Search

The onset of common obesity-linked type 2 diabetes (T2D) is marked by exhaustive failure of pancreatic β-cell functional mass to compensate for insulin resistance and increased metabolic demand, leading to uncontrolled hyperglycemia. Here, the β-cell-deficient obese hyperglycemic/hyperinsulinemic KS db/db mouse model was used to assess consequential effects on β-cell functional recovery by lowering glucose homeostasis and/or improving insulin sensitivity after treatment with thiazolidinedione therapy or glucagon-like peptide 1 receptor agonism alone or in combination with sodium/glucose cotransporter 2 inhibition (SGLT-2i). SGLT-2i combination therapies improved glucose homeostasis, independent of changes in body weight, resulting in a synergistic increase in pancreatic insulin content marked by significant recovery of the β-cell mature insulin secretory population but with limited changes in β-cell mass and no indication of β-cell dedifferentiation. Restoration of β-cell insulin secretory capacity also restored biphasic insulin secretion. These data emphasize that by therapeutically alleviating the demand for insulin in vivo, irrespective of weight loss, endogenous β-cells recover significant function that can contribute to attenuating diabetes. Thus, this study provides evidence that alleviation of metabolic demand on the β-cell, rather than targeting the β-cell itself, could be effective in delaying the progression of T2D. [ABSTRACT FROM AUTHOR]

Obese patients have impaired vasodilator reactivity and increased endothelin 1 (ET-1)-mediated vasoconstriction, two abnormalities contributing to vascular dysfunction. Obestatin, a product of the ghrelin gene, in addition to favorable effects on glucose and lipid metabolism, has shown nitric oxide (NO)-dependent vasodilator properties in experimental models. Given these premises, we compared the effects of exogenous obestatin on forearm flow in lean and obese subjects and assessed its influence on ET-1-dependent vasoconstrictor tone in obesity. In both lean and obese participants, infusion of escalating doses of obestatin resulted in a progressive increase in blood flow from baseline (both P < 0.001). This vasodilation was predominantly mediated by enhanced NO activity, because NG-monomethyl-l-arginine markedly blunted the flow response to obestatin in both groups (both P < 0.05 vs. saline). In obese subjects, antagonism of ETA receptors by BQ-123 increased forearm flow during saline (P < 0.001) but did not induce additional vasodilation (P > 0.05) during obestatin. Circulating obestatin levels were not different between lean and obese participants (P = 0.41). Our findings indicate that obestatin causes NO-dependent vasodilation in the human circulation. This effect is preserved in obesity, where it is accompanied by reduced ET-1-mediated vasoconstriction. These latter observations make obestatin a promising target for vascular prevention in obesity and diabetes. [ABSTRACT FROM AUTHOR]

Few genome-wide association studies (GWAS) of type 2 diabetes (T2D) have been conducted in U.S. Hispanics/Latinos of diverse backgrounds who are disproportionately affected by diabetes. We conducted a GWAS in 2,499 T2D case subjects and 5,247 control subjects from six Hispanic/Latino background groups in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Our GWAS identified two known loci (TCF7L2 and KCNQ1) reaching genome-wide significance levels. Conditional analysis on known index single nucleotide polymorphisms (SNPs) indicated an additional independent signal at KCNQ1, represented by an African ancestry-specific variant, rs1049549 (odds ratio 1.49 [95% CI 1.27-1.75]). This association was consistent across Hispanic/Latino background groups and replicated in the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium. Among 80 previously known index SNPs at T2D loci, 66 SNPs showed consistency with the reported direction of associations and 14 SNPs significantly generalized to the HCHS/SOL. A genetic risk score based on these 80 index SNPs was significantly associated with T2D (odds ratio 1.07 [1.06-1.09] per risk allele), with a stronger effect observed in nonobese than in obese individuals. Our study identified a novel independent signal suggesting an African ancestry-specific allele at KCNQ1 for T2D. Associations between previously identified loci and T2D were generally shown in a large cohort of U.S. Hispanics/Latinos. [ABSTRACT FROM AUTHOR]

FAM3C is a member of the family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia, and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM), and phosphorylated protein kinase B (Akt) and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca2+- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver. [ABSTRACT FROM AUTHOR]

Ten-week-old Zucker diabetic fatty (ZDF) rats at an early stage of diabetes embody metabolic characteristics of obese human patients with type 2 diabetes, such as severe insulin and glucose intolerance in muscle and the liver, excessive postprandial excursion of plasma glucose and insulin, and a loss of metabolic flexibility with decreased lipid oxidation. Metabolic flexibility and glucose flux were examined in ZDF rats during fasting and near-normal postprandial insulinemia and glycemia after correcting excessive postprandial hyperglycemia using treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2-I) for 7 days. Preprandial lipid oxidation was normalized, and with fasting, endogenous glucose production (EGP) increased by 30% and endogenous glucose disposal (E-Rd) decreased by 40%. During a postprandial hyperglycemic-hyperinsulinemic clamp after SGLT2-I treatment, E-Rd increased by normalizing glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake; activation of glucokinase was restored and insulin action was improved, stimulating muscle glucose uptake in association with decreased intracellular triglyceride content. In conclusion, SGLT2-I treatment improves impaired glucose effectiveness in the liver and insulin sensitivity in muscle by eliminating glucotoxicity, which reinstates metabolic flexibility with restored preprandial lipid oxidation and postprandial glucose flux in ZDF rats. [ABSTRACT FROM AUTHOR]

Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals. Herein we show that resveratrol ingestion produces taxonomic and predicted functional changes in the gut microbiome of obese mice. In particular, changes in the gut microbiome were characterized by a decreased relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia and an increased relative abundance of Bacteroides and Parabacteroides Moreover, fecal transplantation from healthy resveratrol-fed donor mice is sufficient to improve glucose homeostasis in obese mice, suggesting that the resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol. [ABSTRACT FROM AUTHOR]

Obesity causes dramatic proinflammatory changes in the adipose tissue immune environment, but relatively little is known regarding how this inflammation responds to weight loss (WL). To understand the mechanisms by which meta-inflammation resolves during WL, we examined adipose tissue leukocytes in mice after withdrawal of a high-fat diet. After 8 weeks of WL, mice achieved similar weights and glucose tolerance values as age-matched lean controls but showed abnormal insulin tolerance. Despite fat mass normalization, total and CD11c+ adipose tissue macrophage (ATM) content remained elevated in WL mice for up to 6 months and was associated with persistent fibrosis in adipose tissue. ATMs in formerly obese mice demonstrated a proinflammatory profile, including elevated expression of interferon-γ, tumor necrosis factor-α, and interleukin-1β. T-cell-deficient Rag1-/- mice showed a degree of ATM persistence similar to that in WT mice, but with reduced inflammatory gene expression. ATM proliferation was identified as the predominant mechanism by which ATMs are retained in adipose tissue with WL. Our study suggests that WL does not completely resolve obesity-induced ATM activation, which may contribute to the persistent adipose tissue damage and reduced insulin sensitivity observed in formerly obese mice. [ABSTRACT FROM AUTHOR]

