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Translation of preclinical findings on the efficacy of dietary interventions for metabolic disease to human clinical studies is challenging due to the predominant use of male rodents in animal research. Our objective was to evaluate a combined high-fat (HF) diet and low-dose streptozotocin (STZ) model for induction of type-2 diabetes (T2D) in male and female C57BL/6J mice. We hypothesized that T2D biomarkers would differ significantly between sexes. Mice were administered either a low-fat (LF) diet (10% kcal from fat), or HF diet (60% kcal from fat) + STZ injections (30 mg/kg/d for 3 days). Both sexes gained weight and developed impaired postprandial oral glucose tolerance on the HF+STZ treatment compared to LF. Only male mice on HF + STZ developed fasting hyperglycemia, fasting hyperinsulinemia and insulin resistance, suggesting that the underlying causes of postprandial hyperglycemia differed between sexes. Principal component analysis of measures such as body weights, glucose and insulin concentrations indicated metabolic derangement for males only on HF+STZ treatment, while LF group males and both groups of females significantly overlapped. Based on our data, we accept our hypothesis that the combined high-fat diet and low-dose STZ model for T2D phenotypes differs significantly in its effect on mice based on sex. The HF diet + low-dose STZ model is not useful for studying insulin resistance in females. Other models are needed to model T2D, and study the effects of dietary interventions in this disease, in females. Sexual dimorphism remains a significant challenge for both preclinical and clinical research., Competing Interests: Conflicts of interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A hallmark of type 2 diabetes (T2D) is β-cell dysfunction and the eventual loss of functional β-cell mass. Therefore, mechanisms that improve or preserve β-cell function could be used to improve the quality of life of individuals with T2D. Studies have shown that monomeric, oligomeric and polymeric cocoa flavanols have different effects on obesity, insulin resistance and glucose tolerance. We hypothesized that these cocoa flavanols may have beneficial effects on β-cell function. INS-1 832/13-derived β-cells and primary rat islets cultured with a monomeric catechin-rich cocoa flavanol fraction demonstrated enhanced glucose-stimulated insulin secretion, while cells cultured with total cocoa extract and with oligomeric or polymeric procyanidin-rich fraction demonstrated no improvement. The increased glucose-stimulated insulin secretion in the presence of the monomeric catechin-rich fraction corresponded with enhanced mitochondrial respiration, suggesting improvements in β-cell fuel utilization. Mitochondrial complex III, IV and V components are up-regulated after culture with the monomer-rich fraction, corresponding with increased cellular ATP production. The monomer-rich fraction improved cellular redox state and increased glutathione concentration, which corresponds with nuclear factor, erythroid 2 like 2 (Nrf2) nuclear localization and expression of Nrf2 target genes including nuclear respiratory factor 1 (Nrf1) and GA binding protein transcription factor alpha subunit (GABPA), essential genes for increasing mitochondrial function. We propose a model by which monomeric cocoa catechins improve the cellular redox state, resulting in Nrf2 nuclear migration and up-regulation of genes critical for mitochondrial respiration, glucose-stimulated insulin secretion and ultimately improved β-cell function. These results suggest a mechanism by which monomeric cocoa catechins exert their effects as an effective complementary strategy to benefit T2D patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

β-Cell insulin secretion is dependent on proper mitochondrial function. Various studies have clearly shown that the Nr4a family of orphan nuclear receptors is essential for fuel utilization and mitochondrial function in liver, muscle, and adipose. Previously, we have demonstrated that overexpression of Nr4a1 or Nr4a3 is sufficient to induce proliferation of pancreatic β-cells. In this study, we examined whether Nr4a expression impacts pancreatic β-cell mitochondrial function. Here, we show that β-cell mitochondrial respiration is dependent on the nuclear receptors Nr4a1 and Nr4a3. Mitochondrial respiration in permeabilized cells was significantly decreased in β-cells lacking Nr4a1 or Nr4a3. Furthermore, respiration rates of intact cells deficient for Nr4a1 or Nr4a3 in the presence of 16 mM glucose resulted in decreased glucose mediated oxygen consumption. Consistent with this reduction in respiration, a significant decrease in glucose-stimulated insulin secretion rates is observed with deletion of Nr4a1 or Nr4a3. Interestingly, the changes in respiration and insulin secretion occur without a reduction in mitochondrial content, suggesting decreased mitochondrial function. We establish that knockdown of Nr4a1 and Nr4a3 results in decreased expression of the mitochondrial dehydrogenase subunits Idh3g and Sdhb. We demonstrate that loss of Nr4a1 and Nr4a3 impedes production of ATP and ultimately inhibits glucose-stimulated insulin secretion. These data demonstrate for the first time that the orphan nuclear receptors Nr4a1 and Nr4a3 are critical for β-cell mitochondrial function and insulin secretion., (Copyright © 2016 the American Physiological Society.)