Kieren J. Mather

Improved endothelial function with metformin in type 2 diabetes mellitus.

OBJECTIVES This study was designed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus. BACKGROUND Abnormalities in vascular endothelial function are well recognized among patients with type 2 (insulin-resistant) diabetes mellitus. Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction. The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been reported. METHODS Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily (n = 29) or placebo (n = 15) for 12 weeks. Before and after treatment, blood flow responses to intraarterial administration of endothelium-dependent (acetylcholine), endothelium-independent (sodium nitroprusside) and nitrate-independent (verapamil) vasodilators were measured using forearm plethysmography. Whole-body insulin resistance was assessed on both occasions using the homeostasis model (HOMA-IR). RESULTS Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo (p = 0.0027 by 2-way analysis of variance), whereas no significant effect was seen on nitroprusside-stimulated (p = 0.27) or verapamil-stimulated (p = 0.40) flows. There was a significant improvement in insulin resistance with metformin (32.5% reduction in HOMA-IR, p = 0.01), and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment (r = -0.659, p = 0.0012). CONCLUSIONS Metformin treatment improved both insulin resistance and endothelial function, with a strong statistical link between these variables. This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus. This has important implications for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus.

Effect of regression from prediabetes to normal glucose regulation on long-term reduction in diabetes risk: results from the Diabetes Prevention Program Outcomes Study.

BACKGROUND Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) in participants who returned to normal glucose regulation at least once during the Diabetes Prevention Program (DPP) compared with those who consistently met criteria for prediabetes. METHODS DPPOS is an ongoing observational study of participants from the DPP randomised trial. For this analysis, diabetes cumulative incidence in DPPOS was calculated for participants with normal glucose regulation or prediabetes status during DPP with and without stratification by previous randomised treatment group. Cox proportional hazards modelling and generalised linear mixed models were used to quantify the effect of previous (DPP) glycaemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per SD in change. Included in this analysis were 1990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo). These studies are registered at ClinicalTrials.gov, NCT00004992 (DPP) and NCT00038727 (DPPOS). FINDINGS Diabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0·44, 95% CI 0·37-0·55, p<0·0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p=0·1722; normal glucose regulation and metformin, p=0·3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of a participant reaching normal glucose regulation status in DPPOS. Specifically, previous achievement of normal glucose regulation (odds ratio [OR] 3·18, 95% CI 2·71-3·72, p<0·0001), increased β-cell function (OR 1·28; 95% CI 1·18-1·39, p<0·0001), and insulin sensitivity (OR 1·16, 95% CI 1·08-1·25, p<0·0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased β-cell function (HR 0·80, 95% CI 0·71-0·89, p<0·0001) and insulin sensitivity (HR 0·83, 95% CI 0·74-0·94, p=0·0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1·31, 95% CI 1·03-1·68, p=0·0304) and lower chance of normal glucose regulation (OR 0·59, 95% CI 0·42-0·82, p=0·0014) than did the placebo group in DPPOS. INTERPRETATION We conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention. Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes independent of previous treatment group. FUNDING US National Institutes of Health.

Obesity, Insulin Resistance, and the Metabolic Syndrome Determinants of Endothelial Dysfunction in Whites and Blacks

Background—Insulin resistance is strongly associated with obesity and other components of the metabolic syndrome (MS). The relative importance of these components in the determination of endothelial function is unknown. Furthermore, there is conflicting evidence about whether ethnic differences exist in the relative importance of these components in regard to other cardiovascular outcomes. We evaluated the contributions of insulin resistance, obesity, and the other components of the MS to impaired endothelial function. Methods and Results—The relationships of the MS components (as defined according the National Cholesterol Education Program) and insulin resistance (estimated using the homeostasis model) with endothelium-dependent vasodilation were examined in 42 white and 55 black subjects. Endothelium-dependent vasodilation was assessed as the increment in leg blood flow (measured by thermodilution) after exposure to methacholine chloride. Waist circumference, glucose, blood pressure, and insulin resistance distributions did not differ between ethnic groups; blacks in our sample had higher HDL cholesterol (1.31 versus 1.09 mmol/L; P<0.001) and lower triglyceride levels (1.01 versus 1.37 mmol/L; P=0.005) than white subjects. In the absence of the MS, black subjects exhibited reduced endothelium-dependent vasodilation compared with white subjects (P=0.005), and both groups demonstrated significantly worse endothelial function when the MS was present (maximal increase in leg blood flow: blacks: 107±9% MS absent, 53±16% MS present; whites: 163±16% MS absent, 54±18% MS absent; P=0.007, MS absent versus present; P=NS for interaction of ethnicity and MS). Multivariable regression analysis examining relationships of endothelial function with the 5 MS components (analyzed as continuous variables) revealed independent relationships only with waist circumference (P=0.01) and systolic blood pressure (P=0.02). Waist circumference was no longer independently associated after adding insulin resistance to the modeling (P=0.02 for log of homeostasis model index of insulin resistance, P=0.02 for systolic blood pressure). Ethnicity still exerted an independent effect on endothelial function after accounting for the above components (P=0.04 for an additional effect of ethnic status on endothelial function), with an ethnic difference in the effect of insulin resistance on endothelial function (P=0.046 for interaction of ethnicity and log of homeostasis model index of insulin resistance). Conclusions—These findings suggest that insulin resistance and systolic blood pressure are the principal determinants of endothelial dysfunction in the MS and that there are ethnic differences in the relative importance of these factors. These differences may imply different benefits from treatments targeting blood pressure or insulin resistance in different ethnic groups.