In individuals with type 2 diabetes with abdominal obesity, hyperfiltration is a risk factor for accelerated glomerular filtration rate (GFR) decline and nephropathy. In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end point trial, consenting patients with type 2 diabetes aged >18 years, with waist circumference >94 (males) or >80 (females) cm, serum creatinine <1.2 mg/dL, and normoalbuminuria were randomized (1:1) with permuted blocks to 6 months of a 25% calorie restricted (CR) or standard diet (SD). Primary outcome was measured GFR (iohexol plasma clearance). Analyses were by modified intention to treat. At 6 months, GFR significantly decreased in 34 patients on CR and did not change appreciably in 36 on SD. Changes were significantly different between the groups. GFR and body weight reduction were correlated. GFR reduction was larger in hyperfiltering (GFR >120 mL/min) than nonhyperfiltering patients and was associated with BMI, waist circumference, blood pressure, heart rate, HbA1c, blood glucose, LDL-to-HDL cholesterol ratio, C-reactive protein, angiotensin II, and albuminuria reduction and with increased glucose disposal rate (measured by hyperinsulinemic-euglycemic clamps). Protein and sodium intake and concomitant treatments were similar between the groups. CR was tolerated well. In patients with type 2 diabetes with abdominal obesity, CR ameliorates glomerular hyperfiltration, insulin sensitivity, and other cardiovascular risk factors, effects that might translate into long-term nephro- and cardioprotection. [ABSTRACT FROM AUTHOR]

Impaired GLUT4-dependent glucose uptake is a contributing factor in the development of whole-body insulin resistance in obese patients and obese animal models. Previously, we demonstrated that transgenic mice engineered to express the human GLUT4 gene under the control of the human GLUT4 promoter (i.e., transgenic [TG] mice) are resistant to obesity-induced insulin resistance. A likely mechanism underlying increased insulin sensitivity is increased glucose uptake in skeletal muscle. The purpose of this study was to investigate the broader metabolic consequences of enhanced glucose uptake into muscle. We observed that the expression of several nuclear and mitochondrially encoded mitochondrial enzymes was decreased in TG mice but that mitochondrial number, size, and fatty acid respiration rates were unchanged. Interestingly, both pyruvate and glutamate respiration rates were decreased in TG mice. Metabolomics analyses of skeletal muscle samples revealed that increased GLUT4 transgene expression was associated with decreased levels of some tricarboxylic acid intermediates and amino acids, whereas the levels of several glucogenic amino acids were elevated. Furthermore, fasting acyl carnitines in obese TG mice were decreased, indicating that increased GLUT4-dependent glucose flux decreases nutrient stress by altering lipid and amino acid metabolism in skeletal muscle. [ABSTRACT FROM AUTHOR]

Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2β2γ3 activity and phosphorylation of ACCβ Ser(221), TBC1D1 Ser(237)/Thr(596), and TBC1D4 Ser(704) Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser(318)/Thr(642) phosphorylation. Interestingly, compared with preexercise, 3 h into exercise recovery, AMPK α2β2γ1 and α1β2γ1 activity were increased concomitant with increased TBC1D4 Ser(318)/Ser(341)/Ser(704) phosphorylation. No differences in these responses were observed between patients with T2D and control subjects. Subjects were also studied by euglycemic-hyperinsulinemic clamps performed at rest and 3 h after exercise. We found no evidence for insulin to regulate AMPK activity. Thus, AMPK signaling is not compromised in muscle of patients with T2D during exercise and insulin stimulation. Our results reveal a hitherto unrecognized activation of specific AMPK complexes in exercise recovery. We hypothesize that the differential regulation of AMPK complexes plays an important role for muscle metabolism and adaptations to exercise. [ABSTRACT FROM AUTHOR]

Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17°C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes beige adipocyte development through the β2-adrenoceptor signaling pathway. This synergistic effect on beige adipocyte biogenesis occurs through an increased half-life of PRDM16, a dominant transcriptional regulator of brown/beige adipocyte development. We document a previously unappreciated molecular circuit that controls beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues. [ABSTRACT FROM AUTHOR]

Insulin resistance is closely related to intramyocellular lipid (IMCL) accumulation, and both are associated with increasing age. It remains to be determined to what extent perturbations in IMCL metabolism are related to the aging process per se. On two separate occasions, whole-body and muscle insulin sensitivity (euglycemic-hyperinsulinemic clamp with 2-deoxyglucose) and fat utilization during 1 h of exercise at 50% VO2max ([U-(13)C]palmitate infusion combined with electron microscopy of IMCL) were determined in young lean (YL), old lean (OL), and old overweight (OO) males. OL displayed IMCL content and insulin sensitivity comparable with those in YL, whereas OO were markedly insulin resistant and had more than twofold greater IMCL in the subsarcolemmal (SSL) region. Indeed, whereas the plasma free fatty acid Ra and Rd were twice those of YL in both OL and OO, SSL area only increased during exercise in OO. Thus, skeletal muscle insulin resistance and lipid accumulation often observed in older individuals are likely due to lifestyle factors rather than inherent aging of skeletal muscle as usually reported. However, age per se appears to cause exacerbated adipose tissue lipolysis, suggesting that strategies to reduce muscle lipid delivery and improve adipose tissue function may be warranted in older overweight individuals. [ABSTRACT FROM AUTHOR]

Genetic studies have identified a glutamate-ammonia ligase gene (GLUL) polymorphism associated with cardiovascular disease morbidity and mortality among people with type 2 diabetes (T2D). We sought to determine whether GLUL rs10911021 is associated prospectively with adjudicated cardiovascular composite end points among overweight/obese individuals with T2D and whether a lifestyle intervention resulting in weight loss could diminish this association. Look AHEAD is a randomized, controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Look AHEAD participants included in this report were 3,845 overweight/obese individuals with T2D who provided consent for genetic analyses. Over a median of 9.6 years of follow-up, the risk (C) allele for GLUL rs10911021 was significantly associated with the primary composite end point of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina among individuals with no history of cardiovascular disease (CVD) at baseline using additive genetic models (hazard ratio 1.17 [95% CI 1.01-1.36]; P = 0.032). Results appeared more consistent in recessive models and among individuals with no known history of CVD at baseline; ILI did not alter these associations. These results extend the association of GLUL rs10911021 to incident CVD morbidity and mortality in the setting of T2D. [ABSTRACT FROM AUTHOR]

Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both non-stratified analysis (P = 2.8 3 10-107) and stratified analyses (all P < 3.3 3 10-30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Recent studies suggest improved outcomes and survival in obese heart failure patients (i.e., the obesity paradox), although obesity and heart failure unfavorably alter cardiac function and metabolism. We investigated the effects of weight loss on cardiac function and metabolism in obese heart failure mice. Obesity and heart failure were induced by feeding mice a high-fat (HF) diet (60% kcal from fat) for 4 weeks, following which an abdominal aortic constriction (AAC) was produced. Four weeks post-AAC, mice were switched to a low-fat (LF) diet (12% kcal from fat; HF AAC LF) or maintained on an HF (HF AAC HF) for a further 10 weeks. After 18 weeks, HF AAC LF mice weighed less than HF AAC HF mice. Diastolic function was improved in HF AAC LF mice, while cardiac hypertrophy was decreased and accompanied by decreased SIRT1 expression, increased FOXO1 acetylation, and increased atrogin-1 expression compared with HF AAC HF mice. Insulin-stimulated glucose oxidation was increased in hearts from HF AAC LF mice, compared with HF AAC HF mice. Thus lowering body weight by switching to LF diet in obese mice with heart failure is associated with decreased cardiac hypertrophy and improvements in both cardiac insulin sensitivity and diastolic function, suggesting that weight loss does not negatively impact heart function in the setting of obesity. [ABSTRACT FROM AUTHOR]

Roux-en-Y gastric bypass (RYGB) improves glycemic control within days after surgery, and changes in insulin sensitivity and β-cell function are likely to be involved. We studied 10 obese patients with type 2 diabetes (T2D) and 10 obese glucose-tolerant subjects before and 1 week, 3 months, and 1 year after RYGB. Participants were included after a preoperative diet-induced total weight loss of -9.2 ± 1.2%. Hepatic and peripheral insulin sensitivity were assessed using the hyperinsulinemic-euglycemic clamp combined with the glucose tracer technique, and β-cell function was evaluated in response to an intravenous glucose-glucagon challenge as well as an oral glucose load. Within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity, and increased insulin clearance, highlighting the liver as an important organ responsible for early effects on glucose metabolism after surgery. Insulin-mediated glucose disposal and suppression of fatty acids did not improve immediately after surgery but increased at 3 months and 1 year; this increase likely was related to the reduction in body weight. Insulin secretion increased after RYGB only in patients with T2D and only in response to oral glucose, underscoring the importance of the changed gut anatomy. [ABSTRACT FROM AUTHOR]

Oxidative stress is purported to be involved in the pathogenesis of obesity-associated insulin resistance. We evaluated whether alterations in levels of circulating uric acid (UA), a systemic antioxidant, affects the following: 1) systemic plasma and saliva) nonenzymatic antioxidant capacity (NEAC); 2) markers of systemic (urinary 8-iso-prostaglandin-F2α) and muscle (carbonylated protein content) oxidative stress; and 3) whole-body insulin sensitivity (percentage increase in glucose uptake during a hyperinsulinemic-euglycemic clamp procedure). Thirty-one obese subjects (BMI 37.1 ± 0.7 kg/m²) with either high serum UA (HUA; 7.1 ± 0.4 mg/dL; n = 15) or normal serum UA (NUA; 4.5 ± 0.2 mg/dL; n = 16) levels were studied; 13 subjects with HUA levels were studied again after reduction of serum UA levels to 0 by infusing a recombinant urate oxidase. HUA subjects had 20-90% greater NEAC, but lower insulin sensitivity 40%) and levels of markers of oxidative stress (30%) than subjects in the NUA group (all P < 0.05). Acute UA reduction caused a 45-95% decrease in NEAC and a 25-40% increase in levels of systemic and muscle markers of oxidative stress (all P < 0.05), but did not affect insulin sensitivity (from 168 ± 25% to 156 ± 17%, P = NS). These results demonstrate that circulating UA is a major antioxidant and might help protect against free-radical oxidative damage. However, oxidative stress is not a major determinant of insulin action in vivo. [ABSTRACT FROM AUTHOR]

Hepatic Notch signaling is inappropriately activated in obese/ insulin-resistant mouse models. Genetic or pharmacologic inhibition of hepatic Notch signaling in obese mice simultaneously improves glucose tolerance and reduces hepatic triglyceride content. As such, we predicted that Notch signaling in human liver would be positively associated with insulin resistance and hepatic steatosis. Here, we systematically survey Notch signaling in liver biopsy specimens, and show active Notch signaling in lean and obese adults, with expression of multiple Notch receptors and ligands. hi morbidly obese patients undergoing bariatric surgery, we show that Notch activation positively correlates with glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxy-kinase (PCK1) expression, key regulators of hepatic glucose output. We used immunofluorescence to identify active Notch signaling in hepatocytes and show highest activity in hyperglycemia, which we confirmed is a direct effect of hyperglycemia and insulin resistance. In a validation cohort of leaner individuals undergoing percutaneous liver biopsy for suspected nonalcoholic fatty liver disease (NAFLD), Notch activity showed independent positive association with insulin resistance and hepatic steatosis. Notably, Notch activity showed stronger correlation with the NAFLD activity score and alanine aminotransferase levels than with steatosis alone, suggesting that Notch activity is associated with nonalcoholic steatohepatitis. hi summary, this study establishes that Notch signaling is activated in and may represent a therapeutic target for patients with obesity-related liver disease. [ABSTRACT FROM AUTHOR]

It has been hypothesized that a greater decline in circulating branched-chain amino acids (BCAAs) after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery than after calorie restriction alone has independent effects on glucose homeostasis, possibly by decreased signaling through the mammalian target of rapamycin (mTOR). We evaluated plasma BCAAs and their C3 and C5 acylcarnitine metabolites, muscle mTOR phosphorylation, and insulin sensitivity (insulin-stimulated glucose Rd) in obese subjects before and after ~20% weight loss induced by RYGB (n = 10, BMI 45.6 ± 6.7 kg/m²) or laparoscopic adjustable gastric banding (LAGB) (n = 10, BMI 46.5 ± 8.8 kg/m²) Weight loss increased insulin-stimulated glucose Rd by ~55%, decreased total plasma BCAA and C3 and C5 acylcarnitine concentrations by 20-35%, and did not alter roTOR phosphorylation; no differences were detected between surgical groups (all P values for interaction >0.05). Insulin-stimulated glucose Rd correlated negatively with plasma BCAAs and with C3 and C5 acylcarnitine concentrations (r values -0.56 to -0.75, P < 0.05) These data demonstrate that weight loss induced by either LAGB or RYGB causes the same decline in circulating BCAAs and their C3 and C5 acylcarnitine metabolites. Plasma BCAA concentration is negatively associated with skeletal muscle insulin sensitivity, but the mechanism(s) responsible for tlfis relationship is not known. [ABSTRACT FROM AUTHOR]

Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery. [ABSTRACT FROM AUTHOR]

Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE-- measured using indirect calorimetry--was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients. [ABSTRACT FROM AUTHOR]

