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Hill S, Deepa SS, Sataranatarajan K, Premkumar P, Pulliam D, Liu Y, Soto VY, Fischer KE, Van Remmen H. Sco2 deficient mice develop increased adiposity and insulin resistance. Mol Cell Endocrinol 2017; 455:103-114. [PMID: 28428045 PMCID: PMC5592144 DOI: 10.1016/j.mce.2017.03.019] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 03/18/2017] [Accepted: 03/20/2017] [Indexed: 10/19/2022]
Abstract
Cytochrome c oxidase (COX) is an essential transmembrane protein complex (Complex IV) in the mitochondrial respiratory electron chain. Mutations in genes responsible for the assembly of COX are associated with Leigh syndrome, cardiomyopathy, spinal muscular atrophy and other fatal metabolic disorders in humans. Previous studies have shown that mice lacking the COX assembly protein Surf1 (Surf1-/- mice) paradoxically show a number of beneficial metabolic phenotypes including increased insulin sensitivity, upregulation of mitochondrial biogenesis, induction of stress response pathways and increased lifespan. To determine whether these effects are specific to the Surf1 mutation or a more general effect of reduced COX activity, we asked whether a different mutation causing reduced COX activity would have similar molecular and physiologic changes. Sco2 knock-in/knock-out (KI/KO) mice in which one allele of the Sco2 gene that encodes a copper chaperone required for COX activity is deleted and the second allele is mutated, have previously been shown to be viable despite a 30-60% reduction in COX activity. In contrast to the Surf1-/- mice, we show that Sco2 KI/KO mice have increased fat mass, associated with reduced β-oxidation and increased adipogenesis markers, reduced insulin receptor beta (IR-β levels in adipose tissue, reduced muscle glucose transporter 4 (Glut4) levels and a impaired response to the insulin tolerance test consistent with insulin resistance. COX activity and protein are reduced approximately 50% in adipose tissue from the Sco2 KI/KO mice. Consistent with the increase in adipose tissue mass, the Sco2 KI/KO mice also show increased hepatosteatosis, elevated serum and liver triglyceride and increased serum cholesterol levels compared to wild-type controls. In contrast to the Surf1-/- mice, which show increased mitochondrial number, upregulation of the mitochondrial unfolded protein response (UPRMT) pathway and no significant change in mitochondrial respiration in several tissues, Sco2 KI/KO mice do not upregulate the UPRMT, and tissue oxygen consumption and levels of several proteins involved in mitochondrial function are reduced in adipose tissue compared to wild type mice. Thus, the metabolic effects of the Sco2 and Surf1-/- mutations are opposite, despite comparable changes in COX activity, illuminating the complex impact of mitochondrial dysfunction on physiology and pointing to an important role for complex IV in regulating metabolism.
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Affiliation(s)
- Shauna Hill
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States
| | - Sathyaseelan S Deepa
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States
| | - Kavithalakshmi Sataranatarajan
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States
| | - Pavithra Premkumar
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States
| | - Daniel Pulliam
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States
| | - Yuhong Liu
- Department of Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, CH 464, Birmingham, AL 35294, United States
| | - Vanessa Y Soto
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States
| | - Kathleen E Fischer
- Department of Biology, University of Alabama at Birmingham, 1720 2nd Avenue South, CH 464, Birmingham, AL 35294, United States
| | - Holly Van Remmen
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, 825 N.E. 13th Street, Oklahoma City, OK 73104, United States; Oklahoma City VA Medical Center, Oklahoma City, OK, United States.
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De Souza AL, Batista GA, Alegre SM. Assessment of insulin sensitivity by the hyperinsulinemic euglycemic clamp: Comparison with the spectral analysis of photoplethysmography. J Diabetes Complications 2017; 31:128-133. [PMID: 27839921 DOI: 10.1016/j.jdiacomp.2016.10.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 09/21/2016] [Accepted: 10/13/2016] [Indexed: 12/12/2022]
Abstract
AIMS We compare spectral analysis of photoplethysmography (PTG) with insulin resistance measured by the hyperinsulinemic euglycemic clamp (HEC) technique. MATERIAL AND METHOD A total of 100 nondiabetic subjects, 43 men and 57 women aged 20-63years, 30 lean, 42 overweight and 28 obese were enrolled in the study. These patients underwent an examination with HEC, and an examination with the PTG spectral analysis and calculation of the PTG Total Power (PTG-TP). Receiver-operating characteristic (ROC) curves were constructed to determine the specificity and sensitivity of PTG-TP in the assessment of insulin resistance. RESULTS There is a moderate correlation between insulin sensitivity (M-value) and PTG-TP (r=- 0.64, p<0.0001). The ROC curves showed that the most relevant cutoff to the whole study group was a PTG-TP>406.2. This cut-off had a sensitivity=95.7%, specificity =84,4% and the area under the ROC curve (AUC)=0.929 for identifying insulin resistance. All AUC ROC curve analysis were significant (p<0.0001). CONCLUSION The use of the PTG-TP marker measured from the PTG spectral analysis is a useful tool in screening and follow up of IR, especially in large-scale studies.
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Affiliation(s)
- Aglecio Luiz De Souza
- Department of Internal Medicine, Faculty of Medical Sciences - State University of Campinas (UNICAMP), Campinas, SP, Brazil.
| | - Gisele Almeida Batista
- Department of Internal Medicine, Faculty of Medical Sciences - State University of Campinas (UNICAMP), Campinas, SP, Brazil
| | - Sarah Monte Alegre
- Department of Internal Medicine, Faculty of Medical Sciences - State University of Campinas (UNICAMP), Campinas, SP, Brazil
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Embleton ND, Korada M, Wood CL, Pearce MS, Swamy R, Cheetham TD. Catch-up growth and metabolic outcomes in adolescents born preterm. Arch Dis Child 2016; 101:1026-1031. [PMID: 27288431 DOI: 10.1136/archdischild-2015-310190] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 04/27/2016] [Accepted: 05/15/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND Accelerated infant weight gain in individuals born full term is linked to cardiovascular risk in adulthood, but data in those born preterm are inconsistent. OBJECTIVE To investigate the association between weight gain in infancy and childhood with later markers of the metabolic syndrome in adolescents who were born preterm. STUDY DESIGN Longitudinal cohort study. SETTING Children born preterm with regular assessments of infant growth had auxology, body composition (dual X-ray absorptiometry), blood pressure, insulin sensitivity and lipid profile determined in adolescence. RESULTS We reviewed 153 children (mean gestation 30.8 weeks, median birth weight 1365 g) of whom 102 consented to venepuncture at a median age of 11.5 years. Adolescent height and weight standard deviation scores (SDS) were similar to population averages (0.01±0.92 and 0.3±1.2, respectively) and did not differ between infants when grouped according to degree of catch-up in weight gain in the immediate postdischarge period to 12 weeks of age. There were no significant associations between infant weight gain (change in weight SDS adjusted for length) and later metabolic outcome. However, there were strong associations between more rapid childhood weight gain (after 1 year of age) and subsequent body composition (higher fat mass %, fat mass index and waist circumference) and metabolic markers (higher fasting insulin, blood pressure and lower insulin sensitivity). CONCLUSIONS The association of rapid weight gain on health is time critical in those born preterm; in early infancy, this does not impact on metabolic status in adolescence, in contrast to rapid weight gain in childhood, which should be discouraged. However, given the critical importance of brain growth in the neonatal period and infancy, further research is needed before strategies that discourage infant weight gain or catch-up can be recommended for infants born preterm.
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Affiliation(s)
- Nicholas D Embleton
- Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK
| | - Murthy Korada
- Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.,Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK
| | - Claire L Wood
- Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Mark S Pearce
- Institute of Health & Society, Newcastle University, Newcastle upon Tyne, UK
| | - Ravi Swamy
- Newcastle Neonatal Service, Royal Victoria Infirmary, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Timothy D Cheetham
- Department of Paediatric Endocrinology, Royal Victoria Infirmary, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK
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Sung KC, Park HY, Kim MJ, Reaven G. Metabolic markers associated with insulin resistance predict type 2 diabetes in Koreans with normal blood pressure or prehypertension. Cardiovasc Diabetol 2016; 15:47. [PMID: 27001495 PMCID: PMC4802716 DOI: 10.1186/s12933-016-0368-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 03/15/2016] [Indexed: 12/03/2022] Open
Abstract
Background Questions remain as to the association between essential hypertension and increased incidence of type 2 diabetes (T2DM). The premise of this analysis is that insulin resistance/compensatory hyperinsulinemia is a major predictor of T2DM, and the greater the prevalence of insulin resistance within any population, normotensive or hypertensive, the more likely T2DM will develop. The hypothesis to be tested is that surrogate estimates of insulin resistance will predict incident T2DM to a significant degree in persons with normal blood pressure or prehypertension. Methods Analysis of data from a population-based survey of 10, 038 inhabitants of rural and urban areas of Korea, ≥40 years-old, initiated in 2001, with measures of demographic and metabolic characteristics at baseline and 8-years later. Participants were classified as having normal blood pressure or prehypertension, and three simple manifestations of insulin resistance related to the pathophysiology of T2DM used to predict incident T2DM: (1) glycemia (plasma glucose concentration 2-hour after 75 g oral glucose challenge = 2-hour PG); (2) hyperinsulinemia (plasma insulin concentration 2-hour after 75 g oral glucose challenge = 2-hour PI); and (3) dyslipidemia (ratio of fasting plasma triglyceride/high/density lipoprotein cholesterol concentration = TG/HDL-C ratio). Results Fully adjusted hazard ratios (HR, 95 % CI) for incident T2DM were highest (P < 0.001) in the quartile of individuals with the highest 2-hour PG concentrations, ranging from 5.84 (3.37–10.1) in women with prehypertension to 12.2 (7.12–21.00) in men with normal blood pressure. T2DM also developed to a significantly greater degree in subjects within the highest quartile of TG/HDL-C ratios, with HRs varying from 2.91 (1.63–2.58) in women with prehypertension (P < 0.001) to 1.77 (1.12–2.81, P < 0.05) in men with prehypertension. The least predictive index of insulin resistance was the 2-hour PI concentration. Subjects with normal blood pressure in the highest quartile of 2-hour PI concentrations were significantly associated with incident T2DM, with HRs of 1.5 (1.02–2.20, P = 0.25) and 2.02 (1.35–3.02, P < 0.001), in men and women, respectively. Finally, incidence of T2DM in the highest quartile was somewhat greater in patients with prehypertension, irrespective of predictor. Conclusions Metabolic variables associated with insulin resistance (glycemia, insulinemia, and dyslipidemia) predict the development of T2DM in patients with either normal blood pressure or prehypertension. Electronic supplementary material The online version of this article (doi:10.1186/s12933-016-0368-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ki-Chul Sung
- Division of Cardiology, Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, #108, Pyung Dong, Jongro-Ku, Seoul, 110-746, Republic of Korea.
