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Aims/Introduction: The time course of chronic kidney disease in young‐onset type 2 diabetes mellitus remains unclear. We compared the trajectories of proteinuria and estimated glomerular filtration rate (eGFR) decline between young‐onset (aged ≤40 years) and late‐onset (aged >40 years) type 2 diabetes mellitus in a Japanese multicenter cohort. Materials and Methods: Participants without diabetic kidney disease were divided into two groups according to age at diagnosis: young‐ and late‐onset. The primary endpoint was eGFR <60 mL/min/1.73 m2, proteinuria or both. Multivariable Cox proportional hazards were calculated to estimate incidence. Results: Among 626 participants with type 2 diabetes mellitus, 78 (12.4%) had young‐onset and 548 (87.6%) had late‐onset diabetes. The incidence of eGFR <60 mL/min/1.73 m2 was lower (16.7% vs 33.5%, P = 0.003), but that of proteinuria was higher (46.2% vs 28.9%, P = 0.002) in the young‐onset type 2 diabetes mellitus group. The Kaplan–Meyer curve showed that young‐onset type 2 diabetes mellitus was associated with a decreased hazard ratio (HR) for eGFR <60 mL/min/1.73 m2 and an increased HR for proteinuria compared with late‐onset type 2 diabetes mellitus. In the multivariate Cox analysis, young‐onset type 2 diabetes mellitus increased the HR (95% confidence interval) of proteinuria (1.53, 95% confidence interval 1.03–2.26), but did not change the eGFR <60 mL/min/1.73 m2 HR. Conclusions: Young‐onset type 2 diabetes mellitus has a lower HR of eGFR <60 mL/min/1.73 m2 and an increased HR of proteinuria compared with late‐onset type 2 diabetes mellitus, indicating that young‐onset type 2 diabetes mellitus has a different time course for the development of proteinuria and subsequent eGFR decline. [ABSTRACT FROM AUTHOR]

Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post‐transcriptional level, are differentially regulated in the circulatory system of young, middle‐aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50–80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT ‐ common vs. GT ‐ longevity) and validated the findings through RT‐qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF‐β, FoxO, AMPK, Pi3K‐Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity. [ABSTRACT FROM AUTHOR]

Expression of peroxisome proliferator-activated receptor [Alpha] (PPAR[Alpha]) and enzymes of fatty acid (FA) oxidation is markedly reduced in the fat-laden, dysfunctional islets of obese, prediabetic Zucker diabetic fatty (fa/fa) rats with mutated leptin receptors (OB-R). Leptin, PPAR[Alpha]/retinoid x receptor ligands, and FA all up-regulate PPAR[Alpha] and enzymes of FA oxidation and stimulate [3H]-palmitate oxidation in normal islets but not in islets from fa/fa rats. Over-expression of normal OB-R in islets of fa/fa rats corrects all of the foregoing abnormalities and reverses the diabetic phenotype. PPAR[Alpha] is a OB-R-dependent factor required for normal fat homeostasis in islet cells.

To determine whether the antidiabetic action of troglitazone (TGZ), heretofore attributed to insulin sensitization, also involves protection of 13 cells from lipoapoptosis, we treated prediabetic Zucker Diabetic Fatty rats with 200 mg/kg per day of TGZ. Their plasma-free fatty acids and triacylglycerol fell to 1.3 mM and 111 mg/dl, respectively, compared with 2.0 mM and 560 mg/dl in untreated controls. Their islet triacylglycerol content was 34% below controls. In islets of control rats, [Beta] cells were reduced by 82% and the islet architecture was disrupted; [Beta]-cell glucose transporter-2 was absent, 85% of their mitochondria were altered, and they were unresponsive to glucose. In treated rats, the loss of [Beta] cells was prevented, as were the loss of [Beta] cell glucose transporter-2, the mitochondrial alterations, and the impairment of glucose-stimulated insulin secretion. We conclude that the antidiabetic effect of TGZ in prediabetic Zucker Diabetic Fatty rats involves prevention of lipotoxicity and lipoapoptosis of [Beta] cells, as well as improvement in insulin sensitivity.

Background and Purpose: γ-Oryzanol, derived from unrefined rice, attenuated the preference for dietary fat in mice, by decreasing hypothalamic endoplasmic reticulum stress. However, no peripheral mechanisms, whereby γ-oryzanol could ameliorate glucose dyshomeostasis were explored. Dopamine D2 receptor signalling locally attenuates insulin secretion in pancreatic islets, presumably via decreased levels of intracellular cAMP. We therefore hypothesized that γ-oryzanol would improve high-fat diet (HFD)-induced dysfunction of islets through the suppression of local D2 receptor signalling.Experimental Approach: Glucose metabolism and regulation of molecules involved in D2 receptor signalling in pancreatic islets were investigated in male C57BL/6J mice, fed HFD and treated with γ-oryzanol . In isolated murine islets and the beta cell line, MIN6 , the effects of γ-oryzanol on glucose-stimulated insulin secretion (GSIS) was analysed using siRNA for D2 receptors and a variety of compounds which alter D2 receptor signalling.Key Results: In islets, γ-oryzanol enhanced GSIS via the activation of the cAMP/PKA pathway. Expression of molecules involved in D2 receptor signalling was increased in islets from HFD-fed mice, which were reciprocally decreased by γ-oryzanol. Experiments with siRNA for D2 receptors and D2 receptor ligands in vitro suggest that γ-oryzanol suppressed D2 receptor signalling and augmented GSIS.Conclusions and Implications: γ-Oryzanol exhibited unique anti-diabetic properties. The unexpected effects of γ-oryzanol on D2 receptor signalling in islets may provide a novel; natural food-based, approach to anti-diabetic therapy. [ABSTRACT FROM AUTHOR]

Brown rice (BR) and white rice (WR) produce different glycaemic responses and their consumption may affect the dietary management of obesity. In the present study, the effects of BR and WR on abdominal fat distribution, metabolic parameters and endothelial function were evaluated in subjects with the metabolic syndrome in a randomised cross-over fashion. In study 1, acute postprandial metabolic parameters and flow- and nitroglycerine-mediated dilation (FMD and NMD) of the brachial artery were determined in male volunteers with or without the metabolic syndrome after ingestion of either BR or WR. The increases in glucose and insulin AUC were lower after ingestion of BR than after ingestion of WR (P= 0·041 and P= 0·045, respectively). FMD values were decreased 60 min after ingestion of WR (P= 0·037 v. baseline), but the decrease was protected after ingestion of BR. In study 2, a separate cohort of male volunteers (n 27) with the metabolic syndrome was randomised into two groups with different BR and WR consumption patterns. The values of weight-based parameters were decreased after consumption of BR for 8 weeks, but returned to baseline values after a WR consumption period. Insulin resistance and total cholesterol and LDL-cholesterol levels were reduced after consumption of BR. In conclusion, consumption of BR may be beneficial, partly owing to the lowering of glycaemic response, and may protect postprandial endothelial function in subjects with the metabolic syndrome. Long-term beneficial effects of BR on metabolic parameters and endothelial function were also observed. [ABSTRACT FROM PUBLISHER]

Discusses the role of enhanced de novo lipogenesis in the pathogenesis of lipotoxic diabetes. Lipogenesis in the leptin-unresponsive pancreatic islets of prediabetic zucker diabetic fatty rats; Induction of chronic hyperleptinemia; Culturing of recombinant leptin with islets isolated from rats; Factors for fat overload that leads to beta-cell dysfunction.