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Chronic inflammation accompanies obesity and limits subcutaneous white adipose tissue (WAT) expandability, accelerating the development of insulin resistance and type 2 diabetes mellitus. MicroRNAs (miRNAs) influence expression of many metabolic genes in fat cells, but physiological roles in WAT remain poorly characterized. Here, we report that expression of the miRNA miR-30a in subcutaneous WAT corresponds with insulin sensitivity in obese mice and humans. To examine the hypothesis that restoration of miR-30a expression in WAT improves insulin sensitivity, we injected adenovirus (Adv) expressing miR-30a into the subcutaneous fat pad of diabetic mice. Exogenous miR-30a expression in the subcutaneous WAT depot of obese mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. High-throughput proteomic profiling and RNA-Seq suggested that miR-30a targets the transcription factor STAT1 to limit the actions of the proinflammatory cytokine interferon-γ (IFN-γ) that would otherwise restrict WAT expansion and decrease insulin sensitivity. We further demonstrated that miR-30a opposes the actions of IFN-γ, suggesting an important role for miR-30a in defending adipocytes against proinflammatory cytokines that reduce peripheral insulin sensitivity. Together, our data identify a critical molecular signaling axis, elements of which are involved in uncoupling obesity from metabolic dysfunction.

AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, being activated during states of low energy charge. Hypothalamic AMPK activity is altered by hormonal and metabolic signals and mediates the feeding response. To determine the effect of diabetes on hypothalamic AMPK activity, we assayed this activity in streptozotocin (STZ)-induced diabetic rats. Compared with control rats, STZ-induced diabetic rats had significant hyperphagia and weight loss. Hypothalamic AMPK phosphorylation and alpha2-AMPK activity were higher and acetyl-CoA carboxylase activity was lower in diabetic rats than in control rats. Chronic insulin treatment or suppression of hypothalamic AMPK activity completely prevented diabetes-induced changes in food intake as well as in hypothalamic AMPK activity and mRNA expression of neuropeptide Y and proopiomelanocortin. Plasma leptin and insulin levels were profoundly decreased in diabetic rats. Intracerebroventricular administration of leptin and insulin reduced hyperphagia and the enhanced hypothalamic AMPK activity in diabetic rats. These data suggest that leptin and insulin deficiencies in diabetes lead to increased hypothalamic AMPK activity, which contributes to the development of diabetic hyperphagia. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Alpha-lipoic acid is an essential cofactor for mitochondrial respiratory enzymes that improves mitochondrial function. We previously reported that alpha-lipoic acid markedly reduced body weight gain in rodents. The purpose of this study was to determine whether alpha-lipoic acid reduces body weight in obese human subjects. Methods: In this randomized, double-blind, placebo-controlled, 20-week trial, 360 obese individuals (body mass index [BMI]≥30 kg/m2 or BMI 27-30 kg/m2 plus hypertension, diabetes mellitus, or hypercholesterolemia) were randomized to alpha-lipoic acid 1200 or 1800 mg/d or placebo. The primary end point was body weight change from baseline to end point. Results: The 1800 mg alpha-lipoic acid group lost significantly more weight than the placebo group (2.1%; 95% confidence interval, 1.4-2.8; P <.05). Urticaria and itching sensation were the most common adverse events in the alpha-lipoic acid groups, but these were generally mild and transient. Conclusion: Alpha-lipoic acid 1800 mg/d led to a modest weight loss in obese subjects. Alpha-lipoic acid may be considered as adjunctive therapy for obesity. [ABSTRACT FROM AUTHOR]

Podocyte injury is an important factor in the pathogenesis of diabetic nephropathy. Podocytes are characterized by large numbers of mitochondria. However, mitochondrial dysfunction as it relates to kidney pathology remains poorly understood. The present study found that podocyte mitochondria in different animal models of diabetes mellitus became elongated with the development of albuminuria, suggesting a change in mitochondrial dynamics. We then treated cells with a combination of glucose, fatty acids, and angiotensin II (GFA) to mimic the diabetic milieu. Cultured podocytes exposed to GFA showed megamitochondria formation and decreased autophagosome degradation. We also found that GFA treatment decreased the binding of the autophagosome to the lysosome. Our results suggest that megamitochondria are common in podocytes during diabetic nephropathy and that insufficient autophagy flux may underlie this effect. These findings have expanded our understanding of the pathogenesis of diabetic nephropathy and identified a potential pharmacological target for treatment. Image 1 • Megamitochondria are commonly observed in the podocytes of diabetic nephropathy. • Megamitochondria in podocytes are hyperpolarized and generate increased ROS production. • Megamitochondria in podocytes of diabetic nephropathy is associated with autophagic flux defect. [ABSTRACT FROM AUTHOR]

