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Although aging is a physiological process to which all organisms are subject, the presence of obesity and type 2 diabetes accelerates biological aging. Recent studies have demonstrated the causal relationships between dietary interventions suppressing obesity and type 2 diabetes and delaying the onset of age-related endocrine changes. Curcumin, a natural antioxidant, has putative therapeutic properties such as improving insulin sensitivity in obese mice. However, how curcumin contributes to maintaining insulin homeostasis in aged organisms largely remains unclear. Thus, the objective of this study is to examine the pleiotropic effect of dietary curcumin on insulin homeostasis in a diet-induced obese (DIO) aged mouse model. Aged (18-20 months old) male mice given a high-fat high-sugar diet supplemented with 0.4% (w/w) curcumin (equivalent to 2 g/day for a 60 kg adult) displayed a different metabolic phenotype compared to mice given a high-fat high-sugar diet alone. Furthermore, curcumin supplementation altered hepatic gene expression profiling, especially insulin signaling and senescence pathways. We then mechanistically investigated how curcumin functions to fine-tune insulin sensitivity. We found that curcumin supplementation increased hepatic insulin-degrading enzyme (IDE) expression levels and preserved islet integrity, both outcomes that are beneficial to preserving good health with age. Our findings suggest that the multifaceted therapeutic potential of curcumin can be used as a protective agent for age-induced metabolic diseases.

Human insulin ( INS ) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene ( Ins2 ) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains β-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide ( IAPP ) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors., (© 2021 by the American Diabetes Association.)

The choroid plexus (ChP) is a highly vascularized tissue found in the brain ventricles, with an apical epithelial cell layer surrounding fenestrated capillaries. It is responsible for the production of most of the cerebrospinal fluid (CSF) in the ventricular system, subarachnoid space, and central canal of the spinal cord, while also constituting the blood-CSF barrier (BCSFB). In addition, epithelial cells of the ChP (EChP) synthesize neurotrophic factors and other signaling molecules that are released into the CSF. Here, we show that insulin is produced in EChP of mice and humans, and its expression and release are regulated by serotonin. Insulin mRNA and immune-reactive protein, including C-peptide, are present in EChP, as detected by several experimental approaches, and appear in much higher levels than any other brain region. Moreover, insulin is produced in primary cultured mouse EChP, and its release, albeit Ca2+ sensitive, is not regulated by glucose. Instead, activation of the 5HT2C receptor by serotonin treatment led to activation of IP3-sensitive channels and Ca2+ mobilization from intracellular storage, leading to insulin secretion. In vivo depletion of brain serotonin in the dorsal raphe nucleus negatively affected insulin expression in the ChP, suggesting an endogenous modulation of ChP insulin by serotonin. Here, we show for the first time to our knowledge that insulin is produced by EChP in the brain, and its release is modulated at least by serotonin but not glucose.

Background: Although type 2 diabetes mellitus (T2DM) is primarily characterized by sustained high levels of circulating glucose, other factors, such as obesity, chronic inflammation, fatty liver, and islet dysfunction significantly contribute to the development of this disease. To date, curcumin (CUR), a natural polyphenol and primary component of turmeric, shows putative therapeutic properties such as reducing the incidence of obesity-related diseases in mice. However, the mechanism by which CUR regulates insulin levels remains unclear. Methods: This study investigates how dietary CUR improves insulin clearance and maintains a proper range of circulating insulin level in the diet-induced obesity (DIO) mouse model. Male C57BL/6 J mice were fed a control, a high fat/high sugar (HFS) or a HFS diet containing 0.4% (w/w) curcumin (HFS + CUR) (N = 16 per group) for 16 weeks. Results: Mice given HFS + CUR had reduced body weight and fat accumulation in the liver and had lower blood insulin levels under fasting conditions compared to mice on HFS alone, resulting from significantly improved insulin clearance via upregulation of hepatic insulin-degrading enzyme (IDE). We also observed restoration of phosphoinositide 3-kinase (PI3K), especially class Ia catalytic subunits, p110α and p110β, and class Ib regulatory subunit, p101, and phosphorylated protein kinase B (AKT) expression levels in liver on HFS + CUR diet. Additionally, HFS + CUR fed mice had significantly smaller islets of Langerhans and increased glucagon contents compared to HFS fed mice, indicating less secretion of insulin in pancreas. The expression of thioredoxin interacting protein (TXNIP), a pro-oxidant and pro-apoptotic protein, was significantly elevated in mouse and human islets cultured under HFS mimicking conditions, which was mitigated by CUR treatment. Conclusions: CUR supplementation in obese subjects may alleviate the burden imposed by HFS diets. Our data indicate administration of dietary CUR reinstates PI3K, AKT and IDE levels in obese mice. Additionally, CUR treatment preserves islet integrity by downregulation of TXNIP transcription levels. Therefore, dietary CUR may have the potential to serve as a novel therapeutic agent to address the underlying links of obesity and T2DM. [ABSTRACT FROM AUTHOR]