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We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC 50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.

Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of β-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss., (© 2018 by the American Diabetes Association.)

Background: The effect of a weight-loss intervention on the masses of lean tissues and organs in humans is not well known., Objective: We studied the effects of a diet and exercise weight-loss intervention on skeletal muscle (SM) mass and selected organs over 2 y using MRI in overweight adults with type 2 diabetes., Design: Participants were 53 women and 39 men [mean ± SD: age 58 ± 7 y; body mass index (BMI; in kg/m 2 ) 32 ± 3] enrolled in the Look AHEAD (Action for Health in Diabetes) trial and randomly assigned to an intensive lifestyle intervention (ILI) or diabetes support and education (DSE) on whom 2 y of data were collected. MRI-derived measurements of SM, heart, liver, kidney, spleen, and pancreas were acquired., Results: Adjusted for baseline weight, height, age, sex, and ethnicity, the ILI group weighed (mean ± SE) 6.6 ± 0.7 kg less after 1 y and 5.2 ± 0.7 kg less after 2 y, whereas the DSE group did not change significantly (-0.4 ± 0.6 and -1.0 ± 0.7 kg after 1 and 2 y, respectively; P-interaction < 0.001). Total SM decreased in both groups during year 1 (-1.4 ± 0.2 kg; P < 0.001) with appendicular SM regained during year 2. Liver and spleen masses decreased in the ILI group (-0.12 ± 0.02 and -0.006 ± 0.003 kg, respectively) but were unchanged in the DSE group (0.00 ± 0.02 and 0.004 ± 0.003 kg, respectively). Kidney mass decreased by 0.013 ± 0.003 kg (P < 0.001) over 2 y in both groups., Conclusions: Decreases in liver (in Caucasians but not African Americans) and spleen were detected after a 6.2-kg weight reduction compared with a control group. SM and kidney mass decreased in both groups. Appendicular SM was regained during the second year whereas trunk SM was not. No evidence of a disproportionate loss of high-metabolic rate organs (heart, liver, kidney, spleen) compared with SM was found., (© 2017 American Society for Nutrition.)

Objective: We aim to characterize the effects on total body fat and distribution of a 1-year intensive lifestyle intervention (ILI) for weight loss in overweight and obese adults with type 2 diabetes and to examine whether changes in adipose tissue (AT) depots were associated with changes in metabolic biomarkers., Research Design and Methods: Participants were 54 females and 38 males (age 57.8 ± 6.7 years [mean ± SD]; BMI 31.7 ± 3.5 kg/m(2)) enrolled in the Look AHEAD (Action for Health in Diabetes) trial randomized to ILI or diabetes support and education (DSE) from whom baseline and 1-year MRI measures of total AT (TAT) and regional (arm, trunk, leg) AT, including subcutaneous AT (SAT), visceral AT (VAT), and intermuscular AT (IMAT), were acquired. We tested whether mean changes in ILI and DSE were equal and, within groups, whether changes were different from zero. Regression models tested whether changes in AT compartments were associated with metabolic variable changes., Results: Body weight changed -0.52 ± 3.62 kg (P = 0.31) in DSE and -7.24 ± 5.40 kg (P < 0.0001) in ILI. Mean ILI changes were different from DSE (P < 0.001 for TAT, SAT, and IMAT and P < 0.01 for VAT in females). Within ILI, SAT and VAT decreased in males and females (P < 0.0001), but IMAT was unchanged (0.00 ± 0.54 kg; P = 0.99). In DSE, SAT and VAT did not change, but IMAT increased by 0.46 ± 0.55 kg (P < 0.001). Controlling for weight loss, reduction of specific AT depots was associated with improvement in metabolic biomarkers., Conclusions: Weight loss of 7-10% from an ILI over 1 year reduced SAT and VAT and prevented an increase in IMAT. Reductions in AT depots were associated with improvements in biomarkers., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Whether lean body mass (LBM) composition, especially skeletal muscle and abdominal organs, differs in adults with type 2 diabetes (T2DM) compared with nondiabetic healthy controls has not been investigated. A subset of African-American and Caucasian participants with T2DM from the Look AHEAD (Action for Health in Diabetes) trial had body composition assessed and compared with a sample of healthy controls. Skeletal muscle mass (SMM), liver, kidneys, and spleen mass were quantified using a contiguous slice magnetic resonance imaging (MRI) protocol. Cardiac mass was quantified by either a cardiac gated MRI protocol or by echocardiography. MRI volumes were converted to mass using assumed densities. Dual-energy X-ray absorptiometry assessed LBM. Using general linear models adjusted for height, weight, sex, age, race, and interactions of diabetes status with race or sex, persons with T2DM (n = 95) had less LBM (49.7 vs. 51.6 kg) and SMM (24.1 vs. 25.4 kg) and larger kidneys (0.40 vs. 0.36 kg) than controls (n = 76) (all P < 0.01). Caucasians with T2DM had larger livers (1.90 vs. 1.60 kg, P < 0.0001) and spleens (0.29 vs. 0.22 kg, P < 0.01), and T2DM men had less cardiac mass than controls (0.25 vs. 0.30 kg, P < 0.001). In this sample, T2DM is characterized by less relative skeletal muscle and cardiac mass in conjunction with larger kidneys, liver, and spleen. Further investigation is needed to establish the causes and metabolic consequences of these race- and sex-specific organ mass differences in T2DM., (Copyright © 2014 the American Physiological Society.)