| | - Hyun-Young Park
- Division of Cardiovascular and Rare Diseases, Center for Biomedical Science, Korea National Institute of Health, 187 Osongsaengmyeng 2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 361-951, Republic of Korea
| | - Min-Ju Kim
- Division of Cardiovascular and Rare Diseases, Center for Biomedical Science, Korea National Institute of Health, 187 Osongsaengmyeng 2-ro, Osong-eup, Heungdeok-gu, Cheongju, Chungbuk, 361-951, Republic of Korea
| | - Gerald Reaven
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA
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Otten J, Ahrén B, Olsson T. Surrogate measures of insulin sensitivity vs the hyperinsulinaemic-euglycaemic clamp: a meta-analysis. Diabetologia 2014; 57:1781-8. [PMID: 24891021 DOI: 10.1007/s00125-014-3285-x] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 04/28/2014] [Indexed: 02/05/2023]
Abstract
AIMS/HYPOTHESIS We aimed to identify which surrogate index of insulin sensitivity has the strongest correlation with the reference measurement, the hyperinsulinaemic-euglycaemic clamp (HEC), to determine which surrogate measure should be recommended for use in large-scale studies. METHODS A literature search (1979-2012) was conducted to retrieve all articles reporting bivariate correlations between the HEC and surrogate measures of insulin sensitivity (in fasting samples or during the OGTT). We performed a random effects meta-analysis for each surrogate measure to integrate the correlation coefficients of the different studies. RESULTS The OGTT-based surrogate measures with the strongest pooled correlations (r) to the HEC were the Stumvoll metabolic clearance rate (Stumvoll MCR; r = 0.70 [95% CI 0.61, 0.77], n = 5), oral glucose insulin sensitivity (OGIS; r = 0.70 [0.57, 0.80], n = 6), the Matsuda index (r = 0.67 [0.61, 0.73], n = 19), the Stumvoll insulin sensitivity index (Stumvoll ISI; r = 0.67 [0.60, 0.72], n = 8) and the Gutt index (r = 0.65 [0.60, 0.69], n = 6). The fasting surrogate indices that correlated most strongly with the HEC and had narrow 95% CIs were the revised QUICKI (r = 0.68 [0.58, 0.77], n = 7), the QUICKI (r = 0.61 [0.55, 0.65], n = 35), the log HOMA-IR (r = -0.60 [-0.66, -0.53], n = 22) and the computer generated HOMA of insulin sensitivity (HOMA-%S; r = 0.57 [0.46, 0.67], n = 5). CONCLUSIONS/INTERPRETATION The revised QUICKI fasting surrogate measure appears to be as good as the OGTT-based Stumvoll MCR, OGIS, Matsuda, Stumvoll ISI and Gutt indices for estimating insulin sensitivity. It can therefore be recommended as the most appropriate index for use in large-scale clinical studies.
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Affiliation(s)
- Julia Otten
- Department of Public Health and Clinical Medicine, Medicine, Umeå University, SE-90 185, Umeå, Sweden,
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Elevated diastolic blood pressure in insulin-resistant polycystic ovarian syndrome patients. Arch Gynecol Obstet 2013; 289:119-22. [DOI: 10.1007/s00404-013-2953-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 07/01/2013] [Indexed: 10/26/2022]
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Dube S, Errazuriz I, Cobelli C, Basu R, Basu A. Assessment of insulin action on carbohydrate metabolism: physiological and non-physiological methods. Diabet Med 2013; 30:664-70. [PMID: 23683103 PMCID: PMC3662485 DOI: 10.1111/dme.12189] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/14/2013] [Indexed: 01/03/2023]
Abstract
Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic β-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action.
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Affiliation(s)
- S Dube
- Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA
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Stuart CA, McCurry MP, Marino A, South MA, Howell MEA, Layne AS, Ramsey MW, Stone MH. Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness. J Clin Endocrinol Metab 2013; 98:2027-36. [PMID: 23515448 PMCID: PMC3644602 DOI: 10.1210/jc.2012-3876] [Citation(s) in RCA: 151] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT The metabolic syndrome, characterized by central obesity with dyslipidemia, hypertension, and hyperglycemia, identifies people at high risk for type 2 diabetes. OBJECTIVE Our objective was to determine how the insulin resistance of the metabolic syndrome is related to muscle fiber composition. DESIGN Thirty-nine sedentary men and women (including 22 with the metabolic syndrome) had insulin responsiveness quantified using euglycemic clamps and underwent biopsies of the vastus lateralis muscle. Expression of insulin receptors, insulin receptor substrate-1, glucose transporter 4, and ATP synthase were quantified with immunoblots and immunohistochemistry. PARTICIPANTS AND SETTING Participants were nondiabetic, metabolic syndrome volunteers and sedentary control subjects studied at an outpatient clinic. MAIN OUTCOME MEASURES Insulin responsiveness during an insulin clamp and the fiber composition of a muscle biopsy specimen were evaluated. RESULTS There were fewer type I fibers and more mixed (type IIa) fibers in metabolic syndrome subjects. Insulin responsiveness and maximal oxygen uptake correlated with the proportion of type I fibers. Insulin receptor, insulin receptor substrate-1, and glucose transporter 4 expression were not different in whole muscle but all were significantly less in the type I fibers of metabolic syndrome subjects when adjusted for fiber proportion and fiber size. Fat oxidation and muscle mitochondrial expression were not different in the metabolic syndrome subjects. CONCLUSION Lower proportion of type I fibers in metabolic syndrome muscle correlated with the severity of insulin resistance. Even though whole muscle content was normal, key elements of insulin action were consistently less in type I muscle fibers, suggesting their distribution was important in mediating insulin effects.
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MESH Headings
- ATP Synthetase Complexes/metabolism
- Adult
- Antigens, CD/metabolism
- Body Mass Index
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/etiology
- Female
- Glucose Transporter Type 4/metabolism
- Humans
- Insulin Receptor Substrate Proteins/metabolism
- Insulin Resistance
- Male
- Metabolic Syndrome/complications
- Metabolic Syndrome/metabolism
- Metabolic Syndrome/pathology
- Middle Aged
- Muscle Fibers, Fast-Twitch/enzymology
- Muscle Fibers, Fast-Twitch/metabolism
- Muscle Fibers, Fast-Twitch/pathology
- Muscle Fibers, Slow-Twitch/enzymology
- Muscle Fibers, Slow-Twitch/metabolism
- Muscle Fibers, Slow-Twitch/pathology
- Obesity/complications
- Quadriceps Muscle/enzymology
- Quadriceps Muscle/metabolism
- Quadriceps Muscle/pathology
- Receptor, Insulin/metabolism
- Risk
- Sedentary Behavior
- Tennessee/epidemiology
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Affiliation(s)
- Charles A Stuart
- Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, P.O. Box 70622, Johnson City, Tennessee 37614-0622, USA.
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Abstract
Limitations in physical fitness, a consistent finding in individuals with both type I and type 2 diabetes mellitus, correlate strongly with cardiovascular and all-cause mortality. These limitations may significantly contribute to the persistent excess cardiovascular mortality affecting this group. Exercise impairments in VO2 peak and VO2 kinetics manifest early on in diabetes, even with good glycemic control and in the absence of clinically apparent complications. Subclinical cardiac dysfunction is often present but does not fully explain the observed defect in exercise capacity in persons with diabetes. In part, the cardiac limitations are secondary to decreased perfusion with exercise challenge. This is a reversible defect. Similarly, in the skeletal muscle, impairments in nutritive blood flow correlate with slowed (or inefficient) exercise kinetics and decreased exercise capacity. Several correlations highlight the likelihood of endothelial-specific impairments as mediators of exercise dysfunction in diabetes, including insulin resistance, endothelial dysfunction, decreased myocardial perfusion, slowed tissue hemoglobin oxygen saturation, and impairment in mitochondrial function. Both exercise training and therapies targeted at improving insulin sensitivity and endothelial function improve physical fitness in subjects with type 2 diabetes. Optimization of exercise functions in people with diabetes has implications for diabetes prevention and reductions in mortality risk. Understanding the molecular details of endothelial dysfunction in diabetes may provide specific therapeutic targets for the remediation of this defect. Rat models to test this hypothesis are under study.
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Affiliation(s)
- Jane E B Reusch
- Denver VA Medical Center, Clermont Street, Denver, CO 80220, USA.
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Abstract
Type 2 diabetic patients are insulin resistant as a result of obesity and a sedentary lifestyle. Nevertheless, it has been known for the past five decades that insulin response to nutrients is markedly diminished in type 2 diabetes. There is now a consensus that impaired glucose regulation cannot develop without insulin deficiency. First-phase insulin response to glucose is lost very early in the development of type 2 diabetes. Several prospective studies have shown that impaired insulin response to glucose is a predictor of future impaired glucose tolerance (IGT) and type 2 diabetes. Recently discovered type 2 diabetes-risk gene variants influence β-cell function, and might represent the molecular basis for the low insulin secretion that predicts future type 2 diabetes. We believe type 2 diabetes develops on the basis of normal but 'weak'β-cells unable to cope with excessive functional demands imposed by overnutrition and insulin resistance. Several laboratories have shown a reduction in β-cell mass in type 2 diabetes and IGT, whereas others have found modest reductions and most importantly, a large overlap between β-cell masses of diabetic and normoglycemic subjects. Therefore, at least initially, the β-cell dysfunction of type 2 diabetes seems more functional than structural. However, type 2 diabetes is a progressive disorder, and animal models of diabetes show β-cell apoptosis with prolonged hyperglycemia/hyperlipemia (glucolipotoxicity). β-Cells exposed in vitro to glucolipotoxic conditions show endoplasmic reticulum (ER) and oxidative stress. ER stress mechanisms might participate in the adaptation of β-cells to hyperglycemia, unless excessive. β-Cells are not deficient in anti-oxidant defense, thioredoxin playing a major role. Its inhibitor, thioredoxin-interacting protein (TXNIP), might be important in leading to β-cell apoptosis and type 2 diabetes. These topics are intensively investigated and might lead to novel therapeutic approaches. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00094.x, 2011).
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Affiliation(s)
- Gil Leibowitz
- Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel
| | - Nurit Kaiser
- Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel
| | - Erol Cerasi
- Endocrine Services, Department of Medicine, Hebrew University Hadassah Medical Center, Jerusalem, Israel
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Ahn HJ, Eom YK, Han KA, Kwon HR, Kim HJ, Park KS, Min KW. The effects of small sized rice bowl on carbohydrate intake and dietary patterns in women with type 2 diabetes. KOREAN DIABETES JOURNAL 2010; 34:166-73. [PMID: 20617077 PMCID: PMC2898930 DOI: 10.4093/kdj.2010.34.3.166] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Accepted: 04/20/2010] [Indexed: 11/10/2022]
Abstract
Background The main source of carbohydrate in the Korean diet is rice, which is usually served in a rice bowl. This study investigated the impact of a meal plan using smaller rice bowls on dietary energy intake and macronutrient composition in overweight or obese patients with type 2 diabetes mellitus. Methods A total of 67 women with type 2 diabetes were enrolled in our study. We divided these participants into three groups: a normal-weight group (NW; body mass index [BMI] < 23 kg/m2; n = 17), an overweight group (OW; 23 ≤ BMI < 25 kg/m2; n = 24) and an obese group (OB; BMI ≥ 25 kg/m2; n = 26). Three-day dietary records were analyzed for total energy intake (TEI) and macronutrient composition both before enrollment and two weeks after patients received instruction in a dietary plan based on using a small (200 mL) rice bowl. Results After the intervention, TEI decreased in the OW and OB groups. Decreased carbohydrate (NW, -4 ± 5%; OW, -4 ± 5%; OB, -3 ± 6%) and increased fat intakes were found in all three groups, which complies with Korean Diabetes Association recommendations. The protein proportion of TEI significantly increased only in the OW group. Body weight decreased both in the OW and OB groups. Conclusion A short-term, small-rice-bowl-based meal plan was effective for body weight control and macronutrient balance in overweight or obese women in Korea with type 2 diabetes.