Background There are limited data regarding the influence of glycemic status on the risk of subclinical coronary atherosclerosis on coronary computed tomographic angiography (CCTA) in asymptomatic individuals. Methods We analyzed 6434 asymptomatic individuals who underwent CCTA. The degree and extent of subclinical coronary atherosclerosis were assessed by CCTA, and ≥ 50% diameter stenosis was defined as significant. Of study participants, 2197 (34.1%), 3122 (48.5%), and 1115 (17.3%) were categorized as normal, prediabetic and diabetic individuals, respectively. Results Compared with normal individuals, there were no statistically differences in the adjusted odds ratios of prediabetic individuals for significant coronary artery stenosis (0.98, 95% confidence interval [CI] 0.80–1.22, p = 0.888), any plaque (0.96, 95% CI 0.86–1.07, p = 0.483), calcified plaque (0.90, 95% CI 0.79–1.01, p = 0.080), non-calcified plaque (1.02, 95% CI 0.88–1.17, p = 0.803), and mixed plaque (1.00, 95% CI 0.82–1.22, p = 0.983). However, adjusted odds ratios for significant coronary artery stenosis (1.71, 95% CI 1.34–2.19, p < 0.001), any plaque (1.45, 95% CI 1.26–1.68, p < 0.001), calcified plaque (1.35, 95% CI 1.15–1.57, p < 0.001), non-calcified plaque (1.33, 95% CI 1.11–1.59, p = 0.002), and mixed plaque (1.64, 95% CI 1.30–2.07, p < 0.001) of diabetic individuals were significantly higher than those of the normal individuals. Conclusion In asymptomatic individuals, diabetic individuals had a higher risk for subclinical coronary atherosclerosis, but prediabetic individuals were not associated with an increased risk of subclinical coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Increased sugar consumption may adversely affect glycemic control in patients with diabetes. Although patients with diabetes are generally thought to prefer sweet tastes, few data are available on the sucrose preference in these individuals. The aim of the present study was to evaluate sucrose preference in patients with type 2 diabetes in comparison with subjects without diabetes. Methods: Sucrose preference was assessed in 200 subjects (100 type 2 diabetes patients and 100 age-, sex- and body mass index (BMI)-matched control subjects). Sucrose preference was evaluated together with sucrose perception (i.e., sucrose sensitivity). Clinical and biochemical factors affecting sucrose taste were also analyzed. Results: Participants with type 2 diabetes preferred lower sucrose concentrations compared with control subjects (p =0.001), although they had a less sensitive palate for sucrose compared with subjects without diabetes (p =0.012). Individual sucrose preference demonstrated a negative relationship with sensitivity to sucrose in control subjects. Notably, this relationship between sucrose preference and sensitivity was completely absent in participants with type 2 diabetes. Male patients with diabetes demonstrated a higher sucrose preference compared with female patients. There were no significant correlations between sucrose preference and glycemic control, duration of diabetes, or anti-diabetic medications. Conclusions: Participants with type 2 diabetes demonstrate a lower preference for sweet tastes than control subjects despite their decreased perception of sucrose. Reduced sucrose preference is not associated with better glycemic control in individuals with diabetes. [Copyright &y& Elsevier]

Abstract: Several lines of evidence have suggested that triglyceride accumulation in skeletal muscle and pancreatic islets is causally related to type 2 diabetes mellitus. We recently showed that α-lipoic acid (ALA), a potent antioxidant and cofactor of mitochondrial respiratory enzymes, reduces body weight of rodents by suppressing food intake and increasing energy expenditure. We sought to determine if ALA can prevent the development of diabetes mellitus in obese Otsuka Long–Evans Tokushima Fatty (OLETF) rats. Most (78%) untreated OLETF rats showed glycosuria at 40 weeks of age, but this was completely prevented by ALA. Compared with untreated OLETF rats, ALA reduced body weight and protected pancreatic β-cells from destruction. ALA also reduced triglyceride accumulation in skeletal muscle and pancreatic islets. These results indicate that ALA prevents diabetes mellitus in obese diabetes-prone rats by reducing lipid accumulation in non-adipose tissue as well as in adipose tissue. [Copyright &y& Elsevier]