Dynamic positron emission tomography (PET) imaging was performed using sequential tracer injections ([(15)O]H2O, [(11)C]3-O-methylglucose [3-OMG], and [(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 · m(-2) · min(-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 [(11)C]3-OMG and [(18)F]FDG uptake despite group differences for tissue perfusion. During insulin-stimulated conditions, IR was clearly evident in T2D (P < 0.01), and [(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 [(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.

Purpose: This study describes baseline physical activity (PA) patterns of individuals with type 2 diabetes mellitus (T2DM) enrolled in the multicenter Look AHEAD Study using an objective measure of PA (accelerometry)., Methods: A total of 2240 participants (age = 59.0 ± 6.8 yr and body mass index (BMI) = 36.5 ± 6.0 kg·m−²) with T2DM provided data for this substudy. Participants were instructed to wear an accelerometer during waking hours for 7 d. Accelerometry data were analyzed to identify periods meeting the criteria of ≥3 MET·min−¹ for Q10 min(moderate- to vigorous-intensity PA (MVPA)) and ≥6 MET·min−¹ for ≥10 min (vigorous-intensity PA (VPA)). Self-reported PA was also assessed with a questionnaire. Accelerometry and self-reported PA data were compared across categories of BMI, sex, race, age, fitness, diabetes medication usage, and history of cardiovascular disease., Results: Self-reported PA was lower at higher levels of BMI, was higher in males, was lowest for African-American/black, and was positively associated with fitness. Multivariate analyses for accelerometer-measured MVPA and VPA showed that more PA bouts per day, minutes per bout, METs per minute, and MET-minutes were associated with higher fitness. For MVPA, bouts per day were higher in men, and METs per minute were higher in women. For VPA, bouts per day was positively associated with increasing age and differed by race/ethnicity. METs per minute were significantly lower at higher levels of BMI and in women. Diabetes medication usage and history of cardiovascular disease were not associated with patterns of PA examined., Conclusions: Results provide information on factors that contribute to PA patterns in adults with T2DM when PA is assessed using both objective and subjective measures. These data may inform interventions to improve PA in adults with T2DM

Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.

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.

Insulin resistance in skeletal muscle in obesity and T2DM is associated with reduced muscle oxidative capacity, reduced expression in nuclear genes responsible for oxidative metabolism, and reduced activity of mitochondrial electron transport chain. The presented study was undertaken to analyze mitochondrial content and mitochondrial enzyme profile in skeletal muscle of sedentary lean individuals and to compare that with our previous data on obese or obese T2DM group. Frozen skeletal muscle biopsies obtained from lean volunteers were used to estimate cardiolipin content, mtDNA (markers of mitochondrial mass), NADH oxidase activity of mitochondrial electron transport chain (ETC), and activity of citrate synthase and beta-hydroxyacyl-CoA dehydrogenase (beta-HAD), key enzymes of TCA cycle and beta-oxidation pathway, respectively. Frozen biopsies collected from obese or T2DM individuals in our previous studies were used to estimate activity of beta-HAD. The obtained data were complemented by data from our previous studies and statistically analyzed to compare mitochondrial content and mitochondrial enzyme profile in lean, obese, or T2DM cohort. The total activity of NADH oxidase was reduced significantly in obese or T2DM subjects. The cardiolipin content for lean or obese group was similar, and although for T2DM group cardiolipin showed a tendency to decline, it was statistically insignificant. The total activity of citrate synthase for lean and T2DM group was similar; however, it was increased significantly in the obese group. Activity of beta-HAD and mtDNA content was similar for all three groups. We conclude that the total activity of NADH oxidase in biopsy for lean group is significantly higher than corresponding activity for obese or T2DM cohort. The specific activity of NADH oxidase (per mg cardiolipin) and NADH oxidase/citrate synthase and NADH oxidase/beta-HAD ratios are reduced two- to threefold in both T2DM and obesity.

