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Huang X, Zhao Y, Liu T, Wu D, Shu J, Yue W, Zhang W, Liu S. β-Cell Function and Insulin Dynamics in Obese Patients With and Without Diabetes After Sleeve Gastrectomy. Diabetes 2024; 73:572-584. [PMID: 37257028 DOI: 10.2337/db22-1048] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 05/24/2023] [Indexed: 06/02/2023]
Abstract
Improved β-cell function seems to be essential for better glucose homeostasis after Roux-en-Y gastric bypass but is less studied after sleeve gastrectomy (SG). We evaluated the effects of SG on β-cell function in obese patients with diabetes (DM group) and without (control group) in response to both oral and intravenous glucose stimulation. The DM group demonstrated impaired insulin sensitivity and insulin response to glucose before surgery. The insulin sensitivity index of both groups significantly improved after SG. In addition, the insulin response to glucose (early insulinogenic index in oral glucose tolerance test and acute insulin response to glucose in an intravenous glucose tolerance test) increased in the DM group but decreased in the control group. As a result, β-cell function improved significantly in both groups after SG since the disposition index (DI) increased in both. However, the DI of the DM group was not restored to the level of control group up to 1 year after SG. Our results support that obese patients, with and without diabetes, could benefit from SG in β-cell function. For obese patients at risk for or who have been diagnosed with diabetes, interventions should be recommended early to preserve or restore β-cell function, and SG could be an effective choice. Further studies are needed for long-term effects. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Xin Huang
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Yian Zhao
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Teng Liu
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Dong Wu
- Division of Pancreatic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | - Jiaxin Shu
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenwen Yue
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenjing Zhang
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shaozhuang Liu
- Division of Bariatric and Metabolic Surgery, Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
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Sheikh S, Stefanovski D, Kilberg MJ, Hadjiliadis D, Rubenstein RC, Rickels MR, Kelly A. Early-phase insulin secretion during mixed-meal tolerance testing predicts β-cell function and secretory capacity in cystic fibrosis. Front Endocrinol (Lausanne) 2024; 15:1340346. [PMID: 38444582 PMCID: PMC10912512 DOI: 10.3389/fendo.2024.1340346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 02/05/2024] [Indexed: 03/07/2024] Open
Abstract
Insulin secretion within 30 minutes of nutrient ingestion is reduced in people with cystic fibrosis (PwCF) and pancreatic insufficiency and declines with worsening glucose tolerance. The glucose potentiated arginine (GPA) test is validated for quantifying β-cell secretory capacity as an estimate of functional β-cell mass but requires technical expertise and is burdensome. This study sought to compare insulin secretion during mixed-meal tolerance testing (MMTT) to GPA-derived parameters in PwCF. Methods Secondary data analysis of CF-focused prospective studies was performed in PwCF categorized as 1) pancreatic insufficient [PI-CF] or 2) pancreatic sufficient [PS-CF] and in 3) non-CF controls. MMTT: insulin secretory rates (ISR) were derived by parametric deconvolution using 2-compartment model of C-peptide kinetics, and incremental area under the curve (AUC) was calculated for 30, 60 and 180-minutes. GPA: acute insulin (AIR) and C-peptide responses (ACR) were calculated as average post-arginine insulin or C-peptide response minus pre-arginine insulin or C-peptide under fasting (AIRarg and ACRarg), ~230 mg/dL (AIRpot and ACRpot), and ~340 mg/dL (AIRmax and ACRmax) hyperglycemic clamp conditions. Relationships of MMTT to GPA parameters were derived using Pearson's correlation coefficient. Predicted values were generated for MMTT ISR and compared to GPA parameters using Bland Altman analysis to assess degree of concordance. Results 85 PwCF (45 female; 75 PI-CF and 10 PS-CF) median (range) age 23 (6-56) years with BMI 23 (13-34) kg/m2, HbA1c 5.5 (3.8-10.2)%, and FEV1%-predicted 88 (26-125) and 4 non-CF controls of similar age and BMI were included. ISR AUC30min positively correlated with AIRarg (r=0.55), AIRpot (r=0.62), and AIRmax (r=0.46) and with ACRarg (r=0.59), ACRpot (r=0.60), and ACRmax (r=0.51) (all P<0.001). ISR AUC30min strongly predicted AIRarg (concordance=0.86), AIRpot (concordance=0.89), and AIRmax (concordance=0.76) at lower mean GPA values, but underestimated AIRarg, AIRpot, and AIRmax at higher GPA-defined β-cell secretory capacity. Between test agreement was unaltered by adjustment for study group, OGTT glucose category, and BMI. Conclusion Early-phase insulin secretion during MMTT can accurately predict GPA-derived measures of β-cell function and secretory capacity when functional β-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify β-cell function and secretory capacity.
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Affiliation(s)
- Saba Sheikh
- Division of Pulmonary and Sleep Medicine, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Darko Stefanovski
- Department of Clinical Studies-New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, United States
| | - Marissa J. Kilberg
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine and Institute for Diabetes, Obesity & Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
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Mittendorfer B, Patterson BW, Magkos F, Yoshino M, Bradley DP, Eagon JC, Klein S. β Cell function after Roux-en-Y gastric bypass surgery or reduced energy intake alone in people with obesity. JCI Insight 2023; 8:e170307. [PMID: 37166995 PMCID: PMC10371232 DOI: 10.1172/jci.insight.170307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 05/08/2023] [Indexed: 05/12/2023] Open
Abstract
BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, (b) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and (c) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes.ResultsDiet-induced progressive WL in people without diabetes progressively decreased BCF. Marked WL after LAGB or RYGB in people without diabetes did not alter BCF. Marked WL after LCD or RYGB in people with diabetes markedly increased BCF, without a difference between groups.ConclusionMarked WL increases BCF in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on BCF is not different from the effect of matched WL after LAGB or LCD alone.trial registrationNCT00981500, NCT02207777, NCT01299519.FundingNIH grants R01 DK037948, P30 DK056341, P30 DK020579, UL1 TR002345.
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Winn NC, Cottam MA, Bhanot M, Caslin HL, Garcia JN, Arrojo e Drigo R, Hasty AH. Weight Cycling Impairs Pancreatic Insulin Secretion but Does Not Perturb Whole-Body Insulin Action in Mice With Diet-Induced Obesity. Diabetes 2022; 71:2313-2330. [PMID: 35802127 PMCID: PMC9630085 DOI: 10.2337/db22-0161] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/03/2022] [Indexed: 01/23/2023]
Abstract
In the setting of obesity and insulin resistance, glycemia is controlled in part by β-cell compensation and subsequent hyperinsulinemia. Weight loss improves glycemia and decreases hyperinsulinemia, whereas weight cycling worsens glycemic control. The mechanisms responsible for weight cycling-induced deterioration in glucose homeostasis are poorly understood. Thus, we aimed to pinpoint the main regulatory junctions at which weight cycling alters glucose homeostasis in mice. Using in vivo and ex vivo procedures we show that despite having worsened glucose tolerance, weight-cycled mice do not manifest impaired whole-body insulin action. Instead, weight cycling reduces insulin secretory capacity in vivo during clamped hyperglycemia and ex vivo in perifused islets. Islets from weight-cycled mice have reduced expression of factors essential for β-cell function (Mafa, Pdx1, Nkx6.1, Ucn3) and lower islet insulin content, compared with those from obese mice, suggesting inadequate transcriptional and posttranscriptional response to repeated nutrient overload. Collectively, these data support a model in which pancreatic plasticity is challenged in the face of large fluctuations in body weight resulting in a mismatch between glycemia and insulin secretion in mice.
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Affiliation(s)
- Nathan C. Winn
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Matthew A. Cottam
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Monica Bhanot
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Heather L. Caslin
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Jamie N. Garcia
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Rafael Arrojo e Drigo
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
| | - Alyssa H. Hasty
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN
- VA Tennessee Valley Healthcare System, Nashville, TN
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Salehi M, DeFronzo R, Gastaldelli A. Altered Insulin Clearance after Gastric Bypass and Sleeve Gastrectomy in the Fasting and Prandial Conditions. Int J Mol Sci 2022; 23:ijms23147667. [PMID: 35887007 PMCID: PMC9324232 DOI: 10.3390/ijms23147667] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 07/01/2022] [Accepted: 07/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background: The liver has the capacity to regulate glucose metabolism by altering the insulin clearance rate (ICR). The decreased fasting insulin concentrations and enhanced prandial hyperinsulinemia after Roux-en-Y gastric-bypass (GB) surgery and sleeve gastrectomy (SG) are well documented. Here, we investigated the effect of GB or SG on insulin kinetics in the fasting and fed states. Method: ICR was measured (i) during a mixed-meal test (MMT) in obese non-diabetic GB (n = 9) and SG (n = 7) subjects and (ii) during a MMT combined with a hyperinsulinemic hypoglycemic clamp in the same GB and SG subjects. Five BMI-matched and non-diabetic subjects served as age-matched non-operated controls (CN). Results: The enhanced ICR during the fasting state after GB and SC compared with CN (p < 0.05) was mainly attributed to augmented hepatic insulin clearance rather than non-liver organs. The dose-response slope of the total insulin extraction rate (InsExt) of exogenous insulin per circulatory insulin value was greater in the GB and SG subjects than in the CN subjects, despite the similar peripheral insulin sensitivity among the three groups. Compared to the SG or the CN subjects, the GB subjects had greater prandial insulin secretion (ISR), independent of glycemic levels. The larger post-meal ISR following GB compared with SG was associated with a greater InsExt until it reached a plateau, leading to a similar reduction in meal-induced ICR among the GB and SG subjects. Conclusions: GB and SG alter ICR in the presence or absence of meal stimulus. Further, altered ICR after bariatric surgery results from changes in hepatic insulin clearance and not from a change in peripheral insulin sensitivity.
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Affiliation(s)
- Marzieh Salehi
- Division of Diabetes, University of Texas Health at San Antonio, San Antonio, TX 78229, USA;
- South Texas Veteran Health Care System, Audie Murphy Hospital, San Antonio, TX 78229, USA
- Correspondence: (M.S.); (A.G.); Tel.: +1-(210)-450-8560 (M.S.)
| | - Ralph DeFronzo
- Division of Diabetes, University of Texas Health at San Antonio, San Antonio, TX 78229, USA;
| | - Amalia Gastaldelli
- Division of Diabetes, University of Texas Health at San Antonio, San Antonio, TX 78229, USA;
- Cardiometabolic Risk Unit, CNR Institute of Clinical Physiology, 56124 Pisa, Italy
- Correspondence: (M.S.); (A.G.); Tel.: +1-(210)-450-8560 (M.S.)
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Suleiman M, Marselli L, Cnop M, Eizirik DL, De Luca C, Femia FR, Tesi M, Del Guerra S, Marchetti P. The Role of Beta Cell Recovery in Type 2 Diabetes Remission. Int J Mol Sci 2022; 23:7435. [PMID: 35806437 PMCID: PMC9267061 DOI: 10.3390/ijms23137435] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 12/11/2022] Open
Abstract
Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Recent evidence indicates, however, that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. Here we review the available information on the recovery of beta cells in (a) non-diabetic individuals previously exposed to metabolic stress; (b) T2D patients following low-calorie diets, pharmacological therapies or bariatric surgery; (c) human islets isolated from non-diabetic organ donors that recover from "lipo-glucotoxic" conditions; and (d) human islets isolated from T2D organ donors and exposed to specific treatments. The improvement of insulin secretion reported by these studies and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells.
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Affiliation(s)
- Mara Suleiman
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1050 Brussels, Belgium; (M.C.); (D.L.E.)
- Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, 1050 Brussels, Belgium
| | - Decio L. Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1050 Brussels, Belgium; (M.C.); (D.L.E.)
| | - Carmela De Luca
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Francesca R. Femia
- Departmental Section of Endocrinology and Metabolism of Transplantation, AOUP Cisanello Hospital, 56124 Pisa, Italy;
| | - Marta Tesi
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Silvia Del Guerra
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (M.S.); (L.M.); (C.D.L.); (M.T.); (S.D.G.)
- Departmental Section of Endocrinology and Metabolism of Transplantation, AOUP Cisanello Hospital, 56124 Pisa, Italy;
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7
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Preservation of Fat-free Mass in the first year after Bariatric Surgery: A systematic review and meta-analysis of 122 studies and 10758 participants. Surg Obes Relat Dis 2022; 18:964-982. [DOI: 10.1016/j.soard.2022.02.022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 02/07/2022] [Accepted: 02/21/2022] [Indexed: 02/07/2023]
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Kelly A, Sheikh S, Stefanovski D, Peleckis AJ, Nyirjesy SC, Eiel JN, Sidhaye A, Localio R, Gallop R, De Leon DD, Hadjiliadis D, Rubenstein RC, Rickels MR. Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance. J Clin Endocrinol Metab 2021; 106:2617-2634. [PMID: 34406395 PMCID: PMC8660013 DOI: 10.1210/clinem/dgab365] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. RESULTS Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.
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Affiliation(s)
- Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Correspondence: Andrea Kelly, MD, MSCE, Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
| | - Darko Stefanovski
- Department of Biostatistics, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA, USA
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Sarah C Nyirjesy
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Jack N Eiel
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Aniket Sidhaye
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Russell Localio
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Robert Gallop
- Department of Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA, USA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald C Rubenstein
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphias, PA, USA
- Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
- Michael R. Rickels, MD, MS, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
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9
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Haghighat N, Ashtari-Larky D, Aghakhani L, Asbaghi O, Hoseinpour H, Hosseini B, Shahabinezhad A, Pourmohammad A, Hosseini SV, Amini M, Clark CCT, Bananzadeh A. How Does Fat Mass Change in the First Year After Bariatric Surgery? A Systemic Review and Meta-Analysis. Obes Surg 2021; 31:3799-3821. [PMID: 34089442 DOI: 10.1007/s11695-021-05512-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/21/2021] [Accepted: 05/26/2021] [Indexed: 12/29/2022]
Abstract
This systematic review and meta-analysis investigated the time-course effect of different type of bariatric surgeries (BS) up to 1 year post-surgery on fat mass (FM) and body fat percentage (BFP) in patients with morbid obesity. We searched PubMed, Scopus, EMBASE, ISI web of science, and Cochrane databases from October 2002 until May 2020 with no restriction in the English language, to find studies examining the effect of BS on FM (kg) and BFP (%) in morbid obese patients. Meta-analysis of 103 studies carried out on data of 18,166 and 14,575 morbid obese patients following BS, showed that BS was associated with a substantial decrease in FM and BFP, respectively, in 1 month (- 8.17 kg [95% CI - 9.07, - 7.27] and - 1.51% [95% CI - 2.56, - 0.46]), 3 months (- 15.75 [95% CI - 17.49, - 14.0] and - 4.90 [95% CI - 5.97, - 3.83]), 6 months (- 22.51 [95% CI - 23.93, - 21.09] and - 8.56% [95% CI - 9.63, - 7.49]), and 12 months (- 29.69 [95% CI - 31.3, - 28.09] and - 13.49% [95% CI - 14.52, - 12.40]) after the surgery. In conclusion, BS was associated with sustained declines in FM and BFP, from 1 to 12 months, with no indication of plateau phase post-surgery post-operatively. The present study emphasizes that post-bariatric care should have more focus on FM loss during 1-year post-surgery to identify the patients at risk for fat loss plateau.
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Affiliation(s)
- Neda Haghighat
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Damoon Ashtari-Larky
- Nutrition and Metabolic Diseases Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ladan Aghakhani
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Asbaghi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran, Tehran, Iran
| | - Hamidreza Hoseinpour
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Babak Hosseini
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Shahabinezhad
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Arash Pourmohammad
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Vahid Hosseini
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Masoud Amini
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Cain C T Clark
- Center for Intelligent Healthcare, Coventry University, Coventry, CV1 5FB, UK
| | - Alimohammad Bananzadeh
- Laparoscopy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. .,Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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10
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Stoica L, Gadea R, Navolan DB, Lazar F, Duta C, Stoian D, Tarta C, Olaru F, Isaic A, Dobrescu A. Plasma ghrelin, adiponectin and leptin levels in obese rats with type 2 diabetes mellitus after sleeve gastrectomy and gastric plication. Exp Ther Med 2021; 21:264. [PMID: 33603871 PMCID: PMC7851650 DOI: 10.3892/etm.2021.9695] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
The prevalence of obesity has increased in recent decades and has become a public health problem. In obesity patients the metabolism of almost all adipokines is markedly dysregulated. Studies regarding levels of ghrelin, leptin, and adiponectin after bariatric surgery reveal contradictory results. The purpose of the present study was to analyze modification of body weight and plasma levels of fasting glucose, ghrelin, adiponectin and leptin, in obese rats with T2DM after sleeve gastrectomy (SG), gastric plication (GP) and sham-operated (SO). Eighteen specimens where randomized to three weight-matched groups: Group SG underwent sleeve gastrectomy (n=6), group GP underwent gastric plication (n=6) and the control group SO underwent sham surgery (n=6). Upon surgery a normal rat chow diet (Bio-Serv® product no. F4031) was fed to the rats until the end of the experiment. Additional blood samples were harvested after 4 weeks. The results revealed that body mass decreased in the SG (783.17±101.39 vs. 658.33±86.57 g; P<0.0001) and the GP (781.33±103.12 vs. 702.33±84.06 g; P=0.004) rats after surgery. There were significant lower fasting glucose levels at 4 weeks postoperative in the SG group compared to the SO group (83.1±12.81 vs. 104.5±9.81 mg/dl; P=0.016). The same trend was observed in the GP group vs. the SO group (86.7±11.43 vs. 104.5±9.81 mg/dl; P=0.026). There was no difference regarding mean glucose levels between the SG group compared to the GP group (P>0.05). Plasma acylated ghrelin and leptin levels decreased four weeks after surgery compared to preoperative levels, while adiponectin levels increased four weeks after surgery in the SG and GP groups, respectively. The present study revealed that plasma glucose levels, ghrelin and leptin levels decreased after SG and GP, while adiponectin levels improved. This suggests that there may be hormonal contribution in weight loss.
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Affiliation(s)
- Laurian Stoica
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania.,2nd Department of Surgery, 'Pius Branzeu' Emergency Clinical County Hospital, 300723 Timisoara, Romania
| | - Ramona Gadea
- Department of Obstetrics and Gynecology, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Dan-Bogdan Navolan
- Department of Obstetrics and Gynecology, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Fulger Lazar
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Ciprian Duta
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania.,2nd Department of Surgery, 'Pius Branzeu' Emergency Clinical County Hospital, 300723 Timisoara, Romania
| | - Dana Stoian
- Department of Endocrinology, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Cristi Tarta
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania.,2nd Department of Surgery, 'Pius Branzeu' Emergency Clinical County Hospital, 300723 Timisoara, Romania
| | - Flavius Olaru
- Department of Obstetrics and Gynecology, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania
| | - Alexandru Isaic
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania.,2nd Department of Surgery, 'Pius Branzeu' Emergency Clinical County Hospital, 300723 Timisoara, Romania
| | - Amadeus Dobrescu
- Department of Surgery, 'Victor Babes' University of Medicine and Pharmacy Timisoara, 300041 Timisoara, Romania.,2nd Department of Surgery, 'Pius Branzeu' Emergency Clinical County Hospital, 300723 Timisoara, Romania
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Evolution of Inflammatory and Oxidative Stress Markers in Romanian Obese Male Patients with Type 2 Diabetes Mellitus after Laparoscopic Sleeve Gastrectomy: One Year Follow-Up. Metabolites 2020; 10:metabo10080308. [PMID: 32731443 PMCID: PMC7464585 DOI: 10.3390/metabo10080308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 12/04/2022] Open
Abstract
Geography is one of the key drivers of the significant variation in the etiopathogenic profile and prevalence of type 2 diabetes mellitus (T2DM) and obesity, therefore geographically based data are fundamental for implementing the appropriate interventions. Presently, the selection criteria of T2DM and obesity patients for laparoscopic sleeve gastrectomy (LSG) have not reached a worldwide consensus—highlighting the need for sharing experts’ guidance in the preoperative evaluation, choice of the interventional procedure, perioperative management and patient long-term care. The aim of the current study was to evaluate the impact of LSG on T2DM (T2DM) remission in Romanian obese male patients, based on a multiparametric, prospective investigation. We have conducted a randomized controlled study on 41 obese male participants with the body mass index (BMI) ≥ 30 kg/m2, aged 30–65 years, which were randomly divided in two study groups: one receiving conventional treatment and the second undergoing LSG. The clinical and anthropometrical parameters, resting metabolic rate, general biochemical status, adipocytes profile, gastrointestinal hormones levels, proinflammatory, oxidant and antioxidant profiles were determined at three time points: V1 (baseline), V2 (after six months) and V3 (after 12 months). Glycated hemoglobin (HbA1c), blood glucose levels, BMI, weight, visceral fat level, HDL-cholesterol, incretin hormones, proinflammatory and the oxidative stress status were significantly improved in the LSG versus conventional treatment group. This is the first study reporting on the evaluation of metabolic surgery impact on Romanian obese male patients with T2DM. Our results confirm that LSG could contribute to T2DM remission in patients with diabesity, but this beneficial effect seems to be critically influenced by the duration of T2DM rather than by the obesity status. Our results show that, in addition to the parameters included in the prediction algorithm, the proinsulin levels, proinsulin/insulin ratio and the visceral fat percentage could bring added value to the assessment of metabolic status.
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12
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Gudipaty L, Rosenfeld NK, Fuller CS, Cuchel M, Rickels MR. Different β-cell secretory phenotype in non-obese compared to obese early type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3295. [PMID: 32017362 PMCID: PMC7864552 DOI: 10.1002/dmrr.3295] [Citation(s) in RCA: 5] [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: 11/20/2019] [Revised: 01/21/2020] [Accepted: 01/26/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Type 2 diabetes (T2D) is characterized by impaired tissue sensitivity to insulin action (ie, insulin resistance) and impaired β-cell insulin secretion. Because obesity contributes importantly to the development of insulin resistance, we sought to determine whether insulin secretory defects would predominate in non-obese compared to obese T2D. METHODS We measured β-cell function and secretory capacity using the glucose-potentiated arginine test in T2D subjects early in the disease course classified as non-obese (BMI <30; n = 12) or obese (BMI ≥30 kg/m2 ; n = 28) and additionally compared responses from non-obese T2D with a non-diabetic control group (n = 12). RESULTS The acute insulin response to glucose potentiation of arginine-induced insulin release was less in non-obese T2D than in controls and associated with impaired β-cell sensitivity to glucose (PG50 ). Proinsulin secretory ratios were increased in non-obese T2D when compared to obese T2D. Obese T2D subjects had reduced insulin sensitivity (M/I) while non-obese T2D subjects had insulin sensitivity that was comparable to controls. CONCLUSIONS In non-obese T2D, insulin secretory defects predominate with impaired β-cell sensitivity to glucose and proinsulin processing in the absence of insulin resistance. Future studies should consider whether different β-cell secretory phenotypes and tissue sensitivity to insulin explain the varying responsiveness to T2D interventions.
