oral C-peptide and Insulin Minimal Models" (n = 3311). Liver fat was quantified by magnetic resonance spectroscopy (n = 1211). Mendelian Randomization was performed using established single nucleotide polymorphisms (SNPs; 115 for liver fat, 155 alanine-aminotransferase, 37 insulin sensitivity, 37 insulin secretion, 72 fasting insulin, 5285 BMI, 163 visceral fat, 270 waist circumference, 442 triglycerides, 620 HDL-Cholesterol, 193 C-reactive protein, 53 lipodystrophy-like phenotypes). RESULTS HIC associated inversely with liver fat (p < 0.003) and insulin sensitivity (p < 0.0001). Both liver fat and HIC were independently associated with insulin sensitivity (p < 0.0001). Neither liver fat nor alanine-aminotransferase were causally linked to HIC, as indicated by Mendelian Randomization (Nliver fat = 1054, NHIC = 2254; Nalanineaminotranferase = 1985, NHIC = 2251). BMI-related SNPs were causally associated with HIC (NBMI = 2772, NHIC = 2259, p < 0.001) but not waist circumference-SNPs (NSNPs-waist circumference = 2751, NHIC = 2280). Genetically determined insulin sensitivity was not causally related to HIC (Ninsulin sensitivity = 2752, NHIC = 2286). C-reactive protein and HDL were causally associated with HIC, with higher C-reactive protein and lower HDL leading to higher HIC (NC-reactive protein = 2660, NHIC = 2240; NHDL = 2694, NHIC = 2275). CONCLUSIONS This Mendelian Randomization analysis does not support a causal link between hepatic steatosis and HIC. Other components of the metabolic syndrome seem to compensate peripheral hyperinsulinemia by increasing hepatic insulin extraction.
Collapse
Affiliation(s)
- Apostolia Lamprinou
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Caroline Willmann
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Jürgen Machann
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Fritz Schick
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Section on Experimental Radiology, Department of Diagnostic and Interventional Radiology, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Sabine S Eckstein
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Roberto Visentin
- Department of Information Engineering, University of Padua, Padua, Italy
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas Peter
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany; Department for Diagnostic Laboratory Medicine, Institute for Clinical Chemistry and Pathobiochemistry, University Hospital of Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Hans-Ulrich Häring
- Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas Fritsche
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Martin Heni
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Robert Wagner
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany; Institute of Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen (IDM), Tübingen, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
| |
Collapse
|
|
8
|
Gastaldelli A, Abdul Ghani M, DeFronzo RA. Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance. Diabetes 2021; 70:377-385. [PMID: 33077684 PMCID: PMC7881859 DOI: 10.2337/db19-1152] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 10/16/2020] [Indexed: 12/20/2022]
Abstract
With the development of insulin resistance (IR), there is a compensatory increase in the plasma insulin response to offset the defect in insulin action to maintain normal glucose tolerance. The insulin response is the result of two factors: insulin secretion and metabolic clearance rate of insulin (MCRI). Subjects (104 with normal glucose tolerance [NGT], 57 with impaired glucose tolerance [IGT], and 207 with type 2 diabetes mellitus [T2DM]), divided in nonobese and obese groups, received a euglycemic insulin-clamp (40 mU/m2 ⋅ min) and an oral glucose tolerance test (OGTT) (75 g) on separate days. MCRI was calculated during the insulin-clamp performed with [3-3H]glucose and the OGTT and related to IR: peripheral (glucose uptake during the insulin clamp), hepatic (basal endogenous glucose production × fasting plasma insulin [FPI]), and adipocyte (fasting free fatty acid × FPI). MCRI during the insulin clamp was reduced in obese versus nonobese NGT (0.60 ± 0.03 vs. 0.73 ± 0.02 L/min ⋅ m2, P < 0.001), in nonobese IGT (0.62 ± 0.02, P < 0.004), and in nonobese T2DM (0.68 ± 0.02, P < 0.03). The MCRI during the insulin clamp was strongly and inversely correlated with IR (r = -0.52, P < 0.0001). During the OGTT, the MCRI was suppressed within 15-30 min in NGT and IGT subjects and remained suppressed. In contrast, suppression was minimal in T2DM. In conclusion, the development of IR in obese subjects is associated with a decline in MCRI that represents a compensatory response to maintain normal glucose tolerance but is impaired in individuals with T2DM.
Collapse
Affiliation(s)
- Amalia Gastaldelli
- Institute of Clinical Physiology, Consiglio Nazionale delle Ricerche (CNR), Pisa, Italy
- University of Texas Health Science Center, San Antonio, TX
| | | | | |
Collapse
|
|
9
|
Moghbeli M, Khedmatgozar H, Yadegari M, Avan A, Ferns GA, Ghayour Mobarhan M. Cytokines and the immune response in obesity-related disorders. Adv Clin Chem 2020; 101:135-168. [PMID: 33706888 DOI: 10.1016/bs.acc.2020.06.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The increasing prevalence of obesity and the associated morbidity and mortality are important public health problems globally. There is an important relationship between an unhealthy lifestyle and increased serum inflammatory cytokines. Adipocytes secrete several pro-inflammatory cytokines involved in the recruitment and activation of macrophages resulting in chronic low-grade inflammation. Increased cytokines in obese individual are related to the progression of several disorders including cardiovascular disease, hypertension, and insulin resistance. In present review we have summarized the crucial roles of cytokines and their inflammatory functions in obesity-related immune disorders.
Collapse
Affiliation(s)
- Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Khedmatgozar
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Yadegari
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee and Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Science, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Majid Ghayour Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| |
Collapse
|
|
10
|
Smith GI, Polidori DC, Yoshino M, Kearney ML, Patterson BW, Mittendorfer B, Klein S. Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics. J Clin Invest 2020; 130:3305-3314. [PMID: 32191646 PMCID: PMC7260030 DOI: 10.1172/jci136756] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 03/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUNDInsulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODSA hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTSInsulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSIONHyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver's maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation.
Collapse
Affiliation(s)
- Gordon I. Smith
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | | | - Mihoko Yoshino
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Monica L. Kearney
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Bruce W. Patterson
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA
| |
Collapse
|
|
11
|
Hammoutene A, Biquard L, Lasselin J, Kheloufi M, Tanguy M, Vion AC, Mérian J, Colnot N, Loyer X, Tedgui A, Codogno P, Lotersztajn S, Paradis V, Boulanger CM, Rautou PE. A defect in endothelial autophagy occurs in patients with non-alcoholic steatohepatitis and promotes inflammation and fibrosis. J Hepatol 2020; 72:528-538. [PMID: 31726115 DOI: 10.1016/j.jhep.2019.10.028] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 10/15/2019] [Accepted: 10/28/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Previous studies demonstrated that autophagy is protective in hepatocytes and macrophages, but detrimental in hepatic stellate cells in chronic liver diseases. The role of autophagy in liver sinusoidal endothelial cells (LSECs) in non-alcoholic steatohepatitis (NASH) is unknown. Our aim was to analyze the potential implication of autophagy in LSECs in NASH and liver fibrosis. METHODS We analyzed autophagy in LSECs from patients using transmission electron microscopy. We determined the consequences of a deficiency in autophagy: (a) on LSEC phenotype, using primary LSECs and an LSEC line; (b) on early stages of NASH and on advanced stages of liver fibrosis, using transgenic mice deficient in autophagy specifically in endothelial cells and fed a high-fat diet or chronically treated with carbon tetrachloride, respectively. RESULTS Patients with NASH had half as many LSECs containing autophagic vacuoles as patients without liver histological abnormalities, or with simple steatosis. LSECs from mice deficient in endothelial autophagy displayed an upregulation of genes implicated in inflammatory pathways. In the LSEC line, deficiency in autophagy enhanced inflammation (Ccl2, Ccl5, Il6 and VCAM-1 expression), features of endothelial-to-mesenchymal transition (α-Sma, Tgfb1, Col1a2 expression) and apoptosis (cleaved caspase-3). In mice fed a high-fat diet, deficiency in endothelial autophagy induced liver expression of inflammatory markers (Ccl2, Ccl5, Cd68, Vcam-1), liver cell apoptosis (cleaved caspase-3) and perisinusoidal fibrosis. Mice deficient in endothelial autophagy treated with carbon tetrachloride also developed more perisinusoidal fibrosis. CONCLUSIONS A defect in autophagy in LSECs occurs in patients with NASH. Deficiency in endothelial autophagy promotes the development of liver inflammation, features of endothelial-to-mesenchymal transition, apoptosis and liver fibrosis in the early stages of NASH, but also favors more advanced stages of liver fibrosis. LAY SUMMARY Autophagy is a physiological process controlling endothelial homeostasis in vascular beds outside the liver. This study demonstrates that autophagy is defective in the liver endothelial cells of patients with non-alcoholic steatohepatitis. This defect promotes liver inflammation and fibrosis at early stages of non-alcoholic steatohepatitis, but also at advanced stages of chronic liver disease.
