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Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([[sup.15]O][H.sub.2]O, [[sup.11]C]3-O-methylglucose [3-OMG], and [[sup.18]F]fluorodeoxyglucose [FDG]) to quantify, respectively, skeletal muscle tissue perfusion (glucose delivery), kinetics of bidirectional glucose transport, and glucose phosphorylation to interrogate the individual contribution and interaction among these steps in muscle insulin resistance (IR) in type 2 diabetes (T2D). PET imaging was performed in normal weight nondiabetic subjects (NW) (n = 5), obese nondiabetic subjects (OB) (n = 6), and obese subjects with T2D (n = 7) during fasting conditions and separately during a 6-h euglycemic insulin infusion at 40 mU x [m.sup.-2] x [m.sup.-1]. Tissue tracer activities were derived specifically within the soleus muscle with PET images and magnetic resonance imaging. During fasting, NW, OB, and T2D subjects had similar [[sup.11]C]3-OMG and [[sup.18]F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [[sup.18]F]FDG uptake by muscle was inversely correlated with systemic IR (P < 0.001). The increase in insulin-stimulated glucose transport was less (P < 0.01) in T2D (twofold) than in NW (sevenfold) or OB (sixfold) subjects. The fractional phosphorylation of [[sup.18]F]FDG during insulin infusion was also significantly lower in T2D (P < 0.01). Dynamic triple-tracer PET imaging indicates that skeletal muscle IR in T2D involves a severe impairment of glucose transport and additional impairment in the efficiency of glucose phosphorylation. Diabetes 2014;63:1058-1068 | DOI: 10.2337/DB13-1249, The rate of glucose uptake into skeletal muscle during insulin-stimulated conditions is a strong determinant of systemic insulin sensitivity (and insulin resistance [IR]). Much of the control of glucose uptake [...]

OBJECTIVE--To characterize the relationships among long-term improvements in peripheral insulin sensitivity (glucose disposal rate [GDR]), fasting glucose, and free fatty acids (FFAs) and concomitant changes in weight and adipose tissue mass and distribution induced by lifestyle intervention in obese individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS--We measured GDR, fasting glucose, and FFAs during a euglycemic clamp and adipose tissue mass and distribution, organ fat, and adipocyte size by dual-energy X-ray absorptiometry, CT scan, and adipose tissue biopsy in 26 men and 32 women in the Look-AHEAD trial before and after 1 year of diet and exercise aimed at weight loss. RESULTS--Weight and fasting glucose decreased significantly (P < 0.0001) and significantly more in men than in women (-12 vs. -8% and -16 vs. -7%, respectively; P < 0.05), while FFAs during hyperinsulinemia decreased and GDR increased significantly (P < 0.00001) and similarly in both sexes (-53 vs. -41% and 63 vs. 43%; P = NS). Men achieved a more favorable fat distribution by losing more from upper compared with lower and from deeper compared with superficial adipose tissue depots (P < 0.01). Decreases in weight and adipose tissue mass predicted improvements in GDR but not in fasting glucose or fasting FFAs; however, decreases in FFAs during hyperinsulinemia significantly determined GDR improvements. Hepatic fat was the only regional fat measure whose change contributed independently to changes in metabolic variables. CONCLUSIONS--Patients with type 2 diabetes undergoing a 1-year lifestyle intervention had significant improvements in GDR, fasting glucose, FFAs and adipose tissue distribution. However, changes in overall weight (adipose tissue mass) and hepatic fat were the most important determinants of metabolic improvements. Diabetes 59:627-633, 2010, Most obese patients with type 2 diabetes have an unfavorable adipose tissue distribution compared with that of similarly obese men and women without type 2 diabetes (1-2). We have shown [...]