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Affiliation(s)
- Lalitha Gudipaty
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Nora K. Rosenfeld
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Carissa S. Fuller
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Marina Cuchel
- Division of Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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Rickels MR, Evans-Molina C, Bahnson HT, Ylescupidez A, Nadeau KJ, Hao W, Clements MA, Sherr JL, Pratley RE, Hannon TS, Shah VN, Miller KM, Greenbaum CJ, the T1D Exchange β-Cell Function Study Group. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J Clin Invest 2020; 130:1850-1862. [PMID: 31895699 PMCID: PMC7108933 DOI: 10.1172/jci134057] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 12/26/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUNDResidual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known.METHODSWe studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017-0.200; n = 16), intermediate (>0.200-0.400; n = 15), or high (>0.400; n = 17). We compared the groups' glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp.RESULTSLow and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group.CONCLUSIONThese results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control.FUNDINGFunding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.
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Affiliation(s)
- Michael R. Rickels
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | | | - Kristen J. Nadeau
- Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Wei Hao
- Benaroya Research Institute, Seattle, Washington, USA
| | | | | | - Richard E. Pratley
- AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, Florida, USA
| | - Tamara S. Hannon
- Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Viral N. Shah
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
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Rothberg AE, Herman WH, Wu C, IglayReger HB, Horowitz JF, Burant CF, Galecki AT, Halter JB. Weight Loss Improves β-Cell Function in People With Severe Obesity and Impaired Fasting Glucose: A Window of Opportunity. J Clin Endocrinol Metab 2020; 105:5624076. [PMID: 31720686 PMCID: PMC7059991 DOI: 10.1210/clinem/dgz189] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/11/2019] [Indexed: 11/19/2022]
Abstract
BACKGROUND In people with obesity, β-cell function may adapt to insulin resistance. We describe β-cell function in people with severe obesity and normal fasting glucose (NFG), impaired fasting glucose (IFG), and type 2 diabetes (T2DM), as assessed before, 3 to 6 months after, and 2 years after medical weight loss to describe its effects on insulin sensitivity, insulin secretion, and β-cell function. METHODS Fifty-eight participants with body mass index (BMI) ≥ 35 kg/m2 (14 with NFG, 24 with IFG, and 20 with T2DM) and 13 normal weight participants with NFG underwent mixed meal tolerance tests to estimate insulin sensitivity (S[I]), insulin secretion (Φ), and β-cell function assessed as model-based Φ adjusted for S(I). All 58 obese participants were restudied at 3 to 6 months and 27 were restudied at 2 years. RESULTS At 3 to 6 months, after a 20-kg weight loss and a decrease in BMI of 6 kg/m2, S(I) improved in all obese participants, Φ decreased in obese participants with NFG and IFG and tended to decrease in obese participants with T2DM, and β-cell function improved in obese participants with NFG and tended to improve in obese participants with IFG. At 2 years, β-cell function deteriorated in participants with NFG and T2DM but remained significantly better in participants with IFG compared to baseline. CONCLUSIONS Short-term weight loss improves β-cell function in participants with NFG and IFG, but β-cell function tends to deteriorate over 2 years. In participants with IFG, weight loss improves longer-term β-cell function relative to baseline and likely relative to no intervention, suggesting that obese people with IFG are a subpopulation whose β-cell function is most likely to benefit from weight loss.
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Affiliation(s)
- Amy E Rothberg
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan
- Correspondence: Amy E. Rothberg, MD, PhD, University of Michigan, Department of Internal Medicine, Domino’s Farms - Lobby G, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106.
| | - William H Herman
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Department of Epidemiology, University of Michigan, Ann Arbor, Michigan
| | - Chunyi Wu
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Heidi B IglayReger
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | | | - Charles F Burant
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Department of Nutritional Sciences, University of Michigan, Ann Arbor, Michigan
| | - Andrzej T Galecki
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Jeffrey B Halter
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- Institute of Gerontology, University of Michigan, Ann Arbor, Michigan
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15
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Kelly A, De Leon DD, Sheikh S, Camburn D, Kubrak C, Peleckis AJ, Stefanovski D, Hadjiliadis D, Rickels MR, Rubenstein RC. Islet Hormone and Incretin Secretion in Cystic Fibrosis after Four Months of Ivacaftor Therapy. Am J Respir Crit Care Med 2019; 199:342-351. [PMID: 30130412 DOI: 10.1164/rccm.201806-1018oc] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
RATIONALE Diabetes is associated with worse cystic fibrosis (CF) outcomes. The CFTR potentiator ivacaftor is suggested to improve glucose homeostasis in individuals with CF. OBJECTIVES To test the hypothesis that clinically indicated ivacaftor would be associated with improvements in glucose tolerance and insulin and incretin secretion. METHODS Oral glucose tolerance tests, mixed-meal tolerance tests, and glucose-potentiated arginine tests were compared preivacaftor initiation and 16 weeks postivacaftor initiation in CF participants with at least one CFTR gating or conductance mutation. Meal-related 30-minute (early phase) and 180-minute incremental area under the curves were calculated as responses for glucose, insulin, C-peptide, and incretin hormones; glucagon-like peptide-1; and glucose-dependent insulinotropic polypeptide. First-phase insulin secretion, glucose potentiation of arginine-induced insulin secretion, and disposition index were characterized by glucose-potentiated arginine stimulation tests. MEASUREMENTS AND MAIN RESULTS Twelve subjects completed the study: six male/six female; seven normal/five abnormal glucose tolerance (oral glucose tolerance test 1-h glucose ≥155 and 2-h glucose <200 mg/dl); of median (minimum-maximum) age (13.8 yr [6.0-42.0]), body mass index-Z of 0.66 (-2.4 to 1.9), and FEV1% predicted of 102 (39-122). Glucose tolerance normalized in one abnormal glucose tolerance subject. Ivacaftor treatment did not alter meal responses except for an increase in early phase C-peptide (P = 0.04). First-phase (P = 0.001) and glucose potentiation of arginine-induced (P = 0.027) insulin secretion assessed by acute C-peptide responses improved after ivacaftor treatment. Consistent with an effect on β-cell function, the disposition index relating the amount of insulin secreted for insulin sensitivity also improved (P = 0.04). CONCLUSIONS Insulin secretion improved following 4 months of clinically indicated ivacaftor therapy in this relatively young group of patients with CF with normal to mildly impaired glucose tolerance, whereas incretin secretion remained unchanged.
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Affiliation(s)
| | | | - Saba Sheikh
- 2 Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Devaney Camburn
- 2 Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Christina Kubrak
- 2 Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | | | - Darko Stefanovski
- 4 Department of Clinical Studies-NCI, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - Denis Hadjiliadis
- 5 Division of Pulmonary & Critical Care Medicine and Cystic Fibrosis Center, Department of Medicine, Hospital of University of Pennsylvania, Philadelphia, Pennsylvania; and
| | | | - Ronald C Rubenstein
- 2 Division of Pulmonary Medicine and Cystic Fibrosis Center, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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16
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Nyirjesy SC, Sheikh S, Hadjiliadis D, De Leon DD, Peleckis AJ, Eiel JN, Kubrak C, Stefanovski D, Rubenstein RC, Rickels MR, Kelly A. β-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL. Pediatr Diabetes 2018; 19:1173-1182. [PMID: 29885044 PMCID: PMC6364976 DOI: 10.1111/pedi.12700] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/09/2018] [Accepted: 05/28/2018] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Patients with pancreatic insufficient cystic fibrosis (PI-CF) meeting standard criteria for normal glucose tolerance display impaired β-cell secretory capacity and early-phase insulin secretion defects. We sought evidence of impaired β-cell secretory capacity, a measure of functional β-cell mass, among those with early glucose intolerance (EGI), defined as 1-hour oral glucose tolerance test (OGTT) glucose ≥155 mg/dL (8.6 mmol/L). METHODS A cross-sectional study was conducted in the Penn and CHOP Clinical & Translational Research Centers. PI-CF categorized by OGTT as normal (PI-NGT: 1-hour glucose <155 mg/dL and 2-hour <140 mg/dL [7.8 mmol/L]; n = 13), PI-EGI (1-hour ≥155 mg/dL and 2-hour <140 mg/dL; n = 13), impaired (PI-IGT: 2-hour ≥140 and <200 mg/dL [11.1 mmol/L]; n = 8), and diabetic (cystic fibrosis-related diabetes, CFRD: 2-hour ≥200 mg/dL; n = 8) participated. Post-prandial glucose tolerance and insulin secretion, and β-cell secretory capacity and demand were derived from mixed-meal tolerance tests (MMTTs), and glucose-potentiated arginine (GPA) tests, respectively. RESULTS PI-EGI had elevated post-prandial glucose with reduced early-phase insulin secretion during MMTT compared to PI-NGT (P < .05). PI-EGI also exhibited impaired acute insulin and C-peptide responses to GPA (P < .01 vs PI-NGT), measures of β-cell secretory capacity. Proinsulin secretory ratios were higher under hyperglycemic clamp conditions in PI-IGT and CFRD (P < .05 vs PI-NGT), and correlated with 1-hour glucose in PI-CF (P < .01). CONCLUSIONS PI-CF patients with 1-hour OGTT glucose ≥155 mg/dL already manifest impaired β-cell secretory capacity with associated early-phase insulin secretion defects. Avoiding hyperglycemia in patients with EGI may be important for preventing excessive insulin demand indicated by disproportionately increased proinsulin secretion.
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Affiliation(s)
- Sarah C Nyirjesy
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jack N Eiel
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Christina Kubrak
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Darko Stefanovski
- Department of Biostatistics, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
| | - Ronald C Rubenstein
- Division of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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Smith EP, Polanco G, Yaqub A, Salehi M. Altered glucose metabolism after bariatric surgery: What's GLP-1 got to do with it? Metabolism 2018; 83:159-166. [PMID: 29113813 DOI: 10.1016/j.metabol.2017.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 10/20/2017] [Accepted: 10/25/2017] [Indexed: 01/20/2023]
Abstract
Bariatric surgery is an effective treatment for obesity. The two widely performed weight-loss procedures, Roux-en-Y gastric bypass (GB) and sleeve gastrectomy (SG), alter postprandial glucose pattern and enhance gut hormone secretion immediately after surgery before significant weight loss. This weight-loss independent glycemic effects of GB has been attributed to an accelerated nutrient transit from stomach pouch to the gut and enhanced secretion of insulinotropic gut factors; in particular, glucagon-like peptide-1 (GLP-1). Meal-induced GLP-1 secretion is as much as tenfold higher in patients after GB compared to non-surgical individuals and inhibition of GLP-1 action during meals reduces postprandial hyperinsulinemia after GB two to three times more than that in persons without surgery. Moreover, in a subgroup of patients with the late complication of postprandial hyperinsulinemic hypoglycemia after GB, GLP1R blockade reverses hypoglycemia by reducing meal stimulated insulin secretion. The role of enteroinsular axis activity after SG, an increasingly popular alternative to GB, is less understood but, similar to GB, SG accelerates nutrient delivery to the intestine, improves glucose tolerance, and increases postprandial GLP-1 secretion. This review will focus on the current evidence for and against the role of GLP-1 on glycemic effects of GB and will also highlight differences between GB and SG.