Collapse
Affiliation(s)
- Adel Hammoutene
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | - Louise Biquard
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | | | | | - Marion Tanguy
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | | | - Jules Mérian
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Nathalie Colnot
- Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | - Xavier Loyer
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Alain Tedgui
- Université de Paris, PARCC, INSERM, F-75015, Paris, France
| | - Patrice Codogno
- Université de Paris, INEM, INSERM, F-75014, Paris, France; CNRS UMR-8253, 75014, Paris, France
| | - Sophie Lotersztajn
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France
| | - Valérie Paradis
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France; Service d'Anatomie Pathologique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France
| | | | - Pierre-Emmanuel Rautou
- Université de Paris, PARCC, INSERM, F-75015, Paris, France; Université de Paris, Centre de recherche sur l'inflammation, Inserm, U1149, CNRS, ERL8252, F-75018, Paris, France; Service d'Hépatologie, DHU Unity, DMU Digest, Hôpital Beaujon, AP-HP, Clichy, France; Centre de Référence des Maladies Vasculaires du Foie, French Network for Rare Liver Diseases (FILFOIE), European Reference Network on Hepatological Diseases (ERN RARE-LIVER).
| |
Collapse
|
|
12
|
Halenova T, Zlatskiy I, Syroeshkin A, Maximova T, Pleteneva T. Deuterium-Depleted Water as Adjuvant Therapeutic Agent for Treatment of Diet-Induced Obesity in Rats. Molecules 2019; 25:E23. [PMID: 31861678 PMCID: PMC6982901 DOI: 10.3390/molecules25010023] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/03/2019] [Accepted: 12/12/2019] [Indexed: 12/26/2022] Open
Abstract
In this study, we present the potential application of deuterium-depleted water (DDW) for the prevention and adjuvant treatment of obesity in rats. We tested the hypothesis that DDW can alleviate diet-induced obesity (DIO) and its associated metabolic impairments. Rats fed a high-fat diet had an increased body weight index (BWI), glucose concentration, and level of certain proinflammatory cytokines; decreased levels of insulin in the serum; decreased tryptophan and serotonin in the brain, and a decreased concentration of some heavy metals in the liver. Drinking DDW at a concentration of 10 ppm deuterium/protium (D/H) ad libitum for 3 weeks restored the BWI, glucose (serum), tryptophan (brain), and serotonin (brain) levels and concentration of Zn in the liver in the DIO animals to those of the controls. The levels of proinflammatory cytokines (IL-1β, IL-6, IFNγ) and anti-inflammatory TNFα were decreased in DIO rats, while anti-inflammatory cytokine (IL-4, IL-10) levels remained at the control levels, which is indicative of a pathophysiological syndrome. In contrast, in groups of rats treated with DDW, a significant increase in anti-inflammatory (IL-4, IL-10) and proinflammatory cytokines (IFNγ) was observed. This finding indicates a reduction in systemic inflammation in obese animals treated with DDW. Similarly, the high-fat diet caused an increased level of oxidative stress products, which was accompanied by decreased activity of both superoxide dismutase and catalase, whereas the administration of DDW decreased the level of oxidative stress and enhanced antioxidant enzyme activities.
Collapse
Affiliation(s)
- Tetiana Halenova
- Taras Shevchenko National University of Kyiv, ESC “Institute of Biology and Medicine”, 64 Volodymyrska Str., 01601 Kyiv, Ukraine;
| | - Igor Zlatskiy
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian; (A.S.); (T.M.); (T.P.)
- State Institute of Genetic and Regenerative Medicine NAMS of Ukraine, 67 Vyshgorodska Str., 04114 Kyiv, Ukraine
| | - Anton Syroeshkin
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian; (A.S.); (T.M.); (T.P.)
| | - Tatiana Maximova
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian; (A.S.); (T.M.); (T.P.)
| | - Tatiana Pleteneva
- Peoples Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St, Moscow 117198, Russian; (A.S.); (T.M.); (T.P.)
| |
Collapse
|
|
13
|
Hodson L, Karpe F. Hyperinsulinaemia: does it tip the balance toward intrahepatic fat accumulation? Endocr Connect 2019; 8:R157-R168. [PMID: 31581129 PMCID: PMC6826170 DOI: 10.1530/ec-19-0350] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Accepted: 09/26/2019] [Indexed: 12/12/2022]
Abstract
In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.
Collapse
Affiliation(s)
- Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, UK
| | - Fredrik Karpe
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC), Oxford University Hospital Trusts, Oxford, UK
| |
Collapse
|
|
14
|
Zarrati M, Aboutaleb N, Cheshmazar E, Shoormasti RS, Razmpoosh E, Nasirinezhad F. The association of obesity and serum leptin levels with complete blood count and some serum biochemical parameters in Iranian overweight and obese individuals. Med J Islam Repub Iran 2019; 33:72. [PMID: 31696066 PMCID: PMC6825403 DOI: 10.34171/mjiri.33.72] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Indexed: 02/06/2023] Open
Abstract
Background: Obesity has been suggested to be well correlated with altered levels of complete blood count (CBC) parameters. In this study, the relationship of body mass index (BMI) and circulating leptin levels with CBC among obese and overweight adults was examined. Methods: CBC and biochemical parameters, WBC and hematological profiles, leptin levels, related factors to liver, and kidney and lipid profiles were measured among 184 obese and overweight people aged 18-60 years. Statistical analysis was performed using SPSS software. To assess the normality of data, the Kolmogorov-Smirnov test was used. Logarithmic transformation was performed for some variables with non-normal distribution. The association between 2 quantitative variables was measured using bivariate correlation (Pearson or Spearman). Pearson correlations and multiple regression analysis were performed to assess the correlation between variables. Simple and multiple regression analyses were performed to predict some variables. P- value <0.05 was considered significant. Results: Hematocrit, insulin, fasting blood sugar, uric acid, TG, LDL-C, VLDL-C, and ALT were positively correlated with BMI (p=0.041, r=0.149 for hematocrit; p≤0.001, r=0.520 for insulin; p≤0.001, r=0.363 for FBS; p≤0.001, r=0.309 for uric acid; p=0.015, r=0.189 for TG; p=0.030, r=161 for LDL-C; p=0.019, r=0.181 for VLDL-C; p≤0.001, r=0.299 for ALT), whereas urea and HDL-C were negatively correlated with BMI (p≤0.001, r=-0.368 for urea; p≤0.001, r=-0.297 for HDL-C). Moreover, LDL-C and insulin were positively correlated with leptin (P = 0.011, r = 0.194 for LDL-C, P = 0.013, r = 0.114 for insulin) and hematocrit, urea, creatinine, TG and VLDL-C were negatively correlated with leptin (p=0.040, r=-0.162 for hematocrit; p≤0.001, r=-0.305 for urea; p=0.007, r=-0.219 for creatinine; p=0.025, r=0.188 for TG; p=0.007, r=-0.218 for VLDL-C). Our analysis showed that white blood cell was positively correlated with leptin (β=17.36, p=0.048). Also, other CBC parameters had no significant correlations with BMI and leptin. Conclusion: According to the findings of this study, BMI had a negative association with urea and HDL-C, while BMI had a positive association with insulin, hematocrit, FBS, uric acid, TG, VLDL-C, LDL-C, and ALT. Furthermore, leptin had a negative association with hematocrit, creatinine, and urea, TG, VLDL-C and a positive association with LDL-C and insulin among the participants of this study.
Collapse
Affiliation(s)
- Mitra Zarrati
- Faculty of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Nahid Aboutaleb
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Elhameh Cheshmazar
- Faculty of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | | | - Elham Razmpoosh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Farinaz Nasirinezhad
- Department of physiology, Basic Science Center, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
15
|
Ye M, Robson PJ, Eurich DT, Vena JE, Xu JY, Johnson JA. Anthropometric changes and risk of diabetes: are there sex differences? A longitudinal study of Alberta's Tomorrow Project. BMJ Open 2019; 9:e023829. [PMID: 31326923 PMCID: PMC6661609 DOI: 10.1136/bmjopen-2018-023829] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 02/19/2019] [Accepted: 06/21/2019] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVES To characterise the sex-specific difference in the association between anthropometric changes and risk of diabetes in the general population in Canada. SETTING AND PARTICIPANTS From 2000 to 2008, Alberta's Tomorrow Project (ATP) invited Alberta's residents aged 35-69 years to a prospective cohort study. A total of 19 655 diabetes-free ATP participants having anthropometrics measured at the baseline and follow-ups were included. DESIGN AND OUTCOME MEASURES A longitudinal study design was used to examine the association between anthropometric changes and risk of diabetes and the sex difference in this association. Changes in weight, body mass index (BMI), waist circumference (WC) and waist-hip-ratio (WHR) were calculated as the difference between baseline and follow-up measures. Diabetes cases were identified using the Canadian National Diabetes Surveillance System algorithm with administrative healthcare data (2000-2015) linked to the ATP cohort. The sex-specific association between anthropometric changes and incidence of diabetes were examined by multivariable Cox regression models. RESULTS Changes in weight, BMI, WC and WHR over time were positively associated with incidence of diabetes in both men and women. The sex difference in risk of diabetes associated with 1 standard deviation (SD) increase in anthropometrics was 0.07 (95% CI -0.02 to 0.14) for weight, 0.08 (95% CI -0.03 to 0.17) for BMI, 0.07 (95% CI -0.02 to 0.15) for WC and 0.09 (95% CI 0.03 to 0.13) for WHR. Similar results were found in sex difference in the associations with changes per 5% and changes per categories (5% loss, ±5%, 5% gain). CONCLUSIONS The positive association between anthropometric changes and risk of diabetes was generally stronger in men than in women. However, this sex-specific difference of approximately 10% of the total risk associated with anthropometric changes had limited significance. For population-based public health programmes aiming to control obesity and incidence of diabetes, it may not be necessary to set up sex-specific goals for anthropometric reduction.
Collapse
Affiliation(s)
- Ming Ye
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Paula J Robson
- CancerControl Alberta, Alberta Health Services, Edmonton, Alberta, Canada
- Agricultural, Food and Nutritional Science, Faculty of Agricultural, Life & Environmental Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - Dean T Eurich
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| | - Jennifer E Vena
- Alberta's Tomorrow Project, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada
| | - Jian-Yi Xu
- Alberta's Tomorrow Project, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada
| | - Jeffrey A Johnson
- School of Public Health, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
16
|
Utzschneider KM, Kahn SE, Polidori DC. Hepatic Insulin Extraction in NAFLD Is Related to Insulin Resistance Rather Than Liver Fat Content. J Clin Endocrinol Metab 2019; 104:1855-1865. [PMID: 30566676 PMCID: PMC6456889 DOI: 10.1210/jc.2018-01808] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 12/14/2018] [Indexed: 02/08/2023]
Abstract
CONTEXT Total insulin clearance is decreased in nonalcoholic fatty liver disease (NAFLD), but the relationship between liver fat and hepatic insulin extraction (HIE) is unknown. OBJECTIVE This cross-sectional study addresses the hypothesis that HIE is reduced in NAFLD and investigates metabolic and/or anthropometric characteristics most closely associated with insulin clearance. PARTICIPANTS Nondiabetic subjects with NAFLD (n = 13) and age- and body mass index (BMI)-matched controls with normal liver enzymes (n = 15) underwent abdominal CT, dual-energy X-ray absorptiometry, oral glucose tolerance test (OGTT), and labeled two-step hyperinsulinemic-euglycemic clamps. OUTCOME MEASUREMENTS Liver fat was estimated by the CT liver/spleen ratio. Hepatic and extrahepatic insulin clearances were modeled using clamp and OGTT data. RESULTS Extrahepatic insulin clearance and HIE were not different between NAFLD and controls and did not correlate with liver fat. HIE was positively correlated with insulin sensitivity [rate of glucose disposal (Rd; low r = +0.7, P < 0.001; high r = +0.6, P = 0.001), adiponectin (r = +0.55, P = 0.004), and insulin-mediated suppression of clamp nonesterified free fatty acid (NEFA; r = +0.67, P < 0.001)] but was not associated with fasting NEFA, insulin-mediated suppression of glucose production, or measures of adiposity. Extrahepatic insulin clearance was positively associated with percent body fat (r = +0.44, P = 0.02) and subcutaneous fat (r = +0.42, P = 0.03) but not BMI, intra-abdominal fat, liver fat, Rd, adiponectin, or NEFA. CONCLUSIONS HIE is not directly associated with hepatic steatosis but is associated with muscle and adipose tissue insulin resistance. The data suggest differential regulation of insulin clearance with extrahepatic insulin clearance being associated with body fat and not insulin sensitivity.