Background: The extent to which adipose tissue (AT) distribution is different between persons with type 2 diabetes (T2DM) and nondiabetic control subjects remains unclear. Objective: The aim of this study was to establish whether total body adiposity and its distribution, quantified by using state-of-the-art whole-body magnetic resonance imaging, differs between these 2 groups. Design: This cross-sectional evaluation included 93 participants (n = 56 women and 37 men) in the Look AHEAD (Action for HEAlth in Diabetes) Trial with T2DM who had a mean ([+ or -] SD) age of 58.3 [+ or -] 6.6 y and body mass index (in kg/[m.sup.2]) of 31.6 [+ or -] 3.1 and 93 healthy non-T2DM control subjects (n = 64 women and 29 men) who had a mean ([+ or -]SD) age of 60.6 [+ or -] 17.1 y and body mass index of 29.6 [+ or -] 3.0. All participants self-reported being of African American or white ancestry. Magnetic resonance imaging-derived in vivo measures of total-body AT (TAT) and its distribution, subcutaneous AT (SAT), visceral AT (VAT), and intermuscular AT (IMAT) were acquired. Linear regression models were developed for each AT compartment to adjust for important covariates of race, sex, age, height, and weight and to examine potential interactions of covariates. Results: These models showed significantly less SAT (African American: -1.2 kg; white: -2.4 kg; both P = 0.001), including less femoral-gluteal SAT, more VAT (African American: 0.7 kg, P < 0.001; white: 1.8 kg, P = 0.007), and more IMAT (0.5 kg, P = 0.001) in the T2DM group. Conclusion: We concluded that AT distribution is significantly altered in T2DM, ie, more VAT and IMAT--2 depots known to exacerbate insulin resistance--and less SAT in persons with T2DM than in healthy control subjects, a novel finding that we posit may compound the risk of insulin resistance.

OBJECTIVE--In obesity and type 2 diabetes, exercise combined with weight loss increases skeletal muscle mitochondrial capacity. It remains unclear whether mitochondrial capacity increases because of weight loss, improvements in insulin resistance, or physical training. In this study, we examined the effects of an intervention of weight loss induced by diet and compared these with those of a similar intervention of weight loss by diet with exercise. Both are known to improve insulin resistance, and we tested the hypothesis that physical activity, rather than improved insulin resistance, is required to increase mitochondrial capacity of muscle. RESEARCH DESIGN AND METHODS--Sixteen sedentary overweight/obese volunteers were randomized to a 16-week intervention of diet (n = 7) or diet plus exercise (n = 9). Insulin sensitivity was measured using euglycemic clamps. Mitochondria were examined in muscle biopsies before and after intervention. We measured mitochondrial content and size by electron microscopy, electron transport chain (ETC) activity, cardiolipin content, and mitochondrial DNA content. Intramyocellular content of lipid (IMCL) and fiber-type distribution were determined by histology. RESULTS--The diet-only and diet plus exercise groups achieved similar weight loss (10.8 and 9.2%, respectively); only the diet plus exercise group improved aerobic capacity. Insulin sensitivity improved similarly in both groups. Mitochondrial content and ETC activity increased following the diet plus exercise intervention but remained unchanged following the diet-only intervention, and mitochondrial size decreased with weight loss despite improvement in insulin resistance. IMCL decreased in the diet-only but not in the diet plus exercise intervention. CONCLUSIONS--Despite similar effects to improve insulin resistance, these interventions had differential effects on mitochondria. Clinically significant weight loss in the absence of increased physical activity ameliorates insulin resistance and IMCL but does not increase muscle mitochondrial capacity in obesity., Mitochondrial oxidative capacity is decreased in skeletal muscle of obese individuals and is correlated with insulin resistance (1). It remains unclear, however, whether reduced mitochondrial capacity in skeletal muscle is [...]

