OBJECTIVE-Based on rodent studies, we examined the hypothesis that increased adipose tissue (AT) mass in obesity without an adequate support of vascularization might lead to hypoxia, macrophage infiltration, and inflammation.RESEARCH DESIGN AND METHODS-Oxygen partial pressure (AT pO 2 ) and AT temperature in abdominal AT (9 lean and 12 overweight/obese men and women) was measured by direct insertion of a polarographic Clark electrode. Body composition was measured by dual-energy X-ray absorptiometry, and insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Abdominal subcutaneous tissue was used for staining, quantitative RT-PCR, and chemokine secretion assay.RESULTS-AT pO 2 was lower in overweight/obese subjects than lean subjects (47 Ϯ 10.6 vs. 55 Ϯ 9.1 mmHg); however, this level of pO 2 did not activate the classic hypoxia targets (pyruvate dehydrogenase kinase and vascular endothelial growth factor [VEGF]). AT pO 2 was negatively correlated with percent body fat (R ϭ Ϫ0.50, P Ͻ 0.05). Compared with lean subjects, overweight/ obese subjects had 44% lower capillary density and 58% lower VEGF, suggesting AT rarefaction (capillary drop out). This might be due to lower peroxisome proliferator-activated receptor ␥1 and higher collagen VI mRNA expression, which correlated with AT pO 2 (P Ͻ 0.05). Of clinical importance, AT pO 2 negatively correlated with CD68 mRNA and macrophage inflammatory protein 1␣ secretion (R ϭ Ϫ0.58, R ϭ Ϫ0.79, P Ͻ 0.05), suggesting that lower AT pO 2 could drive AT inflammation in obesity.CONCLUSIONS-Adipose tissue rarefaction might lie upstream of both low AT pO 2 and inflammation in obesity. These results suggest novel approaches to treat the dysfunctional AT found in obesity. Diabetes 58:718-725, 2009 B oth insulin resistance and ␤-cell failure are present in individuals with type 2 diabetes. Insulin resistance is closely linked to adiposity with a central or visceral pattern, providing a greater risk of insulin resistance and metabolic dysfunction. Adipose tissue (AT) serves as an endocrine organ secreting a variety of autocrine, paracrine, and endocrine factors that can produce or prevent insulin resistance (1). The failure of AT to adequately proliferate and/or differentiate to sequester lipids away from liver, skeletal muscle, and the pancreatic ␤-cell has been proposed as a precursor to type 2 diabetes, broadening the number of potential mechanisms linking obesity to insulin resistance (2).The increase in body fat in obesity should be accompanied by an increase in vascularization, in order to provide adequate oxygen and nutrients (3). In contrast to expectations, obese mice have lower AT capillary density (rarefaction, also known as capillary drop out) and decreased vascular endothelial growth factor (VEGF), the most potent angiogenic factor (4,5). Consistent with this model, preclinical studies suggest that obese AT is hypoxic (6); however, the hypothesis that AT rarefaction might lead to hypoxia remains untested.In humans, short-term whole-body hypoxia decreases i...

Metabolic flexibility of skeletal muscle, that is, the preference for fat oxidation (FOx) during fasting and for carbohydrate oxidation in response to insulin, is decreased during insulin resistance. The aim of this study was to test the hypothesis that the capacity of myotubes to oxidize fat in vitro reflects the donor's metabolic characteristics. Insulin sensitivity (IS) and metabolic flexibility of 16 healthy, young male subjects was determined by euglycemic hyperinsulinemic clamp. Muscle samples were obtained from vastus lateralis, cultured, and differentiated into myotubes. In human myotubes in vitro, we measured suppressibility (glucose suppression of FOx) and adaptability (an increase in FOx in the presence of high palmitate concentration). We termed these dynamic changes in FOx metabolic switching. In vivo, metabolic flexibility was positively correlated with IS and maximal oxygen uptake and inversely correlated with percent body fat. In vitro suppressibility was inversely correlated with IS and metabolic flexibility and positively correlated with body fat and fasting FFA levels. Adaptability was negatively associated with percent body fat and fasting insulin and positively correlated with IS and metabolic flexibility. The interindividual variability in metabolic phenotypes was preserved in human myotubes separated from their neuroendocrine environment, which supports the hypothesis that metabolic switching is an intrinsic property of skeletal muscle. IntroductionObesity and type 2 diabetes are characterized by an increase in body fat, a decrease in insulin-stimulated glucose disposal, and disturbances of oxidative metabolism. Skeletal muscle, the organ responsible for the majority of insulin-stimulated glucose uptake, has a decreased oxidative capacity in obesity and diabetes (1-3) and after weight loss (4-7). Furthermore, Zurlo (8) and others (9-11) showed that decreased fat oxidation (FOx) (represented by a higher respiratory quotient [RQ], the ratio of CO 2 produced to O 2 consumed) is a predictor of weight gain, which suggests the importance of early defects in FOx for future development of obesity and diabetes. Defects in skeletal muscle oxidative capacity and fat metabolism are highly correlated with insulin sensitivity (IS) (1,5,12) and are believed to contribute to the pathogenesis of insulin resistance (13,14).A high-fat diet (HFD) challenges the oxidative machinery of skeletal muscle. Substantial variability exists in the ability of individuals to adapt to HFD by increasing FOx (15). An imbalance between fat intake and FOx results in a positive fat balance (15). Decreased adaptation to HFD has been observed in restrained eaters (16), formerly obese (17, 18) and obese individuals (19), and individuals with a family history of obesity (20). The latter study points toward a possible genetic basis for reduced FOx. Attenuated adaptation to HFD might represent yet another feature of "metabolic inflexibility," the impaired ability of skeletal muscle to switch from carbohydrate to fat oxidation during...