Collapse
Affiliation(s)
- Kristina M Utzschneider
- Division of Endocrinology, Hospital Specialty Medicine, VA Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington
- Correspondence and Reprint Requests: Kristina M. Utzschneider, MD, VA Puget Sound Health Care System, 1660 S. Columbian Way (151), Seattle, Washington 98108. E-mail:
| | - Steven E Kahn
- Division of Endocrinology, Hospital Specialty Medicine, VA Puget Sound Health Care System, Seattle, Washington
- Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, Washington
| | | |
Collapse
|
|
17
|
Høgild ML, Bak AM, Pedersen SB, Rungby J, Frystyk J, Møller N, Jessen N, Jørgensen JOL. Growth hormone signaling and action in obese versus lean human subjects. Am J Physiol Endocrinol Metab 2019; 316:E333-E344. [PMID: 30576246 DOI: 10.1152/ajpendo.00431.2018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Growth hormone (GH) levels are blunted in obesity, but it is not known whether this relates to altered GH sensitivity and whether this influences the metabolic adaptation to fasting. Therefore, we investigated the effect of obesity on GH signal transduction and fasting-induced changes in GH action. Nine obese (BMI 35.7 kg/m2) and nine lean (BMI 21.5 kg/m2) men were studied in a randomized crossover design with 1) an intravenous GH bolus, 2) an intravenous saline bolus, and 3) 72 h of fasting. Insulin sensitivity (hyperinsulinemic, euglycemic clamp) and substrate metabolism (glucose tracer and indirect calorimetry) were measured in studies 1 and 2. In vivo GH signaling was assessed in muscle and fat biopsies. GH pharmacokinetics did not differ between obese and lean subjects, but endogenous GH levels were reduced in obesity. GH signaling (STAT5b phosphorylation and CISH mRNA transcription), and GH action (induction of lipolysis and peripheral insulin resistance) were similar in the two groups, but a GH-induced insulin antagonistic effect on endogenous glucose production only occurred in the obese. Fasting-induced IGF-I reduction was completely abrogated in obese subjects despite a comparable relative increase in GH levels (ΔIGF-I: lean, -66 ± 10 vs. obese, 27 ± 16 µg/l; P < 0.01; ΔGH: lean, 647 ± 280 vs. obese, 544 ± 220%; P = 0.76]. We conclude that 1) GH signaling is normal in obesity, 2) in the obese state, the preservation of IGF-I with fasting and the augmented GH-induced central insulin resistance indicate increased hepatic GH sensitivity, 3) blunted GH levels in obesity may protect against insulin resistance without compromising IGF-I status.
Collapse
Affiliation(s)
- Morten Lyng Høgild
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| | - Ann Mosegaard Bak
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| | - Steen Bønløkke Pedersen
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| | - Jørgen Rungby
- Department of Biomedicine, Aarhus University , Denmark
| | - Jan Frystyk
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| | - Niels Møller
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| | - Niels Jessen
- Department of Clinical Medicine, Aarhus University , Denmark
- Department of Biomedicine, Aarhus University , Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital , Denmark
| | - Jens O L Jørgensen
- Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital , Denmark
- Department of Clinical Medicine, Aarhus University , Denmark
| |
Collapse
|
|
18
|
Bojsen-Møller KN, Lundsgaard AM, Madsbad S, Kiens B, Holst JJ. Hepatic Insulin Clearance in Regulation of Systemic Insulin Concentrations-Role of Carbohydrate and Energy Availability. Diabetes 2018; 67:2129-2136. [PMID: 30348819 DOI: 10.2337/db18-0539] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 07/27/2018] [Indexed: 11/13/2022]
Abstract
Hyperinsulinemia is the hallmark of insulin resistance in obesity, and the relative importance of insulin clearance, insulin resistance, and insulin hypersecretion has been widely debated. On the basis of recent experimental evidence, we summarize existing evidence to suggest hepatic insulin clearance as a major and immediate regulator of systemic insulin concentrations responding within days to altered dietary energy and, in particular, carbohydrate intake. Hepatic insulin clearance seems to be closely associated with opposite alterations in hepatic lipid content and glucose production, providing a potential mechanistic link to hepatic insulin sensitivity. The molecular regulation of insulin clearance in the liver is likely to involve changes in insulin binding and receptor internalization in response to the dietary alterations, the molecular mechanisms of which await further research.
Collapse
Affiliation(s)
- Kirstine N Bojsen-Møller
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Anne-Marie Lundsgaard
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Sten Madsbad
- Department of Endocrinology, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bente Kiens
- Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
| | - Jens Juul Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
19
|
Varghese RT, Man CD, Laurenti MC, Piccinini F, Sharma A, Shah M, Bailey KR, Rizza RA, Cobelli C, Vella A. Performance of individually measured vs population-based C-peptide kinetics to assess β-cell function in the presence and absence of acute insulin resistance. Diabetes Obes Metab 2018; 20:549-555. [PMID: 28862812 PMCID: PMC5946313 DOI: 10.1111/dom.13106] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/22/2017] [Accepted: 08/29/2017] [Indexed: 01/07/2023]
Abstract
AIMS To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate β-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where β-cell function is measured. METHODS Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS These data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during an OGTT.
Collapse
Affiliation(s)
- Ron T. Varghese
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, 200 1 St SW, 5-194 Joseph, Rochester, Minnesota USA
| | - Chiara Dalla Man
- Department of Information Engineering, Universita’ di Padova, Via Gradenigo 6B, Padova, Italy
| | - Marcello C. Laurenti
- Department of Information Engineering, Universita’ di Padova, Via Gradenigo 6B, Padova, Italy
| | - Francesca Piccinini
- Department of Information Engineering, Universita’ di Padova, Via Gradenigo 6B, Padova, Italy
| | - Anu Sharma
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, 200 1 St SW, 5-194 Joseph, Rochester, Minnesota USA
| | - Meera Shah
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, 200 1 St SW, 5-194 Joseph, Rochester, Minnesota USA
| | - Kent R. Bailey
- Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 1 St SW, Rochester, Minnesota USA
| | - Robert A. Rizza
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, 200 1 St SW, 5-194 Joseph, Rochester, Minnesota USA
| | - Claudio Cobelli
- Department of Information Engineering, Universita’ di Padova, Via Gradenigo 6B, Padova, Italy
| | - Adrian Vella
- Division of Endocrinology, Diabetes & Metabolism, Mayo Clinic, 200 1 St SW, 5-194 Joseph, Rochester, Minnesota USA
| |
Collapse
|
|
20
|
Effect of C 60 fullerene nanoparticles on the diet-induced obesity in rats. Int J Obes (Lond) 2018; 42:1987-1998. [PMID: 30401827 DOI: 10.1038/s41366-018-0016-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 11/13/2017] [Accepted: 12/27/2017] [Indexed: 01/04/2023]
Abstract
BACKGROUND Obesity is a growing global health problem. Since increased oxidative stress is one of the key pathological mechanisms underpinning overweight and strongly correlates with progression of obesity-related complications we hypothesized that C60 fullerene nanoparticles, due to their strong antioxidant capacity, could be the promising therapeutic agent in the treatment of this disease. Here we investigated whether the C60 fullerenes can alleviate diet-induced obesity (DIO) and metabolic impairments associated with it. METHODS To determine the effect of C60 fullerenes on some nutritional and metabolic parameters, rats were fed either a normal diet (6.7% fat, 15.27 kJ·g-1) or a high-fat diet (38.8% fat, 28.71 kJ·g-1) for 70 days and were simultaneously treated per os with pristine C60 fullerene aqueous solution (C60FAS; 0.3 mg·kg-1 every other day) since the 28th day from the start of the experiment. RESULTS Rats fed with high fat diet had significantly increased body mass index (BMI), levels of insulin, glucose, glycosilated hemoglobin (HbA1c) and serum pro-inflammatory cytokines compared with control rats fed with low-fat chow. C60 fullerenes normalized the metabolic parameters and partially reduced BMI in DIO animals. Pro-inflammatory cytokines (IL-1b, IL-12, INFγ) were also decreased in serum of DIO rats treated with C60 fullerenes while anti-inflammatory cytokines (IL-4, IL-10) were at the control levels. High fat diet caused the increased level of oxidative stress products, and this was accompanied by decreased activity both the superoxide dismutase and catalase, whereas the administration of C60 fullerenes markedly decreased level of oxidative stress and enhanced antioxidant enzyme activities. CONCLUSION These data indicate that water-soluble pristine C60 fullerenes reduce chronic inflammation, restore glucose homeostasis as well as positively affects on prooxidant-antioxidant homeostasis. C60 fullerenes could be represented as a promising therapeutic agent in the treatment of obesity and its related complications.