The size of adipocytes influences their function suggesting a differential responsiveness to intervention. We hypothesized that weight loss in patients with type 2 diabetes mellitus (T2DM) predominantly decreases the size of large and very-large adipocyte subfractions in parallel with beneficial changes in serum adipokines and improved insulin sensitivity. A total of 44 volunteers from the Look Action for Health in Diabetes trial, who lost weight after 1-year of intense lifestyle intervention, were included. Insulin sensitivity (hyperinsulinemic-euglycemic clamp), size of subcutaneous abdominal adipocytes (osmium fixation), and selected serum adipokines were measured. A 13% weight loss was accompanied by 46% improvement in insulin sensitivity (increased glucose disposal rate from 5.9+/-2.2 to 8.6+/-2.7 mg/min/kg fat-free mass, P<0.05) in parallel with a 36% increase in plasma adiponectin concentration (6.1+/-3.1 to 8.3+/-3.9 microg/ml, P<0.05], but no changes in the proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha. Change in adiponectin correlated with changes in glucose disposal rate (r=0.34, P<0.05). Mean adipocyte size decreased (0.84+/-0.25 to 0.64+/-0.23 microl, P<0.05), mainly due to changes in the large adipocyte subfraction (size 0.75-0.44 microl, relative number 19-26%; P<0.05). Our data suggest that change in the large adipocyte subfraction may contribute to the improvement in insulin sensitivity via an increase in serum adiponectin. Such a relationship, which does not imply cause and effect, could not be obtained by measuring only mean adipocyte size. These data provide support for the measures of adipocyte size distribution in concert with in vitro adipokine secretion and lipolysis in future studies.

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 (+/-SD) age of 58.3 +/- 6.6 y and body mass index (in kg/m(2)) of 31.6 +/- 3.1 and 93 healthy non-T2DM control subjects (n = 64 women and 29 men) who had a mean (+/-SD) age of 60.6 +/- 17.1 y and body mass index of 29.6 +/- 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: 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(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(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 (Delta RQ 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.

We measured gene expression of paracrine regulators involved in adipocyte differentiation within the stromovascular fraction of abdominal subcutaneous adipose tissue from obese individuals with (n=30) and without (n=18) type 2 diabetes mellitus (T2DM). Despite similar adiposity by design, subjects with T2DM had larger adipocytes (0.92+/-0.28 vs. 0.75+/-0.17 microl, p<0.05) than controls. Gene expression of the adipogenic marker aP2 was lower (0.35+/-0.16 vs. 0.58+/-0.27 arbitrary units, p<0.05) whereas the expression of matricellular peptidase, MMP2 was higher (1.65+/-0.17 vs. 1.27+/-0.21, p=0.02) in T2DM vs. controls. The gene expression levels between the aP2 and MMP2 were inversely correlated (r=-0.32, p=0.03). We conclude that early steps of adipogenesis may be impaired in T2DM independently of obesity due, in part, to an upregulation of the MMP2 transcription.

Glyceroneogenesis, that is, formation of triglyceride-glycerol from pyruvate, is a critical component of triglyceride fatty acid cycling in vivo. The quantitative contribution of glyceroneogenesis to triglyceride-glycerol and its hormonal regulation have not been examined in humans. We have quantified the contribution of pyruvate to very low-density lipoprotein (VLDL) triglycerides in subjects with type 2 diabetes mellitus using the deuterium labeling of body water technique. Subjects with type 2 diabetes mellitus were studied before and after a 6-month behavioral intervention therapy, during fasting and during a hyperinsulinemic normoglycemic clamp. Response to glucagon infusion was examined in 5 healthy subjects after an overnight fast. Glyceroneogenesis contributed approximately 54% to VLDL triglyceride-glycerol in type 2 diabetes mellitus as compared with approximately 12% contribution of plasma glucose. There was no effect of insulin plus glucose during hyperinsulinemic clamp on glyceroneogenesis even after clinical interventions, when insulin sensitivity had improved. In healthy subjects, the contribution of triosephosphates to plasma VLDL triglycerides was approximately 45%. Glyceroneogenesis, in contrast to glycolysis, is the predominant source of triglyceride-glycerol carbon for VLDL triglycerides in subjects with type 2 diabetes mellitus. The contribution of glyceroneogenesis to triglyceride-glycerol is not affected by short (4 hours) infusion of insulin in type 2 diabetes mellitus.

