Catherine B. Chan

Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes

Abstract β cells sense glucose through its metabolism and the resulting increase in ATP, which subsequently stimulates insulin secretion. Uncoupling protein-2 (UCP2) mediates mitochondrial proton leak, decreasing ATP production. In the present study, we assessed UCP2s role in regulating insulin secretion. UCP2-deficient mice had higher islet ATP levels and increased glucose-stimulated insulin secretion, establishing that UCP2 negatively regulates insulin secretion. Of pathophysiologic significance, UCP2 was markedly upregulated in islets of ob/ob mice, a model of obesity-induced diabetes. Importantly, ob/ob mice lacking UCP2 had restored first-phase insulin secretion, increased serum insulin levels, and greatly decreased levels of glycemia. These results establish UCP2 as a key component of β cell glucose sensing, and as a critical link between obesity, β cell dysfunction, and type 2 diabetes.

Relationship between objective measures of physical activity and weather: a longitudinal study

BackgroundThe weather may be a barrier to physical activity but objective assessment of this hypothesis is lacking. Therefore we evaluated the effect of temperature, rain or snow, and wind speed on the daily physical activity of adults.MethodsThis report contains data from 25 males (BMI (mean ± SD): 28.7 ± 3.83 kg/m2) and 177 females (BMI: 29.2 ± 5.92 kg/m2) enrolled in an intervention to increase physical activity. Steps/day of the participants was measured by pedometer. Weather data were obtained from Environment Canada. A total of 8,125 observations were included in a mixed linear model analysis.ResultsSignificant weather related variables (at the 5% level) impacting steps/day included: seasonal effects related to the interaction between weekday and month; mean temperature, total rainfall, interactions between gender, BMI and total snow, interactions between maximum wind speed and BMI, and the amount of snow on the ground. The estimated magnitudes for the various effects were modest, ranging from ~1% to ~20%. Thus for an average individual taking ~10,000 steps/day, weather-dependent changes in physical activity could reach 2,000 steps/day.ConclusionWe conclude that weather had modest effects on physical activity of participants in an intervention to increase their activity. It should be stressed that these effects may be different for less or more motivated people. With this in mind, we suggest that the effect of weather on physical activity in the general population needs to be objectively assessed to better understand the barrier it poses, especially as it relates to outdoor recreation or work activities.

Transcriptional regulation of lipid metabolism by fatty acids: a key determinant of pancreatic β-cell function

BackgroundOptimal pancreatic β-cell function is essential for the regulation of glucose homeostasis in both humans and animals and its impairment leads to the development of diabetes. Type 2 diabetes is a polygenic disease aggravated by environmental factors such as low physical activity or a hypercaloric high-fat diet.ResultsFree fatty acids represent an important factor linking excess fat mass to type 2 diabetes. Several studies have shown that chronically elevated free fatty acids have a negative effect on β-cell function leading to elevated insulin secretion basally but with an impaired response to glucose. The transcription factors PPARα, PPARγ and SREBP-1c respond to changing fat concentrations in tissues, thereby coordinating the genomic response to altered metabolic conditions to promote either fat storage or catabolism. These transcription factors have been identified in β-cells and it appears that each may exert influence on β-cell function in health and disease.ConclusionThe role of the PPARs and SREBP-1c as potential mediators of lipotoxicity is an emerging area of interest.

Reactive oxygen species and endothelial function in diabetes.

An increasing body of evidence suggests that oxidant stress is involved in the pathogenesis of many cardiovascular diseases, including hypercholesterolemia, atherosclerosis, hypertension, heart failure and diabetes. Recent studies have also provided important new insights into potential mechanisms underlying the pathogenesis of vascular disease induced by diabetes. Glycosylation of proteins and lipids, which can interfere with their normal function, activation of protein kinase C with subsequent alteration in growth factor expression, promotion of inflammation through the induction of cytokine secretion and hyperglycemia-induced oxidative stress are some of these mechanisms. It is widely accepted that hyperglycemia-induced reactive oxygen species contribute to cell and tissue dysfunction in diabetes. A variety of enzymatic and non-enzymatic sources of reactive oxygen species exist in the blood vessels. These include NADPH oxidase, mitochondrial electron transport chain, xanthine oxidase and nitric oxide synthase. The present article reviews the effects of reactive oxygen species on endothelial function in diabetes and addresses possible therapeutic interventions.

Assessing the effects of weather conditions on physical activity participation using objective measures

Habitual physical activity is an important determinant of health, yet many people are considered to be inactive. Identification of the obstacles to greater participation is necessary for the development of strategies to overcome those obstacles. The weather has been identified as a perceived barrier to participation in physical activity, but exactly which adverse weather conditions are most important, and the extent to which they contribute to decreases in physical activity have rarely been quantified in populations. In the past decade, a small number of studies have used publicly available databases to examine the quantitative effects of weather (e.g., temperature, precipitation, wind) on physical activity in children, adolescents and adults. This review examines our historical, qualitative versus emerging, quantitative understanding of how specific weather conditions affect a population’s activity.