Collapse
|
|
21
|
DiNicolantonio JJ, Mehta V, O'Keefe JH. Is Salt a Culprit or an Innocent Bystander in Hypertension? A Hypothesis Challenging the Ancient Paradigm. Am J Med 2017; 130:893-899. [PMID: 28373112 DOI: 10.1016/j.amjmed.2017.03.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/15/2017] [Accepted: 03/15/2017] [Indexed: 12/21/2022]
Abstract
For decades the notion that an excessive consumption of salt (NaCl) leads to hypertension has persisted. However, this idea is based on opinion, not scientific proof. Despite this, every health organization, agency, and clinicians around the world have been advising salt restriction, especially to hypertensive patients. The present review article suggests that the consumption of a high-salt diet is not the cause of hypertension and that there are other factors, such as added sugars, which are causative for inducing hypertension and cardiovascular disease.
Collapse
Affiliation(s)
| | - Varshil Mehta
- Mount Sinai Hospital, New York, NY; MGM Medical College, Navi Mumbai, India
| | | |
Collapse
|
|
22
|
Kaga H, Tamura Y, Takeno K, Kakehi S, Funayama T, Furukawa Y, Nishitani-Yokoyama M, Shimada K, Daida H, Aoki S, Giacca A, Kanazawa A, Kawamori R, Watada H. Correlates of insulin clearance in apparently healthy non-obese Japanese men. Sci Rep 2017; 7:1462. [PMID: 28469173 PMCID: PMC5431197 DOI: 10.1038/s41598-017-01469-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/30/2017] [Indexed: 01/13/2023] Open
Abstract
Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappearance (Rd) during the clamp and muscle insulin sensitivity was defined as Rd/steady state serum insulin (SSSI) at the second step. Based on the median value of MCRI, the subjects were divided into the low- and high-MCRI groups. Subjects of the low-MCRI group had significant impairment of muscle insulin sensitivity, although Rd levels were comparable between the two groups, probably due to elevated SSSI in the low-MCRI group. Subjects of the low-MCRI group had higher total body fat content and lower VO2peak and showed no deterioration of cardiometabolic risk factors. Our results suggest that low MCRI may be early change to maintain glucose uptake and metabolic status in the face of slight impairment of muscle insulin sensitivity caused by increased adiposity and lower fitness level.
Collapse
Affiliation(s)
- Hideyoshi Kaga
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
| | - Kageumi Takeno
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Saori Kakehi
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Funayama
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasuhiko Furukawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | | | - Kazunori Shimada
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hiroyuki Daida
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Cardiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Shigeki Aoki
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Adria Giacca
- Departments of Physiology and Medicine, Institute of Medical Science and Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
| | - Akio Kanazawa
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
| |
Collapse
|
|
23
|
Paniagua JA. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome. World J Diabetes 2016; 7:483-514. [PMID: 27895819 PMCID: PMC5107710 DOI: 10.4239/wjd.v7.i19.483] [Citation(s) in RCA: 113] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 08/16/2016] [Accepted: 09/07/2016] [Indexed: 02/05/2023] Open
Abstract
Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index (BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome (MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods (fat). However, high-carbohydrate rich (CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering high-density lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.
Collapse
|
|
24
|
Pinkney JH, Nagi DK, Yudkin JS. From ‘Syndrome X’ to the Thrifty Phenotype: A Reappraisal of the Insulin Resistance Theory of Atherogenesis. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/1358863x9300400103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Jonathan H Pinkney
- Department of Medicine, University College London Medical School, London, UK
| | - Dinesh K Nagi
- Department of Medicine, University College London Medical School, London, UK
| | - John S Yudkin
- Department of Medicine, University College London Medical School, London, UK
| |
Collapse
|
|
25
|
Vogt JA, Domzig C, Wabitsch M, Denzer C. Prehepatic secretion and disposal of insulin in obese adolescents as estimated by three-hour, eight-sample oral glucose tolerance tests. Am J Physiol Endocrinol Metab 2016; 311:E82-94. [PMID: 27143555 DOI: 10.1152/ajpendo.00455.2014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 04/25/2016] [Indexed: 01/10/2023]
Abstract
The body compensates for early-stage insulin resistance by increasing insulin secretion. A reliable and easy-to-use mathematical assessment of insulin secretion and disposal could be a valuable tool for identifying patients at risk for the development of type 2 diabetes. Because the pathophysiology of insulin resistance is incompletely understood, assessing insulin metabolism with minimal assumptions regarding its metabolic regulation is a major challenge. To assess insulin secretion and indexes of insulin disposal, our marginalized and regularized absorption approach (MRA) was applied to a sparse sampling oral glucose tolerance test (OGTT) protocol measuring the insulin and C-peptide concentrations. Identifiability and potential bias of metabolic parameters were estimated from published data with dense sampling. The MRA was applied to OGTT data from 135 obese adolescents to demonstrate its clinical applicability. Individual prehepatic basal and dynamic insulin secretion and clearance levels were determined with a precision and accuracy greater than 10% of the nominal value. The intersubject variability in these parameters was approximately four times higher than the intrasubject variability, and there was a strong negative correlation between prehepatic secretion and plasma clearance of insulin. MRA-based analysis provides reliable estimates of insulin secretion and clearance, thereby enabling detailed glucose homeostasis characterization based on restricted datasets that are obtainable during routine patient care.
Collapse
Affiliation(s)
- Josef A Vogt
- Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum Ulm, Ulm, Germany; and
| | - Christian Domzig
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Christian Denzer
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| |
Collapse
|
|
26
|
Changes of insulin sensitivity and secretion after bariatric/metabolic surgery. Surg Obes Relat Dis 2016; 12:1199-205. [PMID: 27568471 DOI: 10.1016/j.soard.2016.05.013] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 05/11/2016] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D) is classically characterized by failure of pancreatic β-cell function and insulin secretion to compensate for a prevailing level of insulin resistance, typically associated with visceral obesity. Although this is usually a chronic, progressive disease in which delay of end-organ complications is the primary therapeutic goal for medical and behavioral approaches, several types of bariatric surgery, especially those that include intestinal bypass components, exert powerful antidiabetes effects to yield remission of T2D in most cases. It has become increasingly clear that in addition to the known benefits of acute caloric restriction and chronic weight loss to ameliorate T2D, bariatric/metabolic operations also engage a variety of weight-independent mechanisms to improve glucose homeostasis, enhancing insulin sensitivity and secretion to varying degrees depending on the specific operation. In this paper, we review the effects of Roux-en-Y gastric bypass, biliopancreatic diversion, and vertical sleeve gastrectomy on the primary determinants of glucose homeostasis: insulin sensitivity, insulin secretion, and, to the lesser extent that it is known, insulin-independent glucose disposal. A full understanding of these effects should help optimize surgical and device-based designs to provide maximal antidiabetes impact, and it holds the promise to identify targets for possible novel diabetes pharmacotherapeutics. These insights also contribute to the conceptual rationale for use of bariatric operations as "metabolic surgery," employed primarily to treat T2D, including among patients not obese enough to qualify for surgery based on traditional criteria related to high body mass index.
Collapse
|
|
27
|
Miyaaki H, Ichikawa T, Taura N, Miuma S, Honda T, Shibata H, Toriyama K, Nakao K. Significance of Hepatic Insulin Clearance in Patients with Chronic Hepatitis C and Non-alcoholic Fatty Liver Disease. Intern Med 2016; 55:1049-54. [PMID: 27150853 DOI: 10.2169/internalmedicine.55.5288] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Objective Hyperinsulinemia plays an important role in the pathophysiological processes of chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD). However, there are few reports on hepatic insulin clearance in patients with these diseases. Methods A total of 74 CHC patients and 37 NAFLD patients were enrolled in this study. We evaluated their hepatic insulin clearance, insulin sensitivity and β-cell function with an oral glucose tolerance test. Results Hepatic insulin clearance in the patients with CHC was significantly correlated with platelets (r=0.271, p=0.020) and liver fibrosis (r=-0.234, p=0.045) and was significantly affected by both steatosis (mild: 0.157±0.078, severe: 0.114±0.053, p=0.024) and fibrosis (mild: 0.167±0.0857, severe: 0.125±0.052, p=0.010). There were no significant differences in (homeostasis model assessment) HOMA-β among steatosis and fibrosis stages. In the NAFLD patients, those with severe fibrosis had significantly reduced hepatic insulin clearance (mild: 0.135±0.045, severe: 0.098±0.031, p=0.013) and significantly increased HOMA-β (mild: 115.6±67.1, severe: 172.8±65.7, p=0.018) compared with the patients with mild fibrosis. Conclusion Liver fibrosis development is associated with hepatic insulin clearance in both the CHC and NAFLD patients.
Collapse
Affiliation(s)
- Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Kabir M, Iyer MS, Richey JM, Woolcott OO, Asare Bediako I, Wu Q, Kim SP, Stefanovski D, Kolka CM, Hsu IR, Catalano KJ, Chiu JD, Ionut V, Bergman RN. CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors. Am J Physiol Endocrinol Metab 2015; 309:E747-58. [PMID: 26306598 PMCID: PMC4609878 DOI: 10.1152/ajpendo.00196.2015] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Accepted: 08/18/2015] [Indexed: 02/06/2023]
Abstract
The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFD+RIM; n = 11) or placebo (HFD+PL; n = 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemic-hyperinsulinemic clamp. The HFD+PL group showed a decrease in MCR; in contrast, the HFD+RIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFD+RIM group, but not in the HFD+PL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFD+RIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway.