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Affiliation(s)
- Eric P Smith
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
| | - Georgina Polanco
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Abid Yaqub
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Marzieh Salehi
- Division of Endocrinology, Diabetes & Metabolism, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Purnell JQ, Johnson GS, Wahed AS, Dalla Man C, Piccinini F, Cobelli C, Prigeon RL, Goodpaster BH, Kelley DE, Staten MA, Foster-Schubert KE, Cummings DE, Flum DR, Courcoulas AP, Havel PJ, Wolfe BM. Prospective evaluation of insulin and incretin dynamics in obese adults with and without diabetes for 2 years after Roux-en-Y gastric bypass. Diabetologia 2018; 61:1142-1154. [PMID: 29428999 PMCID: PMC6634312 DOI: 10.1007/s00125-018-4553-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 11/22/2017] [Indexed: 01/20/2023]
Abstract
AIMS/HYPOTHESIS In this prospective case-control study we tested the hypothesis that, while long-term improvements in insulin sensitivity (SI) accompanying weight loss after Roux-en-Y gastric bypass (RYGB) would be similar in obese individuals with and without type 2 diabetes mellitus, stimulated-islet-cell insulin responses would differ, increasing (recovering) in those with diabetes but decreasing in those without. We investigated whether these changes would occur in conjunction with favourable alterations in meal-related gut hormone secretion and insulin processing. METHODS Forty participants with type 2 diabetes and 22 participants without diabetes from the Longitudinal Assessment of Bariatric Surgery (LABS-2) study were enrolled in a separate, longitudinal cohort (LABS-3 Diabetes) to examine the mechanisms of postsurgical diabetes improvement. Study procedures included measures of SI, islet secretory response and gastrointestinal hormone secretion after both intravenous glucose (frequently-sampled IVGTT [FSIVGTT]) and a mixed meal (MM) prior to and up to 24 months after RYGB. RESULTS Postoperatively, weight loss and SI-FSIVGTT improvement was similar in both groups, whereas the acute insulin response to glucose (AIRglu) decreased in the non-diabetic participants and increased in the participants with type 2 diabetes. The resulting disposition indices (DIFSIVGTT) increased by three- to ninefold in both groups. In contrast, during the MM, total insulin responsiveness did not significantly change in either group despite durable increases of up to eightfold in postprandial glucagon-like peptide 1 levels, and SI-MM and DIMM increased only in the diabetes group. Peak postprandial glucagon levels increased in both groups. CONCLUSIONS/INTERPRETATION For up to 2 years following RYGB, obese participants without diabetes showed improvements in DI that approach population norms. Those with type 2 diabetes recovered islet-cell insulin secretion response yet continued to manifest abnormal insulin processing, with DI values that remained well below population norms. These data suggest that, rather than waiting for lifestyle or medical failure, RYGB is ideally considered before, or as soon as possible after, onset of type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT00433810.
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Affiliation(s)
- Jonathan Q Purnell
- Department of Medicine, The Knight Cardiovascular Institute, Mailcode MDYMI, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR, 97239, USA.
| | - Geoffrey S Johnson
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Abdus S Wahed
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA
| | - Chiara Dalla Man
- Department of Information Engineering, University of Padova, Padova, Italy
| | | | - Claudio Cobelli
- Department of Information Engineering, University of Padova, Padova, Italy
| | | | - Bret H Goodpaster
- Translational Research Institute for Metabolism and Diabetes, Sanford-Burnham Institute, Orlando, FL, USA
| | | | - Myrlene A Staten
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD, USA
| | | | - David E Cummings
- Department of Medicine, University of Washington, Seattle, WA, USA
| | - David R Flum
- Department of Surgery, University of Washington, Seattle, WA, USA
| | | | - Peter J Havel
- Departments of Molecular Biosciences and Nutrition, University of California, Davis, Davis, CA, USA
| | - Bruce M Wolfe
- Department of Surgery, Oregon Health & Science University, Portland, OR, USA
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Kapeluto J, Tchernof A, Biertho L. Surgery for Diabetes: Clinical and Mechanistic Aspects. Can J Diabetes 2018; 41:392-400. [PMID: 28739097 DOI: 10.1016/j.jcjd.2017.05.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 05/16/2017] [Accepted: 05/24/2017] [Indexed: 01/04/2023]
Abstract
According to the most recent publication by the Canadian Public Health Agency, obesity affects 25% of adults. In addition, there is a clear association between the recent rise in obesity and the increased prevalence of type 2 diabetes. Medical therapy for obesity has shown limited long-term effectiveness, and surgical treatment is now recognized by medical authorities as part of the armamentarium for the management of type 2 diabetes in severely obese patients. The current indications for obesity surgery and postoperative management are reviewed. The choice of surgery should balance expected benefits associated with weight loss (including remission rate of type 2 diabetes), side effects and the risks for early and long-term complications. Long-term outcomes of metabolic surgery for diabetes vary according to the type of surgery (ranging between 20% and 90% remission rates) and the underlying metabolic changes. Several controlled trials have been published in recent years confirming the superiority of metabolic surgery over medical treatment for the management of type 2 diabetes associated with severe obesity. Some of the known underlying mechanisms of action include a combination of caloric restriction, hormonal changes, decreased nutrient absorption and changes in bile acids, microbiota and incretins. Further research is needed to clarify the mechanistic changes associated with each surgical procedure and their respective long-term outcomes.
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Affiliation(s)
- Jordanna Kapeluto
- Department of Bariatric Surgery, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
| | - André Tchernof
- Department of Bariatric Surgery, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada
| | - Laurent Biertho
- Department of Bariatric Surgery, Quebec Heart and Lung Institute, Laval University, Quebec City, Quebec, Canada.
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20
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Differences in Anthropometric and Metabolic Parameters Between Subjects with Hypoglycaemia and Subjects with Euglycaemia After an Oral Glucose Tolerance Test Six Months After Laparoscopic Sleeve Gastrectomy. Obes Surg 2017; 26:2747-2755. [PMID: 27112589 DOI: 10.1007/s11695-016-2187-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
BACKGROUND Hypoglycaemia after an oral glucose tolerance test (OGTT) can occur in up to 33 % of subjects after laparoscopic sleeve gastrectomy (LSG). The underlying pathophysiology is not well understood. We aimed to compare the anthropometric and metabolic characteristics of subjects with post-OGTT hypoglycaemia (HYPO) to subjects with post-OGTT euglycaemia (EU) 6 months after LSG. METHODS Eighteen morbidly obese patients with normal glucose tolerance (NGT) were evaluated with an OGTT before and 6 months after LSG. Serum glucose and insulin were measured before and every 30 min after glucose ingestion up to 120'. The patients were categorized as HYPO or EU based on lowest glucose levels 90' to 120' post-OGTT 6 months after LSG (hypoglycaemia defined as glucose levels <60 mg/dl). OGTT derived indices of insulin secretion; insulin sensitivity and beta cell function were also evaluated. RESULTS Eight patients (44.4 %) were categorized as HYPO. Preoperatively, subjects with HYPO had lower BMI (p = 0.02) compared to that with EU. Postoperatively, subjects with HYPO had lower BMI (p = 0.01), lower weight (p = 0.01), and higher percentage of total weight loss (%TWL) (p = 0.03) compared to that with EU. The beta cell function index was higher in the HYPO group postoperatively compared to EU (p = 0.02)-especially during the latter portion of the OGTT. No difference was detected in insulin secretion and insulin sensitivity indices between the two groups preoperatively or postoperatively. CONCLUSIONS Subjects with NGT who developed HYPO 6 months after LSG are leaner, with higher TWL% and higher beta cell function at the latter portion of the OGTT compared to those with EU.
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Piao SJ, Kim SH, Suh YJ, Hong SB, Ahn SH, Seo DH, Park IS, Nam M. Beneficial Effects of Aerobic Exercise Training Combined with Rosiglitazone on Glucose Metabolism in Otsuka Long Evans Tokushima Fatty Rats. Diabetes Metab J 2017; 41:474-485. [PMID: 29199408 PMCID: PMC5741557 DOI: 10.4093/dmj.2017.41.6.474] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 07/26/2017] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Regular aerobic exercise is essential for the prevention and management of type 2 diabetes mellitus and may be particularly beneficial for those treated with thiazolidinediones, since it may prevent associated weight gain. This study aimed to evaluate the effect of combined exercise and rosiglitazone treatment on body composition and glucose metabolism in obese diabetes-prone animals. METHODS We analyzed metabolic parameters, body composition, and islet profiles in Otsuka Long Evans Tokushima Fatty rats after 28 weeks of aerobic exercise, rosiglitazone treatment, and combined exercise and rosiglitazone treatment. RESULTS Combined exercise with rosiglitazone showed significantly less increase in weight and epididymal fat compared to rosiglitazone treatment. Aerobic exercise alone and combined rosiglitazone and exercise treatment led to similar retention of lean body mass. All experimental groups showed a decrease in fasting glucose. However, the combined exercise and rosiglitazone therapy group showed prominent improvement in glucose tolerance compared to the other groups. Rescue of islet destruction was observed in all experimental groups, but was most prominent in the combined therapy group. CONCLUSION Regular aerobic exercise combined with rosiglitazone treatment can compensate for the adverse effect of rosiglitazone treatment and has benefit for islet preservation.
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Affiliation(s)
- Shan Ji Piao
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
- Qingdao Endocrine and Diabetes Hospital, Qingdao, China
| | - So Hun Kim
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Young Ju Suh
- Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Korea
| | - Seong Bin Hong
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Seong Hee Ahn
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Da Hae Seo
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - In Sun Park
- Department of Anatomy, Inha University School of Medicine, Incheon, Korea.
| | - Moonsuk Nam
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea.
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Effects of Helicobacter pylori eradication on insulin resistance and metabolic parameters: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017; 29:153-159. [PMID: 27832037 DOI: 10.1097/meg.0000000000000774] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Previous studies have shown a close relationship between Helicobacter pylori (H. pylori), insulin resistance, and altered metabolic parameters. However, the effects of H. pylori eradication on these conditions remain controversial. We carried out a systematic review and meta-analysis to evaluate the effects of H. pylori eradication on insulin resistance and metabolic parameters. METHODS We searched CENTRAL, MEDLINE, and EMBASE databases from their inception to July 2016. Insulin resistance (HOMA-IR), body weight (BW), BMI, waist circumference, triglycerides (TG), high-density and low-density lipoprotein-cholesterol (HDL-C and LDL-C), and fasting blood glucose (FBG) were compared between patients with and without H. pylori eradication using a random-effects model. We reported pooled mean differences (MD) and 95% confidence intervals (CI) for the change in outcomes. RESULTS Data from five studies showed no difference in HOMA-IR after H. pylori eradication (pooled MD=-0.52, 95% CI: -1.47 to 0.42). Eradication significantly increased BMI (MD=0.36, 95% CI: 0.11-0.60) and BW (MD=1.1, 95% CI: 0.8-1.5), but had no significant effects on TG, LDL-C, HDL-C, or FBG. CONCLUSION H. pylori eradication does not improve insulin resistance, TG, HDL-C, LDL-C, or FBG, but may increase BW and BMI. Further studies are needed to clarify the effect of H. pylori eradication on metabolism.
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Sheikh S, Gudipaty L, De Leon DD, Hadjiliadis D, Kubrak C, Rosenfeld NK, Nyirjesy SC, Peleckis AJ, Malik S, Stefanovski D, Cuchel M, Rubenstein RC, Kelly A, Rickels MR. Reduced β-Cell Secretory Capacity in Pancreatic-Insufficient, but Not Pancreatic-Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance. Diabetes 2017; 66:134-144. [PMID: 27495225 PMCID: PMC5204312 DOI: 10.2337/db16-0394] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Accepted: 08/01/2016] [Indexed: 01/21/2023]
Abstract
Patients with pancreatic-insufficient cystic fibrosis (PI-CF) are at increased risk for developing diabetes. We determined β-cell secretory capacity and insulin secretory rates from glucose-potentiated arginine and mixed-meal tolerance tests (MMTTs), respectively, in pancreatic-sufficient cystic fibrosis (PS-CF), PI-CF, and normal control subjects, all with normal glucose tolerance, in order to identify early pathophysiologic defects. Acute islet cell secretory responses were determined under fasting, 230 mg/dL, and 340 mg/dL hyperglycemia clamp conditions. PI-CF subjects had lower acute insulin, C-peptide, and glucagon responses compared with PS-CF and normal control subjects, indicating reduced β-cell secretory capacity and α-cell function. Fasting proinsulin-to-C-peptide and proinsulin secretory ratios during glucose potentiation were higher in PI-CF, suggesting impaired proinsulin processing. In the first 30 min of the MMTT, insulin secretion was lower in PI-CF compared with PS-CF and normal control subjects, and glucagon-like peptide 1 and gastric inhibitory polypeptide were lower compared with PS-CF, and after 180 min, glucose was higher in PI-CF compared with normal control subjects. These findings indicate that despite "normal" glucose tolerance, adolescents and adults with PI-CF have impairments in functional islet mass and associated early-phase insulin secretion, which with decreased incretin responses likely leads to the early development of postprandial hyperglycemia in CF.