Objective: Pharmacological inhibition with the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin prolongs the action of endogenously secreted incretin hormones leading to improved glycemic control in patients with type 2 diabetes mellitus (T2DM). We undertook a double-blinded, randomized-order, crossover study to examine the vildagliptin mechanisms of action on islet function and glucose utilization., Research Design and Methods: Participants with T2DM (n = 16) who had a baseline hemoglobin A(1c) of 7.1 +/- 0.2% completed a crossover study with 6 wk of treatment with vildagliptin and 6 wk with placebo. At the completion of each arm, participants had a study of postprandial metabolism and a two-step glucose clamp performed at 20 and 80 mU/min x m(2) insulin infusions., Results: Vildagliptin increased postprandial glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide by 3- and 2-fold, respectively, reduced fasting plasma glucose and postprandial plasma glucose by 1.3 +/- 0.3 mmol/liter and 1.6 +/- 0.3 mmol/liter (both P <0.01), and improved glucose responsiveness of insulin secretion by 50% (P < 0.01). Vildagliptin lowered postprandial glucagon by 16% (P <0.01). Examined by glucose clamp, insulin sensitivity and glucose clearance improved after vildagliptin (P < 0.01)., Conclusions: Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.

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 Vo(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 A1C 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.

Insulin resistance (IR) is typically more severe in obese individuals with type 2 diabetes (T2DM) than in similarly obese non-diabetics but whether there are group differences in body composition and whether such differences contribute to the more severe IR of T2DM is uncertain. DEXA and regional CT imaging were conducted to assess adipose tissue (AT) distribution and fat content in liver and muscle in 67 participants with T2DM (F39/M28, age 60 +/- 7 yr, BMI 34 +/- 3 kg/m(2)) and in 35 similarly obese, non-DM volunteers (F20/M15, age 55 +/- 8 yr, BMI 33 +/- 2 kg/m(2)). A biopsy of subcutaneous abdominal AT was done to measure adipocyte size. A glucose clamp was performed at an insulin infusion of 80 mU x min(-1) x m(-2). There was more severe IR in T2DM (6.1 +/- 2.3 vs. 9.9 +/- 3.3 mg x min(-1) x kg FFM(-1); P < 0.01). Group comparisons of body composition parameters was performed after adjusting for the effect of age, gender, race, height and total fat mass (FM). T2DM was associated with less leg FM (-1.2 +/- 0.4 kg, P < 0.01), more trunk FM (+1.1 +/- 0.4 kg, P < 0.05), greater hepatic fat (P < 0.05), and more subfascial adipose tissue around skeletal muscle (P < 0.05). There was a significant group x sex interaction for VAT (P < 0.01), with greater VAT in women with T2DM (P < 0.01). Mean adipocyte size (AS) did not significantly differ across groups, and smaller AS was associated with increased leg FM, whereas larger AS was related to more trunk FM (both P < 0.05). Group differences in IR were less after adjusting for group differences in leg FM, trunk FM, and hepatic fat, but these adjustments only partially accounted for the greater severity of IR in T2DM. In summary, T2DM, compared with similarly obese nondiabetic men and women, is associated with less leg FM and greater trunk FM and hepatic fat.

Objective: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes 1-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: This study consisted of a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with BMI >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 with a diabetes support and education (DSE) condition., Results: Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group (P < 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P < 0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P < 0.001) vs. from 7.3 to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than DSE participants (all P < 0.01)., Conclusions: At 1 year, ILI resulted in clinically significant weight loss in people 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.

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 is uncertain, and the purpose of the current study was to assess this effect., Research Design and Methods: Arterial stiffness was assessed by measuring aortic pulse wave velocity (aPWV) at baseline and at completion of a 1-year weight loss intervention. Metabolic control of type 2 diabetes was also appraised., Results: Mean weight loss at 1 year in 38 volunteers with type 2 diabetes was 7.8%. There were improvements in HbA1c, LDL cholesterol, homeostasis model assessment of insulin resistance, and inflammatory markers (plasminogen activator inhibitor-1, tumor necrosis factor-alpha, interleukin-6, and C-reactive protein). There was also a significant improvement in aPWV at completion of weight loss intervention, from 740 to 690 cm/s (P < 0.05)., Conclusions: Moderate weight loss improves arterial stiffness in type 2 diabetes.