Collapse
MESH Headings
- Animals
- Antigens, CD/drug effects
- Antigens, CD/metabolism
- Cannabinoid Receptor Antagonists/pharmacology
- Cell Adhesion Molecules/drug effects
- Cell Adhesion Molecules/metabolism
- Diet, High-Fat
- Dogs
- Glucose Clamp Technique
- Insulin/metabolism
- Insulin Resistance
- Insulysin/drug effects
- Insulysin/metabolism
- Liver/drug effects
- Liver/metabolism
- Male
- Metabolic Clearance Rate
- Piperidines/pharmacology
- Pyrazoles/pharmacology
- RNA, Messenger/drug effects
- RNA, Messenger/metabolism
- Receptor, Cannabinoid, CB1/antagonists & inhibitors
- Receptors, Adiponectin/drug effects
- Receptors, Adiponectin/genetics
- Receptors, Adiponectin/metabolism
- Rimonabant
- Up-Regulation/drug effects
Collapse
Affiliation(s)
- Morvarid Kabir
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Malini S Iyer
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Joyce M Richey
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Orison O Woolcott
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Isaac Asare Bediako
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Qiang Wu
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Stella P Kim
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Darko Stefanovski
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Cathryn M Kolka
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Isabel R Hsu
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Karyn J Catalano
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Jenny D Chiu
- Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Viorica Ionut
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| | - Richard N Bergman
- Cedars-Sinai Diabetes and Obesity Research Institute, Los Angeles, California; and
| |
Collapse
|
|
29
|
Straznicky NE, Grima MT, Sari CI, Lambert EA, Phillips SE, Eikelis N, Kobayashi D, Hering D, Mariani JA, Dixon JB, Nestel PJ, Karapanagiotidis S, Schlaich MP, Lambert GW. Reduction in peripheral vascular resistance predicts improvement in insulin clearance following weight loss. Cardiovasc Diabetol 2015; 14:113. [PMID: 26297500 PMCID: PMC4546319 DOI: 10.1186/s12933-015-0276-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/09/2015] [Indexed: 02/07/2023] Open
Abstract
Background The hyperinsulinemia of obesity is a function of both increased pancreatic insulin secretion and decreased insulin clearance, and contributes to cardiovascular risk. Whilst weight loss is known to enhance insulin clearance, there is a paucity of data concerning the underlying mechanisms. This study was conducted to examine the inter-relationships between changes in sympathetic nervous system (SNS) activity, vascular function and insulin clearance during a weight loss program. Methods Seventeen non-smoking, un-medicated individuals aged 55 ± 1 years (mean ± SEM), body mass index (BMI) 33.9 ± 1.7 kg/m2, underwent a 4-month hypocaloric diet (HCD), using a modified Dietary Approaches to Stop Hypertension diet, whilst seventeen age- and BMI-matched subjects acted as controls. Insulin sensitivity and insulin clearance were assessed via euglycemic hyperinsulinemic clamp (exogenous insulin clearance); hepatic insulin extraction was calculated as fasting C-peptide to insulin ratio (endogenous insulin clearance); SNS activity was quantified by microneurographic nerve recordings of muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine kinetics; and vascular function by calf venous occlusion plethysmography and finger arterial tonometry. Results Weight loss averaged −8.3 ± 0.6 % of body weight in the HCD group and was accompanied by increased clamp-derived glucose utilization (by 20 ± 9 %, P = 0.04) and exogenous insulin clearance (by 12 ± 5 %, P = 0.02). Hepatic insulin extraction increased from 6.3 ± 0.8 to 7.1 ± 0.9 (P = 0.09). Arterial norepinephrine concentration decreased by −12 ± 5 %, whole-body norepinephrine spillover rate by −14 ± 8 %, and MSNA by −9 ± 5 bursts per 100 heartbeats in the HCD group (P all >0.05 versus control group). Step-wise regression analysis revealed a bidirectional relationship between enhanced exogenous insulin clearance post weight loss and reduction in calf vascular resistance (r = −0.63, P = 0.01) which explained 40 % of the variance. Increase in hepatic insulin extraction was predicted by enhanced finger reactive hyperaemic response (P = 0.006) and improvement in oral glucose tolerance (P = 0.002) which together explained 64 % of the variance. Conclusions Insulin clearance is independently and reciprocally associated with changes in vascular function during weight loss intervention. Trial registration ClinicalTrials.gov: NCT01771042 and NCT00408850
Collapse
Affiliation(s)
- Nora E Straznicky
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Mariee T Grima
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Carolina I Sari
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Elisabeth A Lambert
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. .,Department of Physiology, Monash University, Melbourne, VIC, Australia. .,Department of Physiology, University of Melbourne, Melbourne, VIC, Australia.
| | - Sarah E Phillips
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Nina Eikelis
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Daisuke Kobayashi
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia.
| | - Dagmara Hering
- Laboratory of Neurovascular Hypertension and Kidney Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
| | - Justin A Mariani
- Heart Failure Research Group, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. .,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
| | - John B Dixon
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. .,Department of Primary Health Care, Monash University, Melbourne, VIC, Australia.
| | - Paul J Nestel
- Laboratory of Cardiovascular Nutrition, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
| | - Sofie Karapanagiotidis
- Alfred Baker Medical Unit, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
| | - Markus P Schlaich
- Laboratory of Neurovascular Hypertension and Kidney Disease, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. .,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia. .,Department of Physiology, Monash University, Melbourne, VIC, Australia.
| | - Gavin W Lambert
- Laboratory of Human Neurotransmitters, Baker IDI Heart and Diabetes Institute, P.O. Box 6492, St Kilda Road Central, Melbourne, VIC, 8008, Australia. .,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, VIC, Australia.
| |
Collapse
|
|
30
|
Daniele G, Winnier D, Mari A, Bruder J, Fourcaudot M, Pengou Z, Tripathy D, Jenkinson C, Folli F. Sclerostin and Insulin Resistance in Prediabetes: Evidence of a Cross Talk Between Bone and Glucose Metabolism. Diabetes Care 2015; 38:1509-17. [PMID: 26084344 DOI: 10.2337/dc14-2989] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 04/28/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE A gene mutation of the Wnt/β-catenin signaling cascade is present in rare patients with the insulin resistance syndrome. Sclerostin is a circulating peptide inhibiting Wnt/β-catenin signaling. Our aims were to evaluate serum sclerostin in subjects with prediabetes and to analyze its relationship with insulin resistance and β-cell function. RESEARCH DESIGN AND METHODS We performed a cross-sectional study including 43 healthy normal glucose-tolerant (NGT) individuals and 79 individuals with impaired glucose regulation (IGR), which included subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and combined IFG-IGT, undergoing oral glucose tolerance test (OGTT) and dual-energy X-ray absorptiometry. A subgroup of 18 with NGT and 30 with IGR also underwent a euglycemic-hyperinsulinemic clamp with tracer. RESULTS Sclerostin levels were higher in IGR compared with NGT (50.8 ± 2.4 vs. 38.7 ± 2.3 pmol/L; P = 0.01), positively correlated with HOMA-insulin resistance (IR) (r = 0.62; P < 0.001), and negatively correlated with insulin-mediated total body glucose disposal (r = -0.40; P < 0.001). Fasting endogenous glucose production (EGP) and hepatic and adipose tissue insulin resistance indexes were positively correlated with sclerostin levels (r = 0.48, r = 0.62, and r = 0.61, respectively; P < 0.001). Fasting and OGTT insulin clearance were inversely correlated with sclerostin serum levels (r = -0.52 and r = -0.44, respectively; both P < 0.001). Sclerostin levels were not correlated with β-cell function parameters. In multiple linear regression analysis, the addition of sclerostin levels to the traditional risk factors for insulin resistance improved the r(2) associated with HOMA-IR (r(2) change: 0.055; F change: 28.893; P = 0.001) and insulin-mediated total body glucose disposal (r(2) change: 0.059; F change: 4.938; P = 0.033). CONCLUSIONS Sclerostin levels are increased in individuals with prediabetes and correlated with insulin resistance in skeletal muscle, liver, and adipose tissue. The correlation between sclerostin and insulin clearance at fasting state and during OGTT is novel; thus, studies are needed to explore the potential causal relationship.
Collapse
Affiliation(s)
- Giuseppe Daniele
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Deidre Winnier
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Jan Bruder
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Marcel Fourcaudot
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Zuo Pengou
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Devjit Tripathy
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Christopher Jenkinson
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Franco Folli
- Department of Medicine, Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX Departamento de Clinica Medica, Faculdade de Ciencias Medicas, Obesity and Comorbidities Research Center, Universidade Estadual de Campinas, Campinas, Brazil
| |
Collapse
|
|
31
|
Haugaard SB. Alteration in pancreatic islet function in human immunodeficiency virus. Endocrinol Metab Clin North Am 2014; 43:697-708. [PMID: 25169562 DOI: 10.1016/j.ecl.2014.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Molecular mechanisms behind the defects in insulin production and secretion associated with antihuman immunodeficiency virus (anti-HIV) therapy and the development of HIV-associated lipodystrophy syndrome (HALS) are discussed in this article. Data suggesting insulin resistance on the beta cell and defects in first-phase insulin release of HALS patients are presented. Hepatic extraction of insulin, nonglucose insulin secretagogues and insulin-like growth factor release may exert influence on the demand of circulating insulin and on insulin secretion in HIV-infected patients. Finally, the paucity in understanding the incretin effects in HIV and HIV therapy in relation to insulin secretion is highlighted.
Collapse
Affiliation(s)
- Steen B Haugaard
- Department of Internal Medicine and the Clinical Research Centre, University of Copenhagen Amager Hvidovre Hospitals, Italiensvej 1, DK-2300 Copenhagen S, Denmark.
| |
Collapse
|
|
32
|
Marini MA, Frontoni S, Succurro E, Arturi F, Fiorentino TV, Sciacqua A, Perticone F, Sesti G. Differences in insulin clearance between metabolically healthy and unhealthy obese subjects. Acta Diabetol 2014; 51:257-61. [PMID: 23989864 DOI: 10.1007/s00592-013-0511-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 08/16/2013] [Indexed: 10/26/2022]
Abstract
Metabolically healthy obese (MHO) are relatively insulin sensitive and have a favorable cardio-metabolic risk profile compared with metabolically abnormal obese (MAO). To evaluate whether MAO individuals have a decreased insulin clearance compared with MHO individuals, 49 MHO, 147 MAO, and 172 non-obese individuals were analyzed in this cross-sectional study. Insulin clearance and insulin sensitivity were assessed through euglycemic hyperinsulinemic clamp. MHO subjects exhibited significant lower triglycerides, total cholesterol, 2-h post-challenge glucose, fasting and 2-h post-challenge insulin, steady-state plasma insulin, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase as compared with MAO individuals. Disposition index was higher in MHO subjects as compared with MAO individuals after adjusting for gender and age (P = 0.04). Insulin clearance was significantly lower in MAO individuals as compared with MHO and non-obese individuals. The difference between the two obese subgroups remained significant after adjusting for gender, age, waist circumference, fat mass, and insulin-stimulated glucose disposal (P = 0.03). The hepatic insulin extraction (C-peptide/insulin) in the fasting state was significantly higher in MHO subjects as compared with MAO individuals (P < 0.0001). In univariate analysis adjusted for gender and age, insulin clearance was correlated with hepatic insulin extraction (P = 0.01). In conclusion, insulin clearance differs among obese subjects with different metabolic phenotypes. Impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia observed in MAO individuals.