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Affiliation(s)
- Saba Sheikh
- Division of Pulmonary Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Lalitha Gudipaty
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Denis Hadjiliadis
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Christina Kubrak
- Division of Pulmonary Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Nora K Rosenfeld
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Sarah C Nyirjesy
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Amy J Peleckis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Saloni Malik
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Darko Stefanovski
- Department of Biostatistics, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA
| | - Marina Cuchel
- Division of Translational Medicine and Human Genetics, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Ronald C Rubenstein
- Division of Pulmonary Medicine, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Andrea Kelly
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA
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Bariatric surgery and obesity: influence on the incretins. INTERNATIONAL JOURNAL OF OBESITY SUPPLEMENTS 2016; 6:S32-S36. [PMID: 28685028 DOI: 10.1038/ijosup.2016.8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The gut hormone incretins have an important physiological role in meal-related insulin release and post-prandial glucose control. In addition to weight loss, the incretin hormones have a role in glucose control after bariatric surgery. The release of incretins, and specifically of glucagon-like peptide (GLP)-1, in response to the ingestion of nutrients, is greatly enhanced after gastric bypass (RYGBP). The rapid transit of food from the gastric pouch to the distal ileum is responsible for the greater GLP-1 release after RYGBP. The incretin effect on insulin secretion, or the greater insulin response to oral glucose compared to an isoglycemic intravenous glucose challenge, is severely impaired in patients with type 2 diabetes, but is recovered rapidly after RYGBP. The improvement in insulin secretion rate and β-cell sensitivity to oral glucose after RYGBP is mediated by endogenous GLP-1, and is abolished by exendin 9-39, a specific GLP-1 receptor antagonist. While calorie restriction and weight loss have major effects on the rapid and sustained improvement of fasted glucose metabolism, the enhanced incretin effect is a key player in post-prandial glucose control after RYGBP.
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Salehi M, D'Alessio DA. Mechanisms of surgical control of type 2 diabetes: GLP-1 is the key factor-Maybe. Surg Obes Relat Dis 2016; 12:1230-5. [PMID: 27568473 PMCID: PMC5002889 DOI: 10.1016/j.soard.2016.05.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 05/07/2016] [Accepted: 05/09/2016] [Indexed: 02/06/2023]
Abstract
Bariatric surgery is the most effective treatment for obesity and diabetes. The 2 most commonly performed weight-loss procedures, Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, improve glycemic control in patients with type 2 diabetes independent of weight loss. One of the early hypotheses raised to explain the immediate antidiabetic effect of RYGB was that rapid delivery of nutrients from the stomach pouch into the distal small intestine enhances enteroinsular signaling to promote insulin signaling. Given the tenfold increase in postmeal glucagon-like peptide-1 (GLP-1) response compared to unchanged integrated levels of postprandial glucose-dependent insulinotropic peptide after RYGB, enhanced meal-induced insulin secretion after this procedure was thought to be the result of elevated glucose and GLP-1 levels. In this contribution to the larger point-counterpoint debate about the role of GLP-1 after bariatric surgery, most of the focus will be on RYGB.
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Affiliation(s)
- Marzieh Salehi
- Department of Biomedical Science, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
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26
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Bell DSH. The case for combination therapy as first-line treatment for the type 2 diabetic patient. ACTA ACUST UNITED AC 2016; 5:131-7. [PMID: 16677055 DOI: 10.2165/00024677-200605030-00001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The glycosylated hemoglobin (HbA(1c)) goal in patients with type 2 diabetes mellitus should be to achieve as low a value as can be obtained without causing significant or frequent hypoglycemia. This is best achieved by utilizing agents that lower glucose levels without causing hypoglycemia (thiazolidinediones and metformin). To maintain these low HbA(1c) values and avoid the utilization of insulin secretagogues or insulin, which are associated with hypoglycemia and suboptimal dosing leading to higher HbA(1c) values, drugs that maintain or improve pancreatic beta-cell function (thiazolidinediones and possibly incretin-based therapies) should be utilized. Restoration of first-phase insulin release, as has been shown with thiazolidinediones, will not only improve postprandial hyperglycemia but will also improve postprandial hyperlipidemia, both of which will decrease cardiac risk. Utilizing small doses of two drugs will also result in a decreased incidence of adverse effects compared with a large dose of a single drug. The use of fixed-dose combination oral antihyperglycemics will not only improve compliance but will often decrease costs compared with individual component dual therapy.
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Affiliation(s)
- David S H Bell
- University of Alabama Medical School, Birmingham, Alabama, USA
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27
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Halden TAS, Egeland EJ, Åsberg A, Hartmann A, Midtvedt K, Khiabani HZ, Holst JJ, Knop FK, Hornum M, Feldt-Rasmussen B, Jenssen T. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes. Diabetes Care 2016; 39:617-24. [PMID: 26908914 DOI: 10.2337/dc15-2383] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 02/04/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon-like peptide 1 (GLP-1) during fasting and hyperglycemic conditions, respectively. RESEARCH DESIGN AND METHODS Renal transplant recipients with (n = 12) and without (n = 12) PTDM underwent two separate experimental days with 3-h intravenous infusions of GLP-1 (0.8 pmol/kg/min) and saline, respectively. After 1 h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups. In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P < 0.001), while first- and second-phase insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations and increased first- and second-phase insulin secretion in both groups. CONCLUSIONS PTDM is characterized by reduced glucose-induced insulin secretion and attenuated glucagon suppression during a hyperglycemic clamp. Similar to the case in type 2 diabetes, GLP-1 infusion seems to improve (insulin) or even normalize (glucagon) these pathophysiological defects.
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Affiliation(s)
- Thea A S Halden
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Erlend J Egeland
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway
| | - Anders Åsberg
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway Norwegian Renal Registry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Anders Hartmann
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Karsten Midtvedt
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Hassan Z Khiabani
- Department of Pharmacology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Novo Nordisk Foundation Center for Basic Metabolic Research and Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Bo Feldt-Rasmussen
- Department of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Trond Jenssen
- Section of Nephrology, Department of Transplant Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
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Manaf A, Tjandrawinata RR, Malinda D. Insulin sensitizer in prediabetes: a clinical study with DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:1279-89. [PMID: 27099473 PMCID: PMC4820281 DOI: 10.2147/dddt.s97568] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background The aim of this paper is to evaluate the efficacy and safety of DLBS3233, a novel bioactive fraction derived from Cinnamomum burmanii and Lagerstroemia speciosa, in improving insulin resistance and preserving β-cell performance in patients with impaired glucose tolerance (IGT). Patients and methods Eighty adult subjects with IGT, defined as 2-hour postprandial glucose level of 140–199 mg/dL, were enrolled in this two-arm, 12-week, double-blind, randomized, placebo-controlled preliminary study. Eligible subjects were randomly allocated to receive either DLBS3233 at a dose of 50–100 mg daily or placebo for 12 weeks. The study mainly assessed the improvement of homeostatic model-assessed insulin resistance (HOMA-IR), the 15-minute and 2-hour plasma insulin levels, and the oral disposition index. Results After 12 weeks, DLBS3233 improved insulin resistance better than placebo as reflected by a reduced HOMA-IR (−27.04%±29.41% vs −4.90%±41.27%, P=0.013). The improvement of the first- and second-phase insulin secretion was consistently greater in DLBS3233 group than placebo group (−144.78±194.06 vs −71.21±157.19, P=0.022, and −455.03±487.56 vs −269.49±467.77, P=0.033, respectively). Further, DLBS3233 also significantly better improved oral disposition index than placebo. No serious hypoglycemia, edema, or cardiovascular-related adverse events were found in either groups. Conclusion This study has shown that DLBS3233 at the dose of 50–100 mg once daily was well tolerated, and promisingly efficacious in improving insulin sensitivity as well as preserving β-cell performance in subjects with IGT.
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Affiliation(s)
- Asman Manaf
- Department of Internal Medicine, Faculty of Medicine, University of Andalas, Dr M Djamil Padang Hospital, Padang, Indonesia
| | | | - Desi Malinda
- Department of Internal Medicine, Faculty of Medicine, University of Andalas, Dr M Djamil Padang Hospital, Padang, Indonesia
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Omar BA, Kvist-Reimer M, Enerbäck S, Ahrén B. Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice. Am J Physiol Endocrinol Metab 2016; 310:E81-90. [PMID: 26530152 DOI: 10.1152/ajpendo.00296.2015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 10/30/2015] [Indexed: 11/22/2022]
Abstract
Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.
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Affiliation(s)
- Bilal A Omar
- Department of Clinical Sciences, Lund University, Lund, Sweden; and
| | | | - Sven Enerbäck
- Gothenburg University, Sahlgrenska Hospital, Gothenburg, Sweden
| | - Bo Ahrén
- Department of Clinical Sciences, Lund University, Lund, Sweden; and
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30
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Rickels MR, Goeser ES, Fuller C, Lord C, Bowler AM, Doliba NM, Hegele RA, Cuchel M. Loss-of-function mutations in ABCA1 and enhanced β-cell secretory capacity in young adults. Diabetes 2015; 64:193-9. [PMID: 25125487 PMCID: PMC4274805 DOI: 10.2337/db14-0436] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Loss-of-function mutations affecting the cholesterol transporter ATP-binding cassette transporter subfamily A member 1 (ABCA1) impair cellular cholesterol efflux and are associated with reduced HDL-cholesterol (HDL-C) levels. ABCA1 may also be important in regulating β-cell cholesterol homeostasis and insulin secretion. We sought to determine whether loss-of-function ABCA1 mutations affect β-cell secretory capacity in humans by performing glucose-potentiated arginine tests in three subjects homozygous for ABCA1 mutations (age 25 ± 11 years), eight heterozygous subjects (28 ± 7 years), and eight normal control subjects pair-matched to the heterozygous carriers. To account for any effect of low HDL-C on insulin secretion, we studied nine subjects with isolated low HDL-C with no ABCA1 mutations (age 26 ± 6 years) and nine pair-matched control subjects. Homozygotes for ABCA1 mutations exhibited enhanced oral glucose tolerance and dramatically increased β-cell secretory capacity that was also greater in ABCA1 heterozygous subjects than in control subjects, with no differences in insulin sensitivity. Isolated low HDL-C subjects also demonstrated an increase in β-cell secretory capacity but in contrast to those with ABCA1 mutations, exhibited impaired insulin sensitivity, supporting β-cell compensation for increased insulin demand. These data indicate that loss-of-function mutations in ABCA1 in young adults may be associated with enhanced β-cell secretory capacity and normal insulin sensitivity and support the importance of cellular cholesterol homeostasis in regulating β-cell insulin secretion.
