David E. Kelley

Bio: David E. Kelley is an academic researcher from University of Pittsburgh. The author has contributed to research in topics: Insulin resistance & Insulin. The author has an hindex of 84, co-authored 188 publications receiving 33595 citations. Previous affiliations of David E. Kelley include University of Padua & Queen's University.

Dysfunction of Mitochondria in Human Skeletal Muscle in Type 2 Diabetes

Abstract: Skeletal muscle is strongly dependent on oxidative phosphorylation for energy production. Because the insulin resistance of skeletal muscle in type 2 diabetes and obesity entails dysregulation of the oxidation of both carbohydrate and lipid fuels, the current study was undertaken to examine the potential contribution of perturbation of mitochondrial function. Vastus lateralis muscle was obtained by percutaneous biopsy during fasting conditions from lean (n = 10) and obese (n = 10) nondiabetic volunteers and from volunteers with type 2 diabetes (n = 10). The activity of rotenone-sensitive NADH:O(2) oxidoreductase, reflecting the overall activity of the respiratory chain, was measured in a mitochondrial fraction by a novel method based on providing access for NADH to intact mitochondria via alamethicin, a channel-forming antibiotic. Creatine kinase and citrate synthase activities were measured as markers of myocyte and mitochondria content, respectively. Activity of rotenone-sensitive NADH:O(2) oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:O(2) oxidoreductase activity was lowest in type 2 diabetic subjects and highest in the lean volunteers (lean 0.95 +/- 0.17, obese 0.76 +/- 0.30, type 2 diabetes 0.56 +/- 0.14 units/mU creatine kinase; P < 0.005). Also, citrate synthase activity was reduced in type 2 diabetic patients (lean 3.10 +/- 0.74, obese 3.24 +/- 0.82, type 2 diabetes 2.48 +/- 0.47 units/mU creatine kinase; P < 0.005). As measured by electron microscopy, skeletal muscle mitochondria were smaller in type 2 diabetic and obese subjects than in muscle from lean volunteers (P < 0.01). We conclude that there is an impaired bioenergetic capacity of skeletal muscle mitochondria in type 2 diabetes, with some impairment also present in obesity.

Reduction in Weight and Cardiovascular Disease Risk Factors in Individuals With Type 2 Diabetes: One-Year Results of the Look AHEAD Trial

Abstract: Objective: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes one-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events. Research Design and Methods: A multi-centered randomized controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with body mass index >25 kg/m2 (>27 kg/m2 if taking insulin). An Intensive Lifestyle Intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared to a Diabetes Support and Education (DSE) condition. Results: Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (p Conclusions: At 1 year, ILI resulted in clinically significant weight loss in persons with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk. Trial Registration: clinicaltrials.gov Identifier: NCT00017953

Effect of laparoscopic Roux-en Y gastric bypass on type 2 diabetes mellitus.

Abstract: Since the introduction of Laparoscopic Roux-en-Y gastric bypass (LRYGBP) in the early 1990s, several investigators have demonstrated that LRYGBP is as effective as open roux-en-Y gastric bypass (RYGBP) in achieving significant long-term weight loss (60–80% percent of excess body weight loss [%EWL]) in morbidly obese patients while significantly reducing perioperative morbidity and recovery time.1–5 In 2000, our group reported (n = 275 patients) a mean excess weight loss of 77% (mean body mass index [BMI] reduced from 48 to 27 kg/m2) at 30 months and a major morbidity and mortality rate of 3.3% and 0.4%, respectively.2 Quality of life was significantly improved and all obesity comorbidities, with the exception of depression, were significantly improved or resolved. Although that study did not focus specifically on type 2 diabetes mellitus (T2DM), we did find that 82% of T2DM patients (n = 18) achieved clinical resolution (withdrawal of all antidiabetic medication) whereas the remaining 18% had significant improvement. Other investigators have also demonstrated that not only Roux-en-Y gastric bypass but other bariatric operations may result in significant clinical improvement in T2DM after weight loss.2,5–13 However, little is known concerning the effect of weight loss surgery on the degree of glycemic control that is achieved and its impact on antidiabetic medication requirement. Furthermore, factors that may be associated with postoperative resolution versus improvement in diabetes have not been fully elucidated. The goal of this study then was to evaluate the effect of LRYGBP on morbidly obese patients with T2DM and their related comorbidites and diabetes-specific complications. Our hypothesis was that LRYGBP would result in sustained weight loss that would correspond to significant improvement in glycemic control, leading to clinical resolution or improvement in T2DM and related comorbidites and complications. We specifically evaluated postoperative outcomes, including surgical complications and weight loss as well as changes in fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1C), diabetic medication requirement, and changes in comorbidity and diabetes complications.

Skeletal Muscle Lipid Content and Insulin Resistance: Evidence for a Paradox in Endurance-Trained Athletes