OBJECTIVE--Compared with nondiabetic subjects, type 2 diabetic subjects are metabolically inflexible with impaired fasting fat oxidation and impaired carbohydrate oxidation during a hyperinsulinemic clamp. We hypothesized that impaired insulin-stimulated glucose oxidation is a consequence of the lower cellular glucose uptake rate in type 2 diabetes. Therefore, we compared metabolic flexibility to glucose adjusted for glucose disposal rate in nondiabetic versus type 2 diabetic subjects and in the latter group after 1 year of lifestyle intervention (the Look AHEAD [Action For Health in Diabetes] trial). RESEARCH DESIGN AND METHODS--Macronutrient oxidation rates under fasting and hyperinsulinemic conditions (clamp at 80 mU/[m.sup.2] per min), body composition (dual-energy X-ray absorptiometry), and relevant hormonal/metabolic blood variables were assessed in 59 type 2 diabetic and 42 nondiabetic individuals matched for obesity, sex, and race. Measures were repeated in diabetic participants after weight loss. RESULTS--Metabolic flexibility to glucose (change in respiratory quotient [RQ]) was mainly related to insulin-stimulated glucose disposal rate ([R.sup.2] = 0.46, P < 0.0001) with an additional 3% of variance accounted for by plasma free fatty acid concentration at the end of the clamp (P = 0.03). The impaired metabolic flexibility to glucose observed in type 2 diabetic versus nondiabetic subjects (ΔRQ 0.06 ± 0.01 vs. 0.10 ± 0.01, respectively, P < 0.0001) was no longer observed after adjusting for glucose disposal rate (P = 0.19). Additionally, the increase in metabolic flexibility to glucose after weight loss was accounted for by the concomitant increase in insulin-stimulated glucose disposal rate. CONCLUSIONS--This study suggests that metabolic inflexibility to glucose in type 2 diabetic subjects is mostly related to defective glucose transport., Metabolic flexibility is the capacity of the body to match fuel oxidation to fuel availability. It is typically assessed by the increase in respiratory quotient (RQ) from fasting to glucose/ [...]

OBJECTIVE--Reduced mitochondrial capacity in skeletal muscle occurs in type 2 diabetic patients and in those at increased risk for this disorder, but the extent to which mitochondrial dysfunction in type 2 diabetic patients is remediable by physical activity and weight loss intervention is uncertain. We sought to address whether an intervention of daily moderate-intensity exercise combined with moderate weight loss can increase skeletal muscle mitochondrial content in type 2 diabetic patients and to address the relationship with amelioration of insulin resistance and hyperglycemia. RESEARCH DESIGN AND METHODS--Muscle biopsies were obtained before and after a 4-month intervention to assess mitochondrial morphology, mitochondrial DNA content, and mitochondrial enzyme activities. Glucose control, body composition, aerobic fitness, and insulin sensitivity were measured. RESULTS--In response to a weight loss of 7.1 ± 0.8% and a 12 ± 1.6% improvement in V[O.sub.2max] (P < 0.05), insulin sensitivity improved by 59 ± 21% (P < 0.05). There were significant increases in skeletal muscle mitochondrial density (by 67 ± 17%, P < 0.01), cardiolipin content (55 ± 17%, P < 0.01), and mitochondrial oxidation enzymes. Energy expenditure during physical activity correlated with the degree of improvement in insulin sensitivity (r = 0.84, P < 0.01), and, in turn, improvement in mitochondrial content was a strong correlate of intervention-induced improvement in AIC and fasting plasma glucose. CONCLUSIONS--Intensive short-term lifestyle modifications can restore mitochondrial content and functional capacity in skeletal muscle in type 2 diabetic patients. The improvement in the oxidative capacity of skeletal muscle may be a key component mediating salutary effects of lifestyle interventions on hyperglycemia and insulin resistance., The prevalence of type 2 diabetes continues to increase, and a sedentary lifestyle and obesity are recognized as key risk factors (1,2). Obesity and sedentary habits exacerbate insulin resistance in [...]

Obesity is an important risk factor for cardiometabolic diseases, including diabetes, hypertension, dyslipidemia, and coronary heart disease (CHD). Several leading national and international institutions, including the World Health Organization (WHO) [...]