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Affiliation(s)
- Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Eugen S Goeser
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Carissa Fuller
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Christine Lord
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Anne M Bowler
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nicolai M Doliba
- Department of Biochemistry and Biophysics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Robert A Hegele
- Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
| | - Marina Cuchel
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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Malin SK, Bena J, Abood B, Pothier CE, Bhatt DL, Nissen S, Brethauer SA, Schauer PR, Kirwan JP, Kashyap SR. Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non-remission status after bariatric surgery. Diabetes Obes Metab 2014; 16:1230-8. [PMID: 25132119 PMCID: PMC4227926 DOI: 10.1111/dom.12376] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/02/2014] [Accepted: 08/04/2014] [Indexed: 12/15/2022]
Abstract
AIM To identify the metabolic determinants of type 2 diabetes non-remission status after bariatric surgery at 12 and 24 months. METHODS A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m(2) , age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C-peptide values during a 120-min mixed-meal tolerance test. Body fat, incretins (glucagon-like polypeptide-1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor-α, high-sensitivity C-reactive protein (hs-CRP)] were also assessed. RESULTS At 24 months, 37 patients had available follow-up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and β-cell function (C-peptide0-120 /glucose0-120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs-CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced β-cell function, lower triglyceride levels and fat loss. CONCLUSIONS Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non-remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.
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Affiliation(s)
- Steven K. Malin
- Dept of Pathobiology, Cleveland Clinic, Cleveland OH, USA
- Dept of Nutrition, Case Western Reserve University Cleveland Clinic, Cleveland OH, USA
| | - James Bena
- Dept of Quantitative Health Sciences, Cleveland Clinic, Cleveland OH, USA
| | - Beth Abood
- Dept of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland OH, USA
| | - Claire E. Pothier
- Dept of Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland OH, USA
| | - Deepak L Bhatt
- Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA
| | - Steven Nissen
- Dept of Heart and Vascular, Cleveland Clinic, Cleveland OH, USA
| | - Stacy A. Brethauer
- Dept of Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland OH, USA
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland OH, USA
| | - Philip R. Schauer
- Dept of Bariatric and Metabolic Institute, Cleveland Clinic, Cleveland OH, USA
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland OH, USA
| | - John P. Kirwan
- Dept of Pathobiology, Cleveland Clinic, Cleveland OH, USA
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland OH, USA
- Dept of Nutrition, Case Western Reserve University Cleveland Clinic, Cleveland OH, USA
| | - Sangeeta R. Kashyap
- Dept of Endocrinology, Diabetes and Metabolism, Cleveland Clinic, Cleveland OH, USA
- Metabolic Translational Research Center, Endocrine and Metabolism Institute, Cleveland Clinic, Cleveland OH, USA
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Gudipaty L, Rosenfeld NK, Fuller CS, Gallop R, Schutta MH, Rickels MR. Effect of exenatide, sitagliptin, or glimepiride on β-cell secretory capacity in early type 2 diabetes. Diabetes Care 2014; 37:2451-8. [PMID: 24969577 PMCID: PMC4140159 DOI: 10.2337/dc14-0398] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Agents that augment GLP-1 effects enhance glucose-dependent β-cell insulin production and secretion and thus are hoped to prevent progressive impairment in insulin secretion characteristic of type 2 diabetes (T2D). The purpose of this study was to evaluate GLP-1 effects on β-cell secretory capacity, an in vivo measure of functional β-cell mass, early in the course of T2D. RESEARCH DESIGN AND METHODS We conducted a randomized controlled trial in 40 subjects with early T2D who received the GLP-1 analog exenatide (n = 14), the dipeptidyl peptidase IV inhibitor sitagliptin (n = 12), or the sulfonylurea glimepiride (n = 14) as an active comparator insulin secretagogue for 6 months. Acute insulin responses to arginine (AIRarg) were measured at baseline and after 6 months of treatment with 5 days of drug washout under fasting, 230 mg/dL (glucose potentiation of arginine-induced insulin release [AIRpot]), and 340 mg/dL (maximum arginine-induced insulin release [AIRmax]) hyperglycemic clamp conditions, in which AIRmax provides the β-cell secretory capacity. RESULTS The change in AIRpot was significantly greater with glimepiride versus exenatide treatment (P < 0.05), and a similar trend was notable for the change in AIRmax (P = 0.1). Within each group, the primary outcome measure, AIRmax, was unchanged after 6 months of treatment with exenatide or sitagliptin compared with baseline but was increased with glimepiride (P < 0.05). α-Cell glucagon secretion (AGRmin) was also increased with glimepiride treatment (P < 0.05), and the change in AGRmin trended higher with glimepiride than with exenatide (P = 0.06). CONCLUSIONS After 6 months of treatment, exenatide or sitagliptin had no significant effect on functional β-cell mass as measured by β-cell secretory capacity, whereas glimepiride appeared to enhance β- and α-cell secretion.
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Affiliation(s)
- Lalitha Gudipaty
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Nora K Rosenfeld
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Carissa S Fuller
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Robert Gallop
- Department of Mathematics, West Chester University of Pennsylvania, West Chester, PA
| | - Mark H Schutta
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
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Abstract
To date, weight loss surgeries are the most effective treatment for obesity and glycemic control in patients with type 2 diabetes. Roux-en-Y gastric bypass surgery (RYGB) and sleeve gastrectomy (SG), two widely used bariatric procedures for the treatment of obesity, induce diabetes remission independent of weight loss while glucose improvement after adjustable gastric banding (AGB) is proportional to the amount of weight loss. The immediate, weight-loss independent glycemic effect of gastric bypass has been attributed to postprandial hyperinsulinemia and an enhanced incretin effect. The rapid passage of nutrients into the intestine likely accounts for significantly enhanced glucagon like-peptide 1 (GLP-1) secretion, and postprandial hyperinsulinemia after GB is typically attributed to the combined effects of elevated glucose and GLP-1. For this review we focus on the beneficial effects of the three most commonly performed bariatric procedures, RYGB, SG, and AGB, on glucose metabolism and diabetes remission. Central to this discussion will be the extent to which the effects of surgery are mediated by GLP-1. Better understanding of these mechanisms could provide insight to development of novel therapeutic strategies for treatment of diabetes as well as refinement of surgical techniques.
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Affiliation(s)
- Marzieh Salehi
- Department of Internal Medicine, Division of Endocrinology, Diabetes, & Metabolism, University of Cincinnati College of Medicine, 260 Stetson, Suite 4200, Cincinnati, OH 45219-0547 USA
| | - David A. D’Alessio
- Department of Internal Medicine, Division of Endocrinology, Diabetes, & Metabolism, University of Cincinnati College of Medicine, 260 Stetson, Suite 4200, Cincinnati, OH 45219-0547 USA
- Cincinnati VA Medical Center, Cincinnati, OH USA
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Lee HO, Yim JE, Kim YS, Choue R. Moderate diet-induced weight loss is associated with improved insulin sensitivity in middle-aged healthy obese Korean women. Nutr Res Pract 2014; 8:469-75. [PMID: 25110569 PMCID: PMC4122721 DOI: 10.4162/nrp.2014.8.4.469] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 02/22/2014] [Accepted: 06/03/2014] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND/OBJECTIVE The goal of the present study was to investigate the effects of moderate caloric restriction on β-cell function and insulin sensitivity in middle-aged obese Korean women. SUBJECTS/METHODS Fifty-seven obese pre-menopausal Korean women participated in a 12-week calorie restriction program. Data on total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and fasting serum levels of glucose, insulin, C-peptide, blood pressure, leptin and anthropometrics were collected. A dietary intake assessment was based on three days of food recording. Additionally, β-cell function [homeostasis model assessment of β-cell (HOMA-β), insulinogenic index (ISI), C-peptide:glucose ratio, and area under curve insulin/glucose (AUCins/glu)] and insulin sensitivity [homeostasis model assessment for insulin resistance (HOMA-IR), Quantitative insulin-sensitivity check index (QUICKI) and Matsuda index (MI)] were recorded. RESULTS When calories were reduced by an average of 422 kcal/day for 12 weeks, BMI (-2.7%), body fat mass (-10.2%), and waist circumference (-5%) all decreased significantly (P < 0.05). After calorie restriction, weight, body fat percentage, hip circumference, BP, TC, HDL-C, LDL-C, plasma glucose at fasting, insulin at fasting and 120 min, AUCglu and the insulin area under the curve all decreased significantly (all P < 0.05), while insulin sensitivity (HOMA-IR, QUICKI and Matsuda index) measured by OGTT improved significantly (P < 0.01). CONCLUSIONS Moderate weight loss due to caloric restriction with reduction in insulin resistance improves glucose tolerance and insulin sensitivity in middle-aged obese women and thereby may help prevent the development of type 2 diabetes mellitus.
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Affiliation(s)
- Hye-Ok Lee
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi 446-701, Korea. ; Nutrition Team, Kyung Hee University Hospital at Gangdong, Seoul 134-727, Korea
| | - Jung-Eun Yim
- Department of Food and Nutrition, Changwon National University, Changwon 641-773, Korea
| | - Young-Seol Kim
- Department of Endocrine and Metabolism, Kyung Hee Medical Center, Seoul 130-872, Korea
| | - Ryowon Choue
- Department of Medical Nutrition, Graduate School of East-West Medical Science, Kyung Hee University, Gyeonggi 446-701, Korea. ; Research Institute of Medical Nutrition, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 130-701, Korea
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He C, Yang Z, Lu NH. Helicobacter pylori infection and diabetes: Is it a myth or fact? World J Gastroenterol 2014; 20:4607-4617. [PMID: 24782613 PMCID: PMC4000497 DOI: 10.3748/wjg.v20.i16.4607] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/10/2014] [Accepted: 03/06/2014] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) is one of the most common human bacterial pathogens, and infection causes a wide array of gastric disorders, including simple gastritis, peptic ulcers and gastric malignancies. Gastrointestinal inflammation caused by H. pylori can influence the absorption of glucose and lipids, which are also abnormal in diabetes mellitus. Type 2 diabetes mellitus (T2DM), formerly known as non-insulin-dependent diabetes mellitus or adult-onset diabetes, is a metabolic disorder that is characterized by high levels of blood glucose resulting from insulin resistance and relative insulin deficiency. It is an emerging pandemic and is rapidly becoming a serious threat to public health. Emerging data now indicate a strong relationship between H. pylori infection and the incidence of T2DM. The mechanisms underlying the pathogenesis of diabetes are complex, involving insulin resistance, chronic inflammation, insulin secretion deficiency as a result of pancreas β-cell dysfunction, glucotoxicity, and lipotoxicity. H. pylori infection is known to be involved in the pathogenesis of insulin resistance, and the growing awareness of its role in diabetes is important for the early detection of glucose dysregulation and prevention of T2DM in high-risk communities. This review probes the possible relationship between H. pylori and diabetes according to epidemiological surveys and discusses putative mechanisms underlying this correlation.
