In pancreatic ␤-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 ␤-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 ␤-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.

Uncoupling protein 2 (UCP2) may act as an important regulator of insulin secretion. In this study, beta-cell function in UCP2-deficient mice was examined after a 45% high-fat diet (HFD) to assess its role during the development of diet-induced type 2 diabetes. HFD-fed UCP2 (-/-) mice have lower fasting blood glucose and elevated insulin levels when compared with wild-type (WT) mice. UCP2 (-/-) mice also have enhanced beta-cell glucose sensitivity compared with WT mice after HFD, a result that is due in part to the deterioration of glucose responsiveness in WT mice. HFD-fed UCP2 (-/-) mice have increased insulin secretory capacity as a result of increased pancreatic beta-cell mass and insulin content per islet. Islets from WT mice exposed to 0.5 mmol/l palmitate for 48 h have significantly reduced mitochondrial membrane potential, ATP concentrations, and glucose responsiveness compared with UCP2 (-/-) islets, suggesting that elevated UCP2 in WT mice increases proton leak and decreases mitochondrial ATP production. Highly increased carnitine palmitoyl transferase-1 gene expression in UCP2 (-/-) mice is suggestive of enhanced fatty acid oxidizing capacity, particularly after HFD stress. These results further establish UCP2 as a component in glucose sensing and suggest a possible new aspect of UCP2 function during the progression of type 2 diabetes.

CHAN, CATHERINE B., ELIZABETH SPANGLER, JAMES VALCOUR, AND CATRINE TUDOR-LOCKE.Cross-sectional relationship of pedometer-determined ambulatory activity to indicators of health. Obes Res. 2003; 11:1563-1570. Objective: To describe the cross-sectional relationship between an objective measure of walking (pedometer-determined steps/day) and general indicators of health, a prior diagnosis of one or more components of the metabolic syndrome, and self-reported occupational activity in a generally sedentary working population. Research Methods and Procedures:Steps/day were compared with previous diagnosis of one or more components of the metabolic syndrome (by self-administered questionnaire) and with general health indicators including BMI, waist circumference, resting heart rate, and blood pressure in 182 subjects in Prince Edward Island, Canada. Study participants were volunteer employees recruited from five workplaces where, in general, the job types were moderately or highly sedentary. Results: Steps/day were 7230 Ϯ SD 3447 for women (n ϭ 153) and 8265 Ϯ 2849 (n ϭ 21) for men. Pedometerdetermined steps/day were associated inversely with BMI (r ϭ Ϫ0.4005, p Ͻ 0.0001) in all participants and waist circumference in females only (r ϭ Ϫ0.4303, p Ͻ 0.0001). There was a low correlation between steps/day and diastolic blood pressure in the whole sample (r ϭ Ϫ0.2140, p ϭ 0.0383). Participants who reported a prior diagnosis of one or more components of the metabolic syndrome (hypertension, hypercholesterolemia, heart disease, or type 2 diabetes) took fewer steps/day than healthy participants (p ϭ 0.0254). Pedometer-determined steps/day were positively associated with self-reported occupational activity (p ϭ 0.0002). Discussion: Fewer steps/day are associated with increased BMI, waist circumference, diastolic blood pressure, and components of the metabolic syndrome. Low occupational activity is a contributing factor to low total ambulatory activity.

Stressors such as chronic hyperglycemia or hyperlipidemia may lead to insufficient insulin secretion in susceptible individuals, contributing to type 2 diabetes. The molecules mediating this effect are just beginning to be identified. Uncoupling protein (UCP)-2 may be one such negative modulator of insulin secretion. Accumulating evidence shows that ␤-cell UCP2 expression is upregulated by glucolipotoxic conditions and that increased activity of UCP2 decreases insulin secretion. Mitochondrial superoxide has been identified as a posttranslational regulator of UCP2 activity in islets; thus, UCP2 may provide protection to ␤-cells at one level while simultaneously having detrimental effects on insulin secretion. Interestingly, the latter appears to be the dominant outcome, because UCP2 knockout mice display an increased ␤-cell mass and retained insulin secretion capacity in the face of glucolipotoxicity. Diabetes 53 (Suppl. 1):S136 -S142, 2004 H ealthy pancreatic ␤-cells are poised to respond rapidly and efficiently to acute changes in circulating nutrient availability to maintain metabolic homeostasis. However, it is well recognized that chronic exposure to overnutrition, such as what occurs in obesity, results in a blunting of the insulin response to an acute stimulus. The mechanisms by which this adaptation occurs are hotly debated but, based on recent analyses of gene expression using oligonucleotide microarray technology, include multiple enzymes involved in glucose and fat metabolism (1,2). Key rate-limiting enzymes, such as carnitine palmitoyl transferase (CPT)-1, have been identified as crucial mediators of altered metabolism of fat and glucose leading to impaired insulin secretion (3). Until recently, regulatory proteins that participate specifically in downregulation of insulin secretion have received little attention. The discovery that uncoupling protein (UCP)-2 is present in pancreatic islets and ␤-cell lines (4) has led to the suggestion that such molecules can participate in the long-term adaptation of the ␤-cell to increased nutrient availability and contribute to the suppression of glucose-stimulated insulin secretion (GSIS) (5). UCP2The existence of UCP2 was first described in 1997 in multiple tissues (6 -8), including the pancreas (6). It was subsequently localized in rat (4,5) and human pancreatic (9,10) islets. In general, UCPs function to decrease metabolic efficiency by dissociating substrate oxidation in the mitochondrion from ATP synthesis. This is thought to be accomplished by promoting net translocation of protons from the intermembrane space, across the inner mitochondrial membrane to the matrix, thereby dissipating the potential energy available for conversion of ADP to ATP despite continued oxidation of fuels (11). This uncoupling effect then leads to homologue-and tissue-specific functions such as thermogenesis for UCP1 (12), regulation of free fatty acid (FFA) metabolism and transport for UCP2 and UCP3 (11,13,14), decreasing reactive oxygen species (ROS) formation (UCP1 and UCP2) (15,...

Background:To compare the effectiveness of a theory-based lifestyle physical activity (PA) program delivered to individuals with type 2 diabetes in diabetes education centers by professionals and peers.Methods:Changes over 16 weeks in PA (steps/day) and related variables (weight, waist girth, resting heart rate, systolic and diastolic blood pressures) were compared (RMANOVA) for two groups: 157 participants led by 13 different professionals versus 63 participants led by 5 peer leaders.Results:Overall, the 81 male and 139 female participants (age = 55.7 ± 7.3 years, BMI = 35.2 ± 6.6) showed an incremental change of 4,059 ± 3,563 steps/day, which translates into an extra 37 minutes of daily walking (P < .001). Statistically significant improvements were also seen in weight, waist girth, and blood pressure (all P < .001) and resting heart rate (P < .05). There were no significant differences in outcomes between professional and peer-led groups.Conclusions:A theory-based behavior modification program featuring simple feedback and monitoring tools, and with a proven element of flexibility in delivery, can be effective under real-world conditions while addressing inevitable concerns about resource allocation. Program delivery by peer leaders, in particular, could address a potential obstacle to dissemination by helping to alleviate existing high caseload demands on diabetes educators.