Interleukin (IL)-6 is a pleiotropic hormone that has both proinflammatory and anti-inflammatory actions. AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that among its other actions responds to decreases in cellular energy state by enhancing processes that generate ATP and inhibiting others that consume ATP but are not acutely necessary for survival. IL-6 is synthesized and released from skeletal muscle in large amounts during exercise, and in rodents, the resultant increase in its concentration correlates temporally with increases in AMPK activity in multiple tissues. That IL-6 may be responsible in great measure for these increases in AMPK is suggested by the fact it increases AMPK activity both in muscle and adipose tissue in vivo and in incubated muscles and cultured adipocytes. In addition, we have found that AMPK activity is diminished in muscle and adipose tissue of 3-month-old IL-6 knockout (KO) mice at rest and that the absolute increases in AMPK activity in these tissues caused by exercise is diminished compared with control mice. Except for an impaired ability to exercise and to oxidize fatty acids, the IL-6 KO mouse appears normal at 3 months of age. On the other hand, by age 9 months, it manifests many of the abnormalities of the metabolic syndrome including obesity, dyslipidemia, and impaired glucose tolerance. This, plus the association of decreased AMPK activity with similar abnormalities in a number of other rodents, suggests that a decrease in AMPK activity may be a causal factor. Whether increases in IL-6, by virtue of their effects on AMPK, contribute to the reported ability of exercise to diminish the prevalence of type 2 diabetes, coronary heart disease, and other disorders associated with the metabolic syndrome remains to be determined., Interleukin (IL)-6 is 'a pleiotropic cytokine with a wide range of biological activities including immune regulation, hematopoiesis, inflammation, and oncogenesis' (1). It was initially viewed as a proinflammatory cytokine and [...]

Skeletal muscle accounts for a large proportion of insulin-stimulated glucose utilization. It is generally regarded that much of the control over rates of uptake is posited within the proximal steps of delivery, transport, and phosphorylation of glucose, with glucose transport as the main locus of control. Whether insulin modulates the distribution of control across these steps and in what manner remains uncertain. The current study addressed this in vivo using dynamic positron emission tomography (PET) imaging of human muscle with sequential injections of three tracers ([[sup.15]O][H.sub.2]O, [[sup.11]C]3-O-methyl glucose [3-OMG], and [[sup.18]F]fluoro-deoxy glucose [FDG]) that enabled quantitative determinations of glucose delivery, transport, and its phosphorylation, respectively. Lean, healthy, research volunteers were studied during fasting conditions (n = 8) or during a euglycemic insulin infusion at 30 mU/min per [m.sup.2] (n = 8). PET images were coregistered with magnetic resonance imaging to contrast glucose kinetics in soleus, a highly oxidative muscle, with tibialis anterior, a less oxidative muscle. During fasting conditions, uptake of [[sup.11]C]3-OMG was similar in soleus and tibialis anterior muscles, despite higher delivery to soleus (by 35%; P < 0.01). Uptake of [[sup.18]F]FDG was also similar between muscle during fasting, and glucose transport was found to be the dominant locus of control (90%) for glucose uptake under this condition. Insulin increased uptake of [[sup.11]C]3-OMG substantially and strongly stimulated the kinetics of bidirectional glucose transport. Uptake of [[sup.11]C]3-OMG was higher in soleus than tibialis anterior muscle (by 22%; P < 0.01), a difference partially due to higher delivery, which was again found to be 35% higher to soleus (P < 0.01). The uptake of [[sup.18]F]FDG was 65% greater in soleus compared with tibialis anterior muscle, a larger difference than for [[sup.11]C]3-OMG (P < 0.01), indicating an added importance of glucose phosphorylation in defining insulin sensitivity. Analysis of the distribution of control during insulin-stimulated conditions revealed that most of the control was posited at delivery and transport and was equally divided between these steps. Thus, insulin evokes a broader distribution of control than during fasting conditions in governing glucose uptake into skeletal muscle. This redistribution of control is triggered by the robust stimulation of glucose transport, which in turn unmasks a greater dependence upon delivery and glucose phosphorylation. Diabetes 55:3028-3037, 2006, Insulin accelerates the clearance of glucose from plasma into tissues. Uptake of glucose into skeletal muscle is a powerful determinant of this systemic effect (1,2). It is generally considered that [...]

OBJECTIVE--There is increased stiffness of the large central arteries in type 2 diabetic patients, and obesity is a risk factor. However, the effect of intentional weight loss on arterial stiffness [...]

OBJECTIVE--The objective of this study was to examine the associations between the severity of hepatic steatosis and dyslipidemia in type 2 diabetes, including circulating apolipoprotein B100 (apoB) concentrations and lipoprotein [...]