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Ma X, Hui H, Liu Z, He G, Hu J, Meng J, Guan L, Luo X. Poly-GLP-1, a novel long-lasting glucagon-like peptide-1 polymer, ameliorates hyperglycaemia by improving insulin sensitivity and increasing pancreatic beta-cell proliferation. Diabetes Obes Metab 2009; 11:953-65. [PMID: 19531053 DOI: 10.1111/j.1463-1326.2009.01070.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIM The clinical value of glucagon-like peptide-1 (GLP-1) is restricted because of its short half-life. To overcome this limitation, a new polymer of GLP-1 was developed by prodrug strategy, termed Poly-GLP-1, and its pharmacological properties were investigated. METHODS The in vitro release kinetics of GLP-1 from Poly-GLP-1 was analysed by Western blot. Plasma GLP-1 levels following a single administration of Poly-GLP-1 were determined by enzyme-linked immunosorbent assay. The in vitro effects of Poly-GLP-1 were evaluated using isolated pancreatic islets. The acute effects on glycaemic control and food intake were investigated in C57BL/6J mice s.c. administered with Poly-GLP-1. The chronic effects of Poly-GLP-1 on glycaemic control were further assessed in C57BL/6J and db/db mice treated twice daily for 6 weeks. RESULTS Pro-GLP-1 dose dependently increased insulin secretion and decreased glucose, but did not exhibit the insulinotropic action in isolated pancreatic islets without plasma. The glucose-lowering actions of Poly-GLP-1 (3 nmol/kg) remained no less than 12 h after a single injection. Poly-GLP-1 caused a durable restoration of glycaemic control, food intake and body weight gain in db/db mice following 6-week administration. The chronic treatment with Poly-GLP-1 improved glucose tolerance and insulin sensitivity and increased beta-cell mass and proliferation in db/db mice. There was little effect on normal mice treated in the same manner. CONCLUSIONS Our results indicated that Poly-GLP-1, a novel GLP-1 polymer, has long-lasting and potent effects on glycaemic control in vivo, and these beneficial effects may be because of improvement of insulin sensitivity and promotion of islet growth and function.
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Affiliation(s)
- X Ma
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
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Liu B, Liu WS, Han BQ, Sun YY. Antidiabetic effects of chitooligosaccharides on pancreatic islet cells in streptozotocin-induced diabetic rats. World J Gastroenterol 2007; 13:725-31. [PMID: 17278195 PMCID: PMC4066005 DOI: 10.3748/wjg.v13.i5.725] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of chitooligosaccharides on proliferation of pancreatic islet cells, release of insulin and 2 h plasma glucose in streptozotocin-induced diabetic rats.
METHODS: In vitro, the effect of chitooligosaccharides on proliferation of pancreatic islet cells and release of insulin was detected with optical microscopy, colorimetric assay, and radioimmunoassay respectively. In vivo, the general clinical symptoms, 2 h plasma glucose, urine glucose, oral glucose tolerance were examined after sixty days of feeding study to determine the effect of chitooligosaccharides in streptozotocin-induced diabetic rats.
RESULTS: Chitooligosaccharides could effectively accelerate the proliferation of pancreatic islet cells. Chitooligosaccharides (100 mg/L) had direct and prominent effect on pancreastic β cells and insulin release from islet cells. All concentrations of chitooligosaccharides could improve the general clinical symptoms of diabetic rats, decrease the 2 h plasma glucose and urine glucose, and normalize the disorders of glucose tolerance.
CONCLUSION: Chitooligosaccharides possess various biological activities and can be used in the treatment of diabetes mellitus.
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Affiliation(s)
- Bing Liu
- College of Marine Life Science, Ocean University of China, Qingdao 266003, Shandong Province, China
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14
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Gerson LS, Braun B. Effect of high cardiorespiratory fitness and high body fat on insulin resistance. Med Sci Sports Exerc 2006; 38:1709-15. [PMID: 17019291 DOI: 10.1249/01.mss.0000228365.31821.22] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
PURPOSE High cardiorespiratory fitness (CRF) dramatically lowers risk for cardiometabolic disease in overweight and obese individuals. This effect is likely attributable to the inverse relationship between high CRF and insulin resistance. In this study, the independent effects of high body fat and high CRF on insulin resistance were assessed. METHODS The blood glucose and insulin responses to an oral glucose tolerance test were measured in 10 overweight women with high CRF (OF), 9 lean women with high CRF (LF), and 10 overweight women with low CRF (OU). RESULTS Fasting plasma glucose (P = 0.77), insulin (P = 0.23), and triacylglycerol (P = 0.99) concentrations were similar between OF and LF, with mean values in both groups lower than in OU. The glucose area under the curve (AUC) was not different between LF and OF (P = 0.28) and was significantly higher in OU. Insulin sensitivity, estimated from the composite insulin-sensitivity index (C-ISI), was slightly but significantly lower in OF compared with LF. Similarly, insulin AUC was 43% lower in LF compared with OF, although this difference was not statistically significant (P = 0.08). Insulin AUC was 50% higher (P = 0.04) and C-ISI was 35% lower (P = 0.09) in OU compared with OF. CONCLUSION Compared with lean fit women, estimated insulin sensitivity was only slightly lower and plasma triacylglycerols were almost identical in overweight women with equally high CRF despite a twofold elevation in body fat percentage.
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Affiliation(s)
- Laura S Gerson
- Energy Metabolism Laboratory, Department of Kinesiology, University of Massachusetts, Amherst, MA 01003, USA
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15
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Abstract
Em virtude da associação entre resistência à insulina (RI) e aterosclerose, existe interesse no desenvolvimento de técnicas para se avaliar a sensibilidade à insulina (SI) in vivo. Por ser uma medida de fácil utilização em grandes populações, a insulinemia de jejum tem sido usada para avaliar a SI e fornece uma boa avaliação da sensibilidade hepática, embora não da muscular. O HOMA é um modelo matemático que prediz a SI pelas simples medidas da glicemia e da insulina no jejum e tem boa correlação com o método do clamp euglicêmico hiperinsulinêmico, considerado padrão-ouro na medida da SI. Assim, mostra-se como valiosa alternativa às técnicas mais sofisticadas e trabalhosas na avaliação da RI em humanos, como o método descrito por Bergman. Em nosso meio, encontramos o valor de corte para o diagnóstico da RI quando o Homa-IR for maior que 2,71. O QUICKI é outro método simples, baseado também nas medidas da glicemia e da insulina no jejum, que apresenta boas correlações com marcadores da síndrome metabólica, conseguindo discriminar satisfatoriamente diferentes estados de RI, como graus de obesidade e tolerância à glicose. Métodos diretos de avaliação da SI incluem o teste de tolerância à insulina (K ITT), o teste de supressão de insulina e as técnicas de clamp hiperglicêmico e euglicêmico que são descritas neste artigo. A técnica do clamp euglicêmico e hiperinsulinêmico fornece a mais pura e reprodutível informação sobre a ação da insulina. Os custos envolvidos na sua realização, entretanto, limitam o seu uso.
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16
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Tso TK, Huang HY, Chang CK, Liao YJ, Huang WN. Clinical evaluation of insulin resistance and beta-cell function by the homeostasis model assessment in patients with systemic lupus erythematosus. Clin Rheumatol 2004; 23:416-20. [PMID: 15459813 DOI: 10.1007/s10067-004-0908-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2003] [Accepted: 02/20/2004] [Indexed: 10/26/2022]
Abstract
The aim of this preliminary study was to evaluate insulin resistance and secretion using homeostasis model assessment (HOMA) in patients with systemic lupus erythematosus (SLE). The fasting glucose and insulin concentrations, HOMA insulin resistance (IR), HOMA beta-cell, antidouble-stranded DNA antibodies (anti-dsDNA), C3, C4, and SLE disease activity index (SLEDAI) were determined in a total of 58 female SLE patients. All patients were classified into subgroups according to the presence of anticardiolipin antibodies (aCL+ vs. aCL-) and SLEDAI scores (SLEDAI < 3 vs. SLEDAI > 3). Results showed that SLE patients with and without aCL had significantly higher fasting insulin levels, HOMA IR, and HOMA beta-cells than controls. Similar results were also found in SLE patients with different disease activities. Pearson's correlation analysis showed that there was a highly significant correlation of HOMA IR with fasting insulin concentration in the SLE patients and SLE subgroups overall. However, HOMA beta-cells were positively correlated with HOMA IR and fasting insulin level, but negatively correlated with fasting glucose concentration in SLE patients overall. In conclusion, SLE patients, regardless of the presence of aCL and different disease activities, had a higher risk of insulin resistance and abnormal insulin secretion than age-matched healthy controls, based on fasting insulin concentration, HOMA IR, and HOMA beta-cells.
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Affiliation(s)
- Tim K Tso
- Graduate Institute of Food and Nutrition, Shih Chien University, Taipei, Taiwan
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17
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Martell N, Rodriguez-Cerrillo M, Grobbee DE, López-Eady MD, Fernández-Pinilla C, Avila M, Fernández-Cruz A, Luque M. High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Blood Press 2004; 12:149-54. [PMID: 12875476 DOI: 10.1080/08037050310009950] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVE To determine causes of treatment resistance in patients with refractory hypertension, and to estimate the prevalence of true resistant hypertension. METHODS We studied 50 consecutive patients referred with refractory hypertension after exclusion of hypokalemia and stenosis of the renal artery. Ambulatory blood pressure monitoring was performed in all patients to detect white-coat effect. The patients were hospitalized, antihypertensive drugs were withdrawn and a screening for secondary hypertension was performed. In addition, these patients, and a control group of essential hypertensives controlled with three antihypertensive drugs, underwent a OGTT with 75 g of glucose. RESULTS Primary normokalemic hyperaldosteronism was diagnosed in seven patients. Two patients had a pheochromocytoma and six had white-coat effect. The 35 remaining patients with true resistant hypertension shown significant differences in serum insulin and HOMA IR when compared with the control group. CONCLUSIONS These findings show that among normokalemic treatment-resistant hypertension, the presence of hyperaldosteronism and pheochromocytoma is quite high. Moreover, treatment resistance in hypertensive patients appears to be associated with insulin resistance.
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Affiliation(s)
- Nieves Martell
- Unidad de Hipertension, Hospital Clínico San Carlos, Madrid, Spain.
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18
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Robinson ACJ, Jeffs JAR, Gray RG, Bannister PA, Mather H, Gallagher JJ, Robinson S, Nattrass M, Venkatesan S, Halliday D, Johnston DG. Metabolic effects of Troglitazone in patients with diet-controlled type 2 diabetes. Eur J Clin Invest 2004; 34:29-36. [PMID: 14984435 DOI: 10.1111/j.1365-2362.2004.01274.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND In order to study the mechanisms of action of Troglitazone (TGZ) in vivo in Type 2 diabetes, its effects were studied on glucose metabolism, lipolysis and very low-density lipoprotein (VLDL) apolipoprotein B100 (apoB) kinetics. MATERIALS AND METHODS A placebo-controlled, double-blind study was performed in 24 diet-treated patients randomized to receive TGZ 600 mg day(-1), TGZ 200 mg day(-1) or placebo for 8 weeks. Glucose and glycerol turnover were assessed after an overnight fast, and during sequential low-dose insulin infusions (0.01 U kg(-1) h(-1) followed by 0.015 U kg(-1) h(-1)) using 6,6-2H Glucose and 1,2,3-2H Glycerol. Very low-density lipoprotein apoB secretion was measured using l-13C-leucine, monitoring isotopic enrichment by gas chromatography-mass spectrometry. Treatment effects were analyzed by analysis of covariance, adjusting for baseline. RESULTS Therapy resulted in a significant group differences in fasting plasma glucose adjusting for baseline (P=0.039). This was most evident at TGZ 600 mg daily [glucose decrease from (mean +/- SD) 9.2 +/- 2.7 to 6.6 +/- 0.9 mmol L(-1)]. HbA1c and insulin levels did not change significantly. Plasma nonesterified fatty acid (NEFA) levels decreased (P=0.045), most evidently at TGZ 200 mg daily, but glycerol was not significantly affected. Although no significant effects were observed on VLDL apoB or triglyceride concentrations, there were treatment differences in the absolute secretion rate of VLDL apoB of borderline (P=0.056) statistical significance, with a decrease observed at TGZ 600 mg daily [geometric mean, SD range, 0.94 (0.41-2.15) to 0.40 (0.14-1.13 mg kg(-1) h(-1))]. Very low-density lipoprotein apoB fractional secretion rate and pool size were unaffected. The VLDL triglyceride: apoB molar ratio differed between treatment groups (P=0.013), being higher in the TGZ 600 mg group [5714 (4128-7741) to 8092 (5669-11552)]. Neither glucose nor glycerol rates of appearance were significantly altered by TGZ and nor did TGZ affect their suppression by insulin. DISCUSSION The PPARgamma agonist, troglitazone, decreases fasting glucose and NEFA levels in diet-treated Type 2 diabetes. It may also decrease VLDL particle secretion. These effects would be considered beneficial. The biological importance of the increase in VLDL-triglyceride enrichment warrants further study.