Objective: Our objective was to delineate the potential role of adipogenesis in insulin resistance and type 2 diabetes. Obesity is characterized by an increase in adipose tissue mass resulting from enlargement of existing fat cells (hypertrophy) and/or from increased number of adipocytes (hyperplasia). The inability of the adipose tissue to recruit new fat cells may cause ectopic fat deposition and insulin resistance., Research Methods and Procedures: We examined the expression of candidate genes involved in adipocyte proliferation and/or differentiation [CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBPdelta, GATA domain-binding protein 3 (GATA3), C/EBPbeta, peroxisome proliferator-activated receptor (PPAR) gamma2, signal transducer and activator of transcription 5A (STAT5A), Wnt-10b, tumor necrosis factor alpha, sterol regulatory element-binding protein 1c (SREBP1c), 11 beta-hydroxysteroid dehydrogenase, PPARG angiopoietin-related protein (PGAR), insulin-like growth factor 1, PPARgamma coactivator 1alpha, PPARgamma coactivator 1beta, and PPARdelta] in subcutaneous adipose tissue from 42 obese individuals with type 2 diabetes and 25 non-diabetic subjects matched for age and obesity., Results: Insulin sensitivity was measured by a 3-hour 80 mU/m2 per minute hyperinsulinemic glucose clamp (100 mg/dL). As expected, subjects with type 2 diabetes had lower glucose disposal (4.9 +/- 1.9 vs. 7.5 +/- 2.8 mg/min per kilogram fat-free mass; p < 0.001) and larger fat cells (0.90 +/- 0.26 vs. 0.78 +/- 0.17 microm; p = 0.04) as compared with obese control subjects. Three genes (SREBP1c, p < 0.01; STAT5A, p = 0.02; and PPARgamma2, p = 0.02) had significantly lower expression in obese type 2 diabetics, whereas C/EBPbeta only tended to be lower (p = 0.07)., Discussion: This cross-sectional study supports the hypothesis that impaired expression of adipogenic genes may result in impaired adipogenesis, potentially leading to larger fat cells in subcutaneous adipose tissue and insulin resistance.

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 particle size and numbers., Research Design and Methods: Computed tomography imaging was used to assess hepatic fat content and adipose tissue distribution in 67 men and women with type 2 diabetes, withdrawn from antidiabetic medications preceding the study. Fasting serum lipoprotein number and size was determined by nuclear magnetic resonance. Insulin sensitivity was measured with a glucose clamp and a [6,6-(2)H(2)]glucose isotope infusion., Results: Two-thirds of the cohort had fatty liver. Hepatic steatosis correlated with serum triglycerides (r = 0.40, P < 0.01) and lower HDL cholesterol (r = -0.31, P < 0.05). ApoB and LDL cholesterol did not, being virtually identical in those with or without steatosis. The association between serum triglycerides and hepatic steatosis was largely accounted for by greater triglyceride enrichment in VLDL particles, which were larger. Severe steatosis was also associated with 70% higher small, dense LDL concentrations. Visceral obesity did not fully explain these associations, and hepatic steatosis was better correlated with triglycerides than with hyperglycemia or hepatic insulin resistance (P > 0.05)., Conclusions: The presence of hepatic steatosis in type 2 diabetes does not appear to affect apoB levels, but potentially increases atherogenesis by increasing triglycerides, reducing HDL levels, and increasing small, dense LDL.

The Look AHEAD (Action for Health in Diabetes) study is a multicenter, randomized controlled trial designed to determine whether intentional weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The study began in 2001 and is scheduled to conclude in 2012. A total of 5145 participants have been randomly assigned to a lifestyle intervention or to an enhanced usual care condition (i.e., diabetes support and education). This article describes the lifestyle intervention and the empirical evidence to support it. The two principal intervention goals are to induce a mean loss >or = 7% of initial weight and to increase participants' moderately intense physical activity to > or =175 min/wk. For the first 6 months, participants attend one individual and three group sessions per month and are encouraged to replace two meals and one snack a day with liquid shakes and meal bars. From months 7 to 12, they attend one individual and two group meetings per month and continue to replace one meal per day (which is recommended for the study's duration). Starting at month 7, more intensive behavioral interventions and weight loss medication are available from a toolbox, designed to help participants with limited weight loss. In Years 2 to 4, treatment is provided mainly on an individual basis and includes at least one on-site visit per month and a second contact by telephone, mail, or e-mail. After Year 4, participants are offered monthly individual visits. The intervention is delivered by a multidisciplinary team that includes medical staff who monitor participants at risk of hypoglycemic episodes.