Abstract: We examined the hypothesis that an excess accumulation of intramuscular lipid (IMCL) is associated with insulin resistance and that this may be mediated by the oxidative capacity of muscle. Nine sedentary lean (L) and 11 obese (O) subjects, 8 obese subjects with type 2 diabetes mellitus (D), and 9 lean, exercise-trained (T) subjects volunteered for this study. Insulin sensitivity (M) determined during a hyperinsulinemic (40 mU x m(-2)min(-1)) euglycemic clamp was greater (P < 0.01) in L and T, compared with O and D (9.45 +/- 0.59 and 10.26 +/- 0.78 vs. 5.51 +/- 0.61 and 1.15 +/- 0.83 mg x min(-1)kg fat free mass(-1), respectively). IMCL in percutaneous vastus lateralis biopsy specimens by quantitative image analysis of Oil Red O staining was approximately 2-fold higher in D than in L (3.04 +/- 0.39 vs. 1.40 +/- 0.28% area as lipid; P < 0.01). IMCL was also higher in T (2.36 +/- 0.37), compared with L (P < 0.01). The oxidative capacity of muscle determined with succinate dehydrogenase staining of muscle fibers was higher in T, compared with L, O, and D (50.0 +/- 4.4, 36.1 +/- 4.4, 29.7 +/- 3.8, and 33.4 +/- 4.7 optical density units, respectively; P < 0.01). IMCL was negatively associated with M (r = -0.57, P < 0.05) when endurance-trained subjects were excluded from the analysis, and this association was independent of body mass index. However, the relationship between IMCL and M was not significant when trained individuals were included. There was a positive association between the oxidative capacity and M among nondiabetics (r = 0.37, P < 0.05). In summary, skeletal muscle of trained endurance athletes is markedly insulin sensitive and has a high oxidative capacity, despite having an elevated lipid content. In conclusion, the capacity for lipid oxidation may be an important mediator of the association between excess muscle lipid accumulation and insulin resistance.

Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss.

Abstract: The current study was undertaken to investigate fatty acid metabolism by skeletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean an...

Diagnosis and Management of the Metabolic Syndrome An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement

Abstract: The metabolic syndrome has received increased attention in the past few years. This statement from the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) is intended to provide up-to-date guidance for professionals on the diagnosis and management of the metabolic syndrome in adults. The metabolic syndrome is a constellation of interrelated risk factors of metabolic origin— metabolic risk factors —that appear to directly promote the development of atherosclerotic cardiovascular disease (ASCVD).1 Patients with the metabolic syndrome also are at increased risk for developing type 2 diabetes mellitus. Another set of conditions, the underlying risk factors , give rise to the metabolic risk factors. In the past few years, several expert groups have attempted to set forth simple diagnostic criteria to be used in clinical practice to identify patients who manifest the multiple components of the metabolic syndrome. These criteria have varied somewhat in specific elements, but in general they include a combination of both underlying and metabolic risk factors. The most widely recognized of the metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a pro-inflammatory state as well. Atherogenic dyslipidemia consists of an aggregation of lipoprotein abnormalities including elevated serum triglyceride and apolipoprotein B (apoB), increased small LDL particles, and a reduced level of HDL cholesterol (HDL-C). The metabolic syndrome is often referred to as if it were a discrete entity with a single cause. Available data suggest that it truly is a syndrome, ie, a grouping of ASCVD risk factors, but one that probably has more than one cause. Regardless of cause, the syndrome identifies individuals at an elevated risk for ASCVD. The magnitude of the increased risk can vary according to which components of the syndrome are …

Standards of Medical Care in Diabetes

Abstract: XI. STRATEGIES FOR IMPROVING DIABETES CARE D iabetes is a chronic illness that requires continuing medical care and patient self-management education to prevent acute complications and to reduce the risk of long-term complications. Diabetes care is complex and requires that many issues, beyond glycemic control, be addressed. A large body of evidence exists that supports a range of interventions to improve diabetes outcomes. These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, treatment goals, and tools to evaluate the quality of care. While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided. These standards are not intended to preclude more extensive evaluation and management of the patient by other specialists as needed. For more detailed information, refer to Bode (Ed.): Medical Management of Type 1 Diabetes (1), Burant (Ed): Medical Management of Type 2 Diabetes (2), and Klingensmith (Ed): Intensive Diabetes Management (3). The recommendations included are diagnostic and therapeutic actions that are known or believed to favorably affect health outcomes of patients with diabetes. A grading system (Table 1), developed by the American Diabetes Association (ADA) and modeled after existing methods, was utilized to clarify and codify the evidence that forms the basis for the recommendations. The level of evidence that supports each recommendation is listed after each recommendation using the letters A, B, C, or E.

Sarcopenia: European consensus on definition and diagnosis Report of the European Working Group on Sarcopenia in Older People

Abstract: The European Working Group on Sarcopenia in Older People (EWGSOP) developed a practical clinical definition and consensus diagnostic criteria for age-related sarcopenia. EWGSOP included representatives from four participant organisations, i.e. the European Geriatric Medicine Society, the European Society for Clinical Nutrition and Metabolism, the International Association of Gerontology and Geriatrics-European Region and the International Association of Nutrition and Aging. These organisations endorsed the findings in the final document. The group met and addressed the following questions, using the medical literature to build evidence-based answers: (i) What is sarcopenia? (ii) What parameters define sarcopenia? (iii) What variables reflect these parameters, and what measurement tools and cut-off points can be used? (iv) How does sarcopenia relate to cachexia, frailty and sarcopenic obesity? For the diagnosis of sarcopenia, EWGSOP recommends using the presence of both low muscle mass + low muscle function (strength or performance). EWGSOP variously applies these characteristics to further define conceptual stages as 'presarcopenia', 'sarcopenia' and 'severe sarcopenia'. EWGSOP reviewed a wide range of tools that can be used to measure the specific variables of muscle mass, muscle strength and physical performance. Our paper summarises currently available data defining sarcopenia cut-off points by age and gender; suggests an algorithm for sarcopenia case finding in older individuals based on measurements of gait speed, grip strength and muscle mass; and presents a list of suggested primary and secondary outcome domains for research. Once an operational definition of sarcopenia is adopted and included in the mainstream of comprehensive geriatric assessment, the next steps are to define the natural course of sarcopenia and to develop and define effective treatment.

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes

Abstract: DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1α and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Abstract: BACKGROUND Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. METHODS 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. FINDINGS Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). INTERPRETATION Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)