Elevated Peripheral Brain-Derived Neurotrophic Factor Level Associated With Decreasing Insulin Secretion May Forecast Memory Dysfunction in Patients With Long-Term Type 2 Diabetes

BackgroundWith the progressive course of diabetes and the decline in islet function, the cognitive dysfunction of patients aggravated.ObjectiveWe aimed to investigate the roles of brain-derived neurotrophic factor (BDNF) and the Val66Met polymorphism in mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 169 Chinese patients with T2DM were involved and divided into long-term (diabetes duration >10 years) and short-term (diabetes duration ≤10 years) diabetes, and in each group, the patients were separated as MCI and the control. Demographic characteristics, clinical variables, and cognitive performances were assessed. The plasma BDNF level was measured via enzyme-linked immunosorbent assay. The Val66Met polymorphisms were analyzed.ResultsLong-term T2DM have lower 2 h postprandial C-peptide (p < 0.05). The BDNF level was slightly higher in patients with MCI than in the controls in each duration group without statistical significance. The relationship of BDNF to Montreal Cognitive Assessment was not proven either. However, in the long-term diabetes group, BDNF concentration remained as an independent factor of logical memory test (β = −0.27; p < 0.05), and they were negatively correlated (r = −0.267; p = 0.022); BDNF was also negatively correlated with fasting C-peptide (r = −0.260; p = 0.022), 2 h postprandial C-peptide (r = −0.251; p = 0.028), and homeostasis model assessment of insulin resistance (r = −0.312; p = 0.006). In genotypic groups, BDNF Val/Val performed better in logical memory test than Met/Met and Val/Met.ConclusionElevated peripheral BDNF level associated with declined islet function, when combined with its Val66Met polymorphism, may forecast memory dysfunction in patients with long-term T2DM.

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

Aims/hypothesis Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes. Graphical abstract

Gut Metabolite Trimethylamine N-Oxide Protects INS-1 β-Cell and Rat Islet Function under Diabetic Glucolipotoxic Conditions

Serum accumulation of the gut microbial metabolite trimethylamine N-oxide (TMAO) is associated with high caloric intake and type 2 diabetes (T2D). Impaired pancreatic β-cell function is a hallmark of diet-induced T2D, which is linked to hyperglycemia and hyperlipidemia. While TMAO production via the gut microbiome-liver axis is well defined, its molecular effects on metabolic tissues are unclear, since studies in various tissues show deleterious and beneficial TMAO effects. We investigated the molecular effects of TMAO on functional β-cell mass. We hypothesized that TMAO may damage functional β-cell mass by inhibiting β-cell viability, survival, proliferation, or function to promote T2D pathogenesis. We treated INS-1 832/13 β-cells and primary rat islets with physiological TMAO concentrations and compared functional β-cell mass under healthy standard cell culture (SCC) and T2D-like glucolipotoxic (GLT) conditions. GLT significantly impeded β-cell mass and function by inducing oxidative and endoplasmic reticulum (ER) stress. TMAO normalized GLT-mediated damage in β-cells and primary islet function. Acute 40µM TMAO recovered insulin production, insulin granule formation, and insulin secretion by upregulating the IRE1α unfolded protein response to GLT-induced ER and oxidative stress. These novel results demonstrate that TMAO protects β-cell function and suggest that TMAO may play a beneficial molecular role in diet-induced T2D conditions.

Analysis of Islet Function by Glucagon Enzyme-linked Immunosorbent Assay (ELISA) v1

This Standard Operating Procedure (SOP) is based on the Vanderbilt University Medical Center Human Islet Phenotyping Program (HIPP) Islet Functional Analysis. This SOP provides the HIPP procedure for measuring islet glucagon content and secretion to assess islet function. This SOP defines the assay method used by the Human Islet Phenotyping Program (HIPP) for the qualitative determination of the Purified Human Pancreatic Islet product, post-shipment, manufactured for use in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored research in the Integrated Islet Distribution Program (IIDP). The goal of this SOP is to define the method for quantitative determination of glucagon released after secretagogue stimulation for proving the potency of the human islet preparation shipped by the IIDP.

Analysis of Islet Function by Insulin Enzyme-linked Immunosorbent Assay (ELISA) v1

This Standard Operating Procedure (SOP) is based on the Vanderbilt University Medical Center Human Islet Phenotyping Program (HIPP) Islet Functional Analysis. This SOP provides the HIPP procedure for measuring islet insulin content and secretion to assess islet function. This SOP defines the assay method used by the Human Islet Phenotyping Program (HIPP) for the qualitative determination of the Purified Human Pancreatic Islet product, post-shipment, manufactured for use in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)-sponsored research in the Integrated Islet Distribution Program (IIDP). The goal of this SOP is to define the method for quantitative determination of insulin released after glucose stimulation for proving the potency of the human islet preparation shipped by the IIDP.