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PubMed2006

Antihypertensive therapy in patients with metabolic syndrome.

PURPOSE OF REVIEW: It is amply recognized that the presence of metabolic syndrome is associated with subclinical cardiac, vascular and kidney damage, with an increased risk for cardiovascular and cerebrovascular disease and type 2 diabetes, and, as a consequence, with higher rates of cardiovascular mortality. Metabolic syndrome can be considered as a prediabetic state very frequently associated with arterial hypertension, requiring pharmacological therapy. RECENT FINDINGS: All antihypertensive therapies have been shown to reduce the risk of total major cardiovascular events. Recently, the relevance of the type of hypertensive therapy used to treat hypertensive patients in facilitating the development of diabetes has been demonstrated in different trials. The recognition of the risk present in hypertensive patients with metabolic syndrome for developing diabetes reinforces the need to consider the ideal antihypertensive therapy, either mono or combination, in these patients. SUMMARY: This brief review contains the available evidence showing that an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker is the most suitable therapy to be started in these patients, alone or in combination, due to their capacity to prevent or retard the development of diabetes, and the strong relationship between metabolic syndrome and arterial hypertension, focusing on the advantages and disadvantages of different antihypertensive drugs.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2005

The impact of acute elevation of non-esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes.

OBJECTIVES: Elevations in non-esterified fatty acids (NEFA) have been shown to decrease insulin action and secretion, and are a risk factor for the development of Type 2 diabetes. As women who have had gestational diabetes (GDM) are at increased risk of diabetes, we examined the effect of an acute elevation of NEFA on insulin secretion and action in these women. PATIENTS AND DESIGN: Nineteen women with recent former GDM and 19 age- and BMI-matched postpartum healthy control subjects underwent a 40-min intravenous glucose tolerance test, with and without a preceding 2-h infusion of 20% Intralipid. Insulin action was assessed by glucose disappearance (Kg) and insulin sensitivity (SI); insulin secretion by first phase insulin release (FPIR) and disposition index (DI). RESULTS: NEFA levels were similarly elevated in both groups by the Intralipid infusion (up to 1.140 +/- 0.03 mm). As expected, the lipid infusion significantly reduced Kg (2.15 +/- 0.13 vs. 1.69 +/- 0.09/min, P < 0.001) and SI (3.14 +/- 0.28 vs. 2.13 +/- 0.17/min/mUl/min, P < 0.001) in all subjects, and these were significant within the GDM and control subgroups. FPIR was elevated in the Intralipid study in the total group of women (4.50 +/- 0.50 vs. 5.02 +/- 0.53, P = 0.02), but DI was significantly reduced (12.13 +/- 1.1 vs. 8.83 +/- 0.7, P < 0.001). There was no significant difference, however, in the absolute or percentage change in Kg, SI or FPIR with lipid infusion between the GDM and control groups. GDM status was not a predictor of the response of Kg, SI or FPIR to lipid infusion, rather, adiposity (% fat), average fasting NEFA levels and basal disposition index were associated. CONCLUSION: These data suggest that women with former gestational diabetes, in contrast to other prediabetic states, are not more susceptible to the deleterious effects of an acute elevation in nonesterified fatty acids than matched control subjects.

Adult↗

PubMed1995

The insulin-dependent patient: perceptions and preferences.

Although patients realize that insulin is the missing hormone which keeps them alive and well, they do not regard it as a cure for diabetes because it may cause hypoglycaemia, it does not completely abolish the risk of long-term side-effects, and it does not permit a life-style equivalent to their prediabetic state. Clearly, though, insulin can improve quality of life and significantly reduce the risk of complications. Patients' perceptions of their illness and the available treatment have been explored by several means: letters written to a diabetes specialist nurse by children with diabetes, group discussion at a Young Adult Clinic and responses to questions at the annual Youth Diabetes Conference. Improvements in patient care will stem from physicians' awareness of patients' perceptions and from developments in insulin therapy.

Adolescent↗

PubMed1995

Antihypertensive effects of captopril without adverse effects on glucose tolerance in hyperinsulinemic rhesus monkeys.