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Affiliation(s)
- Marzieh Salehi
- Department of Medicine, Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio
| | - David A. D’Alessio
- Department of Medicine, Division of Endocrinology, University of Cincinnati, Cincinnati, Ohio
- Cincinnati VA Medical Center, Cincinnati, Ohio
- Corresponding author: David A. D’Alessio,
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Raghow R. Bariatric surgery-mediated weight loss and its metabolic consequences for type-2 diabetes. World J Diabetes 2013; 4:47-50. [PMID: 23772272 PMCID: PMC3680623 DOI: 10.4239/wjd.v4.i3.47] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/11/2013] [Indexed: 02/05/2023] Open
Abstract
The worldwide epidemic of obesity and its medical complications are being dealt with a combination of life style changes (e.g., healthier diet and exercise), medications and a variety of surgical interventions. The Roux-en Y gastric bypass (RYGB) and laparoscopic adjustable gastric banding (LAGB) are two of the most common weight loss surgeries for morbid obesity-associated metabolic syndrome and insulin resistance. A vast majority of patients that undergo RYGB and LAGB are known to experience marked weight loss and attenuation of diabetes. A number of recent studies have indicated that the rates of remission in glycemic control and insulin sensitivity are significantly greater in patients that have undergone RYGB. A plausible hypothesis to explain this observation is that the gastric bypass surgery as opposed to the gastric banding procedure impinges on glucose homeostasis by a weight loss-independent mechanism. In a recent paper, Bradley et al have experimentally explored this hypothesis. The authors compared several clinical and laboratory parameters of insulin sensitivity and β-cell function in cohorts of RYGB and LAGB patients before and after they lost approximately 20% of their body mass. After weight loss, both groups of patients underwent similar changes in their intra-abdominal and total adipose tissue volume, hepatic triglyceride and circulating leptin levels. The RYGB patients who lost 20% body mass, manifested higher postprandial output of glucose, insulin and glucagon-like peptide-1; these laboratory parameters remained unchanged in LABG patients. Irrespective of the observed differences in transient responses of RYGB and LAGB patients to mixed meal, the overall glycemic control as judged by glucose tolerance, multi-organ insulin sensitivity and β-cell function were nearly identical in the two groups. Both RYGB and LAGB patient cohorts also experienced similar changes in the expression of a number of pro- and anti-inflammatory markers. Based on these analyses, Bradley et al concluded that similar restoration of insulin sensitivity and b-cell function in non-diabetic obese patients that have undergone RYGB and LAGB were directly due to marked weight loss. These data have important implications for the risk/benefit analysis of weight loss therapy by bariatric procedures.
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Hosseinzadeh-Attar MJ, Golpaie A, Janani L, Derakhshanian H. Effect of weight reduction following bariatric surgery on serum visfatin and adiponectin levels in morbidly obese subjects. Obes Facts 2013; 6:193-202. [PMID: 23615494 PMCID: PMC5644781 DOI: 10.1159/000351162] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 10/07/2012] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVE Adipokines are signaling and mediator proteins secreted from adipose tissue. A novel adipokine, visfatin, was reported as a protein which was mainly expressed in visceral adipose tissue. Controversial results have been shown regarding the changes of adipokines following weight reduction. So we investigated the effects of weight reduction on serum concentrations of adiponectin and visfatin in morbidly obese subjects. METHODS 35 severely obese patients (26 females and 9 males), aged 15-58 years, were studied. Anthropometric parameters and biochemical parameters as well as adiponectin and visfatin were analyzed before and 6 weeks after weight reduction. RESULTS Anthropometric indices decreased significantly. Blood levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride were reduced significantly. The reduction of visfatin and the elevation of adiponectin were significant as well. However, other parameters like fasting glucose and insulin did not change. Moreover, we could not find any significant correlation between the change of serum visfatin and that of adiponectin. CONCLUSIONS 6-week weight reduction after bariatric surgery resulted in decreased serum visfatin and increased adiponectin levels. However, we cannot find any significant correlation between changes of adiponectin, visfatin, BMI, waist circumference, and insulin resistance. Further studies with different design are suggested to clarify these associations.
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Affiliation(s)
| | - Atefeh Golpaie
- Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- *Atefeh Golpaie, Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences, Poursina Ave., Qods St., Tehran (Iran),
| | - Leila Janani
- Epidemiology and Biostatistics Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hoda Derakhshanian
- Department of Nutrition and Biochemistry, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Bradley D, Conte C, Mittendorfer B, Eagon JC, Varela JE, Fabbrini E, Gastaldelli A, Chambers KT, Su X, Okunade A, Patterson BW, Klein S. Gastric bypass and banding equally improve insulin sensitivity and β cell function. J Clin Invest 2012. [PMID: 23187122 DOI: 10.1172/jci64895] [Citation(s) in RCA: 200] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Bariatric surgery in obese patients is a highly effective method of preventing or resolving type 2 diabetes mellitus (T2DM); however, the remission rate is not the same among different surgical procedures. We compared the effects of 20% weight loss induced by laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB) surgery on the metabolic response to a mixed meal, insulin sensitivity, and β cell function in nondiabetic obese adults. The metabolic response to meal ingestion was markedly different after RYGB than after LAGB surgery, manifested by rapid delivery of ingested glucose into the systemic circulation, by an increase in the dynamic insulin secretion rate, and by large, early postprandial increases in plasma glucose, insulin, and glucagon-like peptide-1 concentrations in the RYGB group. However, the improvement in oral glucose tolerance, insulin sensitivity, and overall β cell function after weight loss were not different between surgical groups. Additionally, both surgical procedures resulted in a similar decrease in adipose tissue markers of inflammation. We conclude that marked weight loss itself is primarily responsible for the therapeutic effects of RYGB and LAGB on insulin sensitivity, β cell function, and oral glucose tolerance in nondiabetic obese adults.
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Affiliation(s)
- David Bradley
- Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri 63110, USA
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41
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Dumping Symptoms and Incidence of Hypoglycaemia After Provocation Test at 6 and 12 Months After Laparoscopic Sleeve Gastrectomy. Obes Surg 2012; 22:1600-6. [DOI: 10.1007/s11695-012-0711-3] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Algahim MF, Sen S, Taegtmeyer H. Bariatric surgery to unload the stressed heart: a metabolic hypothesis. Am J Physiol Heart Circ Physiol 2012; 302:H1539-45. [PMID: 22307676 DOI: 10.1152/ajpheart.00626.2011] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Obesity is an independent risk factor for cardiovascular disease. Data from the Framingham Study have reported a higher incidence of heart failure in obese individuals compared with a normal cohort. The body initially copes with the abundance of fuel present in an obese milieu by storing it in adipose tissue. However, when the storage capacity is exceeded, the excess energy is taken up and stored ectopically as fat in vital organs such as the heart. Indeed, intramyocardial lipid overload is present in hearts of obese patients, as well as in hearts of animal models of obesity, and is associated with a distinct gene expression profile and cardiac dysfunction. By imposing a metabolic stress on the heart, obesity causes it to hypertrophy and ultimately to fail. Conventional measures to treat obesity include diet, exercise, and drugs. More recently, weight loss surgery (WLS) has achieved increasing prominence because of its ability to reduce the neurohumoral load, normalize metabolic dysregulation, and improve overall survival. The effects of WLS on systemic metabolic, neurohumoral, and hemodynamic parameters are well described and include an early normalization of serum glucose and insulin levels as well as reduction in blood pressure. WLS is also associated with reverse cardiac remodeling, regression of left ventricular hypertrophy, and improved left ventricular and right ventricular function. By targeting the source of the excess energy, we hypothesize that WLS improves contractile function by limiting exogenous substrate availability to the metabolically overloaded heart. These changes have also been found to be associated with increased levels of adiponectin and improved insulin sensitivity. Taken together, the sustained beneficial effects of WLS on left ventricular mass and function highlight the need to better understand the mechanism by which obesity regulates cardiovascular physiology.
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Affiliation(s)
- Mohamed F Algahim
- Division of Cardiology, Department of Internal Medicine, University of Texas Medical School at Houston, Houston, Texas 77030, USA
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Tarabra E, Pelengaris S, Khan M. A simple matter of life and death-the trials of postnatal Beta-cell mass regulation. Int J Endocrinol 2012; 2012:516718. [PMID: 22577380 PMCID: PMC3346985 DOI: 10.1155/2012/516718] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 12/31/2011] [Indexed: 12/17/2022] Open
Abstract
Pancreatic beta-cells, which secrete the hormone insulin, are the key arbiters of glucose homeostasis. Defective beta-cell numbers and/or function underlie essentially all major forms of diabetes and must be restored if diabetes is to be cured. Thus, the identification of the molecular regulators of beta-cell mass and a better understanding of the processes of beta-cell differentiation and proliferation may provide further insight for the development of new therapeutic targets for diabetes. This review will focus on the principal hormones and nutrients, as well as downstream signalling pathways regulating beta-cell mass in the adult. Furthermore, we will also address more recently appreciated regulators of beta-cell mass, such as microRNAs.
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Affiliation(s)
- Elena Tarabra
- School of Life Sciences, Warwick University, Gibbet Hill Road, Coventry CV4 7AL, UK
- *Elena Tarabra:
| | - Stella Pelengaris
- School of Life Sciences, Warwick University, Gibbet Hill Road, Coventry CV4 7AL, UK
| | - Michael Khan
- School of Life Sciences, Warwick University, Gibbet Hill Road, Coventry CV4 7AL, UK
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Fagerberg B, Kellis D, Bergström G, Behre CJ. Adiponectin in relation to insulin sensitivity and insulin secretion in the development of type 2 diabetes: a prospective study in 64-year-old women. J Intern Med 2011; 269:636-43. [PMID: 21198995 DOI: 10.1111/j.1365-2796.2010.02336.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES To examine how serum adiponectin levels predict the incidence of type 2 diabetes, from different prediabetic states, in relation to insulin sensitivity and β-cell function during 5.5 years of follow-up. METHODS In a population-based cohort of 64-year-old Caucasian women, we assessed glucose tolerance, insulin sensitivity as homeostasis model assessment, insulin secretion as acute insulin response, lifestyle factors and serum concentrations of adiponectin and high-sensitivity C-reactive protein. After 5.5 years of follow-up, 167 women with normal glucose tolerance (NGT) and 174 with impaired glucose tolerance (IGT) at baseline were re-examined and incidence of diabetes was assessed. RESULTS A total of 69 new cases of diabetes were detected during follow-up. Diabetes incidence was independently predicted by low levels of serum adiponectin, insulin resistance and insulin secretion, cigarette smoking, impaired fasting glucose (IFG) and IGT at baseline. Serum adiponectin below 11.54 g L(-1) was associated with an odds ratio of 3.6 (95% confidence interval 1.4-8.6) for future type 2 diabetes. At baseline, a high serum adiponectin concentration correlated positively with high levels of insulin sensitivity and insulin secretion. Women with incident diabetes had lower serum adiponectin levels in the NGT, IFG and IGT groups at baseline compared to those who did not develop diabetes during follow-up. CONCLUSIONS Low adiponectin concentrations were associated with future diabetes independently of insulin secretion and sensitivity, as well as IGT, IFG, smoking and abdominal obesity.
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Affiliation(s)
- B Fagerberg
- Wallenberg Laboratory for Cardiovascular Research at the Center for Cardiovascular and Metabolic Research, Institute of Medicine, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden.
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Hofsø D, Jenssen T, Bollerslev J, Ueland T, Godang K, Stumvoll M, Sandbu R, Røislien J, Hjelmesæth J. Beta cell function after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention. Eur J Endocrinol 2011; 164:231-8. [PMID: 21078684 PMCID: PMC3022337 DOI: 10.1530/eje-10-0804] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE The effects of various weight loss strategies on pancreatic beta cell function remain unclear. We aimed to compare the effect of intensive lifestyle intervention (ILI) and Roux-en-Y gastric bypass surgery (RYGB) on beta cell function. DESIGN One year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104). METHODS One hundred and nineteen morbidly obese participants without known diabetes from the MOBIL study (mean (s.d.) age 43.6 (10.8) years, body mass index (BMI) 45.5 (5.6) kg/m², 84 women) were allocated to RYGB (n = 64) or ILI (n = 55). The patients underwent repeated oral glucose tolerance tests (OGTTs) and were categorised as having either normal (NGT) or abnormal glucose tolerance (AGT). Twenty-nine normal-weight subjects with NGT (age 42.6 (8.7) years, BMI 22.6 (1.5) kg/m², 19 women) served as controls. OGTT-based indices of beta cell function were calculated. RESULTS One year weight reduction was 30% (8) after RYGB and 9% (10) after ILI (P < 0.001). Disposition index (DI) increased in all treatment groups (all P<0.05), although more in the surgery groups (both P < 0.001). Stimulated proinsulin-to-insulin (PI/I) ratio decreased in both surgery groups (both P < 0.001), but to a greater extent in the surgery group with AGT at baseline (P < 0.001). Post surgery, patients with NGT at baseline had higher DI and lower stimulated PI/I ratio than controls (both P < 0.027). CONCLUSIONS Gastric bypass surgery improved beta cell function to a significantly greater extent than ILI. Supra-physiological insulin secretion and proinsulin processing may indicate excessive beta cell function after gastric bypass surgery.