β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment

OBJECTIVE This article examines the foundation of β-cell failure in type 2 diabetes (T2D) and suggests areas for future research on the underlying mechanisms that may lead to improved prevention and treatment. RESEARCH DESIGN AND METHODS A group of experts participated in a conference on 14–16 October 2013 cosponsored by the Endocrine Society and the American Diabetes Association. A writing group prepared this summary and recommendations. RESULTS The writing group based this article on conference presentations, discussion, and debate. Topics covered include genetic predisposition, foundations of β-cell failure, natural history of β-cell failure, and impact of therapeutic interventions. CONCLUSIONS β-Cell failure is central to the development and progression of T2D. It antedates and predicts diabetes onset and progression, is in part genetically determined, and often can be identified with accuracy even though current tests are cumbersome and not well standardized. Multiple pathways underlie decreased β-cell function and mass, some of which may be shared and may also be a consequence of processes that initially caused dysfunction. Goals for future research include to 1) impact the natural history of β-cell failure; 2) identify and characterize genetic loci for T2D; 3) target β-cell signaling, metabolic, and genetic pathways to improve function/mass; 4) develop alternative sources of β-cells for cell-based therapy; 5) focus on metabolic environment to provide indirect benefit to β-cells; 6) improve understanding of the physiology of responses to bypass surgery; and 7) identify circulating factors and neuronal circuits underlying the axis of communication between the brain and β-cells.

Hyperinsulinemia in polycystic ovary syndrome correlates with increased cardiovascular risk independent of obesity

OBJECTIVE To assess the role of insulin resistance, independent of obesity, in determining cardiovascular risk among women with the polycystic ovarian syndrome (PCOS). DESIGN Cross-sectional study examining the relationships between hyperinsulinemia, composite cardiovascular risk scores, and prevalence of individual risk factors among lean and obese women with PCOS and healthy controls. SETTING University-based tertiary care outpatient endocrinology clinic. PATIENT(S) 57 women with clinically defined PCOS and 45 unselected healthy age-matched controls. INTERVENTION(S) Clinical and anthropomorphic measurements and laboratory determinations of insulin and lipid levels. MAIN OUTCOME MEASURE(S) Fasting serum insulin and a cardiovascular risk score. RESULTS Hyperinsulinemic women with PCOS carried more cardiovascular risk than their normoinsulinemic counterparts, who in turn had more risk than the control women (P=.004 by analysis of covariance). In addition to the lipid changes expected with insulin resistance (high triglyceride and low HDL cholesterol levels), there was an excess of LDL cholesterol among the women with PCOS (P=.006 by analysis of covariance). Across the range of body mass index, women with PCOS had greater insulin resistance than controls, suggesting that PCOS itself and body mass index both contribute to the observed insulin resistance. CONCLUSIONS Our data support the hypothesis that insulin resistance in PCOS is a determinant of overall cardiovascular risk independent of obesity. The mechanism of this relationship remains uncertain and is the subject of ongoing research.

Adiponectin, change in adiponectin, and progression to diabetes in the diabetes prevention program

OBJECTIVE— To determine whether baseline adiponectin levels or intervention-associated change in adiponectin levels were independently associated with progression to diabetes in the Diabetes Prevention Program (DPP). RESEARCH DESIGN AND METHODS— Cox proportional hazards analysis was used to evaluate the contribution of adiponectin and treatment-related change in adiponectin to risk of progression to diabetes. RESULTS— Baseline adiponectin was a strong independent predictor of incident diabetes in all treatment groups (hazard ratio per ∼3 μg/ml higher level; 0.61 in the lifestyle, 0.76 in the metformin, and the 0.79 in placebo groups; all P < 0.001, P = 0.13 comparing groups). Baseline differences in adiponectin between sexes and race/ethnicity groups were not reflected in differences in diabetes risk. DPP interventions increased adiponectin levels ([means ± SE] 0.83 ± 0.05 μg/ml in the lifestyle group, 0.23 ± 0.05 μg/ml in the metformin group, and 0.10 ± 0.05 μg/ml in the placebo group; P < 0.001 for increases versus baseline, P < 0.01 comparing groups). These increases were associated with reductions in diabetes incidence independent of baseline adiponectin levels in the lifestyle and placebo groups but not in the metformin subjects (hazard ratio 0.72 in the lifestyle group (P < 0.001), 0.92 in the metformin group (P = 0.18), and 0.89 in the placebo group; P = 0.02 per ∼1 μg/ml increase, P = 0.02 comparing groups). In the lifestyle group, adjusting for change in weight reduced, but did not remove, the effect of increased adiponectin. CONCLUSIONS— Adiponectin is a powerful marker of diabetes risk in subjects at high risk for diabetes, even after adjustment for weight. An increase in adiponectin in the lifestyle and placebo groups was associated with a reduction in diabetes risk. However, these changes in adiponectin were comparatively small and less strongly related to diabetes outcome than baseline adiponectin levels.

