Trefoil factor 3 in perinatal pancreas is increased by gestational low protein diet and associated with accelerated ß-cell maturation.

The endocrine pancreas expands markedly in the first postnatal days and the insulin producing ß-cells initiate a functional maturation preceded by a morphological change of the islets of Langerhans. Trefoil factor 3 (TFF3) is a secreted peptide expressed in intestinal epithelia, where it promotes migration, but its role in the pancreas is not characterized. The aim of this study was to examine the expression and function of TFF3 in perinatal rat pancreas, ex vivo cultured fetal rat pancreas and in the rat ß-cell line INS-1E. Control or gestational low-protein diet perinatal rat pancreas was harvested at embryonic day 20 (E20), day of birth (P0) and postnatal day 2 (P2). TFF3 mRNA was upregulated 4.5-fold at P0 vs. E20 and downregulated again at P2. In protein-undernourished pups induction of TFF3 at P0 was further increased to 9.7-fold and was increased at P2. TFF3 caused tyrosine phosphorylation of EGFR in INS-1E ß-cells, and purified recombinant TFF3 increased both attachment and spreading of INS-1E ß-cells. In ex vivo cultures of collagenase digested fetal rat pancreas, a model of perinatal ß-cell maturation, TFF3 increased cellular spreading as well as insulin mRNA levels. TFF3 also increased the expression of Pref1/Dlk1 that shares similarities in expression and regulation with TFF3. These results suggest that TFF3 may promote adhesion and spreading of cells to accelerate ß-cell maturation. This study indicates a functional role for TFF3 in pancreatic ß-cell maturation in the perinatal period, which is altered by low protein diet during gestation.

Skeletal Muscle to Pancreatic ß-Cell Cross-talk: The Effect of Humoral Mediators Liberated by Muscle Contraction and Acute Exercise on ß-Cell Apoptosis.

CONTEXT: Mechanisms explaining exercise-induced ß-cell health are unknown. OBJECTIVE: This study aimed to define the role of muscle contraction and acute exercise-derived soluble humoral mediators on ß-cell health. DESIGN: In vitro models were used. SETTING: University. PARTICIPANTS: Healthy subjects. INTERVENTION(S): Conditioned media (CM) were collected from human skeletal muscle (HSkM) cells treated with or without electrical pulse stimulation (EPS). Antecubital and femoral venous blood serum were collected before and after an exercise bout. CM and sera with or without IL-6 neutralization were used to incubate insulin-producing INS-1 cells and rat islets for 24 h in the presence or absence of proinflammatory cytokines (IL-1ß+IFN-γ). MAIN OUTCOME MEASURE(S): INS-1 and islet apoptosis and accumulated insulin secretion. RESULTS: IL-1ß+IFN-γ increased INS-1 and islet apoptosis and decreased insulin secretion. EPS-treated HSkM cell CM did not affect these variables. Exercise-conditioned antecubital but not femoral sera prevented IL-1ß+IFN-γ-induced INS-1 and islet apoptosis. Femoral sera reduced insulin secretion under normal and proinflammatory conditions in INS-1 but not islet cells. EPS increased HSkM cell IL-6 secretion and exercise increased circulating IL-6 levels in antecubital and femoral serum. IL-6 neutralization demonstrated that muscle-derived IL-6 prevents INS-1 and islet apoptosis in the absence of IL-1ß+IFN-γ, but augments apoptosis under proinflammatory conditions, and that muscle-derived IL-6 supports islet insulin secretion in the absence of IL-1ß+IFN-γ. CONCLUSIONS: Unidentified circulating humoral mediators released during exercise prevent proinflammatory cytokine-induced ß-cell apoptosis. Muscle-derived mediators released during exercise suppress ß-cell insulin secretion. Furthermore, muscle-derived IL-6 seems to prevent ß-cell apoptosis under normal conditions but contributes to ß-cell apoptosis under proinflammatory conditions.

Impact of fetal and neonatal environment on beta cell function and development of diabetes.

The global epidemic of diabetes is a serious threat against health and healthcare expenses. Although genetics is important it does not explain the dramatic increase in incidence, which must involve environmental factors. Two decades ago the concept of the thrifty phenotype was introduced, stating that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes. As the pancreatic beta cells are crucial in the regulation of metabolism this article will describe the influence of normal pregnancy on the beta cells in both the mother and the fetus and how various conditions like diabetes, obesity, overnutrition and undernutrition during and after pregnancy may influence the ability of the offspring to adapt to changes in insulin demand later in life. The influence of environmental factors including nutrients and gut microbiota on appetite regulation, mitochondrial activity and the immune system that may affect beta cell growth and function directly and indirectly is discussed. The possible role of epigenetic changes in the transgenerational transmission of the adverse programming may be the most threatening aspect with regard to the global diabetes epidemics. Finally, some suggestions for intervention are presented.