The current study addresses a novel hypothesis of subcellular distribution of mitochondrial dysfunction in skeletal muscle in type 2 diabetes. Vastus lateralis muscle was obtained by percutaneous biopsy from 11 volunteers with type 2 diabetes; 12 age-, sex-, and weight-matched obese sedentary nondiabetic volunteers; and 8 lean volunteers. Subsarcolemmal and intermyofibrillar mitochondrial fractions were isolated by differential centrifugation and digestion techniques. Overall electron transport chain activity was similar in type 2 diabetic and obese subjects, but subsarcolemmal mitochondria electron transport chain activity was reduced in type 2 diabetic subjects (0.017 [+ or -] 0.003 vs. 0.034 [+ or -] 0.007 units/mU creatine kinase [CK], P = 0.01) and sevenfold reduced compared with lean subjects (P < 0.01). Electron transport chain activity in intermyofibrillar mitochondria was similar in type 2 diabetic and obese subjects, though reduced compared with lean subjects. A reduction in subsarcolemmal mitochondria was confirmed by transmission electron microscopy. Although mtDNA was lower in type 2 diabetic and obese subjects, the decrement in electron transport chain activity was proportionately greater, indicating functional impairment. Because of the potential importance of subsarcolemmal mitochondria for signal transduction and substrate transport, this deficit may contribute to the pathogenesis of muscle insulin resistance in type 2 diabetes., Skeletal muscle has a high reliance on oxidative phosphorylation. Distribution of energy within myocytes is served not only by the ATP-phosphocreatine shuttle but also by subcellular compartmentalization of mitochondria in [...]

Background: Skeletal muscle lipid is associated with obesity and type 2 diabetes and may be altered by diet, physical activity, and weight loss. Objective: We explored the utility of magnetic resonance imaging (MRI) for quantifying the lipid concentration of muscle tissue in vivo. Design: Fat-selective MR images of the lower leg were taken in 8 normal-weight [body mass index (in kg/[m.sup.2]) [less than or equal to] 24.9] and 8 obese (body mass index > 29.9) subjects to obtain spatial maps of lipid signal intensity within muscle tissue. Fast-spiral-sequence (echo time = 5.6-13.8 ms, repetition time = 1 s, 8 interleaves) MRI scans were conducted at 3.0 T by using an extremity transmit-receive coil. Lipid concentrations within muscle were determined from manually drawn regions of interest in the tibialis anterior (TA), soleus, and medial head of the gastrocnemius (MHG) muscle groups. Results: There was extremely good agreement (mean [R.sup.2] = 0.985) between the fat signal intensity and the actual lipid concentration of standards containing 2.5, 5.0, and 10.0 g lipid/dL, which were placed on the subject's leg during each scan. The lipid content of both the soleus (2.99 [+ or -] 0.37 g/dL) and the MHG (3.80 [+ or -] 0.68 g/dL) was higher (P < 0.05) than that of the TA (1.83 [+ or -] 0.28 g/dL). Lipid content was more than two-fold higher (P < 0.05) in the MHG of obese subjects (5.48 [+ or -] 1.18 g/dL) than in the MHG of normal-weight subjects (2.54 [+ or -] 0.47 g/dL), but did not differ significantly in the TA or soleus. Conclusions: MRI can be used to quantify lipid within human muscle tissue. MRI can also be used to detect differences in muscle lipid content among various muscle groups and between normal-weight and obese subjects. KEY WORDS Skeletal muscle, triacylglycerol, obesity, body fat, magnetic resonance imaging

OBJECTIVE--Moderate weight loss is recommended for overweight and obese patients with type 2 diabetes, and conjunctive use of weight loss medication has been advocated. The current study examined weight loss-dependent [...]