Insulin Action in the Vasculature: Physiology and Pathophysiology

Studies to date have provided convincing evidence that insulin has an important role in the normal functioning of the vasculature from the perspective of the regulated delivery of nutrients to a tissue bed. This is mediated by an effect on the endothelium analogous to other endothelial responses, and insulin resistance is reflected in, and in part due to, impaired vasodilatory actions of insulin. Because insulin normally stimulates the net production of nitric oxide, which is beneficial in both the short term for vasomotion and antithrombosis, and the long term for inhibition of smooth muscle cell growth and migration, vascular insulin resistance also has important implications for vascular pathophysiology. Further, recent evidence suggests that the hyperinsulinemia accompanying insulin resistance may aggravate this situation by augmenting the endothelial production and release of endothelin-1. The investigation of insulin resistance in the vasculature provides not only a unique and physiologically relevant window onto vascular pathology, but also an opportunity for therapeutic targeting in individuals affected by the clinical states of insulin resistance. The present review highlights the importance of insulin sensitivity in the maintenance of endothelial function and explores the relationships between vascular insulin resistance and whole body glucose disposal. In addition, the recent evidence linking insulin to endothelin-1 production is discussed. Improving insulin sensitivity with insulin sensitizers such as rosiglitazone may represent an important advance in our ability to improve vascular dysfunction in diabetes.

Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study.

Diabet. Med. 30, 46–55 (2013)

Effects of Resistance Training on Adiposity and Metabolism after Spinal Cord Injury

PURPOSE This pilot work was conducted to evaluate the effects of neuromuscular electrical stimulation resistance training (RT) of the paralyzed knee extensor muscle groups on skeletal muscle and intramuscular fat (IMF) cross-sectional areas, trunk visceral adipose tissue (VAT), carbohydrate, and lipid profiles in men with spinal cord injury. METHODS Nine individuals with motor complete spinal cord injury were randomly assigned to an RT + diet group (n = 5) or a diet group (n = 4). The RT + diet underwent 12 wk of progressive RT, twice weekly, to the knee extensor muscle groups using neuromuscular electrical stimulation and ankle weights. Weekly feedback was provided to both groups to maintain a standard diet. Magnetic resonance imaging and a whole-body dual-energy x-ray absorptiometric images were obtained before and 1 wk after interventions. Participants underwent a metabolic study after a 12-h overnight fast to measure fasting and postchallenge plasma glucose, insulin, and lipid profiles. RESULTS Skeletal muscle hypertrophy was detected in the whole thigh, knee extensors, and flexors in the RT + diet group compared with the diet group. VAT cross-sectional area, VAT/subcutaneous adipose tissue ratio at L5-S3, and percent IMF decreased significantly in the RT + diet group. Plasma insulin area under the curve decreased in the RT + diet group but not in the diet group. Fasting triglycerides and cholesterol/HDL decreased in the RT + diet group. CONCLUSIONS Twice-weekly evoked RT to the paralyzed lower extremities resulted in significant skeletal muscle hypertrophy that was associated with reduction in VAT, VAT/subcutaneous adipose tissue ratio, and percent IMF. Significant improvements in insulin profile and lipid metabolism were noted in the RT + diet when compared with diet alone.

Mechanotransduction of shear in the endothelium: basic studies and clinical implications.

The endothelium plays an integral role in the development and progression of atherosclerosis. Hemodynamic forces, particularly shear stress, have a powerful influence on endothelial phenotype and function; however, there is no clear consensus on how endothelial cells sense shear. Nevertheless, multiple endothelial cell signal transduction pathways are activated when exposed to shear stress in vitro. The type of shear, laminar or oscillatory, impacts which signal transduction pathways are initiated as well as which subsequent genes are up- or down-regulated, thereby influencing endothelial phenotype and function. Recently, human studies have examined the impact of shear stress and different shear patterns at rest and during exercise on endothelial function. Current evidence supports the theory that augmented exercise-induced shear stress contributes to improved endothelial function following acute exercise and exercise training, whereas retrograde shear initiates vascular dysfunction. The purpose of this review is to examine the current theories on how endothelial cells sense shear stress, to provide an overview on shear stress-induced signal transduction pathways and subsequent gene expression, and to review the current literature pertaining to shear stress and shear patterns at rest as well as during exercise in humans and the related effects on endothelial function.