In obesity, skeletal muscle accumulates triglyceride. Recent work from Hulver and colleagues (2005) in the October issue of Cell Metabolism implicates stearoyl-CoA desaturase as part of the underlying molecular mechanism.

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 +/- 0.003 vs. 0.034 +/- 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.

Muscle contains the largest reservoir of glycogen (Glyc), a depot that is closely regulated and with influence on insulin sensitivity. The current study examines muscle Glyc in type 2 diabetes mellitus (T2DM) and obesity and with respect to muscle fiber type, intramyocellular lipid content (IMCL), and mitochondrial function (oxidative enzyme activity; OX-Enz). There is increasing interest in the relation of IMCL and mitochondrial dysfunction with insulin resistance (IR), yet the association with muscle Glyc has not been examined with regard to these parameters. Using a quantitative histological approach specific to muscle fiber types, we assessed muscle Glyc, IMCL, and OX-Enz in vastus lateralis obtained by percutaneous biopsy in lean nondiabetic (L; n = 16), obese nondiabetic (Ob; n = 15), and T2DM volunteers (n = 14). Insulin sensitivity was estimated using homeostasis model assessment (HOMA)-IR. Muscle Glyc was reduced in T2DM, a deficit evident for type IIa fibers, yet minor in types I and IIb fibers. Low Glyc in T2DM correlated with fasting hyperglycemia. Also, in T2DM and Ob, there was significantly higher IMCL and lower OX-Enz in all fiber types. The IMCL-to-OX-Enz ratio, especially for type I fibers, correlated strongly with IR. Similarly, a Glyc-to-OX-Enz ratio correlated with IR, particularly for type IIb fibers. This ratio tended to be higher in Ob and T2DM. In summary, there is decreased muscle Glyc in T2DM yet a disproportional Glyc-to-OX-Enz relationship that is related to IR, although not as robustly as the IMCL-to-OX-Enz ratio.

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 and -independent effects of the intestinal lipase inhibitor orlistat at 6 months of treatment, using behavioral intervention (Int) combined with randomized, double-blinded, placebo (P)-controlled treatment with orlistat (O)., Research Design and Methods: Metabolic control, insulin sensitivity (IS), regional fat distribution, and fat content in liver and muscle were measured in 39 volunteers with type 2 diabetes in whom all antidiabetic medication was withdrawn 1 month preceding randomization. Weight loss was equivalent in the Int+O and Int+P groups, respectively (-10.3 +/- 1.3 vs. -8.9 +/- 1.1%), and there were identical decreases in visceral adipose tissue (VAT), fat mass (FM), thigh adiposity, and hepatic steatosis., Results: Weight loss resulted in substantial improvement (P < 0.001) in HbA(1c) (-1.6 +/- 0.3 vs. -1.0 +/- 0.4%; NS between groups). IS improved significantly more with orlistat (Delta2.2 +/- 0.4 vs. Delta1.2 +/- 0.4 mg. min(-1). kg(-1) fat-free mass [FFM]; P < 0.05), and plasma free fatty acid (FFA) levels were strongly correlated with IS (r = 0.56; P < 0.001). Orlistat caused greater reductions in fasting plasma FFA (Delta-154 +/- 22 vs. Delta-51 +/- 33 micro mol/l; P < 0.05), insulin-suppressed FFA (Delta-119 +/- 23 vs. Delta-87 +/- 34 micro mol/l; P < 0.05), and fasting plasma glucose (FPG; -62 +/- 9 vs. -32 +/- 8 mg/dl; P = 0.02). Changes in HbA(1c) were correlated with DeltaIS (r = -0.41; P < 0.01) but not with weight loss per se., Conclusions: At equivalent weight loss, conjunctive use of orlistat resulted in greater improvement in FFA levels and IS.

Objective: There is an increased prevalence of macrovascular disease in type 2 diabetes. The pathogenesis has been related to metabolic risk factors, insulin resistance, and obesity. One of the strongest predictors is the presence of subclinical atherosclerosis. This study was designed to examine the relationship between obesity and regional patterns of adiposity, insulin resistance, and five independent measures of subclinical atherosclerosis., Research Methods and Procedures: Fifty-two overweight and obese men and women with type 2 diabetes of relatively short known duration were examined. Measures of subclinical vascular disease were assessment of arterial stiffness by pulse wave velocity, ultrasound measurement of the carotid artery intimal-medial thickness and plaque index, and measurement of the extent of coronary and aortic calcification using electron beam computed tomography. Insulin resistance was measured using the hyperinsulinemic euglycemic clamp. Body composition was measured using DXA and computed tomography., Results: Adiposity was a strong determinant of pulse wave velocity. Carotid intimal-medial thickness was correlated with age, low-density lipoprotein-cholesterol, and hyperglycemia, but not with adiposity. Hyperglycemia and plasma activator inhibitor-1 were significant correlates of the carotid artery plaque index. Coronary calcium scores were significantly correlated with age and interleukin-6 and significantly and negatively correlated to insulin sensitivity index., Discussion: These findings suggest that obesity may play an important role in the early phase of subclinical macrovascular disease related to vessel stiffness, whereas hyperglycemia and insulin resistance in conjunction with other risk factors have important roles in progression from vessel stiffness to atheroma formation in type 2 diabetes.