Nutritional recommendations, long recognized as an important aspect of diabetes mellitus treatment, have also been an area of persistent controversy, particularly regarding the proportions and types of carbohydrate and fat. This review addresses the role of sugars within medical nutrition therapy for diabetes mellitus. Nutritional recommendations for diabetes mellitus treatment were revised recently. The new guidelines do not specifically restrict intake of sugars, although general recommendations are made for including fiber, whole grains, vegetables, and fruits within dietary selections containing starches. For carbohydrates, the principle focus is on overall caloric amounts. In type 1 diabetes the most effective approach to the control of postprandial hyperglycemia continues to be adjustment of premeal doses of insulin on the basis of carbohydrate counting. In type 2 diabetes, in addition to a focus on caloric content of carbohydrate, consideration continues to be given to the role of the glycemic index as a determinant of postprandial hyperglycemia and overall metabolic control. Nevertheless, consensus recommendations do not support widespread use of the glycemic index. An area of some change is a more clear endorsement of including monounsaturated fatty acids. Current recommendations are that monounsaturated fatty acids and carbohydrates combined should provide 60-70% of daily energy intake, with individual flexibility in the respective proportions, whereas intake of saturated fats is limited to < 10% of energy intake. This new emphasis reflects greater awareness of the importance of responding to individual and cultural dietary preferences and the need to address treatment of both hyperglycemia and dyslipidemia in diabetes mellitus. KEY WORDS Diabetes mellitus, nutrition, diet, sugars, starch, glycemic index

Skeletal muscle insulin resistance entails dysregulation of both glucose and fatty acid metabolism. This study examined whether a combined intervention of physical activity and weight loss influences fasting rates of fat oxidation and insulin-stimulated glucose disposal. Obese (BMI >30 kg/[m.sup.2]) volunteers (9 men and 16 women) without diabetes, aged 39 ± 4 years, completed 16 weeks of moderate-intensity physical activity combined with caloric reduction. Body composition was determined by dual-energy X-ray absorptiometry and computed tomography. Glucose disposal rates ([R.sub.d]) were measured during euglycemic hyperinsulinemia (40 mU * [m.sup.-2] * [min.sup.-1]), and substrate oxidation was determined via indirect calorimetry. Fat mass and regional fat depots were reduced and V[O.sub.2max] improved by 19%, from 38.8 ± 1.2 to 46.0 ± 1.0 ml * kg fat-free mass [(FFM).sup.-1] * [min.sup.-1] (P < 0.05). Insulin sensitivity improved 49 ± 10% (6.70 ± 0.40 to 9.51 ± 0.51 mg * [min.sup.-1] * kg FF[M.sup.-1]; p < 0.05). Rates of fat oxidation following an overnight fast increased (1.16 ± 0.06 to 1.36 ± 0.05 mg * [min.sup.-1] * kg FF[M.sup.-1]; P < 0.05), and the proportion of energy derived from fat increased from 38 to 52%. The strongest predictor of the improved insulin sensitivity was enhanced fasting rates of fat oxidation, accounting for 52% of the variance. In conclusion, exercise combined with weight loss enhances postabsorptive fat oxidation, which appears to be a key aspect of the improvement in insulin sensitivity in obesity., Obesity and physical inactivity are risk factors for the development of type 2 diabetes and other aspects of the metabolic syndrome and are attributed to insulin resistance (1-5). Currently, it [...]

We tested the hypothesis that weight loss alleviates insulin resistance in skeletal muscle within the proximal steps of glucose metabolism, namely substrate delivery, glucose transport, and glucose phosphorylation. In obese subjects with and without type 2 diabetes, in vivo skeletal muscle assessments were obtained with dynamic positron emission tomography (PET) imaging performed during euglycemic clamps at moderate hyperinsulinemia (40 mU * [min.sup.-1] * [m.sup.-2]), using [sup.15]O][H.sub.2]O and [[sup.18]F]fluoro-deoxyglucose ([[sup.18]F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [[sup.18]F]FDG PET data were analyzed using both a novel muscle-specific compartmental model and a compartmental model originally developed for the brain and often used for [[sup.18]F]FDG muscle image quantification. Weight loss in obese subjects with (n = 9) and without (n = 9) type 2 diabetes over a 4-month intervention was substantial (14 [+ or -] 2 kg, P < 0.05). Muscle insulin resistance, assessed by insulin-stimulated [[sup.18]F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [[sup.18]F]FDG transport and phosphorylation improved substantially in both groups, whereas tissue blood flow did not change. In particular, clinically significant weight loss fully corrected insulin resistance in type 2 diabetes at the step of glucose phosphorylation and largely, but incompletely, corrected insulin resistance at the glucose transport step., Obesity induces insulin resistance in skeletal muscle, and insulin resistance is severe in obesity complicated by type 2 diabetes (1-4). Weight loss has long been the cornerstone of therapy for [...]