Based on evidence that patients with type 2 diabetes (T2DM), obese insulin-resistant individuals, and lean insulin-resistant offspring of parents with T2DM have ~30% less mitochondria in their muscles than lean control subjects, it appears to be widely accepted that mitochondrial "deficiency" is responsible for insulin resistance. The proposed mechanism for this effect is an impaired ability to oxidize fat, resulting in lipid accumulation in muscle. The purpose of this counterpoint article is to review the evidence against the mitochondrial deficiency concept. This evidence includes the findings that 1) development of insulin resistance in laboratory rodents fed high-fat diets occurs despite a concomitant increase in muscle mitochondria; 2) mitochondrial deficiency severe enough to impair fat oxidation in resting muscle causes an increase, not a decrease, in insulin action; and 3) most of the studies comparing fat oxidation in insulin-sensitive and insulin-resistant individuals have shown that fat oxidation is higher in T2DM patients and obese insulin-resistant individuals than in insulin-sensitive control subjects. In conclusion, it seems clear, based on this evidence, that the 30% reduction in muscle content of mitochondria in patients with T2DM is not responsible for insulin resistance. [ABSTRACT FROM AUTHOR]

The stress protein heat shock protein 60 (Hsp60) induces secretion of proinflammatory mediators from murine adipocytes. This study aimed to study Hsp60 as a mediator of adipose tissue inflammation and skeletal muscle cell (SkMC) insulin sensitivity and to quantify plasma Hsp60 concentrations in lean and obese individuals. Regulation of Hsp60 release and Hsp60-induced cytokine secretion and signaling was measured in human adipocytes and SkMCs. Adipocytes exhibited higher Hsp60 release than preadipocytes and SkMCs, which was further stimulated by cytokines and Toll-like receptor (TLR)-4 activation. Hsp60 activated extracellular signal-related kinase (ERK)-1/2, Jun NH2terminal kinase (JNK), p38, nuclear factor (NF)-κB, and impaired insulin-stimulated Akt phosphorylation in adipocytes. Furthermore, Hsp60 stimulated adipocytes to secrete tumor necrosis factor-α, interleukin (IL)-6, and IL-8. In SkMCs, Hsp60 activated ERK1/2, JNK, and NF-κB and inhibits insulin signaling and insulin-stimulated glucose uptake. SkMCs released IL-6, IL-8, and monocyte chemo-attractant protein-1 on Hsp60 stimulation. Plasma Hsp60 was higher in obese males than in lean males and correlated positively with BMI, blood pressure, leptin, and homeostasis model assessment-insulin resistance. In summary, Hsp60 is released by human adipocytes, increased in plasma of obese humans, and induces insulin resistance. This is accompanied by activation of proinflammatory signaling in human adipocytes and SkMCs. Thus, Hsp60 might be a factor underlying adipose tissue inflammation and obesity-associated metabolic disorders. [ABSTRACT FROM AUTHOR]

The article examines the relationship between systemic concentrations of nonesterified fatty acids (NEFA) and obesity/insulin resistance, as well as the adipose tissue in the obese state with regard to its adaptation for NEFA release. Function of NEFA is discussed. It is stated that plasma NEFA concentrations increase in obese individuals and that this could lead to the insulin resistance that is usually associated with obesity.

OBJECTIVE--Leptin therapy improves insulin sensitivity in people with leptin deficiency, but it is not known whether it improves insulin action in people who are not leptin deficient. The purpose of the current study was to determine whether leptin treatment has weight loss-independent effects on insulin action in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS--We conducted a randomized. placebo-controlled trial in obese subjects (BMI: 35.4 ± 0.6 kg/m² mean ± SE) with newly diagnosed type 2 diabetes. Subjects were randomized to treatment with placebo (saline), low-dose (30 mg/day), or high-dose (80 mg/day) recombinant methionyl human (r-Met hu) leptin for 14 days. Multiorgan insulin sensitivity before and after treatment was evaluated by using the hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled tracer infusions to measure glucose, glycerol, and fatty acid kinetics. RESULTS--Low-dose and high-dose leptin treatment resulted in a threefold (P < 0.01) and 150-fold (P < 0.001) increase in basal plasma leptin concentrations, respectively. However, neither low-dose nor high-dose therapy had an effect on insulin-mediated suppression of glucose, glycerol, or palmitate rates of appearance into plasma compared with placebo. In addition, leptin treatment did not increase insulin-mediated stimulation of glucose disposal compared with placebo (14.3 ± 3.1, 18.4 ± 3.6, 16.7 ± 2.4 vs. 17.5 ± 2.5, 20.7 ± 3.0, 19.1 ± 3.3 µmol/kg body wt/min before vs. after treatment in the placebo, low-dose, and high-dose leptin groups, respectively). CONCLUSIONS--r-Met hu leptin does not have weight loss-independent, clinically important effects on insulin sensitivity in obese people with type 2 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Regional differences among adipose depots in capacities for fatty acid storage, susceptibility to hypoxia, and inflammation likely contribute to complications of obesity. We defined the properties of endothelial cells (EC) isolated from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) biopsied in parallel from obese subjects. RESEARCH DESIGN AND METHODS--The architecture and properties of the fat tissue capillary network were analyzed using immunohistochemistry and flow cytometry. CD34+/CD31+ EC were isolated by immunoselection/depletion. Expression of chemokines, adhesion molecules, angiogenic factor receptors, as well as lipogenic and senescence-related genes were assayed by real-time PCR. Fat cell size and expression of hypoxia-dependent genes were determined in adipocytes from both fat depots. RESULTS--Hypoxia-related genes were more highly expressed in VAT than SAT adipocytes. VAT adipocytes were smaller than SAT adipocytes. Vascular density and EC abundance were higher in VAT. VAT-EC exhibited a marked angiogenic and inflammatory state with decreased expression of metabolism-related genes, including endothelial lipase, GPIHBP1, and PPAR gamma. VAT-EC had enhanced expression of the cellular senescence markers, IGFBP3 and γ-H2AX, and decreased expression of SIRT1. Exposure to VAT adipocytes caused more EC senescence-associated β-galactosidase activity than SAT adipocytes, an effect reduced in the presence of vascular endothelial growth factor A (VEGFA) neutralizing antibodies. CONCLUSIONS--VAT-EC exhibit a more marked angiogenic and proinflammatory state than SAT-EC. This phenotype may be related to premature EC senescence. VAT-EC may contribute to hypoxia and inflammation in VAT. Diabetes 59:2755-2763, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Low cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL. RESEARCH DESIGN AND METHODS--We included 138 overweight to obese, otherwise healthy subjects (aged 43.6 ± 8.9 years, BMI 33.8 ± 4 kg/m2). Body composition was estimated by bioimpedance analyses. Abdominal fat distribution, intramyocellular, and IHL were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate an individual's CRF. Insulin sensitivity was determined during an oral glucose tolerance test. RESULTS--For all subjects, CRF was related to insulin sensitivity (r = 0.32, P < 0.05), IHL (r = -0.27, P < 0.05), and visceral (r = -0.25, P < 0.05) and total fat mass (r = -0.32, P < 0.05), but not to intramyocellular lipids (r = -0.08, NS). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat, and fitness (r2 = -0.43, P < 0.01, 2 = -0.34, and 2 = 0.29, P < 0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r = 0.16, NS), whereas it remained significant when adjusted for visceral or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels. CONCLUSIONS--Our study suggests that the positive effect of increased CRF on insulin sensitivity in overweight to obese subjects may be mediated indirectly through IHL reduction. Diabetes 59:1640-1647, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Peptide YY3-36 (PYY3-36, a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3-36 and oxyntomodulin can be additive. RESEARCH DESIGN AND METHODS--Twelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3-36 or oxyntomodulin or combined PYY3-36/oxyntomodulin. RESULTS--Energy intake during coadministration of PYY3-36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone. CONCLUSIONS--The anorectic effects of PYY3-36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto-/- mice are lean and Fro+/- mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO. RESEARCH DESIGN AND METHODS--We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants. RESULTS--We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals. CONCLUSIONS--Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme. Diabetes 59:311-318, 2010 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Insulin resistance in skeletal muscle is an early phenomenon in the pathogenesis of type 2 diabetes. Studies of insulin resistance usually are highly focused. However, approaches that give a more global picture of abnormalities in insulin resistance are useful in pointing out new directions for research. In previous studies, gene expression analyses show a coordinated pattern of reduction in nuclear-encoded mitochondrial gene expression in insulin resistance. However, changes in mRNA levels may not predict changes in protein abundance. An approach to identify global protein abundance changes involving the use of proteomics was used here. RESEARCH DESIGN AND METHODS--Muscle biopsies were obtained basally from lean, obese, and type 2 diabetic volunteers (n = 8 each); glucose clamps were used to assess insulin sensitivity. Muscle protein was subjected to mass spectrometry-based quantification using normalized spectral abundance factors. RESULTS--Of 1,218 proteins assigned, 400 were present in at least haft of all subjects. Of these, 92 were altered by a factor of 2 in insulin resistance, and of those, 15 were significantly increased or decreased by ANOVA (P < 0.05). Analysis of protein sets revealed patterns of decreased abundance in mitochondrial proteins and altered abundance of proteins involved with cytoskeletal structure (desmin and alpha actinin-2 both decreased), chaperone function (TCP-1 subunits increased), and proteasome subunits (increased). CONCLUSIONS--The results confirm the reduction in mitochondrial proteins in insulin-resistant muscle and suggest that changes in muscle structure, protein degradation, and folding also characterize insulin resistance. Diabetes 59:33-42, 2010 [ABSTRACT FROM AUTHOR]