Uncoupling protein-2: evidence for its function as a metabolic regulator

Uncoupling protein-2, discovered in 1997, belongs to a family of inner mitochondrial membrane proteins that, in general, function as carriers. The function(s) of uncoupling protein-2 have not yet been definitively described. However, mounting evidence suggests that uncoupling protein-2 could act in multiple tissues as a regulator of lipid metabolism. A role as a modulator of reactive oxygen species as a defence against infection is also postulated. In this review, a brief overview of the general and specific properties of uncoupling protein-2 is given and evidence for metabolic and immune regulatory functions is summarized. Uncoupling protein-2 could have particular importance in the regulation of lipid metabolism in adipose tissue and skeletal muscle. In addition, its ability to inhibit insulin secretion could also promote fat utilization over storage. Inhibition by uncoupling protein-2 of reactive oxygen species formation in macrophages and other tissues could have implications for regulation of immune function. The possibility of functions of uncoupling protein-2 in other tissues such as the brain are beginning to emerge. [Diabetologia (2002) 45: 174–187]

Limited Mitochondrial Permeabilization Is an Early Manifestation of Palmitate-induced Lipotoxicity in Pancreatic β-Cells

Involvement of the mitochondrial permeability transition (MPT) pore in early stages of lipotoxic stress in the pancreatic β-cell lines MIN6 and INS-1 was the focus of this study. Both long term (indirect) and acute (direct) effects of fatty acid (FA) application on β-cell susceptibility to Ca2+-induced MPT induction were examined using both permeabilized and intact β-cells. Long term exposure to moderate (i.e. below cytotoxic) levels of the saturated FA palmitate sensitized β-cell mitochondria to MPT induced by Ca2+. Long term exposure to palmitate was significantly a more efficient inducer of MPT than the unsaturated FA oleate, although upon acute application both caused similar MPT activation. Application of antioxidants, inhibitors of the ceramide pathway, or modifiers of membrane fluidity did not protect β-cell mitochondria from FA exposure. However, significant protection was provided by co-application of the unsaturated FA oleate in a phosphatidylinositol 3-kinase-dependent manner. Characterization of MPT pore opening in response to moderate palmitate treatment revealed the opening of a unique form of MPT in β-cells as it encompassed features of both low and high conductance MPT states. Specifically, this MPT showed solute selectivity, characteristic of a low conductance MPT; however, it affected mitochondrial respiration and membrane potential in a way typical of a high conductance MPT. Activation of the full-size/high conductance form of MPT required application of high levels of FA that reduced growth and initiated apoptosis. These findings suggest that in the β-cell, MPTs can act as both initiators of cell death and as versatile modulators of cell metabolism, depending on the mode of the MPT pore induced.

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

Aims/hypothesisAlthough insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes.Materials and methodsCirculating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function.ResultsInsulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice.Conclusions/interpretationOur studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction.

UCP2 is highly expressed in pancreatic α-cells and influences secretion and survival

In pancreatic β-cells, uncoupling protein 2 (UCP2) influences mitochondrial oxidative phosphorylation and insulin secretion. Here, we show that α-cells express significantly higher levels of UCP2 than do β-cells. Greater mitochondrial UCP2-related uncoupling was observed in α-cells compared with β-cells and was accompanied by a lower oxidative phosphorylation efficiency (ATP/O). Conversely, reducing UCP2 activity in α-cells was associated with higher mitochondrial membrane potential generated by glucose oxidation and with increased ATP synthesis, indicating more efficient metabolic coupling. In vitro, the suppression of UCP2 activity led to reduced glucagon secretion in response to low glucose; however, in vivo, fasting glucagon levels were normal in UCP2−/− mice. In addition to its effects on secretion, UCP2 played a cytoprotective role in islets, with UCP2−/− α-cells being more sensitive to specific death stimuli. In summary, we demonstrate a direct role for UCP2 in maintaining α-cell function at the level of glucose metabolism, glucagon secretion, and cytoprotection.

The Neuronal Ca2+ Sensor Protein Visinin-like Protein-1 Is Expressed in Pancreatic Islets and Regulates Insulin Secretion

Visinin-like protein-1 (VILIP-1) is a member of the neuronal Ca2+ sensor protein family that modulates Ca2+-dependent cell signaling events. VILIP-1, which is expressed primarily in the brain, increases cAMP formation in neural cells by modulating adenylyl cyclase, but its functional role in other tissues remains largely unknown. In this study, we demonstrate that VILIP-1 is expressed in murine pancreatic islets and β-cells. To gain insight into the functions of VILIP-1 in β-cells, we used both overexpression and small interfering RNA knockdown strategies. Overexpression of VILIP-1 in the MIN6β-cell line or isolated mouse islets had no effect on basal insulin secretion but significantly increased glucose-stimulated insulin secretion. cAMP accumulation was elevated in VILIP-1-overexpressing cells, and the protein kinase A inhibitor H-89 attenuated increased glucose-stimulated insulin secretion. Overexpression of VILIP-1 in isolated mouse β-cells increased cAMP content accompanied by increased cAMP-responsive element-binding protein gene expression and enhanced exocytosis as detected by cell capacitance measurements. Conversely, VILIP-1 knockdown by small interfering RNA caused a reduction in cAMP accumulation and produced a dramatic increase in preproinsulin mRNA, basal insulin secretion, and total cellular insulin content. The increase in preproinsulin mRNA in these cells was attributed to enhanced insulin gene transcription. Taken together, we have shown that VILIP-1 is expressed in pancreatic β-cells and modulates insulin secretion. Increased VILIP-1 enhanced insulin secretion in a cAMP-associated manner. Down-regulation of VILIP-1 was accompanied by decreased cAMP accumulation but increased insulin gene transcription.