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Affiliation(s)
- A C J Robinson
- Department of Endocrinology, Imperial College Faculty of Medicine, St. Mary's Hospital, London, UK
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19
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Diamond MP, Chauhan S, Kruger M, Subramanian M. Values of fasting glucose levels, glucose tolerance tests, and glucose-insulin ratios as predictors of glucose tolerance. Fertil Steril 2003; 80:1022-5. [PMID: 14556827 DOI: 10.1016/s0015-0282(03)01016-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To examine the ability to use parameters obtainable from an oral glucose tolerance test to predict insulin action as determined under hyperinsulinemic, hyperglycemic conditions. DESIGN Prospective clinical investigation. SETTING University medical center clinical research unit. PATIENT(S) Healthy male volunteers. INTERVENTION(S) Oral glucose tolerance test and hyperglycemic (+125 mg/dL) clamp studies. MAIN OUTCOME MEASURE(S) Glucose and insulin (I) levels, rate of glucose uptake (M) under hyperglycemic conditions, and M/I ratios. RESULT(S) Among individuals with normal glucose tolerance, as assessed by an oral glucose tolerance test, the fasting insulin level is the glucose tolerance test parameter that correlates best with insulin action during a hyperglycemic clamp. CONCLUSION(S) Measurement of fasting serum insulin levels in conjunction with an oral glucose tolerance test improves the ability to assess insulin action. Such combinations may improve the ability to diagnose insulin-resistant states.
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Affiliation(s)
- Michael P Diamond
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Wayne State University/Detroit Medical Center, Hutzel Hospital, Detroit, Michigan 48201, USA.
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20
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Tuan CY, Abbasi F, Lamendola C, McLaughlin T, Reaven G. Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. Am J Cardiol 2003; 92:606-10. [PMID: 12943888 DOI: 10.1016/s0002-9149(03)00735-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
In this study, a specific measurement of insulin-mediated glucose disposal was used in 490 healthy volunteers to classify subjects as being insulin resistant. We then made standard measurements of plasma glucose and insulin concentrations to see how useful they would be as surrogate markers of insulin resistance.
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Affiliation(s)
- Cheng-Yang Tuan
- Stanford University School of Medicine, Stanford, California 94305, USA
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21
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Moro E, Gallina P, Pais M, Cazzolato G, Alessandrini P, Bittolo-Bon G. Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes. Metabolism 2003; 52:616-9. [PMID: 12759893 DOI: 10.1053/meta.2003.50102] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The current study retrospectively examined the association between insulin resistance and plasma triglycerides (TG) in a group of subjects with normal glucose tolerance. Among 1,434 subjects consecutively undergoing a standard oral glucose tolerance test (OGTT) between 1993 and 1998, 567 (age, 15 to 78 years) were classified as having a normal glucose tolerance according to the 1999 World Health Organization (WHO) criteria and were selected for the study. Serum insulin was measured by radioimmunoassay (INSI-CTK, Dia Sorin, Saluggia, Italy). Intra-assay and interassay coefficients of variation for the method were less than 4% and less than 8.5%, respectively. Insulin resistance was calculated by a homeostasis model assessment (HOMA(IR) = fasting serum insulin [mU/mL] x fasting blood glucose [mmol/L]/22.5). A very significant correlation was found between HOMA(IR) and plasma TG (r = 0.27, P < 1.02E(-10)). Multiple regression analyses confirmed plasma TG as independent variables explicative of HOMA(IR). When subjects were evaluated according to tertiles of TG, those in the upper two tertiles were older (P <.001) and presented higher body mass index (BMI) values (P <.0001) in comparison to subjects in the lower tertile. A positive trend (analysis of variance [ANOVA]) was found in regard to systolic (P <.05) and diastolic blood pressure (P <.0001), fasting blood glucose (P <.01), fasting serum insulin (P <.0001), and total cholesterol (P <.0001), while a negative trend was found in regard to high-density lipoprotein cholesterol (HDL-C) (P <.0001). Insulin resistance, calculated as HOMA(IR), was higher in the upper two tertiles of TG in comparison to the lower tertile (P <.001 and P <.0001, respectively), with a statistically significant trend for the entire group (first tertile, 1.85 +/- 0.94; second tertile, 2.28 +/- 1.10; third tertile, 2.65 +/- 1.71; ANOVA: P <.0001). In conclusion, this study shows an association between high levels of circulating TG and insulin resistance in patients with normal glucose tolerance seen in an atherosclerosis prevention clinic. This association is also present at levels of plasma TG considered to be normal and is associated with a cluster of cardiovascular risk factors.
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Affiliation(s)
- E Moro
- Second Department of Internal Medicine and Metabolic Diseases, Regional Hospital, Venice, Italy
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22
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McLaughlin T, Abbasi F, Lamendola C, Liang L, Reaven G, Schaaf P, Reaven P. Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation 2002; 106:2908-12. [PMID: 12460870 DOI: 10.1161/01.cir.0000041046.32962.86] [Citation(s) in RCA: 244] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Plasma C-reactive protein (CRP) concentrations are increased in obese and/or hyperinsulinemic individuals. The goal of this study was to determine if the relation between insulin resistance and CRP was independent of obesity. METHODS AND RESULTS Plasma CRP concentrations were measured before and after 3 months of calorie restriction in 38 healthy, obese women. Steady-state plasma glucose (SSPG) concentration during a 180-minute infusion of octreotide, glucose, and insulin was used to stratify participants into insulin-resistant (IR, n=20) or insulin-sensitive (n=18) groups, similar in terms of mean age (46+/-2 versus 44+/-2 years), body mass index (32.0+/-0.4 versus 31.4+/-0.3 kg/m2), and waist circumference (96+/-2 versus 95+/-2 cm). Mean CRP (0.39+/-0.08 versus 0.12+/-0.03 mg/dL, P=0.003) concentrations were higher in the IR group, as were day-long plasma glucose and insulin responses (P<0.001). There was a significant correlation at baseline between CRP and day-long plasma integrated insulin response (r=0.47, P=0.001) but not between CRP and body mass index (r=0.14) or waist circumference (r=0.10). Weight loss was similar in the two groups (8.7+/-0.9 versus 8.4+/-0.8 kg) but was associated with significant (P<0.001) decreases in SSPG and CRP concentrations in the IR group only. Regression analysis showed that SSPG and day-long plasma insulin response were the only significant predictors of CRP concentration. CONCLUSIONS CRP concentrations are elevated predominantly in obese individuals who are also insulin resistant and fall in parallel with weight loss-associated improvements in insulin resistance. The relation between CRP concentrations and insulin resistance is independent of obesity.
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Arima H, Kiyohara Y, Kato I, Tanizaki Y, Kubo M, Iwamoto H, Tanaka K, Abe I, Fujishima M. Alcohol reduces insulin-hypertension relationship in a general population: the Hisayama study. J Clin Epidemiol 2002; 55:863-9. [PMID: 12393073 DOI: 10.1016/s0895-4356(02)00441-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Insulin resistance may be a factor in the etiology of hypertension, and habitual alcohol intake may modify this relationship. We prospectively examined this hypothesis in 1,133 nonhypertensive, nondiabetic Japanese subjects, aged 40-79 years. Alcohol drinkers were more frequent among men than women at baseline (57.7 vs. 8.2%). The age-adjusted incidence of hypertension significantly increased with the elevating baseline insulin levels in women (P =.003 for trend), but not in men. The age- and sex-adjusted insulin levels and insulin resistance index decreased with elevating alcohol intake, while fasting glucose levels remained unchanged, suggesting that alcohol improves insulin sensitivity. Among nondrinkers, the age-adjusted incidence of hypertension significantly increased with elevating insulin tertiles in both sexes (P =.048 and.002 for trend in men and women, respectively), but not among drinkers. Our findings suggest a close association between insulin resistance and the incidence of hypertension in Japanese. However, alcohol modified and reduced this relationship.
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Affiliation(s)
- Hisatomi Arima
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka City, Japan.
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Kuo CS, Hwu CM, Kwok CF, Hsiao LC, Weih MJ, Lee SH, Lee YS, Ho LT. Surrogate estimates of insulin sensitivity in Chinese diabetic patients and their offspring. Diabet Med 2002; 19:735-40. [PMID: 12207809 DOI: 10.1046/j.1464-5491.2002.00668.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS To evaluate the relationship between surrogate measures of insulin sensitivity and results from euglycaemic insulin clamp in Chinese diabetic patients and their offspring. METHODS The study included 59 volunteers from 20 diabetic families. Each participant completed a 75-g oral glucose tolerance test (OGTT) and a euglycaemic insulin clamp. We tested the correlation of surrogate measures of insulin sensitivity with M-values and M/I ratios (the amount of glucose infused during 90-120 min of the clamp was defined as M, and the mean values of plasma insulin during 90-120 min as I) from the euglycaemic insulin clamp. These measures included fasting insulin (FPI), insulin at 120 min of OGTT, insulin area under the curve of OGTT, fasting glucose-to-insulin ratio, homeostasis model assessment for insulin sensitivity (HOMA-IR and HOMA %S) and the Matsuda-DeFronzo index from OGTT. RESULTS The Matsuda-DeFronzo index closely correlated to M-value and M/I in 21 diabetic, 38 non-diabetic individuals and the 59 participants overall (with M-value, r = 0.68, 0.84 and 0.84; with M/I, r = 0.71, 0.72 and 0.75, respectively, all P < 0.001). Without OGTT, HOMA %S was a good surrogate index for diabetic (correlated to M-value and M/I, r = 0.71 and 0.68, P = 0.001) and for non-diabetic subjects (to M-value, r = 0.73; to M/I, r = 0.55, both P < 0.001). FPI was as good as HOMA %S and Matsuda-DeFronzo index. CONCLUSIONS The Matsuda-DeFronzo index, HOMA %S and FPI are good surrogate estimates of insulin sensitivity in Chinese diabetic subjects and their offspring.
