Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance and mitochondrial lipid oxidation and also enhances insulin sensitivity (IS). It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests with tracers were conducted in mice ranging from 4 to 21 months of age, fed a low-fat diet (LFD) or high-fat diet (HFD) with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Values for an IS index derived for peripheral tissues (IS-P) and one for the liver (IS-L) were steeply decreased by aging and an HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In young animals fed an LFD, RW access enhanced the IS-P concomitantly with the muscle β-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease; however this only occurred in animals fed an LFD. Therefore, this study indicates that endurance exercise can improve the age-dependent decline in organ-specific IS if paired with a healthy diet.

The advanced cessation of lactation elevates the risk of programmed obesity and obesity-related metabolic disorders in adulthood. This study used multiomic analysis to investigate the mechanism behind this phenomenon and the effects of leucine supplementation on ameliorating programmed obesity development. Wistar/SD rat offspring were subjected to early weaning (EW) at day 17 (EWWIS and EWSD groups) or normal weaning at day 21 (CWIS and CSD groups). Half of the rats from the EWSD group were selected to create a new group with 2-month leucine supplementation at day 150. The results showed that EW impaired lipid metabolic gene expression and increased insulin, neuropeptide Y, and feed intake, inducing obesity in adulthood. Six lipid metabolism-related genes (Acot1, Acot2, Acot4, Scd, Abcg8, and Cyp8b1) were influenced by EW during the entire experimental period. Additionally, adult early-weaned rats exhibited cholesterol and fatty acid β-oxidation disorders, liver taurine reduction, cholestasis, and insulin and leptin resistance. Leucine supplementation partly alleviated these metabolic disorders and increased liver L-carnitine, retarding programmed obesity development. This study provides new insights into the mechanism of programmed obesity development and the potential benefits of leucine supplementation, which may offer suggestions for life planning and programmed obesity prevention.

Sphingolipids are thought to promote skeletal muscle insulin resistance. Deoxysphingolipids (dSLs) are atypical sphingolipids that are increased in the plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle is unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared with athletes and lean individuals and are inversely related to insulin sensitivity. Furthermore, we observed a significant reduction in muscle dSL content in individuals with obesity who completed a combined weight loss and exercise intervention. Increased dSL content in primary human myotubes caused a decrease in insulin sensitivity associated with increased inflammation, decreased AMPK phosphorylation, and altered insulin signaling. Our findings reveal a central role for dSL in human muscle insulin resistance and suggest dSLs as therapeutic targets for the treatment and prevention of type 2 diabetes.

The glucose homeostasis system ensures that the circulating glucose level is maintained within narrow physiological limits both in the fasting (or basal) state and following a nutrient challenge. Although glucose homeostasis is traditionally conceptualized as a single overarching system, evidence reviewed here suggests that basal glycemia and glucose tolerance are governed by distinct control systems. Specifically, whereas glucose tolerance appears to be determined largely by interactions between insulin secretion and insulin sensitivity, basal-state glucose homeostasis is predominated by insulin-independent mechanisms governed largely by the brain. In addition to a new perspective on how glucose homeostasis is achieved, this "dual control system" hypothesis offers a feasible and testable explanation for observations that are otherwise difficult to reconcile and sheds new light on the integration of central and peripheral metabolic control mechanisms. The implications of this model for the pathogenesis and treatment of impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes are also discussed.

Cystic fibrosis (CF) is a recessive disorder arising from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is expressed in numerous tissues, with high expression in the airways, small and large intestine, pancreatic and hepatobiliary ducts, and male reproductive tract. CFTR loss in these tissues disrupts regulation of salt, bicarbonate, and water balance across their epithelia, resulting in a systemic disorder with progressive organ dysfunction and damage. Pancreatic exocrine damage ultimately manifests as pancreatic exocrine insufficiency that begins as early as infancy. Pancreatic remodeling accompanies this early damage, during which abnormal glucose tolerance can be observed in toddlers. With increasing age, however, insulin secretion defects progress such that CF-related diabetes (CFRD) occurs in 20% of teens and up to half of adults with CF. The relevance of CFRD is highlighted by its association with increased morbidity, mortality, and patient burden. While clinical research on CFRD has greatly assisted in the care of individuals with CFRD, key knowledge gaps on CFRD pathogenesis remain. Furthermore, the wide use of CFTR modulators to restore CFTR activity is changing the CFRD clinical landscape and the field's understanding of CFRD pathogenesis. For these reasons, the National Institute of Diabetes and Digestive and Kidney Diseases and the Cystic Fibrosis Foundation sponsored a CFRD Scientific Workshop, 23-25 June 2021, to define knowledge gaps and needed research areas. This article describes the findings from this workshop and plots a path for CFRD research that is needed over the next decade.