The rhesus monkey (Macaca mulatta), which has been found to develop spontaneous obesity, non-insulin dependent diabetes mellitus (NIDDM; Type 2), and hypertension, was used to evaluate the potential blood pressure-lowering effects of captopril as well as the specific effects, if any, on the prediabetic state. Intravenous and oral glucose tolerance testing was carried out with oral captopril dosing. Results showed that captopril significantly decreased both systolic and diastolic blood pressure in all monkeys and significantly decreased fasting plasma glucose levels. Based on these preliminary studies in monkeys, we conclude that captopril exerted antihypertensive effects without adverse effects on glucose metabolism.

Animals↗

PubMed1999

Etiology of the metabolic syndrome: potential role of insulin resistance, leptin resistance, and other players.

Obesity and Type 2 diabetes are now major public health issues in developed nations and have reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican-Americans, African-Americans, and Australian Aborigines. These groups all show hyperinsulinemia and insulin resistance, which have been demonstrated to be future predictors of Type 2 diabetes and have also been suggested as key factors in the etiology of the Metabolic Syndrome. It is now increasingly recognized that Type 2 diabetes is part of a cluster of cardiovascular disease (CVD) risk factors comprising the Metabolic Syndrome. This group is at very high risk of atherosclerosis because each of the risk factors in the Metabolic Syndrome cluster in its own right is an important CVD risk factor. They also contribute cumulatively to atherosclerosis. A key strategy in reducing macrovascular disease lies in the better understanding of the Metabolic Syndrome--glucose intolerance, hypertension, hyperlipidemia, and central obesity. Although it has been suggested that hyperinsulinemia/insulin resistance is the central etiological factor for the Metabolic Syndrome, epidemiological data do not support the idea that this can account for all of the cluster abnormalities. We have animal and human data suggesting that hyperleptinemia rather than, or synergistically with, hyperinsulinemia may play a central role in the genesis of the CVD risk factor cluster that constitutes the syndrome. Studies in Psammomys obesus (the Israeli sand rat) suggest hyperinsulinemia/insulin resistance is an early metabolic lesion in the development of obesity and Type 2 diabetes. This animal also develops other features of the Metabolic Syndrome, making it an excellent model to investigate etiology. Psammomys, when placed on an ad libitum laboratory diet, develops hyperinsulinemia, insulin resistance, impaired glucose tolerance, diabetes, and dyslipidemia. It also develops hyperleptinemia and leptin insensitivity, and hyperleptinemia is correlated with insulin resistance independent of changes in body weight. It is likely that a similar sequence occurs in the transition from the prediabetic state to Type 2 diabetes in humans. More recently, other potential players in the etiology of the Metabolic Syndrome have been suggested including endothelial dysfunction and acetylation-stimulating protein (ASP). It has been suggested that endothelial dysfunction may be an antecedent for both Type 2 diabetes and the Metabolic Syndrome. In addition, ASP is a serious new candidate for an important role in insulin resistance. The ASP pathway plays a critical role in fatty acid metabolism and storage, and it has been suggested that ineffective storage of fatty acids by adipocytes due to a defect in the ASP pathway may lead to insulin resistance and Type 2 diabetes.

Acetylation↗

PubMed2002

The lymphocyte as a cellular model to study insights into the pathophysiology of diabetes and its complications.

Blood cells from subjects with hypertension and/or diabetes mellitus have been successfully studied in the past to gain insight into pathological alterations of several signal transduction pathways. Diabetes mellitus is also considered to be a disease of abnormal cellular Ca2+ metabolism, as metabolic derangements of Ca2+ transport have been noticed both in the prediabetic state and as a consequence of hyperglycemia and oxidative stress. In this report, we used peripheral blood lymphocytes from type 2 diabetes patients and control subjects to study and delineate different mechanisms of Ca2+ turnover that determine the level of cytosolic calcium (Ca(i)). While demonstrating the specific Ca2+ turnover alterations, we suggest that insights into the pathophysiology of diabetic complications originating from signal transduction defects could be conveniently studied using blood cell types such as lymphocytes and that such studies could lead to the identification of new molecular drug targets.

Calcium↗

PubMed2002

Effects of pioglitazone in nondiabetic patients with arterial hypertension: a double-blind, placebo-controlled study.

