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Vesiculin derived from IGF-II drives increased islet cell mass in a mouse model of pre-diabetes.

ABSTRACT: Pancreatic islet-cell function and volume are both key determinants of the maintenance of metabolic health. Insulin resistance and islet-cell dysfunction often occur in the earlier stages of type 2 diabetes (T2D) progression. The ability of the islet cells to respond to insulin resistance by increasing hormone output accompanied by increased islet-cell volume is key to maintaining blood glucose control and preventing further disease progression. Eventual β-cell loss is the main driver of full-blown T2D and insulin-dependency. Researchers are targeting T2D with approaches that include those aimed at enhancing the function of the patient's existing β-cell population, or replacing islet β-cells. Another approach is to look for agents that enhance the natural capacity of the β-cell population to expand. Here we aimed to study the effects of a new putative β-cell growth factor on a mouse model of pre-diabetes. We asked whether: 1) 4-week's treatment with vesiculin, a two-chain peptide derived by processing from IGF-II, had any measurable effect on pre-diabetic mice vs vehicle; and 2) whether the effects were the same in non-diabetic littermate controls. Although treatment with vesiculin did not alter blood glucose levels over this time period, there was a doubling of the Proliferating Cell Nuclear Antigen (PCNA) detectable in the islets of treated pre-diabetic but not control mice and this was accompanied by increased insulin- and glucagon-positive stained areas in the pancreatic islets.

SUBMITTER: Lee KL

PROVIDER: S-EPMC8632304 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGestational diabetes mellitus (GDM) is a common complication of pregnancy. It may predispose offspring to increased fat mass (FM) and the development of obesity, however few data from Latin America exist.ObjectiveTo investigate the influence of GDM on newborn FM in mother-newborn pairs recruited from a public maternity care center in São Paulo, Brazil.MethodsData were collected cross-sectionally in 2013-2014 from 72 mothers diagnosed with GDM, and 211 mothers with normal glucose tolerance (NGT). Newborn FM was evaluated by air-displacement plethysmography (PEA POD), and relevant demographic and obstetric data were collected from hospital records. Associations between maternal GDM status and newborn FM were investigated by multiple linear regression analysis, with adjustment for maternal age, pre-pregnancy BMI, gestational weight gain, type of delivery, sex of the child, and gestational age.ResultsFM was greater in GDM versus NGT newborns in a bivariable model (Median (IQR), GDM: 0.35 (0.3) kg vs. NGT: 0.27 (0.2) kg, p = 0.02), however GDM status was not a significant predictor of FM with adjustment for other variables. Rather, pre-pregnancy BMI (coefficient (?) 1.46; 95% confidence interval (CI) 0.66, 2.27), gestational weight gain (? 1.32; 95% CI 0.49, 2.15), and male sex (? -17.8; 95% CI -27.2, -8.29) predicted newborn FM. Analyzing GDM and NGT groups separately, pre-pregnancy BMI (? 6.75; 95% CI 2.36, 11.1) and gestational weight gain (? 5.64; 95% CI 1.16, 10.1) predicted FM in the GDM group, while male sex alone predicted FM in the NGT group (? -12.3; 95% CI -18.3, -6.34).ConclusionsCombined model results suggest that in our cohort, pre-pregnancy BMI and gestational weight gain are more important risk factors for increased neonatal FM than GDM. However, group-specific model results suggest that GDM status may contribute to variation in the relationship between maternal/offspring factors and FM. Our use of a binary GDM variable in the combined model may have precluded clearer results on this point. Prospective cohort studies including data on maternal pre-pregnancy BMI, GWG, and glycemic profile are needed to better understand associations among these variables and their relative influence on offspring FM.

Project description:A leading hypothesis for the decimation of insulin-producing ?-cells in type 2 diabetes attributes the cause to islet amyloid polypeptide (IAPP) for its deleterious effects on the cell membranes. This idea has produced extensive investigations on human IAPP (hIAPP) and its interactions with lipid bilayers. However, it is still difficult to correlate the peptide-lipid interactions with its effects on islet cells in culture. The hIAPP fibrils have been shown to interact with lipids and damage lipid bilayers, but appear to have no effect on islet cells in culture. Thus, a modified amyloid hypothesis assumes that the toxicity is caused by hIAPP oligomers, which are not preamyloid fibrils or protofibrils. However, so far such oligomers have not been isolated or identified. The hIAPP monomers also bind to lipid bilayers, but the mode of interaction is not clear. Here, we performed two types of experiments that, to our knowledge, have not been done before. We used x-ray diffraction, in conjunction with circular dichroism measurement, to reveal the location of the peptide bound to a lipid bilayer. We also investigated the effects of hIAPP on giant unilamellar vesicles at various peptide concentrations. We obtained the following qualitative results. Monomeric hIAPP binds within the headgroup region and expands the membrane area of a lipid bilayer. At low concentrations, such binding causes no leakage or damage to the lipid bilayer. At high concentrations, the bound peptides transform to ?-aggregates. The aggregates exit the headgroup region and bind to the surface of lipid bilayers. The damage by the surface bound ?-aggregates depends on the aggregation size. The initial aggregation extracts lipid molecules, which probably causes ion permeation, but no molecular leakage. However, the initial ?-aggregates serve as the seed for larger fibrils, in the manner of the Jarrett-Lansbury seeded-polymerization model, that eventually disintegrate lipid bilayers by electrostatic and hydrophobic interactions.

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Vesiculin derived from IGF-II drives increased islet cell mass in a mouse model of pre-diabetes.

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