OBJECTIVE -- We examined whether regional adipose tissue distribution, specifically that of skeletal muscle fat and Visceral abdominal fat aggregation, is characteristic of elderly individuals with hyperinsulinemia, type 2 diabetes, [...]

There is no optimal method to measure insulin resistance or insulin secretion in large clinical studies or in clinical practice. The convenient methods that have been proposed as suitable for [...]

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.sub.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.sub.2] oxidoreductase was normalized to creatine kinase activity, as was citrate synthase activity. NADH:[O.sub.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., Metabolism of both glucose and fatty acids by skeletal muscle is impaired in type 2 diabetes (1,2). The manifestations of insulin-resistant glucose metabolism include reduced glucose transport and phosphorylation and [...]

OBJECTIVE -- Weight loss improves glycemic control, lipid profiles, and blood pressure in patients with type 2 diabetes. However, successful long-term weight loss is difficult for these patients, particularly those [...]

It has been postulated that glucose transport is the principal site of skeletal muscle insulin resistance in obesity and type 2 diabetes, though a distribution of control between glucose transport [...]

This article investigates the effects of physical activity on blood glucose homeostasis in patients with Type 2 diabetes and diabetes prevention. Findings indicate that although exercise does not significantly influence glucose control in diabetics, high physical activity levels are associated with a reduced risk of developing Type 2 diabetes.

Two isoforms of hexokinase (type I and type II) are expressed in skeletal muscle; however, the intracellular distribution of these hexokinase isoforms in human skeletal muscle is unclear. The current [...]

In obesity and type 2 diabetes, skeletal muscle has been observed to have a reduced oxidative enzyme activity, increased glycolytic activity, and increased lipid content. These metabolic characteristics are related [...]

Exercise increases plasma glucose utilization in people with non-insulin-dependent diabetes mellitus (NIDDM). People with NIDDM exercised and were tested for substrate utilization and glucose turnover. The measured increase in glucose utilization mediated decline in glucose concentrations. However, carbohydrate and fat oxidation were found to be similar in people with NIDDM and people without this condition.

Whether visceral adipose tissue has a uniquely powerful association with insulin resistance or whether subcutaneous abdominal fat shares this link has generated controversy in the area of body composition and [...]

Although the relationship between the actions of cholesteryl ester transfer protein (CETP) and atherosclerosis is complex, a strong body of evidence suggests that its activity (cholesteryl ester transfer [CET]) is [...]

Skeletal muscle insulin resistance in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) is characterized by decreased glucose uptake. Although reduced glycogen synthesis is thought to be the predominant cause for [...]

A study describes the baseline (PA) patterns of obese adults with type 2 diabetes mellitus (T2DM) enrolled in the Look AHEAD study. Results identify factors that influence PA patterns in obese adults with T2DM when measured using both objective and subjective measures of PA.

DAVID E. KELLEY, MD [1,2] BRET H. GOODPASTER, PHD [1] An aspect of regional adiposity and insulin resistance Recent evidence derived from four independent methods indicates that an excess triglyceride [...]

Insulin resistance (IR) of skeletal muscle (SK) in Ob and DM is associated with impaired glucose transport and phosphorylation (GPHOS), as demonstrated with several in vivo approaches. HK catalylzes GPHOS [...]

SM IR is nearly always present and usually severe in type 2 DM, nonetheless, it is not uniform in severity. Therefore, it is important to better understand the factors that [...]

The three rate constant [[sup.18]F]FDG model (3K) has been extensively used to measure glucose metabolism in human brain and heart with PET, and recently also in human skeletal muscle. However, [...]