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Affiliation(s)
- C S Kuo
- Section of Endocrinology and Metabolism, Department of Medicine, Tapei Veterans Hospital, Tapei, Taiwan
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25
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Feldstein CA, Akopian M, Renauld A, Olivieri AO, Cauterucci S, Garrido D. Insulin resistance and hypertension in postmenopausal women. J Hum Hypertens 2002; 16 Suppl 1:S145-50. [PMID: 11986914 DOI: 10.1038/sj.jhh.1001362] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The aim of the study was to elucidate the role of hyperinsulinaemia/insulin resistance in hypertension of lean postmenopausal women. Twenty-four women with essential hypertension (systolic/diastolic > or =140/90 mm Hg) and a body mass index (BMI) less than 26 kg/m(2) not receiving antihypertensive treatment or who had been without treatment for a 4-week washout period, and 10 normotensive postmenopausal weight- and aged-matched controls were compared. Both groups were not receiving hormone replacement therapy. Hip and waist circumferences were measured and waist/hip ratios were calculated. Casual blood pressure was measured in triplicate. Neither the fasting plasma glucose nor serum insulin levels in hypertensive women and normotensives differed significantly. During 2 h oral glucose (75 g)-tolerance test the mean plasma glucose levels after 30 min (172.5 +/- 40.24 mg/dl vs. 143.67 +/- 20.16 mg/dl), 60 min (134.88 +/- 38.78 mg/dl vs. 112.33 +/- 5.44 mg/dl) and 120 min (116.08 +/- 26.65 mg/dl vs. 95.56 +/- 20.17 mg/dl) were significantly higher in hypertensives than that for normotensives (P < 0.05 for all three comparisons). The mean serum insulin levels of hypertensive women were significantly higher than that in normotensives after 15 min (92.04 +/- 59.90 microU/ml vs. 54.89 +/- 33.67 microU/ml) and 120 min (49.63 +/- 44.45 microU/ml vs. 19.22 +/- 24.10 microU/ml; P< 0.05 for both comparisons). The mean serum insulin: plasma glucose ratio for hypertensive women was significantly higher than that for normotensives after 15 min (0.596 +/- 0.46 vs. 0.359 +/- 0.20 microU/mg), 60 min (0.406 +/- 0.30 vs. 0.329 +/- 0.25 microU/mg) and 120 min (0.436 +/- 0.35 vs. 0.205 +/- 0.26 microU/mg) (P < 0.05 for all three comparisons). Significant correlations were observed between the daytime period and 24-h average ambulatory systolic blood pressure and the area under the serum insulin curve (r = 0.41 and 0.36, respectively). For non-dippers we found higher fasting insulinaemias but the AUC(insulin) did not differ. Plasma glucose levels did not differ either during fasting or during OGTT (AUC(glucose)). Insulinogenic index was higher in dippers than in non-dippers. We conclude that in lean, postmenopausal hypertensive women insulin resistance is increased compared with age- and weight-matched normotensive women. Also, hyperinsulinaemia correlates with ambulatory systolic blood pressure. Thus, insulin resistance may possibly be involved as a pathogenetic factor in lean, postmenopausal hypertensive women.
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Affiliation(s)
- C A Feldstein
- Hypertension Program, Hospital de Clinicas San Martin Buenos Aires School of Medicine and Health Sciences Institute School of Medicine (Barcelo Foundation), Av Las Heras 2191 (1127), Buenos Aires, Argentina.
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Ergin T, Lembet A, Duran H, Kuscu E, Bagis T, Saygili E, Batioglu S. Does insulin secretion in patients with one abnormal glucose tolerance test value mimic gestational diabetes mellitus? Am J Obstet Gynecol 2002; 186:204-9. [PMID: 11854636 DOI: 10.1067/mob.2002.119634] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE The purpose of this study was to investigate the insulin response to a 3-hour oral glucose tolerance test and to compare the insulin levels in the gestational diabetes mellitus and single abnormal test value groups with a nondiabetic control group. STUDY DESIGN One hundred ten Turkish women with uncomplicated pregnancy participated in this prospective controlled study between 24 to 28 weeks of gestation. A 100-g 3-hour oral glucose tolerance test was given, and glucose and insulin plasma levels were assayed. The subjects were classified according to established criteria. Early-phase insulin secretion was assessed by the insulinogenic index. Total insulin secretion was assessed by mean insulin level during the oral glucose tolerance test; insulin resistance was assessed by fasting insulin concentration and by the use of the homeostasis model. Data were analyzed by the Student t test and 1-way analysis of variance, with posthoc Bonferroni correction. RESULTS The fasting insulin levels of patients with normal oral glucose tolerance test results were significantly lower than those of patients with gestational diabetes mellitus and a single value abnormality (P <.001 and P <.005, respectively). The insulinogenic index as a marker of early-phase insulin secretion was significantly lower in gestational diabetes mellitus, compared with that of patients with normal oral glucose tolerance test results (P <.05). The worsening of glycemic profile from normal oral glucose tolerance test results to gestational diabetes mellitus was associated with an increase in the homeostasis model; no significant difference was found between gestational diabetes mellitus and a single value abnormality group in terms of both the homeostasis model and the insulinogenic index. Values for total insulin secretion were highest in gestational diabetes mellitus, followed by the single value abnormality group, both significantly differing from the values of patients with normal oral glucose tolerance test results (P <.001 and P <.005, respectively). CONCLUSION In this prospective study of Turkish subjects, we found a striking similarity in terms of patient characteristics between the gestational diabetes mellitus group and the single value abnormality group. Additionally, when we used fasting insulin level and insulin resistance as 2 separate criteria of analysis, patients with single value abnormality were indistinguishable from patients with gestational diabetes mellitus; both groups were significantly different from the normal oral glucose tolerance test group. Our findings suggest that a single abnormal test value on an oral glucose tolerance test should be regarded as a pathologic finding and that the patient with a single abnormal test value may be treated similarly to the patient with gestational diabetes mellitus.
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Affiliation(s)
- Tolga Ergin
- Department of Obstetrics and Gynecology, Başkent University School of Medicine, Ankara, Turkey
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Porte D. Clinical importance of insulin secretion and its interaction with insulin resistance in the treatment of type 2 diabetes mellitus and its complications. Diabetes Metab Res Rev 2001; 17:181-8. [PMID: 11424231 DOI: 10.1002/1520-7560(200105/06)17:3<181::aid-dmrr197>3.0.co;2-1] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Type 2 diabetes primarily develops from pathogenic defects in the mechanisms of insulin secretion and hepatic and peripheral insulin action. The consequent disruption of normal glucose metabolism involves a number of organ systems and is ultimately manifested in fasting and daytime hyperglycemia. Chronically elevated blood glucose concentrations determine the progression of the disease by further exacerbating insulin resistance and causing beta-cell exhaustion in addition to decreasing their responsiveness to glucose. The beta-cell secretory dysfunction is characterized by the lack of the early phase of glucose-induced insulin secretion and the insufficient and delayed late phase of secretion. Glycemic levels in patients with type 2 diabetes are directly related to the risk of developing microvascular and macrovascular complications, the main cause of the morbidity and mortality associated with this disease. The goal of treatment is to decrease the risk and delay the progression of these complications by improving glycemic control. Current oral antidiabetic agents, used as monotherapy or in combination, include traditional insulin secretagogues, insulin sensitizers and inhibitors of carbohydrate absorption. A greater understanding of the pathophysiology of type 2 diabetes and recent findings on the significance of meal-related glycemia to overall glycemic control are expanding the therapeutic options for treating this disease.
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Affiliation(s)
- D Porte
- University of California and VA San Diego Healthcare System, 111G, Diabetes and Metabolism Division, 3350 La Jolla Village Drive, San Diego, CA 92161, USA.
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Facchini FS, Humphreys MH, DoNascimento CA, Abbasi F, Reaven GM. Relation between insulin resistance and plasma concentrations of lipid hydroperoxides, carotenoids, and tocopherols. Am J Clin Nutr 2000; 72:776-9. [PMID: 10966898 DOI: 10.1093/ajcn/72.3.776] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND It is not known whether total circulating lipid hydroperoxides are increased in insulin-resistant individuals and whether this correlates with depletion of liposoluble antioxidant vitamins that are consumed during lipid peroxidation. OBJECTIVE The goal of this study was to define the relation between resistance to insulin-mediated glucose disposal and plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins in healthy volunteers. DESIGN Insulin-mediated glucose disposal was determined in 36 healthy, nondiabetic volunteers by measuring their steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations in response to a 180-min constant infusion of octreotide, insulin, and glucose. In addition, fasting plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins were determined by using the FOX 2 assay and liquid chromatography. RESULTS Statistically significant direct relations were observed between SSPG and mean arterial blood pressure (r = 0.44, P: = 0.008) and plasma lipid hydroperoxide concentrations (r = 0.42, P: = 0.01), whereas significant inverse correlations were found between SSPG and alpha-carotene (r = -0.58, P: = 0.0002), beta-carotene (r = -0.49, P: = 0.004), lutein (r = -0.35, P: = 0.04), alpha-tocopherol (r = -0. 36, P: = 0.04), and delta-tocopherol (r = -0.45, P: = 0.007). CONCLUSIONS Variations in insulin-mediated glucose disposal in healthy individuals are significantly related to plasma concentrations of lipid hydroperoxides and liposoluble antioxidant vitamins. These findings suggest that total plasma lipid peroxidation is increased in insulin-resistant individuals at an early, preclinical stage, ie, well before the development of glucose intolerance and type 2 diabetes.
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Affiliation(s)
- F S Facchini
- Department of Medicine, Division of Nephrology, San Francisco General Hospital, CA 94110, USA.
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Abbasi F, McLaughlin T, Lamendola C, Reaven GM. The relationship between glucose disposal in response to physiological hyperinsulinemia and basal glucose and free fatty acid concentrations in healthy volunteers. J Clin Endocrinol Metab 2000; 85:1251-4. [PMID: 10720071 DOI: 10.1210/jcem.85.3.6450] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
This study was initiated to see if defects in the ability of physiological hyperinsulinemia (approximately 60 microU/mL) to stimulate glucose uptake in healthy, nondiabetic volunteers are associated with increases in concentrations of plasma glucose and free fatty acid (FFA) when measured at basal insulin concentrations (approximately 10 microU/mL). We recruited 22 volunteers (12 women and 10 men) for these studies, with a (mean +/- SEM) body mass index of 24.8 +/- 0.5 kg/m2. Resistance to insulin-mediated glucose disposal during physiological hyperinsulinemia was determined by suppressing endogenous insulin and determining the steady-state plasma glucose (SSPG) and steady-state plasma insulin (SSPI) concentrations at the end of a 3-h infusion, period during which glucose (267 mg/m2 x min) and insulin (32 mU/m2 x min) were infused at a constant rate. Glucose, insulin and FFA concentrations were also measured in response to infusion rates of glucose (50 mg/m2 x min) and insulin (6 mU/m2 x min). The SSPI concentration (mean +/- SEM) during physiological hyperinsulinemia was 64 +/- 3 microU/mL), in contrast to 12 +/- 0.4 microU/mL during the basal insulin study. The results demonstrated a significant relationship between SSPG concentration in response to physiological hyperinsulinemia (SSPG60) and SSPG(Basal) (r = 0.57, P < 0.01) and FFA(Basal) (r = 0.73, P < 0.001). Furthermore, FFA(Basal) and SSPG(Basal) were significantly correlated (r = 0.47, P < 0.05). Comparison of the seven most insulin-resistant and seven most insulin sensitive individuals (SSPG60 values of 209 +/- 16 vs. 64 +/- 8 mg/dL) revealed that the insulin-resistant group also had significantly higher SSPG(Basal) (105 +/- 5 vs. 78 +/- 7 mg/dL, P < 0.01) and FFA(Basal) (394 +/- 91 vs. 104 +/- 41, P < 0.02) concentrations. However, random fasting plasma glucose and FFA concentrations of the two groups were not different. The results presented demonstrate that individual differences in the ability of elevated insulin concentrations to stimulate muscle glucose disposal are significantly correlated with variations in insulin regulation of plasma glucose and FFA concentrations at basal insulin concentrations.