Collapse
Affiliation(s)
- Maria A Marini
- Department of Systems Medicine, University of Rome-Tor Vergata, Rome, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H. The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest 2013; 123:4513-24. [PMID: 24051378 DOI: 10.1172/jci68807] [Citation(s) in RCA: 178] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2013] [Accepted: 07/11/2013] [Indexed: 12/30/2022] Open
Abstract
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic β cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.
Collapse
|
|
34
|
Salinari S, Carr RD, Guidone C, Bertuzzi A, Cercone S, Riccioni ME, Manto A, Ghirlanda G, Mingrone G. Nutrient infusion bypassing duodenum-jejunum improves insulin sensitivity in glucose-tolerant and diabetic obese subjects. Am J Physiol Endocrinol Metab 2013; 305:E59-E66. [PMID: 23651846 DOI: 10.1152/ajpendo.00559.2012] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The mechanisms of type 2 diabetes remission after bariatric surgery is still not fully elucidated. In the present study, we tried to simulate the Roux-en-Y gastric bypass with a canonical or longer biliary limb by infusing a liquid formula diet into different intestinal sections. Nutrients (Nutrison Energy) were infused into mid- or proximal jejunum and duodenum during three successive days in 10 diabetic and 10 normal glucose-tolerant subjects. Plasma glucose, insulin, C-peptide, glucagon, incretins, and nonesterified fatty acids (NEFA) were measured before and up to 360 min following. Glucose rate of appearance (Ra) and insulin sensitivity (SI), secretion rate (ISR), and clearance were assessed by mathematical models. SI increased when nutrients were delivered in mid-jejunum vs. duodenum (SI × 10⁴ min⁻¹·pM⁻¹: 1.11 ± 0.44 vs. 0.62 ± 0.22, P < 0.015, in controls and 0.79 ± 0.34 vs. 0.40 ± 0.20, P < 0.05, in diabetic subjects), whereas glucose Ra was not affected. In controls, Sensitivity of NEFA production was doubled in mid-jejunum vs. duodenum (2.80 ± 1.36 vs. 1.13 ± 0.78 × 10⁶, P < 0.005) and insulin clearance increased in mid-jejunum vs. duodenum (2.05 ± 1.05 vs. 1.09 ± 0.38 l/min, P < 0.03). Bypass of duodenum and proximal jejunum by nutrients enhances insulin sensitivity, inhibits lipolysis, and increases insulin clearance. These results may further our knowledge of the effects of bariatric surgery on both insulin resistance and diabetes.
Collapse
Affiliation(s)
- Serenella Salinari
- Department of Computer and System Science, University of Rome La Sapienza, Rome, Italy.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Lee CC, Lorenzo C, Haffner SM, Wagenknecht LE, Goodarzi MO, Stefanovski D, Norris JM, Rewers MJ, Hanley AJ. Components of metabolic syndrome and 5-year change in insulin clearance - the Insulin Resistance Atherosclerosis Study. Diabetes Obes Metab 2013; 15:441-7. [PMID: 23216702 PMCID: PMC3810428 DOI: 10.1111/dom.12049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2012] [Revised: 11/09/2012] [Accepted: 12/03/2012] [Indexed: 11/30/2022]
Abstract
AIMS Cross-sectional evidence indicates that abdominal adiposity, hypertension, dyslipidaemia and glycaemia are associated with reduced metabolic clearance rate of insulin (MCRI). Little is known about the progression of MCRI and whether components of metabolic syndrome are associated with the change in MCRI. In this study, we examined the association between components of metabolic syndrome and the 5-year change of MCRI. METHODS At baseline and 5-year follow-up, we measured fasting plasma triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), waist circumference (WC) and fasting blood glucose (FBG) in 784 non-diabetic participants in the Insulin Resistance Atherosclerosis Study. MCRI, insulin sensitivity (SI ) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests. RESULTS We observed a 29% decline of MCRI at follow-up. TG, systolic BP and WC at baseline were inversely associated with a decline of MCRI regression models adjusted for age, sex, ethnicity, smoking, alcohol consumption, energy expenditure, family history of diabetes, BMI, SI and AIR [β = -0.057 (95% confidence interval, CI: -0.11, -0.0084) for TG, β = -0.0019 (95% CI: -0.0035, -0.00023) for systolic BP and β = -0.0084 (95% CI: -0.013, -0.0039) for WC; all p < 0.05]. Higher HDL cholesterol at baseline was associated with an increase in MCRI [multivariable-adjusted β = 0.0029 (95% CI: 0.0010, 0.0048), p = 0.002]. FBG at baseline was not associated with MCRI at follow-up [multivariable-adjusted β = 0.0014 (95% CI: -0.0026, 0.0029)]. CONCLUSIONS MCRI declined progressively over 5 years in a non-diabetic cohort. Components of metabolic syndrome at baseline were associated with a significant change in MCRI.
Collapse
Affiliation(s)
- C. Christine Lee
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | - Carlos Lorenzo
- Division of Clinical Epidemiology, University of Texas Health Science Centre, San Antonio, TX, USA
| | - Steven M. Haffner
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Lynne E. Wagenknecht
- Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Mark O. Goodarzi
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Darko Stefanovski
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jill M. Norris
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Aurora, CO, USA
| | - Marian J. Rewers
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
| | - Anthony J. Hanley
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada
| |
Collapse
|
|
36
|
Lee CC, Haffner SM, Wagenknecht LE, Lorenzo C, Norris JM, Bergman RN, Stefanovski D, Anderson AM, Rotter JI, Goodarzi MO, Hanley AJ. Insulin clearance and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study. Diabetes Care 2013; 36:901-7. [PMID: 23223351 PMCID: PMC3609510 DOI: 10.2337/dc12-1316] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We aimed to identify factors that are independently associated with the metabolic clearance rate of insulin (MCRI) and to examine the association of MCRI with incident type 2 diabetes in nondiabetic Hispanics and African Americans. RESEARCH DESIGN AND METHODS We investigated 1,116 participants in the Insulin Resistance Atherosclerosis Study (IRAS) Family Study with baseline examinations from 2000 to 2002 and follow-up examinations from 2005 to 2006. Insulin sensitivity (S(I)), acute insulin response (AIR), and MCRI were determined at baseline from frequently sampled intravenous glucose tolerance tests. MCRI was calculated as the ratio of the insulin dose over the incremental area under the curve of insulin. Incident diabetes was defined as fasting glucose ≥126 mg/dL or antidiabetic medication use by self-report. RESULTS We observed that S(I) and HDL cholesterol were independent positive correlates of MCRI, whereas fasting insulin, fasting glucose, subcutaneous adipose tissue, visceral adipose tissue, and AIR were independent negative correlates (all P < 0.05) at baseline. After 5 years of follow-up, 71 (6.4%) participants developed type 2 diabetes. Lower MCRI was associated with a higher risk of incident diabetes after adjusting for demographics, lifestyle factors, HDL cholesterol, indexes of obesity and adiposity, and insulin secretion (odds ratio 2.01 [95% CI 1.30-3.10], P = 0.0064, per one-SD decrease in loge-transformed MCRI). CONCLUSIONS Our data showed that lower MCRI predicts the incidence of type 2 diabetes.
Collapse
Affiliation(s)
- C Christine Lee
- Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Zhang Y, Kent JW, Lee A, Cerjak D, Ali O, Diasio R, Olivier M, Blangero J, Carless MA, Kissebah AH. Fatty acid binding protein 3 (fabp3) is associated with insulin, lipids and cardiovascular phenotypes of the metabolic syndrome through epigenetic modifications in a Northern European family population. BMC Med Genomics 2013; 6:9. [PMID: 23510163 PMCID: PMC3608249 DOI: 10.1186/1755-8794-6-9] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2012] [Accepted: 03/06/2013] [Indexed: 11/13/2022] Open
Abstract
Background Fatty acid-binding proteins (FABPs) play regulatory roles at the nexus of lipid metabolism and signaling. Dyslipidemia in clinical manifestation frequently co-occurs with obesity, insulin resistance and hypertension in the Metabolic Syndrome (MetS). Animal studies have suggested FABPs play regulatory roles in expressing MetS phenotypes. In our family cohort of Northern European descent, transcript levels in peripheral white blood cells (PWBCs) of a key FABPs, FABP3, is correlated with the MetS leading components. However, evidence supporting the functions of FABPs in humans using genetic approaches has been scarce, suggesting FABPs may be under epigenetic regulation. The objective of this study was to test the hypothesis that CpG methylation status of a key regulator of lipid homeostasis, FABP3, is a quantitative trait associated with status of MetS phenotypes in humans. Methods We used a mass-spec based quantitative method, EpiTYPER®, to profile a CpG island that extends from the promoter to the first exon of the FABP3 gene in our family-based cohort of Northern European descent (n=517). We then conducted statistical analysis of the quantitative relationship of CpG methylation and MetS measures following the variance-component association model. Heritability of each methylation and the effect of age and sex on CpG methylation were also assessed in our families. Results We find that methylation levels of individual CpG units and the regional average are heritable and significantly influenced by age and sex. Regional methylation was strongly associated with plasma total cholesterol (p=0.00028) and suggestively associated with LDL-cholesterol (p=0.00495). Methylation at individual units was significantly associated with insulin sensitivity, lipid particle sizing and diastolic blood pressure (p<0.0028, corrected for multiple testing for each trait). Peripheral white blood cell (PWBC) expression of FABP3 in a separate group of subjects (n=128) negatively correlated with adverse profiles of metabolism (βWHR = −0.72; βLDL-c = −0.53) while positively correlated with plasma adiponectin (β=0.24). Further, we show that differential methylation of FABP3 affects binding activity with nuclear proteins from heart tissue. This region that we found under methylation regulation overlaps with a region actively modified by histone codes in the newly available ENCODE data. Conclusions Our findings suggest that DNA methylation of FABP3 strongly influences MetS, and this may have important implications for cardiovascular disease.