In obesity and Type 2 diabetes, skeletal muscle has increased lipid content (MusFAT), and this is related to the severity of insulin resistance (IR). In addition, in these disorders, skeletal [...]

A Reexamination For many years, the Randle glucose fatty acid cycle has been invoked to explain insulin resistance in skeletal muscle of patients with type 2 diabetes or obesity. Increased [...]

Background: Adipose tissue (AT) content of the thigh is generally not considered to be associated with insulin resistance (IR), but it is unclear whether the distribution of AT in the thigh is a determinant of IR. Objective: We investigated whether subcompartments of AT within the thigh are determinants of IR. Design: Midthigh AT, muscle composition, and insulin sensitivity were compared in 11 obese patients with type 2 diabetes mellitus (DM); 40 obese, glucose-tolerant (GT) and 15 lean, GT volunteers; and 38 obese subjects who completed a weight-loss program. Midthigh AT area measured with computed tomography was partitioned into 3 components: subcutaneous AT (SCAT), AT beneath the fascia (SFAT), and AT infiltrating muscle groups (IMAT). Muscle attenuation characteristics were determined. Results: Obese DM and obese GT subjects had lower insulin sensitivity than lean GT subjects. SCAT was greater in obesity, yet did not correlate with insulin sensitivity. SFAT was [approximately equals] 8% of total thigh AT and correlated with insulin sensitivity. IMAT was highest in obese DM, and although it accounted for only [approximately equals] 3% of thigh AT, it was a strong correlate of insulin sensitivity. Mean attenuation was highest in lean subjects and was associated with higher insulin sensitivity. Weight loss reduced the amount of thigh AT, the proportion of thigh IMAT, and the amount of low-density thigh muscle. Conclusions: SFAT and IMAT are markers of IR in obesity and DM although they are much smaller than SCAT, which does not predict IR. Muscle composition reflecting increased fat content is also associated with IR. Am J Clin Nutr 2000;71:885-92. KEY WORDS Insulin resistance, skeletal muscle, adipose tissue, weight loss, thigh adipose tissue, thigh muscle, obesity, insulin sensitivity, type 2 diabetes mellitus, non-insulin-dependent diabetes mellitus, adult-onset diabetes mellitus, computed tomography, glucose tolerance, body composition, regional fat distribution

The study of skeletal muscle (SM) metabolism using of 2-deoxy-2[[sup.18] F]fluoro-D-glucose ([[sup.18] F]FDG) in combination with positron emission tomography (PET) imaging provides a new perspective for assessing insulin resistance. Because [...]

The current study examined in vivo insulin regulation of glucose transport and phosphorylation in obese subjects with (n=12) and without (n= 13) type 2 DM in comparison to healthy, lean [...]

Episodic paralysis is an unusual complication of overactive toxic thyroid condition. The clinical findings in 10 patients with thyrotoxic periodic paralysis were reviewed. All 10 patients were young men with an average age of 28.4 years. The condition has been found in many racial and ethnic groups, but is believed to occur most frequently in Orientals. Eight of the patients were white, one Oriental and one Hispanic. The first attack of paralysis occurred within three months of symptoms of increased thyroid activity. Quadriplegia, paralysis of all extremities, developed in six patients and paraplegia, usually affecting the lower extremities, appeared in four. Measurements of thyroid hormone showed the thyroid hormone T3 to be elevated in all patients. Electrophysiologic studies of nerve conduction proved normal. Characteristic electric changes were found in muscles following prolonged exercise. Medical staff witnessed acute attacks in three different patients and were able to monitor blood levels of potassium during an acute episode in six patients. In all cases the value of potassium was abnormal. The cause of the condition remains unknown, but speculation involves changes in the ability of sodium to move across cell membranes. Sodium ions are extremely important in the maintenance of electrophysiologic conditions in the body and are related to the mechanism of impulse conduction and muscle contraction. The electrophysiologic evidence also points to the muscle cell as the location of the defect which results in the paralysis.

Weight loss (WL) decreases regional depots of adipose tissue and improves insulin sensitivity, two parameters that correlate before WL. To examine the potential relation of WL-induced change in regional adiposity [...]