The authors comment on an article on the recruitment of brown adipose tissue (BAT) in obese humans, by Hanssen and colleagues, published within the issue. The study found no significant relationship between BAT and percent body fat, but BAT activity was found to be inversely related to age before and after cold acclimation. The authors concluded that BAT plays a key role in metabolic regulation.

OBJECTIVE--We examined preadipocyte differentiation in obese and nonobese individuals and the effect of cytokines and wingless-type MMTV (mouse mammary tumor virus) integration site family, member 3A (Wnt3a) protein on preadipocyte differentiation and phenotype. RESEARCH DESIGN AND METHODS--Abdominal subcutaneous adipose tissue biopsies were obtained from a total of 51 donors with varying BMI. After isolation of the adipose and stromalvascular cells, inflammatory cells (CD14- and CD45-positive cells) were removed by immune magnetic separation. CD133-opositive cells, containing early progenitor cells, were also isolated and quantified. The CD14- and CD45-negative preadipocytes were cultured with tumor necrosis factor (TNF)-α, interleukin (IL)-6, resistin, or Wnt3a with or without a differentiation cocktail. RESULTS--The number of preadipocytes able to differentiate to adipose cells was negatively correlated with both BMI and adipocyte cell size of the donors, whereas the number of CD133-positive cells was positively correlated with BMI, suggesting an impaired differentiation of preadipocytes in obesity. Cultured preadipocytes, like freshly isolated mature adipocytes, from obese individuals had an increased expression of mitogenactivated protein 4 kinase 4 (MAP4K4), which is known to inhibit peroxisome proliferator-activated receptoro-γinduction. TNF-α, but not IL-6 or resistin, increased Wntl0b, completely inhibited the normal differentiation of the preadipocytes, and instead induced a proinflammatory and macrophage-like phenotype of the cells. CONCLUSIONS--The apparent number of preadipocytes in the abdominal subcutaneous tissue that can undergo differentiation is reduced in obesity with enlarged fat cells, possibly because of increased MAP4K4 levels. TNF-α promoted a macrophage-like phenotype of the preadipocytes, including several macrophage markers. These results document the plasticity of human preadipocytes and the inverse relationship between lipid storage and proinflammatory capacity. Diabetes 58:1550-1557, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted. RESEARCH DESIGN AND METHODS--Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 ± 1 years (mean ± SE) with BMI 31.6 ± 0.6 kg/m², who fulfilled the Adult Treatment Panel HI criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program. RESULTS--Body weight decreased by 8.1 ± 0.9 and 8.4 ± 1.1 kg and resting norepinephrine spillover by 94 ± 31 and 166 ± 58 ng/min (all P ≤ 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged -3 ± 25 versus 73 ± 24 ng/min at 30 min (P = 0.039), 36 - 21 versus 115 ± 28 ng/min at 60 min (P = 0.045), 9 ± 21 versus 179 ± 50 ng/min at 90 min (P < 0.001), and 40 ± 48 versus 106 - 39 ng/min at 120 min (P = 0.24). CONCLUSIONS--Weight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis. Diabetes 58: 1126-1132, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To quantitate plasma ceramide subspecies concentrations in obese subjects with type 2 diabetes arid relate these plasma levels to the severity of insulin resistance. Ceramides are a putative mediator of insulin resistance and lipotoxicity, and accumulation of ceramides within tissues in obese and diabetic subjects has been well described. RESEARCH DESIGN AND METHODS--We analyzed fasting plasma ceramide subspecies by quantitative tandem mass spectrometry in 13 obese type 2 diabetic patients and 14 lean healthy control subjects. Results were related to insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp technique and with plasma tumor necrosis factor-α (TNF-α)levels, a marker of inflammation. Ceramide species (C18:1, 18:0, 20:0, 24:1, and 24:0) were quantified using electrospray ionization tandem mass spectrometry after separation with high-performance liquid chromatography. RESULTS--Insulin sensitivity (mg ⋅ kg[sup -1] ⋅ min[sup -1]) was lower in type 2 diabetic patients (4.90 ± 0.3) versus control subjects (9.6 ± 0.4) (P < 0.0001). Type 2 diabetic subjects had higher (P < 0.05) concentrations of C18:0, C20:0, C24:1, and total ceramide. Insulin sensitivity was inversely correlated with C18:0, C20:0, C24:1, C24:0, and total ceramide (all P < 0.01). Plasma TNF-α concentration was increased (P < 0.05) in type 2 diabetic subjects and correlated with increased C18:1 and C18:0 ceramide subspecies. I CONCLUSIONS--Plasma ceramide levels are elevated in type 2 diabetic subjects and may contribute to insulin resistance through activation of inflammatory mediators, such as TNF-α. [ABSTRACT FROM AUTHOR]