Insulin resistance is associated with metabolic inflexibility, impaired switching of substrate oxidation from fatty acids to glucose in response to insulin. Impaired switching to fat oxidation in response to a high-fat diet (HFD) is hypothesized to contribute to insulin resistance. The objective of this study was to test the hypothesis that defects in substrate switching in response to insulin and a HFD are linked to reduced mitochondrial biogenesis and occur before the development of diabetes. Metabolic flexibility was measured in young sedentary men with (n ‫؍‬ 16) or without (n ‫؍‬ 34) a family history of diabetes by euglycemichyperinsulinemic clamp. Flexibility correlated with fat oxidation measured in a respiratory chamber after a 3-day HFD. Muscle mitochondrial content was higher in flexible subjects with high fat oxidation after a HFD and contributed 49% of the variance. Subjects with a family history of diabetes were inflexible and had reduced HFD-induced fat oxidation and muscle mitochondrial content but did not differ in the amount of body or visceral fat. Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance. Diabetes 56:720 -727, 2007 A high-fat diet (HFD) is a risk factor for obesity and has been implicated in the development of insulin resistance (1). A short-term HFD, as well as a lipid infusion, causes insulin resistance (2-4), reduces oxidative metabolism in skeletal muscle in rats (5), and downregulates genes of oxidative phosphorylation and mitochondrial biogenesis, such as peroxisome proliferator-activated ␥ coactivator-1␣ (PGC-1␣) (6). Moreover, oxidative phosphorylation and PGC-1␣ gene expression are decreased in insulin resistance (7,8). Taken together, these findings point to HFD, reduced oxidative capacity, and lipotoxicity in the pathophysiology of insulin resistance (9,10).Substantial interindividual variability exists in the change of fat oxidation during adaptation to a HFD (11). Impaired fat oxidation during adaptation to a HFD is observed in restrained eaters (12), postobese (13) and obese (14) individuals, and in individuals with a family history of obesity (15), pointing toward a possible genetic basis for reduced fat oxidation (1). Impaired substrate switching in response to insulin (metabolic inflexibility) and dietary stimuli (attenuated adaptation to a HFD) are hypothesized to contribute to obesity and insulin resistance (1,16).Metabolic inflexibility, as defined by Kelley and Mandarino (17), represents impaired substrate switching in skeletal muscle in insulin resistance. Healthy lean individuals who are flexible rely on lipids as a main source of fuel under fasting conditions and readily switch to carbohydrate oxidation in response to insulin infusion (18). On the contrary, the inflexible muscle of an insulin-resistant individual is characterized by lower fasting ...

Mitochondrial capacity is not associated with insulin action in T2DM.

OBJECTIVE To provide a comprehensive evaluation of chromium (Cr) supplementation on metabolic parameters in a cohort of Type 2 DM subjects representing a wide phenotype range and to evaluate changes in “responders” and “non-responders”. DESIGN After pre-intervention testing to assess glycemia, insulin sensitivity (assessed by euglycemic clamps), Cr status, body composition, subjects were randomized in a double-blind fashion to placebo or 1,000 μg Cr. A sub-study was performed to evaluate 24 hour energy balance/substrate oxidation and myocellular/intra-hepatic lipid content. RESULTS There was not a consistent effect of chromium supplementation to improve insulin action across all phenotypes. Insulin sensitivity was negatively correlated to soleus and tibialis muscle intramyocellular lipids and intra-hepatic lipid content. Myocellular lipids were significantly lower in subjects randomized to Cr. At pre-intervention, “responders”, defined as insulin sensitivity change from baseline > 10%, had significantly lower insulin sensitivity and higher fasting glucose and A1c when compared to placebo and “non-responders”, i.e. insulin sensitivity change from baseline < 10%. Clinical response was significantly correlated (p < 0.001) to the baseline insulin sensitivity, fasting glucose and A1c. There was no difference in Cr status between “responders”, and “non-responders”. CONCLUSIONS Clinical response to chromium is more likely in insulin resistant subjects who have more elevated fasting glucose and A1c levels. Cr may reduce myocellular lipids and enhance insulin sensitivity in subjects with type 2 DM independent of effects on weight or hepatic glucose production. Thus, modulation of lipid metabolism by Cr in peripheral tissues may represent a novel mechanism of action.

Background and Aims-Considerable controversy exists regarding use of chromium (Cr) supplementation to modulate carbohydrate metabolism in subjects with diabetes. Recently, we reported that Cr supplementation, provided as 1000 ug/day as Cr picolinate, enhanced insulin

No abstract

No abstract