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Affiliation(s)
- F Abbasi
- Department of Medicine, Stanford University School of Medicine, California 94080, USA
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Zemva A, Zemva Z. Ventricular ectopic activity, left ventricular mass, hyperinsulinemia, and intracellular magnesium in normotensive patients with obesity. Angiology 2000; 51:101-6. [PMID: 10701717 DOI: 10.1177/000331970005100202] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Insulin resistance, a well-known feature of obesity, is associated with several pathological changes, which are potentially arrhythmogenic. Ventricular ectopic activity in normotensive obese patients has not been studied in detail. Therefore the authors designed a study to investigate potential relationships among ventricular ectopic activity, left ventricular mass, hyperinsulinemia, and intracellular magnesium concentration in obese patients. Thirty-two obese patients and 32 nonobese control subjects, who were referred to outpatient department because of ventricular ectopy, participated in the study. The groups were matched for age and gender. All had normal glucose tolerance. All subjects underwent a 75-g glucose tolerance test, and blood samples were obtained at 30, 60, and 120 minutes thereafter for determination of glucose and insulin concentrations. Echocardiography was performed and left ventricular mass index was calculated. The number of ventricular ectopic beats per hour (VEB/hour) was recorded by 24-hour ECG Holter monitoring. Plasma and erythrocyte magnesium concentrations were determined by atomic absorption spectrophotometer. Obese patients had higher body weight, body mass index, heart rate, and left ventricular mass index. Obese subjects had higher fasting insulin as well as insulin/glucose ratio and broader area under the curve of insulin (AUC-I) compared to nonobese subjects. Insulin sensitivity appeared to be lower in the obese group. Holter monitoring showed more VEB/hour in the obese group. Magnesium concentration in serum and in erythrocytes was lower in obese persons. In the obese group a positive correlation was found between left ventricular mass index and fasting insulin (r=0.345, p=0.027), insulin/glucose index (r=0.351, p=0.049), and AUC-I (r=0.405, p=0.011). The number of VEB/hour in obese patients was in positive correlation with age (r=0.681, p<0.001), left ventricular mass index (r=0.542, p=0.001), fasting insulin (r=0.380, p=0.016), and AUC-I (r=0.493, p=0.002) and in negative correlation with magnesium concentration in erythrocytes (r=-0.457, p=0.004). Multiple regression analysis showed that age and AUC-I are the only determinants of VEB/hour and together explained 56% of the variability in the obese subjects. It appears that in obese normotensive subjects, ventricular ectopic beats are related to age, insulin resistance, left ventricular mass index, and decreased intracellular magnesium content.
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Affiliation(s)
- A Zemva
- Clinical Center of Ljubljana, Department for Nuclear Medicine, Slovenia
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Grandi AM, Zanzi P, Fachinetti A, Gaudio G, Ceriani L, Bertolini A, Guasti L, Venco A. Insulin and diastolic dysfunction in lean and obese hypertensives: genetic influence. Hypertension 1999; 34:1208-14. [PMID: 10601120 DOI: 10.1161/01.hyp.34.6.1208] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We investigated the influence of genetic predisposition to hypertension by studying the relation between insulin sensitivity and left ventricular (LV) mass and function in untreated lean and obese hypertensives. We selected 50 lean hypertensives with normotensive parents (negative family history of hypertension [F-]), 64 lean hypertensives with 1 or both parents hypertensive (positive family history of hypertension [F+]), 40 obese F- hypertensives, and 43 obese F+ hypertensives. The 4 groups were comparable regarding age, gender, 24-hour blood pressure profile, and known duration of hypertension. We measured glucose, insulin, and C-peptide during fasting and during an oral glucose tolerance test; LV morphology and function were assessed by digitized M-mode echocardiography. Glucose (fasting and test) levels were normal in all and similar among the 4 groups. Insulin and C-peptide (fasting and stimulated) levels were higher in obese hypertensives than in lean hypertensives; at similar body mass index, insulin and C-peptide levels were higher in F+ than in F- groups. Compared with lean hypertensives, obese hypertensives had greater LV mass index; LV systolic function was normal in all and similar among the groups. The indices of LV diastolic function were significantly lower in F+ than in F- groups. LV mass index did not correlate with metabolic parameters; the indices of LV diastolic function were inversely correlated with insulin area during test in only the 2 F+ groups. In conclusion, genetic predisposition to hypertension is associated with a reduced insulin sensitivity and affects the response of the myocardium to increased insulin levels, inducing a greater impairment of diastolic function. Insulin sensitivity and genetic predisposition to hypertension seem to have no influence on LV mass.
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Affiliation(s)
- A M Grandi
- Internal Medicine, Department of Clinical and Biological Sciences, Faculty of Medicine, University of Insubria, Varese, Italy
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ter Maaten JC, Voordouw JJ, Bakker SJ, Donker AJ, Gans RO. Salt sensitivity correlates positively with insulin sensitivity in healthy volunteers. Eur J Clin Invest 1999; 29:189-95. [PMID: 10202374 DOI: 10.1046/j.1365-2362.1999.00445.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The aim of the study was to assess the relationship between insulin sensitivity and salt sensitivity in healthy subjects who display a wide range of insulin sensitivity. As a secondary objective, we assessed the relationship between salt sensitivity and the other characteristics of the insulin resistance syndrome. STUDY DESIGN Forty-seven normotensive volunteers (age 34 +/- 15 years) with a normal glucose tolerance test were selected. We measured insulin sensitivity using the hyperinsulinaemic euglycaemic clamp (50 mU kg-1 h-1), blood pressure, waist-to-hip ratio, fasting insulin levels, serum lipids and uric acid levels. In a subset of 21, representing a wide range of insulin sensitivity, salt sensitivity was determined as the difference in mean arterial blood pressure (MAP) at the end of a high-salt diet (10 g of NaCl per day for 1 week) vs. a low-salt diet (2 g of NaCl per day for 1 week). RESULTS Insulin sensitivity (M/I value, range 0.49-4.41 mg kg-1 min-1 per pmol L-1 x 100) was negatively correlated with MAP (r = -0.54, P < 0. 001) and waist-to-hip ratio (r = - 0.59, P < 0.001) but positively correlated with salt sensitivity (r = 0.47, P = 0.03). Salt sensitivity also correlated with high-density lipoprotein (HDL)-cholesterol (r = 0.46, P = 0.038) but not with waist-to-hip ratio, fasting insulin levels, low-density lipoprotein cholesterol, serum triglycerides or serum uric acid. CONCLUSIONS In healthy normotensive subjects who display a wide range of insulin sensitivity, as measured with the euglycaemic clamp technique, salt sensitivity correlates positively with insulin sensitivity and HDL-cholesterol, but not with the other characteristics of the insulin resistance syndrome.
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Affiliation(s)
- J C ter Maaten
- University Hospital Vrije Universiteit, Amsterdam, The Netherlands
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34
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Affiliation(s)
- D C Whitelaw
- Manny Cussins Centre, St James's University Hospital, Leeds, UK
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35
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Pedrinelli R, Penno G, Dell'Omo G, Bandinelli S, Giorgi D, Di Bello V, Nannipieri M, Navalesi R, Mariani M. Transvascular and urinary leakage of albumin in atherosclerotic and hypertensive men. Hypertension 1998; 32:318-23. [PMID: 9719061 DOI: 10.1161/01.hyp.32.2.318] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Increased urine albumin is associated with atherosclerotic disease and predicts cardiovascular morbidity and mortality in nondiabetic populations. This finding is frequently postulated to reflect the impact of atherosclerotic damage on glomerular and systemic capillary permeability, an interesting but as yet untested hypothesis. The transcapillary escape rate of albumin (TERalb, the 1-hour decline rate of intravenous 125I-albumin, a measure of capillary macromolecular permeability), albuminuria, lipid levels, echocardiographic wall thickness, and insulin responses to oral glucose were measured in 30 untreated dipstick-negative lean men and clinically stable atherosclerotic peripheral vascular disease; tolerance to oral glucose was a requirement for inclusion in the study. Because hypertension per se might influence TERalb, the sample included either normotensive (n=18, 118+/-6/72+/-7 mm Hg) or hypertensive (n=12, 141+/-7/84+/-6 mmHg by 24-hour blood pressure monitoring) arteriopathic patients; 11 normal age- and gender-matched subjects (121+/-7/76+/-5 mmHg) were used as control subjects. TERalb was higher in patients (10.7+/-3.2 versus 7.4+/-1.7%/h, P<0.013), a difference that persisted after postload glucose, insulin, and lipid levels were accounted for by covariance analysis; atherosclerosis and hypertension together did not further impair vascular permeation to albumin. In contrast with TERalb, albuminuria was elevated only in the hypertensive subgroup; the 2 variables showed no relationship, even when the data were analyzed separately in normotensive and hypertensive subgroups. Urine albumin correlated positively with 24-hour blood pressure and wall thickness. Thus, systemic capillary permeability is altered in nondiabetic atherosclerotic patients independently from blood pressure levels, but this abnormality is not reflected by proportionate changes in albuminuria.
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Affiliation(s)
- R Pedrinelli
- Dipartimento di Cardiologia, Angiologia, e Pneumologia, Università di Pisa, Italy.
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Facchini FS, Carantoni M, Jeppesen J, Reaven GM. Hematocrit and hemoglobin are independently related to insulin resistance and compensatory hyperinsulinemia in healthy, non-obese men and women. Metabolism 1998; 47:831-5. [PMID: 9667230 DOI: 10.1016/s0026-0495(98)90121-4] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
In this study, we evaluated the relationship between resistance to insulin-mediated glucose disposal and hematocrit (Hct) and hemoglobin (Hgb) concentrations in 150 normal, healthy volunteers: 100 men and 50 women. Insulin resistance was defined as the steady-state plasma glucose (SSPG) concentration at the end of a 180-minute infusion of somatostatin, insulin, and glucose. Since the steady-state plasma insulin (SSPI) concentrations are similar in all individuals, the SSPG concentrations provide a direct measure of insulin resistance: the higher the SSPG, the more insulin-resistant the subject. The results indicated that SSPG was significantly (P < .001) related to Hct and Hgb in both men and women, with correlation coefficients (r) ranging from 0.38 to 0.43. A series of other variables were also related to Hct and Hgb, including blood pressure, plasma glucose and insulin responses to oral glucose, and plasma triglyceride and high-density lipoprotein (HDL) concentrations. When multiple regression analysis was used to evaluate these relationships, the only variables that were consistently found to be associated with Hct and Hgb were insulin resistance and plasma insulin response to oral glucose. Thus, these results suggest that Hct and Hgb concentrations be added to the cluster of variables related to insulin resistance and compensatory hyperinsulinemia.
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Rainwater DL, Mitchell BD, Mahaney MC, Haffner SM. Genetic relationship between measures of HDL phenotypes and insulin concentrations. Arterioscler Thromb Vasc Biol 1997; 17:3414-9. [PMID: 9437187 DOI: 10.1161/01.atv.17.12.3414] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We used data from the San Antonio Family Heart Study to determine the HDL correlates of the insulin resistance syndrome (IRS), as reflected by insulin concentrations in nondiabetic subjects. We measured insulin concentrations both in the fasting state and 2 hours after a glucose challenge (2-hour insulin) and we assessed seven aspects of HDL phenotype, including size and concentration of both lipid and protein components. Measurements were obtained from 1202 nondiabetic members of 42 families. Initial quantitative genetic analyses revealed that a substantial portion of phenotypic variation in the nine variables was due to genes (heritabilities, h2, ranged from 0.32 to 0.47). We then conducted a series of bivariate genetic analyses, which indicated that there were significant additive genetic correlations (ie, pleiotropy) between the two measures of insulin and five of seven HDL measures tested, including concentrations of HDL cholesterol (fasting insulin only) and triglyceride, and HDL size distributions of apoAI, apoAII, and cholesterol; concentrations of apoAI and apoAII were not genetically related to either insulin measure. Increased insulin levels were associated with relatively smaller HDL phenotypes, and considering a similar association with small, dense LDLs, this finding suggests a common effect of insulin resistance on particle size distributions for these lipoproteins. Thus, these results suggest the existence of genes that pleiotropically influence variation in both HDLs and insulin levels and therefore contribute to the clustering of proatherogenic traits in the IRS.