OBJECTIVE--11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates cortisol from cortisone. 11β-HSD1 mRNA and activity are increased in vitro in subcutaneous adipose tissue from obese patients. Inhibition of 11β-HSD1 is a promising therapeutic approach in type 2 diabetes. However, release of cortisol by 11β-HSD1 from adipose tissue and its effect on portal vein cortisol concentrations have not been quantified in Vivo. RESEARCH DESIGN AND METHODS--Six healthy men underwent 9,11,12,12-[²2H][sub 4]-cortisol infusions with simultaneous sampling of arterialized and superficial epigastric vein blood sampling. Four men with stable chronic liver disease and a transjugular intrahepatic porto-systemic shunt in situ underwent tracer infusion with simultaneous sampling from the portal vein, hepatic vein, and an arterialized peripheral vein. RESULTS--Significant cortisol and 9,12,12-[²H][sub 3]-cortisol release were observed from subcutaneous adipose tissue (15.0 [95% CI 0.4-29.5] and 8.7 [0.2-17.2] pmol ⋅ min[sup -1] ⋅ 100 g[sup -1] adipose tissue, respectively). Splanchnic release of cortisol and 9,12,12-[²H][sub 3]-cortisol (13.5 [3.6-23.5] and 8.0 [2.6-13.5] nmol/min, respectively) was accounted for entirely by the liver; release of cortisol from visceral tissues into portal vein was not detected. CONCLUSIONS--Cortisol is released from subcutaneous adipose tissue by 11β-HSD1 in humans, and increased enzyme expression in obesity is likely to increase local glucocorticoid signaling and contribute to whole-body cortisol regeneration. However, Visceral adipose 11β-HSD1 activity is insufficient to increase portal vein cortisol concentrations and hence to influence intrahepatic glucocorticoid signaling. Diabetes 58:46-53, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To determine the contribution of liver and viscera to splanchnic cortisol production in humans. RESEARCH DESIGN AND METHODS--D4 cortisol was infused intravenously; arterial, portal venous, and hepatic venous blood was sampled; and liver and visceral fat were biopsied in subjects undergoing bariatric surgery. RESULTS--Ratios of arterial and portal vein D4 cortisol/ cortisoltotal (0.06 ± 0.01 vs. 0.06 ± 0.01) and D4 cortisol/D3 cortisol (1.80 ± 0.14 vs. 1.84 ± 0.14) did not differ, indicating that no visceral cortisol production or conversion of D4 cortisol to D3 cortisol via 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1) occurred. Conversely, ratios of both D4 cortisol to cortisoltotal (0.05 ± 0.01; P < 0.05) and D4 cortisol to D3 cortisol (1.33 ± 0.11; P < 0.001) were lower in the hepatic vein than in the portal vein, indicating production of both cortisol and D3 cortisol by the liver. The viscera did not produce either cortisol (-8.1 ± 2.6 µg/min) or D3 cortisol (-0.2 ± 0.1 µg/min). In contrast, the liver produced both cortisol (22.7 ± 3.90 µg/min) and D3 cortisol (1.9 ± 0.4 µg/min) and accounted for all splanchnic cortisol and D3 cortisol production. Additionally, 11β-HSD-1 mRNA was approximately ninefold higher (P < 0.01) in liver than in visceral fat. Although 11β-HSD-2 gene expression was very low in visceral fat, the viscera released cortisone (P < 0.001) and D3 cortisone (P < 0.01) into the portal vein. CONCLUSIONS--The liver accounts for all splanchnic cortisol production in obese nondiabetic humans. In contrast, the viscera releases cortisone into the portal vein, thereby providing substrate for intrahepatic cortisol production. Diabetes 58:39-45, 2009 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To study the role of the ENPP1 Q121 variant on glucose homeostasis in whites from Italy. RESEARCH DESIGN AND METHODS--We conducted case-control studies in 764 adults (from two independent samples of 289 nonobese and 485 obese individuals) and 240 overweight/ obese children undergoing oral glucose tolerance testing (OGTT). Early-phase insulin secretion and insulin sensitivity (the insulinogenic index and the insulin sensitivity index) and their interplay (the disposition index) were calculated. RESULTS--In adult subjects, glucose profiles during OGTT were significantly (P = 2 x 10[sup -2]) different across K121Q genotype groups and higher in QQ than KK individuals (P = 5 x 10[sup -2]). The insulinogenic index was significantly reduced in QQ (18.5 ± 3.4) compared with both KK (31.6 ± 1.0; P = 2.2 x 10[sup -7]) and KQ (30.5 ± 1.5; P = 3.2 x 10[sup -6]) individuals. KQ individuals also showed a reduced insulin sensitivity index compared with KK subjects (P = 3.6 x 10[sup -2]). The disposition index was lower in QQ carriers than in KQ and KK individuals (P = 8 x 10[sup -3] and 4 x 10[sup -4], respectively) and lower in KQ than in KK individuals (P = 3 x 10[sup -2]). Data obtained in overweight/obese children were very similar to those observed in adults, with QQ individuals showing (compared with KQ and KK subjects) a reduced insulinogenic index (P = 7 x 10[sup -3] and 2 x 10[sup -2], respectively) and disposition index (P = 2 x 10[sup -2] and 7 x 10[sup -3], respectively). CONCLUSIONS--Homozygous carriers of the ENPP1 Q121 variant are characterized by an altered glucose homeostasis. Reduced early-phase insulin secretion and inefficient interplay between insulin secretion and sensitivity, which occur at early ages, are major determinants of this defect. Diabetes 57: 3360-3364, 2008 [ABSTRACT FROM AUTHOR]

The article discusses the sensitivity of human obesity to environmental conditions. It notes that aside from the increasing ease of access to high-energy palatable food and lack of physical activity, obesity can also be associated with inherited variation in the efficiency of central control mechanisms affecting eating behavior. It adds that an enlightened public attitude towards people with obesity may be obtained by placing emphasis on the profound biological basis for inter-individual differences in achieving a healthy food intake.