Hypertension is often associated with insulin resistance, dyslipidemia and obesity, which indicate a prediabetic state and increased risk of cardiovascular disease. Pioglitazone treatment of patients with type 2 diabetes reduces insulin resistance and improves lipid profiles. The present double-blind placebo-controlled study is the first study to report effects of pioglitazone in non-diabetic patients with arterial hypertension. Following a one week run-in, 60 patients were randomized to receive either pioglitazone (45 mg/day) or placebo for 16 weeks. Insulin sensitivity (M-value) increased by 1.2 +/- 1.7 mg/min/kg with pioglitazone compared with 0.4 +/- 1.4 mg/min/kg (P = 0.022) with placebo. HOMA index was decreased (-22.5 +/- 45.8) by pioglitazone but not by placebo (+0.8 +/- 26.5; P < 0.001). Decreases in fasting insulin and glucose were significantly (P = 0.002 and P = 0.004, respectively) greater with pioglitazone than placebo. Body weight did not change significantly with either treatment. HDL-cholesterol was increased and apolipoprotein B was decreased to a significantly greater extent with pioglitazone. There was a significantly (P = 0.016) greater decrease from baseline in diastolic blood pressure with pioglitazone. These changes would suggest improved glucose metabolism and a possible reduction in risk of cardiovascular disease with pioglitazone treatment of non-diabetic patients with arterial hypertension.

Apolipoproteins B↗

PubMed2003

Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus.

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.

Adult↗

PubMed2005

Postprandial interleukin-6 release from skeletal muscle in men with impaired glucose tolerance can be reduced by weight loss.

CONTEXT: Obesity and type 2 diabetes mellitus are associated with increased levels of IL-6, a marker of inflammation. OBJECTIVE: This study addressed the question of whether IL-6 was released from skeletal muscle after a high-fat meal in men with impaired glucose tolerance (IGT), a prediabetic state, and whether IL-6 release could be reduced by weight loss. DESIGN: Skeletal muscle metabolism was studied in men with IGT (n = 11) and compared with men with normal glucose tolerance (NGT, n = 9), matched for body mass index and age. IL-6 flux over skeletal muscle was measured with the forearm model. Eight IGT men were willing to participate in a 12-wk weight loss program and were tested again. RESULTS: IL-6, but not C-reactive protein or TNF-alpha receptor 1 and 2, was released by skeletal muscle. Muscle IL-6 release was higher in IGT than in NGT during fasting (IGT = 2.26 +/- 1.89 vs. NGT = 0.87 +/- 0.48 fmol x 100 ml tissue(-1) x min(-1), P = 0.04) and after a meal (mean area under the curve per minute: IGT = 3.48 +/- 2.63 vs. NGT = 1.37 +/- 0.75 fmol x 100 ml tissue(-1) x min(-1); P = 0.03). In the IGT men, body weight loss resulted in a decrease of postprandial IL-6 release from skeletal muscle (-52%; P = 0.04), reaching levels of the obese, NGT controls. CONCLUSION: The present data suggest that a high-fat meal can evoke IL-6 release from muscle and that the IL-6 release is a consequence rather than a cause of the obese, insulin-resistant, and/or IGT state.

Aged↗

PubMed2000

Risk for diabetes mellitus in middle-aged Caucasian male participants of the PROCAM study: implications for the definition of impaired fasting glucose by the American Diabetes Association. Prospective Cardiovascular Münster.

The criteria of the American Diabetes Association and the WHO for the diagnosis of diabetes mellitus are controversially discussed. In a prospective population study, we evaluated the data of 3,737 men, aged 36-60 yr, without diabetes mellitus and with fasting serum glucose levels less than 7 mmol/L at entry into the study who had at least 1 repeat examination during a follow-up of 4-10 yr. During a mean follow-up of 6.3 yr, 200 men developed diabetes mellitus. They differed significantly from 3,537 men by body mass index, fasting serum levels of glucose, high density lipoprotein cholesterol, and family history positive for diabetes mellitus. Receiver operating curve analysis revealed that a glucose level of 5.72 mmol/L was the best discriminatory cut-off. Upon global risk estimation by multiple logistic function (MLF) analysis, 69.6% of all diabetes mellitus incidences occurred in the highest quintile as defined by the MLF algorithm. The relative risk of a men in this quintile was 8.7 compared to that in the residual population. The performance of risk assessment by MLF as estimated by the area under the receiver operator characteristic curve was similar to fasting glucose levels. Global risk estimation by multiple risk factors does not improve the prediction of diabetes mellitus by fasting glucose in middle-aged men. The lower discriminatory cut-off of 5.72 mmol/L glucose may help to reduce the previously reported discordance between impaired fasting glucose (American Diabetes Association) and impaired glucose tolerance (WHO) in diagnosis of the prediabetic state.