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Affiliation(s)
- D Hofsø
- Department of Medicine, Morbid Obesity Centre, Vestfold Hospital Trust, Tønsberg, Norway.
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Lin E, Liang Z, Frediani J, Davis SS, Sweeney JF, Ziegler TR, Phillips LS, Gletsu-Miller N. Improvement in ß-cell function in patients with normal and hyperglycemia following Roux-en-Y gastric bypass surgery. Am J Physiol Endocrinol Metab 2010; 299:E706-12. [PMID: 20716694 PMCID: PMC2980357 DOI: 10.1152/ajpendo.00405.2010] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 08/11/2010] [Indexed: 01/14/2023]
Abstract
Glycemic disorders resolve following Roux-en-Y gastric bypass (RYGB) surgery, but early and longer-term mechanisms regarding effects on β-cell dysfunction as well as relationships with decreasing adiposity are not well understood. We evaluated longitudinal changes in peripheral insulin sensitivity (Si), the acute insulin response to glucose (AIRg), and the composite estimate of β-cell function, the disposition index (DI), over 24 mo via frequently sampled intravenous glucose tolerance testing in severely obese women who had fasting normoglycemia (n = 16) and hyperglycemia (n = 11) before RYGB surgery; homeostatic model assessment (HOMA-IR) estimated insulin resistance; air displacement plethysmography determined adipose tissue mass. At baseline, subjects with normoglycemia had adequate DI associated with elevated AIRg, but DI was markedly reduced in subjects with hyperglycemia. Within 1-6 mo post-RYGB, glycemic control was normalized in subjects with hyperglycemia related to reduced HOMA-IR (-54% at 1 mo, P < 0.005) and increased DI (23-fold at 6 mo vs. baseline, P < 0.05). Over 24 mo, DI improved in subjects with hyperglycemia (15-fold vs. baseline, P < 0.005) and also modestly in subjects with normoglycemia (58%, P < 0.05), due largely to increased Si. Decreasing adiposity correlated with longer-term HOMA-IR and Si values at 6 and 24 mo, respectively. In patients exhibiting fasting hyperglycemia before surgery, β-cell function improved early following RYGB, due largely to increases in insulin secretion. For both normoglycemic and hyperglycemic subjects, further improvement or stabilization of β-cell function over the 2 yr is due largely to improved Si associated with reduced adiposity.
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Affiliation(s)
- Edward Lin
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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Briatore L, Salani B, Andraghetti G, Maggi D, Adami GF, Scopinaro N, Cordera R. Beta-cell function improvement after biliopancreatic diversion in subjects with type 2 diabetes and morbid obesity. Obesity (Silver Spring) 2010; 18:932-6. [PMID: 20186136 DOI: 10.1038/oby.2010.28] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In subjects with obesity and type 2 diabetes mellitus (T2DM), biliopancreatic diversion (BPD) improves glucose stimulated insulin secretion, whereas the effects on other secretion mechanisms are still unknown. Our objective was to evaluate the early effects of BPD on nonglucose-stimulated insulin secretion. In 16 morbid obese subjects (9 with T2DM and 7 with normal fasting glucose (NFG)), we measured insulin secretion after glucose-dependent arginine stimulation test and after intravenous glucose tolerance test (IVGTT) before and 1 month after BPD. After surgery the mean weight lost was 13% in both groups. The acute insulin response during IVGTT was improved in T2DM after BDP (from 55 +/- 10 to 277 +/- 91 pmol/l, P = 0.03). A reduction of insulin response to arginine was observed in NFG, whereas opposite was found in T2DM. In particular, acute insulin response to arginine at basal glucose concentrations (AIR(basal)) was reduced but insulin response at 14 mmol/l of plasma glucose (AIR(14)) was increased. Therefore, after BPD any statistical difference in AIR(14) between NFG and T2DM disappeared (1,032 +/- 123 for NFG and 665 +/- 236 pmol/l for T2DM, P = ns). The same was observed for Slope(AIR), a measure of glucose potentiation, reduced in T2DM before BPD but increased after surgery, when no statistically significant difference resulted compared with NFG (Slope(AIR) after BPD: 78 +/- 11 in NFG and 56 +/- 18 pmol/l in T2DM, P = ns). In conclusion, in obese T2DM subjects 1 month after BPD we observed a great improvement of both glucose- and nonglucose-stimulated insulin secretions. The mechanisms by which BDP improve insulin secretion are still unknown.
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Affiliation(s)
- Lucia Briatore
- Department of Endocrinology and Medicine, University of Genova, Genoa, Italy
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Geloneze B, Pereira JA, Pareja JC, Lima MMDO, Lazarin MACT, Souza ICPD, Tambascia MA, Chaim E, Muscelli E. Overcoming metabolic syndrome in severe obesity: adiponectin as a marker of insulin sensitivity and HDL-cholesterol improvements after gastric bypass. ACTA ACUST UNITED AC 2010; 53:293-300. [PMID: 19466223 DOI: 10.1590/s0004-27302009000200022] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2009] [Accepted: 02/28/2009] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To assess the relationship between adiponectin and metabolic parameters in severely obese women during surgical-induced weight loss. METHODS Nineteen lean (CT - BMI:21.2 +/- 0.3 kg.m(2)), 14 overweight/class II obese (OB/OW - BMI: 29.7 +/- 0.7 kg/m(2)) and 8 morbidly obese (OBIII - BMI: 56.4 +/- 3.6 kg/m(2)) were evaluated by hyperinsulinemic-euglycemic clamp, adiponectin, and lipids. OBIII were evaluated at 5th and 16th month post-operatively. RESULTS Compared to lean, obese groups had lower adiponectin (OB/OW: 9.4 +/- 0.9, OBIII: 7.1 +/- 1.3 versus 12.2 +/- 0.9 ng/dL; p < 0.01), lower HDL-cholesterol (OB/OW:1.05 +/- 0.05, OBIII: 0.88 +/- 0.04 versus 1.22 +/- 0.07 mmol/L; p < 0.01) and insulin resistance-IR (glucose uptake, M-value - OB/OW: 43.6 +/- 2.7, OBIII: 32.4 +/- 3.2 versus 20.0 +/- 1.8 umol/kgFFM.min; p < 0.001). Considering all subjects, adiponectin levels were inversely correlated to BMI and waist circumference, and directly to M-value and HDL-cholesterol (p < 0.01). During weight loss, improvements in IR (Study III: 36.1 +/- 3.9 umol/kg/FFM.min, p < 0.0001), adiponectin (11.8 +/- 1.4 ng/dL, p = 0.006) and HDL-cholesterol were observed (1.10 +/- 0.04 mmol/L, p = 0.007). Moreover, HDL-cholesterol improvement was significantly and independently related to variations of adiponectin and BMI (r(2) = 0.86; p < 0.0002). CONCLUSIONS The improvements of IR and adiponectin were related to surgical-induced weight loss, suggesting an important role of adiponectin in HDL-cholesterol regulation.
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Affiliation(s)
- Bruno Geloneze
- Laboratório de Investigação em Metabolismo e Diabetes, Universidade Estadual de Campinas, Rua Carlos Chagas 420, Campinas, SP, Brazil.
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Rickels MR, Mueller R, Teff KL, Naji A. {beta}-Cell secretory capacity and demand in recipients of islet, pancreas, and kidney transplants. J Clin Endocrinol Metab 2010; 95:1238-46. [PMID: 20097708 PMCID: PMC2841536 DOI: 10.1210/jc.2009-2289] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
CONTEXT beta-Cell secretory capacity, a measure of functional beta-cell mass, is often impaired in islet transplant recipients, likely because of a low engrafted beta-cell mass, although calcineurin inhibitor toxicity is often cited as the explanation. OBJECTIVE We sought to determine whether use of the calcineurin inhibitor tacrolimus was associated with reduced beta-cell secretory capacity or with increased beta-cell secretory demand independent of engrafted islet mass. DESIGN AND PARTICIPANTS We compared metabolic measures in five intraportal islet recipients vs. 10 normal controls and in seven portally-drained pancreas-kidney and eight nondiabetic kidney recipients vs. nine kidney donor controls. All transplant groups received comparable exposure to tacrolimus, and each transplant group was matched for kidney function to its respective control group. INTERVENTION AND MAIN OUTCOME MEASURES All participants underwent glucose-potentiated arginine testing where acute insulin responses to arginine (5 g) were determined under fasting (AIR(arg)), 230 mg/dl (AIR(pot)), and 340 mg/dl (AIR(max)) clamp conditions, and AIR(max) gives the beta-cell secretory capacity. Insulin sensitivity (M/I) and proinsulin secretory ratios (PISRs) were assessed to determine whether tacrolimus increased beta-cell secretory demand. RESULTS Insulin responses were significantly lower than normal in the islet group for AIR(arg) (P < 0.05), AIR(pot) (P < 0.01), and AIR(max) (P < 0.01), whereas responses in the pancreas-kidney and kidney transplant groups were not different than in the kidney donor group. M/I and PISRs were not different in any of the transplant vs. control groups. CONCLUSIONS Impaired beta-cell secretory capacity in islet transplantation is best explained by a low engrafted beta-cell mass and not by a deleterious effect of tacrolimus.
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Affiliation(s)
- Michael R Rickels
- University of Pennsylvania School of Medicine, 700 Clinical Research Building, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149, USA.
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Carpentier AC, Bourbonnais A, Frisch F, Giacca A, Lewis GF. Plasma nonesterified Fatty Acid intolerance and hyperglycemia are associated with intravenous lipid-induced impairment of insulin sensitivity and disposition index. J Clin Endocrinol Metab 2010; 95:1256-64. [PMID: 20097711 DOI: 10.1210/jc.2009-1932] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
CONTEXT It is currently unclear why susceptibility to lipid-induced impairment of beta-cell function varies in different populations. OBJECTIVE The aim of the study was to determine whether mild hyperglycemia may be associated with nonesterified fatty acid (NEFA) intolerance and increased iv lipid-induced lipotoxic effect on the beta-cell. DESIGN AND SETTING The study consisted of an experimental design with control group conducted at an academic clinical research center. PARTICIPANTS Twenty-six overweight or obese individuals (12 with normal glucose tolerance, nine with impaired glucose tolerance or type 2 diabetes, and five subjects who previously had impaired glucose tolerance or type 2 diabetes but at the time of study had normal glucose tolerance after biliopancreatic diversion). INTERVENTIONS We assessed insulin sensitivity (S(I)) and beta-cell function [insulin disposition index (DI)] after an overnight iv infusion of heparin + Intralipid (HI) vs. normal saline for 16 h using a stepwise, incremental iv glucose infusion followed by a hyperglycemic clamp. MAIN OUTCOME MEASURES We measured S(I), DI, HI-induced change in plasma NEFA, and its association with HI-induced change in S(I) and DI. RESULTS HI resulted in significant reduction in S(I) and DI across the three groups of participants. HI-induced elevation of plasma NEFA was higher in hyperglycemic vs. normoglycemic groups. Both fasting glucose level and the magnitude of HI-induced NEFA elevation were associated with the reduction in S(I) (P = 0.007 and P = 0.01, respectively) and DI (P = 0.001 and P = 0.007, respectively). CONCLUSION Mild hyperglycemia and NEFA intolerance to iv lipid are associated with susceptibility to lipid-induced reduction in S(I) and DI.
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Affiliation(s)
- André C Carpentier
- Division of Endocrinology, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4.
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