The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 +/- 0.5 kg/m2] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU. m-2. min-1) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [2H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r = -0.57, P < 0.0001) and less strongly but significantly associated with BMI (r = -0.42, P < 0.001) and FM (r = -0.37, P < 0.001), but only weakly associated with subcutaneous adiposity (r = -0.29; P < 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r = -0.44; P < 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P < 0.001) and had higher levels of plasma free fatty acids (P < 0.01) and more severe dyslipidemia (P < 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r = -0.34; P < 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.

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 x min(-1) x m(-2)), using [(15)O]H(2)O and [(18)F]fluoro-deoxyglucose ([(18)F]FDG) to quantify tissue perfusion and glucose metabolism. Dynamic [(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 [(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 +/- 2 kg, P < 0.05). Muscle insulin resistance, assessed by insulin-stimulated [(18)F]FDG uptake, decreased threefold in diabetic subjects and twofold in nondiabetic subjects (P < 0.001). Kinetic parameters for [(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.

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, and impaired glucose tolerance (IGT)., Research Design and Methods: A total of 2,964 elderly men and women (mean age 73.6 years) were recruited for cross-sectional comparisons of diabetes or glucose tolerance, generalized obesity with dual-energy X-ray absorptiometry, and regional body fat distribution with computed tomography. RESULTS-Approximately one-third of men with type 2 diabetes and less than half of women with type 2 diabetes were obese (BMI > or =30 kg/m(2)). Despite similar amounts of subcutaneous thigh fat, intermuscular fat was higher in subjects with type 2 diabetes and IGT than in subjects with normal glucose tolerance (NGT) (11.2 +/- 9.4, 10.3 +/- 5.8, and 9.2 +/- 5.9 cm(2) for men; 12.1 +/- 6.1, 10.9 +/- 6.5, and 9.4 +/- 5.3 cm(2) for women; both P < 0.0001). Visceral abdominal fat was also higher in men and women with type 2 diabetes and IGT than in subjects with NGT (172 +/- 79, 163 +/- 72, and 145 +/- 66 cm(2) for men; 162 +/- 66, 141 +/- 60, and 116 +/- 54 cm(2) for women; both P < 0.0001 across groups). Higher rates of intermuscular fat and visceral abdominal fat were associated with higher fasting insulin in normal-weight (BMI <25 kg/m(2)) men (r = 0.24 for intermuscular fat, r = 0.37 for visceral abdominal fat, both P < 0.0001) and women (r = 0.20 for intermuscular fat, r = 0.40 for visceral abdominal fat, both P < 0.0001). These associations were not found in obese subjects., Conclusions: Elderly men and women with normal body weight may be at risk for metabolic abnormalities, including type 2 diabetes, if they possess an inordinate amount of muscle fat or visceral abdominal fat.

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.

Unlabelled: 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 treated with insulin. The aim of this study was to assess the effect of orlistat, a gastrointestinal lipase inhibitor, on weight loss, glycemic control, and cardiovascular risk factors in overweight or obese insulin-treated type 2 diabetic patients., Research Design and Methods: This study was a 1-year multicenter, randomized, double-blind, placebo-controlled trial of orlistat (120 mg three times a day) or placebo combined with a reduced-calorie diet in overweight or obese adults (BMI 28-40 kg/m(2)) with type 2 diabetes treated with insulin alone or combined with oral agents, but with suboptimal metabolic control (HbA(1c) 7.5-12.0%). Outcome measurements included changes in body weight, glycemic control, blood pressure, and serum lipids. RESULTS; After 1 year, the orlistat group lost significantly more weight (-3.89 +/- 0.3% of baseline body weight, means +/- SE) than the placebo group (-1.27 +/- 0.3%, P < 0.001). Orlistat treatment, compared with placebo, produced greater decreases in HbA(1c) (-0.62 +/- 0.08 vs. -0.27 +/- 0.08%, P = 0.002), fasting serum glucose (-1.63 +/- 0.3 vs. -1.08 +/- 0.3 mmol/l, P = 0.02), and the required doses of insulin and other diabetic medications. Orlistat also produced greater improvements than placebo in serum total cholesterol (P = 0.0002) and LDL cholesterol concentrations (P = 0.001) and LDL/HDL ratio (P = 0.01). CONCLUSIONS; Orlistat therapy produces clinically significant weight loss, with improvements in glycemic control and cardiovascular disease risk factors, in overweight or obese patients with type 2 diabetes who have suboptimal metabolic control with insulin therapy.