OBJECTIVE--The precise molecular mechanisms contributing to the development of insulin resistance, impaired glucose tolerance (IGT), and type 2 diabetes are largely unknown. Altered endogenous glucocorticoid metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active cortisol from cortisone, and 5α-reductase (5αR), which inactivates cortisol, has been implicated. RESEARCH DESIGN AND METHODS--A total of 101 obese patients (mean age 48 ± 7 years, BMI 34.4 ± 4.3 kg/m², 66 women, 35 men) underwent 75-g oral glucose tolerance testing (OGTT), body composition analysis (dual-energy X-ray absorptiometry), assessment of glucocorticoid metabolism (24-h urine steroid metabolite analysis by gas chromatography/mass spectrometry), and subcutaneous abdominal adipose tissue biopsies. RESULTS--A total of 22.7% of women had IGT compared with 34.2% of men. Two women and five men were diagnosed with type 2 diabetes. In women, adipose 11β-HSD1 expression was increased in patients with IGT and correlated with glucose levels across the OGTT (R = 0.44, P < 0.001) but was independent of fat mass. Total glucocorticoid secretion was higher in men with and without IGT (normal 13,743 ± 863 vs. 7,453 ± 469 µg/24 h, P < 0.001; IGT 16,871 ± 2,113 vs. 10,133 ± 1,488 µg/24 h, P < 0.05), and in women, it was higher in those with IGT (7,453 ± 469 vs. 10,133 ± 1,488 µg/24 h, P < 0.001). In both sexes, 5αR activity correlated with fasting insulin (men R = 0.53, P = 0.003; women R = 0.33, P = 0.02), insulin secretion across an OGTT (men R = 0.46, P = 0.01; women R = 0.40, P = 0.004), and homeostasis model assessment of insulin resistance (men R = 0.52, P = 0.004; women R = 0.33, P = 0.02). CONCLUSIONS--Increased adipose 11β-HSD1 expression in women may contribute to glucose intolerance. Enhanced 5αR activity in both sexes is associated with insulin resistance but not body composition. Augmented glucocorticoid inactivation may serve as a compensatory, protective mechanism to preserve insulin sensitivity. Diabetes 57:2652-2660, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown. RESEARCH DESIGN AND METHODS--We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations. RESULTS--Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 x 10[sup 10]). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years). CONCLUSIONS--We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it. Diabetes 57:25112518, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE--To examine fat biopsy samples from lean insulin-sensitive and obese insulin-resistant nondiabetic individuals for evidence of endoplasmic reticulum (ER) stress. RESEARCH DESIGN AND METHODS--Subcutaneous fat biopsies were obtained from the upper thighs of six lean and six obese nondiabetic subjects. Fat homogenates were used for proteomic (two-dimensional gel and MALDI-TOF/TOF), Western blot, and RT-PCR analysis. RESULTS--Proteomic analysis revealed 19 differentially upregulated proteins in fat of obese subjects. Three of these proteins were the ER stress-related unfolded protein response (UPR) proteins calreticulin, protein disulfide-isomerase A3, and glutathione-S-transferase P. Western blotting revealed upregulation of several other UPR stress-related proteins, including calnexin, a membrane-bound chaperone, and phospho c-jun NH[sub 2]-terminal kinase (JNK)-1, a downstream effector protein of ER stress. RT-PCR analysis revealed upregulation of the spliced form of X-box binding protein-is, a potent transcription factor and part of the proximal ER stress sensor inositol-requiring enzyme-1 pathway. CONCLUSIONS--These findings represent the first demonstration of UPR activation in subcutaneous adipose tissue of obese human subjects. As JNK can inhibit insulin action and activate proinflammatory pathways, ER stress activation of JNK may be a link between obesity, insulin resistance, and inflammation. Diabetes 57:2438-2444, 2008 [ABSTRACT FROM AUTHOR]

The article presents abstracts of research on clinical treatment for obesity, which includes articles on body volume index, factor structure of the power of food scale in obese patients with diabetes, and correlation between gamma glutamyl transferase levels and metabolic syndrome parameters in young obese.

This section presents abstracts of research on diabetes and hormone secretion and exocytosis, including "A Role for Adipose Triglycerlde Lipase in Fuel-Stimulated Insulin Secretion," "C Peptide Measurement in Patients With Type 1 Diabetes From a Multiethnic Population," and "Cross-Sectional and Longitudinal Changes in Insulin Secretion Are Associated With Soluble Leptin Receptor Concentrations in Severely Obese Women Undergoing Weight Loss."

The article presents abstracts on medical topics which include the effects of fructose consumption in overweight and obese men and women, the biomarker for consumption of sweets in the atherosclerosis risk in communities magnetic resonance imaging study, and the effect of eight weeks of red wine and vodka on insulin sensitivity in insulin resistant individuals.

OBJECTIVE--Triglyceride-rich lipoproteins, primarily chylomicrons, can contribute to plasma free fatty acid (FFA) concentrations via spillover of fatty acids during intravascular hydrolysis into the venous effluent of some tissues. The present study was undertaken to determine whether spillover occurs in the splanchnic bed of humans. RESEARCH DESIGN AND METHODS--Arterial and hepatic venous blood was sampled in postabsorptive (n = 6; study A) and postprandial (n = 5; study B) obese humans during infusion of carbon-labeled (14C or C) oleate and 3H triolein, the latter incorporated into a lipid emulsion as a surrogate for chylomicrons. Spillover was determined by measuring production of 3H oleate. RESULTS--Splanchnic spillover was higher than nonsplanchnic systemic spillover in both study A (60 ± 7 vs. 24 ± 6%; P < 0.01) and study B (54 ± 3 vs. 16 ± 5%; P < 0.005). Because portal vein sampling is not feasible in humans, assumptions regarding actual spillover in nonhepatic splanchnic tissues were required for the spillover calculation. A mathematical model was developed and demonstrated that nonhepatic splanchnic spillover rates in study A and study B of 69 and 80%, respectively, provided the best fit with the data. There was preferential splanchnic uptake of triglyceride fatty acids compared with FFAs in study B (fractional extraction 61 ± 3 vs. 33 ± 2%; P < 0.005). CONCLUSIONS--These data confirm previous studies indicating that the transport of FFAs and triglyceride fatty acids are partitioned in tissues and indicate that splanchnic spillover from triglyceride-rich lipoproteins may be a significant source of both portal venous and systemic FFAs. Diabetes 56:2878-2884, 2007 [ABSTRACT FROM AUTHOR]