Adult↗

PubMed2004

Reduced amount and disrupted temporal pattern of spontaneous exercise in diabetic rats.

INTRODUCTION/PURPOSE: The beneficial effects of exercise for subjects with diabetes or prediabetic states are well established. However, the converse, that is, the effect of diabetes on spontaneous exercise performance, is not as well defined. Mice with mdx muscular dystrophy not only reduce total spontaneous running distance, but also decrease the duration of periods during which they are active, suggesting a defect in endurance. Studies tested the hypothesis that Type I diabetes causes similar changes in spontaneous exercise performance. METHODS: Wistar rats received streptozotocin to produce a model of Type I diabetes or buffer alone, and had access to running wheels for the next 8 wk. RESULTS: Diabetic rats had elevated serum glucose levels (689 +/- 85 vs 270 +/- 21 mg x dL(-1), P = 0.0003) but normal serum bicarbonate levels. After 8 wk, diabetic rats were running for considerably lower distances than normal animals (daily distance 182 +/- 58 vs 4981 +/- 1373 m, P = 0.006). Furthermore, the average consecutive running time was much shorter in diabetic than normal rats (16 +/- 1 vs 40 +/- 6 min, P = 0.004). Differences in running behavior between diabetic and normal mice were absent early after injection of streptozotocin, but were fully established by week 4 for both total distance and consecutive running times. CONCLUSION: Severe untreated Type I diabetes in rats reduces spontaneous exercise in a manner similar to that seen in mdx mouse muscular dystrophy, with reduced running distance and consecutive running times.

Animals↗

PubMed1998

Central role of the adipocyte in insulin resistance.

Mechanisms of insulin resistance in subjects at risk for type 2 diabetes remain to be elucidated. Insulin acts slowly in vivo, but rapidly in vitro, suggesting that the pathway insulin traverses from B-cell to insulin sensitive tissue may be altered in diabetes. An important component of that pathway is transport of insulin across the capillary endothelium. Several groups have demonstrated that insulin resistance may result from reduced capillary permeability to insulin--it remains to be determined whether reduced permeability contributes to insulin resistance in any stage leading to type 2 diabetes. Interestingly, the transport of insulin across the endothelial barrier not only limits the rate of insulin to stimulate glucose uptake by skeletal muscle, but appears also to determine the rate at which insulin suppresses liver glucose output. Because the liver circulation is fenestrated, it is not possible that insulin transport into the liver is the rate determining step for suppression of liver glucose output. An alternative hypothesis was considered--that insulin is transported into an extrahepatic tissue. A "second signal" is generated by the extrahepatic tissue, the signal is released into the blood, and the signal in turn controls hepatic glucose output. Several lines of evidence suggest that the second signal is free fatty acids (FFA): 1) There is a strong correlation between FFA and liver glucose output under a variety of experimental conditions. 2) If FFA are maintained at basal concentrations during insulin administration, glucose output fails to decline. 3) If FFA are reduced independent of insulin administration, glucose output is reduced. These three points support the concept that insulin, by regulating adipocyte lipolysis, controls liver glucose production. Thus, the adipocyte is a critical mediator between insulin and liver glucose output. Evidence that FFA also suppress skeletal muscle glucose uptake and insulin secretion from the B-cell supports the overall central role of the adipocyte in the regulation of glycemia. Insulin resistance at the fat cell may be an important component of the overall regulation of glycemia because of the relationships between FFA and glucose production, glucose uptake, and insulin release. It is possible that insulin resistance at the adipocyte itself can be a major cause of the dysregulation of carbohydrate metabolism in the prediabetic state.

Adipocytes↗

PubMed2000

Islet autoantibodies and insulin dependent diabetes mellitus in cystic fibrosis.

Cystic fibrosis-related diabetes mellitus (CF-DM) is thought to be secondary to beta-cell destruction by fibrous tissue replacing the exocrine pancreas. The aim of this study was to investigate the hypothesis that other factors may also be responsible. Glutamic acid decarboxylase (GAD) and islet cell (IA-2) antibodies were measured by quantitative ELISA in a group of patients with CF (n=30) in comparison to a group of newly diagnosed DM type 1 (IDDM) patients (n=30) and normal subjects (n=30). GAD antibodies were positive (>32 ng/ml) in 50% of the CF, 93% of the IDDM and 0% of the control group. IA-2 antibodies were detected (>0.9 U/ml) in 40% of the CF, 93% of the IDDM and 0% of the control group. Among the fifteen CF patients with positive GAD and IA-2 antibodies, four already had IDDM and another five abnormally low (<45 mU/l) first phase insulin response (FPIR) indicating a prediabetic state. We conclude that factors other than mechanical may be involved in the development of CFDM. The presence of autoantibodies predicting IDDM supports the hypothesis that CF-DM may have a multifactorial pathogenesis.