The inability of insulin to stimulate glucose metabolism in skeletal muscle is a classic characteristic of type 2 diabetes, but this insulin resistance entails altered patterns of lipid metabolism as well. An association between intracellular triglyceride and insulin resistance has been well established in both human and animal studies of obesity-related insulin resistance and type 2 diabetes. Skeletal muscle's ability to select substrate for fuel metabolism, a metabolic flexibility, is also lost in insulin resistance, and defects in fatty acid metabolism during fasting or postabsorptive conditions likely play an important role in lipid oversupply to insulin-resistant muscle. These impairments appear to be at least indirectly centered on the ability of mitochondria to oxidize fatty acids, possibly through mediation of lipid metabolite levels such as ceramide or diacylglycerol, which are known to directly attenuate insulin signaling. Moreover, periodic use of muscle triglyceride by exercise may mediate the association between muscle triglyceride and insulin resistance. Thus, it appears that skeletal muscle triglyceride is perhaps a surrogate for other lipid species having a more direct effect on insulin action. Defining mechanisms by which dysregulation of fatty acid metabolism and persistent lipid oversupply alter insulin action may help to target more effective strategies to prevent or treat type 2 diabetes.

The prevalence of Type 2 diabetes mellitus (DM-2) is increasing throughout the world and poses a major public health concern. With the majority of patients DM-2 are overweight or obese and weight loss is generally recommended, both as a first-line therapy and as an adjunct to pharmacological therapies. However, it is generally acknowledged that weight loss, a difficult goal for many overweight and obese individuals, is especially difficult for those with DM-2 and there is interest in whether pharmacological adjuncts may be useful for this purpose. Orlistat is an intestinal lipase inhibitor previously approved for the treatment of obesity. During the past several years, clinical trials have been completed concerning the use of orlistat in the treatment of overweight or obese patients with DM-2. The purpose of this review is to examine the results of these clinical trials. Data on > 2500 orlistat-treated patients with DM-2 are reviewed and summarised. Orlistat therapy led to greater weight loss and improved metabolic control in overweight and obese patients with DM-2.

Animal studies have shown diabetes-induced changes in the state and function of the serotonin neuroreceptor system. Diabetes also has induced structural and functional alterations in hippocampus and been associated with altered hypothalamopituitary adrenal axis regulation. In this study, serotonin-1A (5-HT(1A)) receptor binding was measured in humans with type 2 diabetes (n=6) and healthy controls (n=6), using positron emission tomography (PET) and [carbonyl-11C]WAY 100635. Significantly greater 5-HT(1A) receptor binding was detected in mesial temporal cortex, including hippocampus (P<0.05) for type 2 subjects (relative to controls). Within the type 2 group, glycosylated hemoglobin and stressed plasma cortisol levels were positively correlated (P<0.02). These findings support previous studies that suggest serotonergic underpinnings to the neurobiology of diabetes and have shown diabetes-induced neurological changes in hippocampus.

Skeletal muscle contains the majority of the body's glycogen stores and a similar amount of readily accessible energy as intramyocellular triglyceride (imTG). While a number of factors have been considered to contribute to the pathogenesis of insulin resistance (IR) in obesity and type 2 diabetes mellitus (DM), this review will focus on the potential role of skeletal muscle triglyceride content. In obesity and type 2 DM, there is an increased content of lipid within and around muscle fibers. Changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, almost certainly contribute to accumulation of imTG and to the pathogenesis of both obesity and type 2 DM. In metabolic health, skeletal muscle physiology is characterized by the capacity to utilize either lipid or carbohydrate fuels, and to effectively transition between these fuels. We will review recent findings that indicate that in type 2 DM and obesity, skeletal muscle manifests inflexibility in the transition between lipid and carbohydrate fuels. This inflexibility in fuel selection by skeletal muscle appears to be related to the accumulation of imTG and is an important aspect of IR of skeletal muscle in obesity and type 2 DM.