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Affiliation(s)
- D L Rainwater
- Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
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Jones CN, Pei D, Staris P, Polonsky KS, Chen YD, Reaven GM. Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals. J Clin Endocrinol Metab 1997; 82:1834-8. [PMID: 9177392 DOI: 10.1210/jcem.82.6.3979] [Citation(s) in RCA: 88] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Plasma glucose and insulin responses to a graded i.v. infusion of glucose were compared in two groups of glucose-tolerant women divided on the basis of their insulin sensitivity. Resistance to insulin-mediated glucose disposal was measured using the insulin suppression test, and the women studied were chosen to represent the highest and lowest quartiles of insulin resistance seen in the normal population. The sensitivity of the pancreatic beta-cell to glucose was assessed by measuring the glucose, insulin, and C peptide concentrations in response to continuous graded i.v. infusions of glucose at rates of 1, 2, 3, 4, 6, and 8 mg/kg x min for 40 min each. In addition, insulin secretion rates in response to the graded glucose infusion, calculated over each sampling period, were derived from deconvolution of peripheral plasma C peptide concentrations, using a two-compartment model of C peptide kinetics and standard parameters for C peptide clearance. Although plasma glucose concentrations were only slightly higher throughout the glucose infusion, the insulin concentrations were approximately doubled in the insulin-resistant subjects. When expressed as a function of the molar increments in plasma glucose achieved during the glucose infusion studies, the insulin-resistant women had a 90% higher (684 +/- 55 vs. 360 +/- 36 pmol/L x mmol/L; P < 0.001) total integrated plasma insulin response as the glucose concentration was increased from 5 to 9 mmol/L. However, the total integrated insulin secretory rate was only increased by 37% (1494 +/- 133 vs. 1093 +/- 125 pmol/mmol/L x min; P < 0.05) in the insulin-resistant group. This discrepancy suggested that insulin clearance was lower in the insulin-resistant subjects, and the calculation of this value, as the ratio of the total secretion of insulin to the area under the plasma insulin curve, was significantly lower in the insulin-resistant group (1.25 +/- 0.05 vs. 1.87 +/- 0.16 L/min x m2; P < 0.005). These results show that the hyperinsulinemia of insulin resistance results from an increase in insulin secretion secondary to a shift to the left of the glucose-stimulated insulin response curve as well as a decrease in insulin clearance.
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Affiliation(s)
- C N Jones
- Department of Medicine, Stanford University School of Medicine, California 94305, USA
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Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. Diabetologia 1996; 39:1201-7. [PMID: 8897008 DOI: 10.1007/bf02658507] [Citation(s) in RCA: 82] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The relative importance of insulin resistance and abnormal insulin secretion as risk factors for the development of impaired glucose tolerance (IGT) is controversial. Few prospective data are available on metabolic precursors of IGT. We examined the relation of fasting serum insulin level (as a marker of insulin resistance) and change in insulin/glucose ratio (delta I30/ delta G30) over the first 30 min after glucose ingestion (as a marker of insulin secretion) as predictors of the 7-year development of IGT in 839 Mexican Americans and non-Hispanic whites with normal glucose tolerance at baseline from the San Antonio Heart Study. IGT eventually developed in 148 subjects. When modelled separately, fasting serum insulin (odds ratio (OR) = 2.60, 95% confidence interval (CI) = 1.58, 4.28, p < 0.005), but not delta I30/ delta G30 (OR = 0.80, 95% CI = 0.50, 1.27, p = 0.339) predicted the development of IGT. However, when both variables were included in the same logistic regression model, fasting serum insulin (OR = 3.50, 95% CI = 1.97, 6.21, p < 0.001) and low delta I30/ delta G30 (OR = 0.48, 95% CI = 0.28, 0.82, p = 0.008) both predicted IGT. These results were basically unchanged after further adjustment for obesity, body fat distribution and fasting plasma glucose level. We conclude that both decreased insulin secretion (as assessed by low delta I30/ delta G30) and increased insulin resistance (as assessed by fasting serum insulin) predict the development of IGT and are thus early precursors of non-insulin-dependent diabetes mellitus; further studies of insulin secretion should take into account the level of basal insulin resistance.
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Affiliation(s)
- S M Haffner
- Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7873, USA
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Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation 1996; 93:1809-17. [PMID: 8635260 DOI: 10.1161/01.cir.93.10.1809] [Citation(s) in RCA: 462] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Reduced insulin sensitivity has been proposed as an important risk factor in the development of atherosclerosis. However, insulin sensitivity is related to many other cardiovascular risk factors, including plasma insulin levels, and it is unclear whether an independent role of insulin sensitivity exists. Large epidemiological studies that measure insulin sensitivity directly have not been conducted. METHODS AND RESULTS The Insulin Resistance Atherosclerosis Study (IRAS) evaluated insulin sensitivity (SI) by the frequently sampled intravenous glucose tolerance test with analysis by the minimal model of Bergman. IRAS measured intimal-medial thickness (IMT) of the carotid artery as an index of atherosclerosis by use of noninvasive B-mode ultrasonography. These measures, as well as factors that may potentially confound or mediate the relationship between insulin sensitivity and atherosclerosis, were available in relation to 398 black, 457 Hispanic, and 542 non-Hispanic white IRAS participants. There was a significant negative association between SI and the IMT of the carotid artery both in Hispanics and in non-Hispanic whites. This effect was reduced but not totally explained by adjustment for traditional cardiovascular disease risk factors, glucose tolerance, measures of adiposity, and fasting insulin levels. There was no association between SI and the IMT of the carotid artery in blacks. The association between SI and the IMT was stronger for the internal carotid artery than for the common carotid artery in all ethnic groups. CONCLUSIONS Higher levels of insulin sensitivity are associated with less atherosclerosis in Hispanics and non-Hispanic whites but not in blacks. This effect is partially mediated by traditional cardiovascular risk factors.
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Affiliation(s)
- G Howard
- Department of Public Health Sciences, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1063, USA
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Miura K, Nakagawa H, Nishijo M, Tabata M, Morikawa Y, Ishizaki M, Yoshita K, Kawano S. Blood pressure and urinary C-peptide excretion in subjects with varying degrees of glucose tolerance. Blood Press 1996; 5:148-53. [PMID: 8790925 DOI: 10.3109/08037059609062123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
To determine whether blood pressure is associated with 24-h urinary C-peptide excretion in subjects with varying degrees of glucose tolerance, we studied 247 Japanese men aged 30-69 who had never been treated with antihypertensive medications or with insulin. Plasma glucose and insulin responses during a 75-g oral glucose tolerance test, blood pressure and body mass index were obtained and urinary C-peptide excretion, in total and per kg body weight, were examined by 24-h urine collection. In monovariate analyses, urinary C-peptide excretion per kg body weight increased significantly as the blood pressure level rose (p < 0.05). After adjustment for age and body mass index by analysis of covariance, this relationship remained significant (p < 0.05), where adjusted mean values (+/- SEM) of urinary C-peptide per kg body weight were 1.56 +/- 0.05 microgram/24h/kg in the normotensive group and 2.04 +/- 0.17 microgram/24h/kg in the hypertensive (stage 2-4) group. When stratified simultaneously by glucose tolerance status and blood pressure level, adjusted mean values of urinary C-peptide per kg body weight were significantly higher in diabetic hypertensives than in diabetic normotensives. These results suggest that increase in 24-h urinary C-peptide excretion, i.e. 24-h insulin secretion, might contribute to an elevation of blood pressure both in normal and diabetic individuals.
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Affiliation(s)
- K Miura
- Department of Public Health, Kanazawa Medical University, Ishikawa, Japan
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Ohya Y, Abe I, Fujii K, Ohmori S, Onaka U, Kobayashi K, Fujishima M. Hyperinsulinemia and left ventricular geometry in a work-site population in Japan. Hypertension 1996; 27:729-34. [PMID: 8613232 DOI: 10.1161/01.hyp.27.3.729] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The present study was designed to test whether hyperglycemia or hyperinsulinemia influences left ventricular mass and geometry. An echocardiogram and 75-g oral glucose tolerance test were performed in 210 normotensive and 180 mildly to moderately hypertensive male workers in a bus company who were free from cardiac diseases and were not taking medication for hypertension and diabetes mellitus. When we divided subjects into four groups according to the left ventricular geometric pattern using left ventricular mass index of 110 g/m2 and relative wall thickness (ratio of 2 x posterior wall thickness to end-diastolic left ventricular diameter) of 0.44, body mass index and systolic blood pressure were higher in those with concentric hypertrophy and eccentric hypertrophy. In addition, hemoglobin A(Ic) level and the sum of fasting and 2-hour postload serum glucose levels were higher in subjects with concentric hypertrophy. In subjects without diabetes mellitus (n=336), 2-hour postload serum insulin level and the sum of fasting and 2-hour postload serum insulin levels tended to be higher in those with concentric hypertrophy and concentric remodeling. In multiple regression analysis, the sum of glucose levels (or hemoglobin A(Ic) level) in all subjects and the sum of insulin (or 2-hour postload insulin) levels in subjects without diabetes mellitus significantly correlated with relative wall thickness, independent of age, systolic blood pressure, and body mass index. Neither glucose nor insulin levels correlated with left ventricular mass index. Our results suggest that hyperglycemia and hyperinsulinemia may promote concentric changes in the left ventricle in normotensive and mildly to moderately hypertensive men.
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Affiliation(s)
- Y Ohya
- Second Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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43
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Mitchell BD, Kammerer CM, Mahaney MC, Blangero J, Comuzzie AG, Atwood LD, Haffner SM, Stern MP, MacCluer JW. Genetic analysis of the IRS. Pleiotropic effects of genes influencing insulin levels on lipoprotein and obesity measures. Arterioscler Thromb Vasc Biol 1996; 16:281-8. [PMID: 8620344 DOI: 10.1161/01.atv.16.2.281] [Citation(s) in RCA: 111] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Insulin resistance is part of a metabolic syndrome that also includes non-insulin-dependent diabetes mellitus, dyslipidemia, obesity, and hypertension. It has been hypothesized that insulin resistance represents the primary physiological defect underlying this syndrome. Since insulin resistance is at least partially genetically determined, we hypothesized that genes influencing insulin resistance would have pleiotropic effects on a number of other traits, including triglyceride (TG) and HDL cholesterol levels, body mass index (BMI) and body fat distribution, and blood pressure levels. To investigate this hypothesis, we analyzed data obtained from individuals in 41 families enrolled in the San Antonio Family Heart Study. Statistical methods that take advantage of the relatedness among individuals were used to differentiate between genetic and nongenetic (ie, environmental) contributions to phenotypic variation between traits. Serum levels of fasting and 2-hour insulin (measured in 767 and 743 nondiabetic family members, respectively) were used as a measure of insulin resistance. The genetic correlations were high between insulin levels (both fasting and 2-hour) and each of the following: BMI, HDL level, waist-to-hip ratio, and subscapular-to-triceps ratio, indicating that the same gene, or set of genes, influences each pair of traits. In contrast, the genetic correlations of insulin levels with systolic and diastolic blood pressures were low. We have previously shown that a single diallelic locus accounts for 31% of the phenotypic variation in 2-hour insulin levels in this population. We conducted a bivariate segregation analysis to see if the common genetic effects on insulin and these other traits could be attributable to this single locus. These results indicated a significant effect of the 2-hour insulin locus on fasting insulin levels (P = .02) and BMI (P = .05), with the "high" insulin allele associated with higher levels of fasting insulin but lower levels of BMI. There was no detectable effect of this locus on HDL level, TG level, subscapular-to-triceps ratio, or blood pressure. Overall, these results suggest that a common set of genes influencing insulin levels also influences other insulin resistance syndrome-related traits, although for the most part this pleiotropy is not attributable to the 2-hour insulin level major locus.