Adolescent↗

PubMed2005

Prevalence of impaired fasting glucose and its relationship with cardiovascular disease risk factors in US adolescents, 1999-2000.

OBJECTIVE: PEDIATRICS (ISSN 0031 4005). Published in the public domain by the American Academy of Pediatrics. Several studies have reported increases in the occurrence of type 2 diabetes in youths. People with prediabetic states such as impaired fasting glucose (IFG) are at increased risk for developing diabetes and cardiovascular disease (CVD). The objective of this study was to examine the prevalence of IFG and its relationship with overweight and CVD risk factors in a nationally representative sample of US adolescents who were aged 12 to 19 years. METHODS: We used data from the 1999-2000 National Health and Nutrition Examination Survey (NHANES). Adolescents who had fasted for 8 hours or more were included in the study (n = 915). IFG was defined as a fasting glucose of 100 to 125 mg/dL. Participants were classified as overweight when their age- and gender-specific BMI was > or = 95th percentile and as at-risk for overweight when their BMI was > or = 85th and < 95th percentile. RESULTS: In 1999-2000, the prevalence of IFG in US adolescents was 7.0% and was higher in boys than in girls (10.0% vs 4.0%). Prevalence of IFG was higher in overweight adolescents (17.8%) but was similar in those with normal weight and those who were at risk for overweight (5.4% vs 2.8%). The prevalence of IFG was significantly different across racial/ethnic groups (13.0%, 4.2%, and 7% in Mexican Americans, non-Hispanic black individuals, and non-Hispanic white individuals, respectively). Adolescents with IFG had significantly higher mean hemoglobin A1c, fasting insulin, total and low-density lipoprotein cholesterol, triglycerides, and systolic blood pressure and lower high-density lipoprotein cholesterol than those with normal fasting glucose concentrations. CONCLUSIONS: These data, representing 27 million US adolescents, reveal a very high prevalence of IFG (1 in 10 boys and 1 in 25 girls) among adolescents; the condition affects 1 in every 6 overweight adolescents. Adolescents with IFG have features of insulin resistance and worsened CVD risk factors. Evidence for prevention is still forthcoming in this age group.

Adolescent↗

PubMed2003

Metformin: new understandings, new uses.

Metformin, a biguanide, has been available in the US for the treatment of type 2 diabetes mellitus for nearly 8 years. Over this period of time, it has become the most widely prescribed antihyperglycaemic agent. Its mechanism of action involves the suppression of endogenous glucose production, primarily by the liver. Whether the drug actually has an insulin sensitising effect in peripheral tissues, such as muscle and fat, remains somewhat controversial. Nonetheless, because insulin levels decline with metformin use, it has been termed an 'insulin sensitiser'. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular outcomes in patients with diabetes. Cardiovascular disease, impaired glucose tolerance and the polycystic ovary syndrome are now recognised as complications of the insulin resistance syndrome, and there is growing interest in the management of this extraordinarily common metabolic disorder. While diet and exercise remain the cornerstone of therapy for insulin resistance, pharmacological intervention is becoming an increasingly viable option. We review the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits it provides over and above its effect on glucose levels alone. We also discuss its potential role for a variety of insulin resistant and prediabetic states, including impaired glucose tolerance, obesity, polycystic ovary syndrome and the metabolic abnormalities associated with HIV disease.

Anti-Obesity Agents↗

PubMed1982

Transplantation of islet cells across major histocompatibility barriers after total lymphoid irradiation and infusion of allogeneic bone marrow cells.