OBJECTIVE--Lipin 1 plays critical roles in controlling energy metabolism. We sought to determine the expression of lipin 1 isoforms (lipin 1α and -β) in liver and adipose tissue of obese subjects and to evaluate cellular mechanisms involved in the regulation of lipin 1 expression by physiologic stimuli. RESEARCH DESIGN AND METHODS--The expression of lipin 1α and -β was quantified in liver and adipose tissue of extremely obese (average BMI 60.8 kg/m²) human subjects undergoing gastric bypass surgery (GBS). Second, the expression of lipin 1 was evaluated in HepG2 cells in response to overexpression of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α under normal or hyperinsulinemic conditions. RESULTS--The expression of lipin 1β in liver and adipose tissue was inversely related to BMI, fasting plasma insulin concentration, and the homeostasis model assessment of insulin resistance but was significantly increased by marked weight loss and insulin sensitization following GBS. Hepatic lipin 1β mRNA levels were strongly correlated with the expression of PGC-1α, and overexpression of PGC-1α in HepG2 cells increased lipin 1 expression. Conversely, hyperinsulinemic culture conditions downregulated the expression of lipin 1β, PGC-1α, and their known target genes involved in mitochondrial metabolism in HepG2 cells. Finally, overexpression of lipin 1β or PGC-1α reversed the effect of hyperinsulinemia on the expression of their target genes. CONCLUSIONS--These studies suggest that hepatic lipin 1β and PGC-1α expression are downregulated by obesity and obesity-related metabolic perturbations in human subjects, likely due to alterations in insulin concentration or sensitivity. Diabetes 56:2395-2399, 2007 [ABSTRACT FROM AUTHOR]

We tested the hypothesis of a lower respiratory capacity per mitochondrion in skeletal muscle of type 2 diabetic patients compared with obese subjects. Muscle biopsies obtained from 10 obese type 2 diabetic and 8 obese nondiabetic male subjects were used for assessment of 3hydroxy-Acyl-CoA-dehydrogenase (HAD) and citrate synthase activity, uncoupling protein (UCP)3 content, oxidative stress measured as 4-hydroxy-2-nonenal (HNE), fiber type distribution, and respiration in isolated mitochondria. Respiration was normalized to citrate synthase activity (mitochondrial content) in isolated mitochondria. Maximal ADP-stimulated respiration (state 3) with pyruvate plus malate and respiration through the electron transport chain (ETC) were reduced in type 2 diabetic patients, and the proportion of type 2X fibers were higher in type 2 diabetic patients compared with obese subjects (all P < 0.05). There were no differences in respiration with palmitoyl-L-carnitine plus malate, citrate synthase activity, HAD activity, UCP3 content, or oxidative stress measured as HNE between the groups. In the whole group, state 3 respiration with pyruvate plus malate and respiration through ETC were negatively associated with A1C, and the proportion of type 2X fibers correlated with markers of insulin resistance (P < 0.05). In conclusion, we provide evidence for a functional impairment in mitochondrial respiration and increased amount of type 2X fibers in muscle of type 2 diabetic patients. These alterations may contribute to the development of type 2 diabetes in humans with obesity. Diabetes 56:1592-1599, 2007 [ABSTRACT FROM AUTHOR]

We sought to assess whether direct uptake of circulating free fatty acids (FFAs) by adipocytes occurs in vivo in overnight postabsorptive humans and, if so, whether there are regional differences in uptake between lean and obese women and men. We used bolus injections of radiolabeled FFA tracers followed by carefully timed adipose tissue biopsies. First, we validated a method to measure direct adipocyte FFA uptake and then quantitated this process using the modified methods in normal-weight postabsorptive men and women. We then used a continuous infusion of radiolabeled FFA to measure direct and indirect (VLDL) regional adipose tissue uptake in obese men and women. Direct FFA uptake was greater in women than men: 8.2 ± 0.6 vs. 4.0 ± 0.5% (P < 0.0001) of FFAs were taken up by subcutaneous adipose tissue, respectively. Abdominal subcutaneous fat took up FFAs more avidly than femoral fat in men, but this did not occur in women. Similar sex and regional difference were found to occur in obese women and men. Gene expression of fatty acid transporters was greater in abdominal than femoral fat in men (P < 0.05) but not in women (P = 0.80). We observed sex- and site-specific recycling of circulating FFAs into subcutaneous fat. This is a novel FFA disposal pathway that may also play a role in the development or maintenance of body fat distribution. Regional variations in facilitated fatty acid transport may contribute to this process. Diabetes 56:1369-1375, 2007 [ABSTRACT FROM AUTHOR]

Although excess visceral fat is associated with noninfectious inflammation, it is not clear whether visceral fat is simply associated with or actually causes metabolic disease in humans. To evaluate the hypothesis that visceral fat promotes systemic inflammation by secreting inflammatory adipokines into the portal circulation that drains visceral fat, we determined adipokine arteriovenous concentration differences across visceral fat, by obtaining portal vein and radial artery blood samples, in 25 extremely obese subjects (mean ± SD BMI 54.7 ± 12.6 kg/m2) during gastric bypass surgery at Barnes-Jewish Hospital in St. Louis, Missouri. Mean plasma interleukin (IL)-6 concentration was ∼50% greater in the portal vein than in the radial artery in obese subjects (P = 0.007). Portal vein IL-6 concentration correlated directly with systemic C-reactive protein concentrations (r = 0.544, P = 0.005). Mean plasma leptin concentration was ∼20% lower in the portal vein than in the radial artery in obese subjects (P = 0.0002). Plasma tumor necrosis factor-α, resistin, macrophage chemoattractant protein-1, and adiponectin concentrations were similar in the portal vein and radial artery in obese subjects. These data suggest that visceral fat is an important site for IL-6 secretion and provide a potential mechanistic link between visceral fat and systemic inflammation in people with abdominal obesity. Diabetes 56:1010-1013, 2007 [ABSTRACT FROM AUTHOR]

The normal action of insulin to vasodilate and redistribute blood flow in support of skeletal muscle metabolism is impaired in insulin-resistant states. Increased endogenous endothelin contributes to endothelial dysfunction in obesity and diabetes. Here, we test the hypothesis that increased endogenous endothelin action also contributes to skeletal muscle insulin resistance via impairments in insulin-stimulated vasodilation. We studied nine lean and seven obese humans, measuring the metabolic and hemodynamic effects of insulin (300 mU ⋅ m-2 ⋅ min-1) alone and during femoral artery infusion of BQ123 (an antagonist of type A endothelin receptors, 1 µmol/min). Endothelin antagonism augmented skeletal muscle responses to insulin in obese subjects through changes in both leg blood flow (LBF) and glucose extraction. Insulin-stimulated LBF was significantly increased in obese subjects only. These changes, combined with differential effects on glucose extraction, resulted in augmented insulin-stimulated leg glucose uptake in obese subjects (54.7 ± 5.7 vs. 107.4 ± 18.9 mg/min with BQ123), with no change in lean subjects (103.7 ± 11.4 vs. 88.9 ± 16.3, P = 0.04 comparing BQ123 across groups). BQ123 allowed augmented leg glucose extraction in obese subjects even in the face of NOS antagonism. These findings suggest that increased endogenous endothelin action contributes to insulin resistance in skeletal muscle of obese humans, likely through both vascular and tissue effects. Diabetes 56:728-734, 2007 [ABSTRACT FROM AUTHOR]