Collapse
Affiliation(s)
- Yi Zhang
- TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Catalano KJ, Bergman RN, Ader M. Increased Susceptibility to Insulin Resistance Associated with Abdominal Obesity in Aging Rats**. ACTA ACUST UNITED AC 2012; 13:11-20. [PMID: 15761159 DOI: 10.1038/oby.2005.4] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Recent data have suggested that the insulin resistance observed with aging may be more related to adiposity than aging per se. We asked whether the insulin resistance observed in aged rats was comparable (both in magnitude and location) to that of fat-fed rats. RESEARCH METHODS AND PROCEDURES We performed hyperinsulinemic (5 mU/min per kg) euglycemic clamps with tracer in conscious, 6-hour fasted young (YL), fat-fed young (YF), fat-fed old (OF), and calorically restricted old (OL) rats. RESULTS Intraabdominal fat measurements showed that OF and YF rats were more obese than YL (p<or=0.001; YF>OF>YL). Caloric restriction not only prevented age-related obesity but also reduced the ratio of intraabdominal fat to lean body mass (LBM) compared with YL (OL: 0.59+/-0.05 vs. YL: 1.07+/-0.04; p=0.017). Despite similar incremental insulin, YF and OF rats required 40% less infused glucose to maintain euglycemia than YL and OL rats (p<0.001). Insulin-stimulated glucose uptake (Si(Rd): DeltaRd/(DeltaInsulin x Glucose(SS)) was impaired in OF rats (OF: 14.03+/-1.79 vs. YL: 23.08+/-1.87x10(3) dL/min x kg LBM per pM; p=0.004) and improved in OL rats (29.41+/-1.84x10(3) dL/min x kg LBM per pM; p=0.031) compared with YL. Despite greater obesity, YF rats did not exhibit lower SiRd compared with OF rats (p=0.58). In contrast, the ability of insulin to suppress endogenous glucose production (EGP; Si(EGP): DeltaEGP/(DeltaInsulin x GlucoseSS) was not impaired in OF rats (OF vs. YL; p=0.61) but was markedly impaired in YF rats by approximately 75% (1.72+/-0.66x10(3) dL/min x kg per pM; p=0.013). Surprisingly, separate regression analysis for old and young animals revealed that old rats exhibited a significantly steeper regression between Si (Rd and EGP) and adiposity than young rats (p<0.05). Thus, older rats showed a proportionately greater decrement in insulin sensitivity with an equivalent increase in adiposity. DISCUSSION These data suggest that, in rodents, youth affords significant protection against obesity-induced insulin resistance.
Collapse
Affiliation(s)
- Karyn J Catalano
- Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, 1333 San Pablo St., MMR 624, Los Angeles, CA 90033, USA
| | | | | |
Collapse
|
|
39
|
Sex and life expectancy. ACTA ACUST UNITED AC 2012; 9:390-401. [PMID: 23164528 DOI: 10.1016/j.genm.2012.10.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 09/14/2012] [Accepted: 10/11/2012] [Indexed: 11/21/2022]
Abstract
BACKGROUND A sexual dimorphism in human life expectancy has existed in almost every country for as long as records have been kept. Although human life expectancy has increased each year, females still live longer, on average, than males. Undoubtedly, the reasons for the sex gap in life expectancy are multifaceted, and it has been discussed from both sociological and biological perspectives. However, even if biological factors make up only a small percentage of the determinants of the sex difference in this phenomenon, parity in average life expectancy should not be anticipated. OBJECTIVE The aim of this review is to highlight biological mechanisms that may underlie the sexual dimorphism in life expectancy. METHODS Using PubMed, ISI Web of Knowledge, and Google Scholar, as well as cited and citing reference histories of articles through August 2012, English-language articles were identified, read, and synthesized into categories that could account for biological sex differences in human life expectancy. RESULTS The examination of biological mechanisms accounting for the female-based advantage in human life expectancy has been an active area of inquiry; however, it is still difficult to prove the relative importance of any 1 factor. Nonetheless, biological differences between the sexes do exist and include differences in genetic and physiological factors such as progressive skewing of X chromosome inactivation, telomere attrition, mitochondrial inheritance, hormonal and cellular responses to stress, immune function, and metabolic substrate handling among others. These factors may account for at least a part of the female advantage in human life expectancy. CONCLUSIONS Despite noted gaps in sex equality, higher body fat percentages and lower physical activity levels globally at all ages, a sex-based gap in life expectancy exists in nearly every country for which data exist. There are several biological mechanisms that may contribute to explaining why females live longer than men on average, but the complexity of the human life experience makes research examining the contribution of any single factor for the female advantage difficult. However, this information may still prove important to the development of strategies for healthy aging in both sexes.
Collapse
|
|
40
|
Jensen MD, Nielsen S, Gupta N, Basu R, Rizza RA. Insulin clearance is different in men and women. Metabolism 2012; 61:525-30. [PMID: 22000585 PMCID: PMC3274596 DOI: 10.1016/j.metabol.2011.08.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2011] [Revised: 08/22/2011] [Accepted: 08/23/2011] [Indexed: 11/29/2022]
Abstract
Insulin is often infused based upon total body weight (TBW) or fat-free mass (FFM) for glucose clamp protocols. We observed greater insulin concentrations in men than women using this approach and examined whether splanchnic insulin extraction accounts for the differences. Whole-body insulin clearance was measured during a pancreatic clamp study (somatostatin to inhibit islet hormone secretion) including 13 adults (6 men); and whole-body insulin clearance was measured during a euglycemic, hyperinsulinemic clamp study including 27 adults (13 men). Femoral artery and hepatic vein blood samples were collected to measure splanchnic insulin balance. For the pancreatic clamp study, insulin was infused at rates of 0.5, 1.0, and 2.0 mU/kg of TBW per minute; and for the euglycemic, hyperinsulinemic clamp study, insulin was infused at 2.5 mU/kg of FFM per minute. Significantly greater arterial insulin concentrations were found in men than women. Splanchnic plasma flow was similar in men and women in both protocols. Splanchnic insulin extraction and the fraction of infused insulin removed by splanchnic bed were significantly greater in men than in women. However, whole-body insulin clearance was greater in women than men. Infusing insulin per body weight or FFM results in higher plasma insulin concentrations in men than women. Splanchnic insulin extraction is greater in men, indicating that greater peripheral insulin clearance in women accounts for the sex differences we observed. This finding has implications for insulin clamp study design and raises the question of which tissues take up more insulin in women.
Collapse
|
|
41
|
Lee SW, Lee S, Kim SH, Kim TH, Kang BS, Yoo SH, Lee MK, Koh WJ, Kang WS, Kim HJ. Parameters measuring beta-cell function are only valuable in diabetic subjects with low body mass index, high blood glucose level, or long-standing diabetes. Yonsei Med J 2011; 52:939-47. [PMID: 22028157 PMCID: PMC3220257 DOI: 10.3349/ymj.2011.52.6.939] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
PURPOSE The aim of this study was to identify the most precise and clinically practicable parameters that predict future oral hypoglycemic agent (OHA) failure in patients with type 2 diabetes, and to determine whether these parameters are valuable in various subgroups. MATERIALS AND METHODS We took fasting blood samples from 231 patients for laboratory data and standard breakfast tests for evaluation of pancreatic beta-cell function. Hemoglobin A1c (HbA1c) levels were tested, and we collected data related to hypoglycemic medications one year from the start date of the study. RESULTS Fasting C-peptide, postprandial insulin and C-peptide, the difference between fasting and postprandial insulin, fasting beta-cell responsiveness (M0), postprandial beta-cell responsiveness (M1), and homeostasis model assessment-beta (HOMA-B) levels were significantly higher in those with OHA response than in those with OHA failure. The area under the curve (AUC) of the receiver operating characteristic (ROC) measured with postprandial C-peptide to predict future OHA failure was 0.720, and the predictive power for future OHA failure was the highest of the variable parameters. Fasting and postprandial C-peptide, M0, and M1 levels were the only differences between those with OHA response and those with OHA failure among diabetic subjects with low body mass index, high blood glucose level, or long-standing diabetes. CONCLUSION In conclusion, postprandial C-peptide was most useful in predicting future OHA failure in type 2 diabetic subjects. However, these parameters measuring beta-cell function are only valuable in diabetic subjects with low body mass index, high blood glucose level, or long-standing diabetes.
Collapse
Affiliation(s)
- Seung Won Lee
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Sangheun Lee
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Se Hwa Kim
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Tae Ho Kim
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Byung Soo Kang
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Seung Hoon Yoo
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Min Kyung Lee
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Won Jun Koh
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Won Sik Kang
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| | - Hyeong Jin Kim
- Department of Internal Medicine, Myongji Hospital, Kwandong University College of Medicine, Goyang, Korea
| |
Collapse
|
|
42
|
Valdés ER, Lattes KA, Muñoz HS, Barja PY, Papapietro KV. First-trimester adiponectin and subsequent development of preeclampsia or fetal growth restriction. Gynecol Obstet Invest 2011; 72:152-6. [PMID: 21912074 DOI: 10.1159/000328418] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Accepted: 04/01/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS The evidence regarding the utility of assessing first-trimester adiponectin (ApN) serum levels in early prediction of preeclampsia (PE) and fetal growth restriction (FGR) is contradictory. This study aims to determine the role of maternal serum ApN levels as an early predictor of PE and FGR. METHODS A prospective case-control study among a pregnant population who attended their 11- to 14-week ultrasound scan at the University of Chile's Clinical Hospital's Fetal Medicine Unit. We included patients who developed PE or FGR (10 cases per group) and 35 healthy controls. We determined ApN levels in blood samples from these 55 patients using a commercial ELISA kit and assessed the relationship of ApN levels with variables like development of PE, FGR, weight at birth and maternal BMI. RESULTS There were no significant differences among first-trimester ApN serum levels in the groups. Average concentrations were 8, 6.8 and 10.8 ng/ml for the control, PE and FGR groups, respectively. CONCLUSION In our study, maternal serum ApN levels were not useful in predicting subsequent development of PE and FGR. However, maternal serum ApN concentration adjusted by BMI was significantly higher during the first trimester in women who later developed FGR.