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Affiliation(s)
- B D Mitchell
- Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Tex 78228-0147, USA.
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Haffner SM, Mykkänen L, Robbins D, Valdez R, Miettinen H, Howard BV, Stern MP, Bowsher R. A preponderance of small dense LDL is associated with specific insulin, proinsulin and the components of the insulin resistance syndrome in non-diabetic subjects. Diabetologia 1995; 38:1328-36. [PMID: 8582543 DOI: 10.1007/bf00401766] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recently, the presence of small dense low density lipoprotein (LDL) has been postulated to be a stronger risk factor for coronary heart disease than large LDL. While small dense LDL has been associated with individual components of the insulin resistance syndrome such as hypertension, high triglyceride level, low high density (HDL) cholesterol, and diabetes mellitus, there has been little work exploring whether LDL size is decreased in subjects with multiple metabolic disorders. We examined the association of LDL size and pattern to specific insulin (which does not cross-react with proinsulin), proinsulin, increased triglyceride, decreased HDL, hypertension and impaired glucose tolerance in 488 non-diabetic subjects from the San Antonio Heart Study. LDL size was significantly related to specific insulin, proinsulin and the fasting proinsulin/insulin ratio. Small dense LDL was significantly associated with high triglyceride level, decreased HDL cholesterol, hypertension and impaired glucose tolerance. LDL size (A) decreased in a stepwise fashion with increasing number of the metabolic disorders described above (zero 262.6 +/- 9.4; one 257.0 +/- 9.3; two 256.4 +/- 9.4; three 249.0 +/- 9.1; and four 244.9 +/- 9.0). These results were similar in men and women and in non-Hispanic whites and Mexican Americans. The association between LDL size and the number of metabolic disorders remained statistically significant even after adjustment for obesity, body fat distribution, gender, ethnicity, proinsulin and insulin concentrations. Furthermore, decreases in LDL size are also significantly associated with both a selective beta-cell defect (as estimated by the fasting proinsulin/insulin ratio) and insulin resistance (as estimated by the fasting insulin concentrations) although the association was somewhat stronger for the latter. We conclude that small dense LDL may form part of the insulin resistance syndrome in non-diabetic subjects.
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Affiliation(s)
- S M Haffner
- Department of Medicine, University of Texas Health Science Center at San Antonio 78284-7873, USA
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Cerasi E. Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible? Diabetologia 1995; 38:992-7. [PMID: 7589888 DOI: 10.1007/bf00400591] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- E Cerasi
- Department of Endocrinology and Metabolism, Hebrew University Hadassah Medical Centre, Jerusalem, Israel
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Goodfriend TL, Egan B, Stepniakowski K, Ball DL. Relationships among plasma aldosterone, high-density lipoprotein cholesterol, and insulin in humans. Hypertension 1995; 25:30-6. [PMID: 7843750 DOI: 10.1161/01.hyp.25.1.30] [Citation(s) in RCA: 61] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
To investigate the pathogenesis of hypertension in patients with obesity and insulin resistance and to explore the role of plasma lipids, we studied 30 subjects at the end of 7 days of low (20 mEq/d) then high (200 mEq/d) sodium diets. Glucose and insulin tolerance tests were performed at the end of each week and blood and urine collected for measurements of plasma aldosterone, renin activity, electrolytes, insulin, and lipoproteins. There was a strong negative correlation between plasma aldosterone and high-density lipoprotein cholesterol during both diets. There were weaker positive correlations between plasma aldosterone and insulin or triglycerides. When the aldosterone-renin ratio was the dependent variable and the correlation controlled for serum potassium, the inverse relationship with high-density lipoprotein cholesterol and the positive correlation with insulin remained, but only during the high salt diet. Subjects were divided into three groups based on high-density lipoprotein cholesterol. Subjects with the lowest high-density lipoprotein cholesterol levels showed the highest aldosterone, plasma triglycerides, body mass index, and waist-to-hip ratio. Those subjects also demonstrated the greatest resistance to insulin action on glucose and plasma unesterified fatty acids. There was a weak direct correlation between plasma aldosterone and systolic blood pressure during the high salt diet. These data suggest that high aldosterone levels may be a link between dyslipidemia, insulin resistance, and hypertension, a relationship made more evident by high salt intake.
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Lembo G, Iaccarino G, Rendina V, Volpe M, Trimarco B. Insulin blunts sympathetic vasoconstriction through the alpha 2-adrenergic pathway in humans. Hypertension 1994; 24:429-38. [PMID: 7916334 DOI: 10.1161/01.hyp.24.4.429] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
We investigated the mechanisms underlying the insulin-induced attenuation of sympathetic forearm vasoconstriction in healthy humans. In 5 subjects, we applied 20 mm Hg lower body negative pressure for 30 minutes in control conditions and during a 60-minute infusion of insulin (0.05 mU/kg per minute) in the brachial artery and measured forearm norepinephrine kinetics and hemodynamics. In 11 subjects, we applied graded lower body negative pressure at 5, 10, 15, and 20 mm Hg for 5 minutes each in control conditions and during the simultaneous intrabrachial administration of insulin (0.05 mU/kg per minute) (5 subjects) or insulin plus ouabain (3.5 micrograms/min per liter) (6 subjects) to investigate whether insulin acts through a potentiation of the vascular smooth muscle Na+,K(+)-ATPase. To assess a possible effect of insulin on a specific adrenergic receptor pathway, in a further study group we evaluated (1) the forearm vascular response to intrabrachial infusion of the alpha 1-adrenergic receptor agonist phenylephrine (0.5, 1, and 2 micrograms/kg per minute; n = 7) and of the alpha 2-adrenergic receptor agonist BHT-933 (0.5, 1, 2, and 4 micrograms/kg per minute; n = 9), and (2) the effects of intra-arterial infusion of prazosin (0.5 microgram/100 mL per minute) alone or combined with insulin on the forearm vascular response to graded lower body negative pressure (7 subjects). Insulin blunted the peak increase in forearm vascular resistance (from 13 +/- 2 to 6 +/- 2 U, P < .05) but not the rise in forearm norepinephrine spillover induced by 20 mm Hg lower body negative pressure (from 8.3 +/- 1.8 to 11.1 +/- 3.5 pmol/min per liter, P = NS). Ouabain administration did not prevent the insulin-induced attenuation of the forearm vasoconstrictive response to graded lower body negative pressure. Insulin infusion in the brachial artery did not modify the forearm vasoconstriction induced by intra-arterial infusion of phenylephrine but significantly reduced the increase in forearm vascular resistance induced by BHT-933 (F = 6.111, P < .001). Finally, intra-arterial infusion of prazosin significantly attenuated the forearm vasoconstriction induced by graded lower body negative pressure. The residual vasoconstrictive response was abolished by insulin infusion. Taken together, these findings suggest that insulin interacts with the sympathetic nervous system at the vascular level predominantly through the alpha 2-adrenergic vasoconstrictive pathway.
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Affiliation(s)
- G Lembo
- Department of Internal Medicine, School of Medicine, Federico II University, Naples, Italy
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Henriksen JE, Alford F, Handberg A, Vaag A, Ward GM, Kalfas A, Beck-Nielsen H. Increased glucose effectiveness in normoglycemic but insulin-resistant relatives of patients with non-insulin-dependent diabetes mellitus. A novel compensatory mechanism. J Clin Invest 1994; 94:1196-204. [PMID: 8083360 PMCID: PMC295197 DOI: 10.1172/jci117436] [Citation(s) in RCA: 71] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60 +/- 0.14 vs 1.59 +/- 0.18, x 10(-2) min-1, NS). However, insulin sensitivity (Si) was reduced (3.49 +/- 0.43 vs 4.80 +/- 0.61, x 10(-4) min-1 per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93 +/- 0.14 vs 1.52 +/- 0.16, x 10(-2) min-1, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63 +/- 0.48 vs 6.88 +/- 0.45, mU/liter, NS) nor first phase insulin responsiveness (Phi1) (3.56 +/- 0.53 vs 4.13 +/- 0.62, mU/liter min-1 per mg/dl, NS) were increased in the relatives. Phi1 was reduced for the degree of insulin resistance in the relatives so that the Phi1 x Si index was lower in the relatives (11.5 +/- 2.2 vs 16.7 +/- 2.0, x 10(-4) min-2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance within normal limits in these "normoinsulinemic" relatives of NIDDM patients.
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Affiliation(s)
- J E Henriksen
- Department of Endocrinology M, Odense University Hospital, Denmark
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Lemne C, Efendic S, Hamsten A, De Faire U. Impaired glucose and insulin metabolism in borderline hypertension. Blood Press 1994; 3:287-94. [PMID: 7866592 DOI: 10.3109/08037059409102276] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
This study investigated glucose and insulin metabolism in borderline hypertension (BHT) defined as repeated diastolic blood pressures (DBP) of 85-94 mmHg. Seventy-five BHT and 75 age-matched normotensive (NT, DBP < or = 80 mmHg) men were recruited from a population screening programme. Plasma lipoproteins were determined and an oral glucose tolerance test was performed (WHO criteria). Fasting insulin was significantly higher in the BHT group (17.2 vs 14.2 mU/ml, p < 0.001), whereas fasting blood glucose levels were similar in the two groups, indicating a reduced insulin sensitivity. The BHT group had significantly lower levels of HDL cholesterol and higher levels of plasma triglycerides, VLDL cholesterol and VLDL triglycerides. When adjusted for BMI these differences disappeared, whereas the basal insulin levels remained significantly elevated (F = 10.7, p < 0.001). These results indicate that an altered glucose and insulin metabolism is present already in the early stages of hypertension. They also suggest that these disturbances are only partly dependent on BMI. This supports the hypothesis that reduced insulin sensitivity could be of importance in the early phases of essential hypertension.
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Affiliation(s)
- C Lemne
- Department of Medicine, King Gustaf V Research Institute, Stockholm, Sweden
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50
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Ohmura T, Ueda K, Kiyohara Y, Kato I, Iwamoto H, Nakayama K, Nomiyama K, Ohmori S, Yoshitake T, Shinkawa A. The association of the insulin resistance syndrome with impaired glucose tolerance and NIDDM in the Japanese general population: the Hisayama study. Diabetologia 1994; 37:897-904. [PMID: 7806019 DOI: 10.1007/bf00400945] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
To elucidate the risk factors for initiating glucose intolerance, the relevant factors were explored in a cross-sectional survey conducted in a sample population aged 40-79 years old selected from a Japanese community, Hisayama, Japan in 1988. A 75-g oral glucose tolerance test was used to classify 1,073 men (72.5% of the entire population in the same age range) and 1,407 women (80.5%) into normal, impaired glucose tolerance and diabetes mellitus groups. In all age and sex groups with normal glucose tolerance, the sum of fasting and 2-h post-load insulin values varied widely and demonstrated significant positive correlations with triglycerides, body mass index, waist-hip ratio, systolic and diastolic blood pressure, while it negatively correlated to HDL cholesterol (p < 0.05). Insulin resistance was presumed to develop in normal glucose tolerance subjects with hyperinsulinaemia. The sum of the insulin concentrations, triglycerides, body mass index, waist-hip ratio and blood pressure levels was significantly associated with impaired glucose tolerance in all age and sex groups after adjustment for age (p < 0.05) and was also related to diabetes in either all or some age and sex groups, respectively (p < 0.05). It was shown that glucose intolerance in the general population was associated with the factors related to insulin resistance. These cross-sectional data, therefore, support the hypothesis that insulin resistance is the primary defect in the development of glucose intolerance in the Japanese general population. However, a further prospective study is still needed in order to confirm this hypothesis.
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Affiliation(s)
- T Ohmura
- Second Department of Internal Medicine, Faculty of Medicine Kyushu University, Fukuoka, Japan
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