Diabetic Lewis rats (AgB1/L) were evaluated as recipients of allogeneic Wistar-Furth (AgB2/2) isolated adult islets without the use of standard recipient immunosuppression. One group was treated with fractionated total lymphoid irradiation (TLI) and Wistar-Furth bone marrow cell reconstitution to proven chimerism prior to islet transplantation. This group returned to a prediabetic state following Wistar-Furth islet transplantation without any evidence of rejection for 100 days posttransplant. A second group of Lewis rats received only TLI without bone marrow treatment. They gave a varying result following islet transplantation with one recipient showing evidence of prolonged islet survival. A third chimeric control group did not receive isolated islets and did not alter their diabetic state. A fourth group was not given TLI nor donor bone marrow cells and uniformly rejected their allogeneic islets by 7 days. Thus, allogeneic adult islets will survive across major rat histocompatibility barriers using TLI and donor bone marrow chimerism as the only form of immunosuppression.

Animals↗

PubMed1999

Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: a 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents.

Insulin resistance is the best prediction factor for the clinical onset of type 2 diabetes. It was suggested that intramuscular triglyceride store may be a primary pathogenic factor for its development. To test this hypothesis, 14 young lean offspring of type 2 diabetic parents, a model of in vivo insulin resistance with increased risk to develop diabetes, and 14 healthy subjects matched for anthropomorphic parameters and life habits were studied with 1) euglycemic-hyperinsulinemic clamp to assess whole body insulin sensitivity, 2) localized 1H nuclear magnetic resonance (NMR) spectroscopy of the soleus (higher content of fiber type I, insulin sensitive) and tibialis anterior (higher content of fiber type IIb, less insulin sensitive) muscles to assess intramyocellular triglyceride content, 3) 13C NMR of the calf subcutaneous adipose tissue to assess composition in saturated/unsaturated carbons of triglyceride fatty acid chains, and 4) dual X-ray energy absorption to assess body composition. Offspring of diabetic parents, notwithstanding normal fat content and distribution, were characterized by insulin resistance and increased intramyocellular triglyceride content in the soleus (P < 0.01) but not in the tibialis anterior (P = 0.19), but showed a normal content of saturated/unsaturated carbons in the fatty acid chain of subcutaneous adipocytes. Stepwise regression analysis selected intramyocellular triglyceride soleus content and plasma free fatty acid levels as the main predictors of whole body insulin sensitivity. In conclusion, 1H and 13C NMR spectroscopy revealed intramyocellular abnormalities of lipid metabolism associated with whole body insulin resistance in subjects at high risk of developing diabetes, and might be useful tools for noninvasively monitoring these alterations in diabetes and prediabetic states.

Adult↗

PubMed2001

Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action.

In pancreatic beta-cells, glucose metabolism signals insulin secretion by altering the cellular array of messenger molecules. ATP is particularly important, given its role in regulating cation channel activity, exocytosis, and events dependent upon its hydrolysis. Uncoupling protein (UCP)-2 is proposed to catalyze a mitochondrial inner-membrane H(+) leak that bypasses ATP synthase, thereby reducing cellular ATP content. Previously, we showed that overexpression of UCP-2 suppressed glucose-stimulated insulin secretion (GSIS) in isolated islets (1). The aim of this study was to identify downstream consequences of UCP-2 overexpression and to determine whether insufficient insulin secretion in a diabetic model was correlated with increased endogenous UCP-2 expression. In isolated islets from normal rats, the degree to which GSIS was suppressed was inversely correlated with the amount of UCP-2 expression induced. Depolarizing the islets with KCl or inhibiting ATP-dependent K(+) (K(ATP)) channels with glybenclamide elicited similar insulin secretion in control and UCP-2-overexpressing islets. The glucose-stimulated mitochondrial membrane ((m)) hyperpolarization was reduced in beta-cells overexpressing UCP-2. ATP content of UCP-2-induced islets was reduced by 50%, and there was no change in the efflux of Rb(+) at high versus low glucose concentrations, suggesting that low ATP led to reduced glucose-induced depolarization, thereby causing reduced insulin secretion. Sprague-Dawley rats fed a diet with 40% fat for 3 weeks were glucose intolerant, and in vitro insulin secretion at high glucose was only increased 8.5-fold over basal, compared with 28-fold in control rats. Islet UCP-2 mRNA expression was increased twofold. These studies provide further strong evidence that UCP-2 is an important negative regulator of beta-cell insulin secretion and demonstrate that reduced (m) and increased activity of K(ATP) channels are mechanisms by which UCP-2-mediated effects are mediated. These studies also raise the possibility that a pathological upregulation of UCP-2 expression in the prediabetic state could contribute to the loss of glucose responsiveness observed in obesity-related type 2 diabetes in humans.

Adenosine Triphosphate↗