Collapse
Affiliation(s)
- Enrique R Valdés
- Fetal Medicine Unit, Department of Obstetrics and Gynecology, University of Chile Clinical Hospital, Santiago de Chile, Chile.
| | | | | | | | | |
Collapse
|
|
43
|
Kanat M, Norton L, Winnier D, Jenkinson C, DeFronzo RA, Abdul-Ghani MA. Impaired early- but not late-phase insulin secretion in subjects with impaired fasting glucose. Acta Diabetol 2011; 48:209-17. [PMID: 21553243 DOI: 10.1007/s00592-011-0285-x] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2011] [Accepted: 04/11/2011] [Indexed: 12/21/2022]
Abstract
Subjects with impaired fasting glucose (IFG) are at increased risk for type 2 diabetes. We recently demonstrated that IFG subjects have increased hepatic insulin resistance with normal insulin sensitivity in skeletal muscle. In this study, we quantitated the insulin secretion rate from deconvolution analysis of the plasma C-peptide concentration during an oral glucose tolerance test (OGTT) and compared the results in IFG subjects with those in subjects with impaired glucose tolerance (IGT) and normal glucose tolerance (NGT). One hundred and one NGT subjects, 64 subjects with isolated IGT, 24 subjects with isolated IFG, and 48 subjects with combined (IFG + IGT) glucose intolerance (CGI) received an OGTT. Plasma glucose, insulin, and C-peptide concentrations were measured before and every 15 min after glucose ingestion. Insulin secretion rate (ISR) was determined by deconvolution of plasma C-peptide concentration. Inverse of the Matsuda index of whole body insulin sensitivity was used as a measure of insulin resistance; 56 subjects also received a euglycemic hyperinsulinemic clamp. The insulin secretion/insulin resistance (disposition) index was calculated as the ratio between incremental area under the ISR curve (∆ISR[AUC]) to incremental area under the glucose curve (∆G[AUC]) factored by the severity of insulin resistance (measured by Matsuda index during OGTT or glucose disposal during insulin clamp). Compared to NGT, the insulin secretion/insulin resistance index during first 30 min of OGTT was reduced by 47, 49, and 74% in IFG, IGT, and CGI, respectively (all < 0.0001). The insulin secretion/insulin resistance index during the second hour (60-120 min) of the OGTT in subjects with IFG was similar to that in NGT (0.79 ± 0.6 vs. 0.72 ± 0.5, respectively, P = NS), but was profoundly reduced in subjects with IGT and CGI (0.31 ± 0.2 and 0.19 ± 0.11, respectively; P < 0.0001 vs. both NGT and IFG). Early-phase insulin secretion is impaired in both IFG and IGT, while the late-phase insulin secretion is impaired only in subjects with IGT.
Collapse
Affiliation(s)
- Mustafa Kanat
- Diabetes Division, University of Texas Health Science Center, San Antonio, 78229, USA
| | | | | | | | | | | |
Collapse
|
|
44
|
Curry TB, Roberts SK, Basu R, Basu A, Schroeder D, Joyner MJ, Miles JM. Gastric bypass surgery is associated with near-normal insulin suppression of lipolysis in nondiabetic individuals. Am J Physiol Endocrinol Metab 2011; 300:E746-51. [PMID: 21304064 PMCID: PMC3074944 DOI: 10.1152/ajpendo.00596.2010] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We hypothesized that individuals who have undergone gastric bypass have greater insulin sensitivity that obese subjects but less compared with lean. We measured free fatty acid (FFA) and glucose kinetics during a two-step, hyperinsulinemic euglycemic clamp in nondiabetic subjects who were 38 ± 5 mo post-gastric bypass surgery (GB; n = 15), in lean subjects (L; n = 15), and in obese subjects (O; n = 16). Fasting FFAa were not significantly different between the three study groups but during both doses of insulin were significantly higher in O than in either GB or L. The effective insulin concentration resulting in half-maximal suppression of FFA was similar in L and GB and significantly less in both groups compared with O. Glucose infusion rates during low-dose insulin were not significantly different in GB compared with either L or O. During high-dose insulin, glucose infusion rates were significantly greater in GB than in O but less than in L. Endogenous glucose production in GB was significantly lower than O only during low dose of insulin. We conclude that gastric bypass is associated with improvements in adipose tissue insulin sensitivity to levels similar to lean, healthy persons and also with improvements in the response of glucose metabolism to insulin. These changes may be due to preferential reduction in visceral fat and decreased FFA availability. However, some differences in insulin sensitivity in GB remain compared with L. Residual insulin resistance may be related to excess total body fat or abnormal lipolysis and requires further study.
Collapse
Affiliation(s)
- Timothy B Curry
- Depts. of Anesthesiology, Mayo Clinic, Rochester, MN 55905, USA.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
|
|
46
|
Shen Z, Wang S, Ye Y, Yin M, Yang X, Jiang K, Liu Y. Clinical study on the correlation between metabolic syndrome and colorectal carcinoma. ANZ J Surg 2010; 80:331-6. [PMID: 20557506 DOI: 10.1111/j.1445-2197.2009.05084.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Although metabolic syndrome (MS) has received a lot of attention in recent years, the correlation between MS and colorectal carcinoma is still not very clear. This study aims at exploring the relationship between MS and colorectal carcinoma. METHODS Data was collected from 507 cases of colorectal carcinoma and 507 cases of healthy patients between January 2002 and March 2007 to establish the database. The patients with colorectal cancer were divided into two groups based on the presence of MS. Multivariate analysis of these data for the overall survival and recurrence was performed with the Cox proportional hazard model. Variables examined by multivariate analysis were sex , age, location, histotype, differentiation, tumour, node, metastasis (TNM) stage, the number of lymph nodes detected, etc. RESULTS The existence of MS in the colorectal carcinoma group was clearly more than that in the control group. The existence of two to four types of abnormal metabolic diseases was significantly more in the colorectal cancer group than in the control group. MS is one of the important elements that can independently influence the survival (odds ratio (OR) = 1.501, 95% confidence interval (CI) = 1.057-2.131) and have the highest risk with worse survival compared with other parameters. CONCLUSION There is a close relationship between MS and colorectal carcinoma, and MS is a significantly independent element that influences the survival of the colorectal carcinoma. Decreasing the incidence of MS maybe play a role in improving therapeutic efficacy and prognosis of the cancer.
Collapse
Affiliation(s)
- Zhanlong Shen
- Department of Gastroenterological Surgery, Peking University, People's Hospital, Beijing, China
| | | | | | | | | | | | | |
Collapse
|
|
47
|
Uranga RM, Bruce-Keller AJ, Morrison CD, Fernandez-Kim SO, Ebenezer PJ, Zhang L, Dasuri K, Keller JN. Intersection between metabolic dysfunction, high fat diet consumption, and brain aging. J Neurochem 2010; 114:344-61. [PMID: 20477933 PMCID: PMC2910139 DOI: 10.1111/j.1471-4159.2010.06803.x] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high-fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high-fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.
Collapse
Affiliation(s)
- Romina M. Uranga
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
- Instituto de Investigaciones Bioquímicas de Bahía Blanca, Universidad Nacional del Sur and Consejo Nacional de Investigaciones Científicas y Técnicas, Bahía Blanca, Argentina
| | | | - Christopher D. Morrison
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| | - Sun Ok Fernandez-Kim
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| | - Philip J. Ebenezer
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| | - Le Zhang
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| | - Kalavathi Dasuri
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| | - Jeffrey N. Keller
- Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA
| |
Collapse
|
|
48
|
Janghorbani M, Amini M. Comparison of body mass index with abdominal obesity indicators and waist-to-stature ratio for prediction of type 2 diabetes: The Isfahan diabetes prevention study. Obes Res Clin Pract 2010; 4:e1-e82. [PMID: 24345623 DOI: 10.1016/j.orcp.2009.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2009] [Revised: 07/08/2009] [Accepted: 07/18/2009] [Indexed: 10/20/2022]
Abstract
OBJECTIVES The aim of this study was to compare the ability of the body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR) and waist-to-stature ratio (WSR) to predict progression to diabetes in non-diabetic first-degree relatives (FDRs) of patients with type 2 diabetes. METHODS A total of 704 non-diabetics FDRs 20-70 years old in 2003-2005 were followed through 2008 for the occurrence of type 2 diabetes mellitus. At baseline and through follow-ups, participants were underwent a standard 75 g 2-h oral glucose tolerance test. Prediction of progression to type 2 diabetes was assessed with area under the receiver operating characteristic (ROC) curves based upon measurement of BMI, WC, WHR and WSR. RESULTS The incidence of type 2 diabetes was 3.3% per year in men and 4.8% in women. BMI, WC and WSR were related to diabetes. These three obesity indicators have similar associations with incident diabetes. Areas under the ROC curves were 0.625 for BMI, 0.620 for WC, 0.611 for WSR and 0.538 for WHR. CONCLUSIONS These data indicate that BMI was as strong as WC or WSR in predicting progression to diabetes.
Collapse
Affiliation(s)
- Mohsen Janghorbani
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Masoud Amini
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
|
49
|
Després JP, Lamarche B. Effects of diet and physical activity on adiposity and body fat distribution: implications for the prevention of cardiovascular disease. Nutr Res Rev 2009; 6:137-59. [PMID: 19094306 DOI: 10.1079/nrr19930010] [Citation(s) in RCA: 183] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- J P Després
- Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Quebec GIV 4G2, Canada
| | | |
Collapse
|
|
50
|
Kissebah AH, Peiris AN, Evans DJ. Mechanisms associating body fat distribution to glucose intolerance and diabetes mellitus: window with a view. ACTA MEDICA SCANDINAVICA. SUPPLEMENTUM 2009; 723:79-89. [PMID: 3293360 DOI: 10.1111/j.0954-6820.1987.tb05931.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- A H Kissebah
- Department of Medicine, Medical College of Wisconsin, Milwaukee
| | | | | |
Collapse
|