Short-Term High-Starch, Low-Protein Diet Induces Reversible Increase in ß-cell Mass Independent of Body Weight Gain in Mice.

Long-term exposure to a high starch, low-protein diet (HSTD) induces body weight gain and hyperinsulinemia concomitantly with an increase in ß-cell mass (BCM) and pancreatic islets number in mice; however, the effect of short-term exposure to HSTD on BCM and islet number has not been elucidated. In the present study, we investigated changes in body weight, plasma insulin levels, BCM and islet number in mice fed HSTD for 5 weeks followed by normal chow (NC) for 2 weeks. BCM and islet number were increased in mice fed HSTD for 5 weeks compared with those in mice fed NC. On the other hand, mice fed HSTD for 5 weeks followed by NC for 2 weeks (SN) showed decreased BCM and insulin levels, compared to mice fed HSTD for 7 weeks, and no significant differences in these parameters were observed between SN and the control NC at 7 weeks. No significant difference in body weight was observed among HSTD, NC and SN fed groups. These results suggest that a high-starch diet induces an increase in BCM in a manner independent of body weight gain, and that 2 weeks of NC feeding is sufficient for the reversal of the morphological changes induced in islets by HSTD feeding.

Functional adenosine triphosphate-sensitive potassium channel is required in high-carbohydrate diet-induced increase in ß-cell mass.

AIMS/INTRODUCTION: A high-carbohydrate diet is known to increase insulin secretion and induce obesity. However, whether or not a high-carbohydrate diet affects ß-cell mass (BCM) has been little investigated. MATERIALS AND METHODS: Both wild-type (WT) mice and adenosine triphosphate-sensitive potassium channel-deficient (Kir6.2KO) mice were fed normal chow or high-starch (ST) diets for 22 weeks. BCM and the numbers of islets were analyzed by immunohistochemistry, and gene expression levels in islets were investigated by quantitative real-time reverse transcription polymerase chain reaction. MIN6-K8 ß-cells were stimulated in solution containing various concentrations of glucose combined with nifedipine and glimepiride, and gene expression was analyzed. RESULTS: Both WT and Kir6.2KO mice fed ST showed hyperinsulinemia and body weight gain. BCM, the number of islets and the expression levels of cyclinD2 messenger ribonucleic acid were increased in WT mice fed ST compared with those in WT mice fed normal chow. In contrast, no significant difference in BCM, the number of islets or the expression levels of cyclinD2 messenger ribonucleic acid were observed between Kir6.2KO mice fed normal chow and those fed ST. Incubation of MIN6-K8 ß-cells in high-glucose media or with glimepiride increased cyclinD2 expression, whereas nifedipine attenuated a high-glucose-induced increase in cyclinD2 expression. CONCLUSIONS: These results show that a high-starch diet increases BCM in an adenosine triphosphate-sensitive potassium channel-dependent manner, which is mediated through upregulation of cyclinD2 expression.

Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain.

Both high-fat (HFD) and high-carbohydrate (ST) diets are known to induce weight gain. Glucose-dependent insulinotropic polypeptide (GIP) is secreted mainly from intestinal K cells upon stimuli by nutrients such as fat and glucose, and it potentiates glucose-induced insulin secretion. GIP is well known to contribute to HFD-induced obesity. In this study, we analyzed the effect of ST feeding on GIP secretion and metabolic parameters to explore the role of GIP in ST-induced weight gain. Both wild-type (WT) and GIP receptor deficient ( GiprKO) mice were fed normal chow (NC), ST, or moderate (m)HFD for 22 wk. Body weight was measured, and then glucose tolerance tests were performed. Insulin secretion from isolated islets also was analyzed. WT mice fed ST or mHFD displayed weight gain concomitant with increased plasma GIP levels compared with WT mice fed NC. WT mice fed mHFD showed improved glucose tolerance due to enhanced insulin secretion during oral glucose tolerance tests compared with WT mice fed NC or ST. GiprKO mice fed mHFD did not display weight gain. On the other hand, GiprKO mice fed ST showed weight gain and did not display obvious glucose intolerance. Glucose-induced insulin secretion was enhanced during intraperitoneal glucose tolerance tests and from isolated islets in both WT and GiprKO mice fed ST compared with those fed NC. In conclusion, enhanced GIP secretion induced by mHFD-feeding contributes to increased insulin secretion and body weight gain, whereas GIP is marginally involved in weight gain induced by ST-feeding.

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice.

Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and ß-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain.

S100B impairs glycolysis via enhanced poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase in rodent muscle cells.

S100 calcium-binding protein B (S100B), a multifunctional macromolecule mainly expressed in nerve tissues and adipocytes, has been suggested to contribute to the pathogenesis of obesity. To clarify the role of S100B in insulin action and glucose metabolism in peripheral tissues, we investigated the effect of S100B on glycolysis in myoblast and myotube cells. Rat myoblast L6 cells were treated with recombinant mouse S100B to examine glucose consumption, lactate production, glycogen accumulation, glycolytic metabolites and enzyme activity, insulin signaling, and poly(ADP-ribosyl)ation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Glycolytic metabolites were investigated by enzyme assays or metabolome analysis, and insulin signaling was assessed by Western blot analysis. Enzyme activity and poly(ADP-ribosyl)ation of GAPDH was evaluated by an enzyme assay and immunoprecipitation followed by dot blot with an anti-poly(ADP-ribose) antibody, respectively. S100B significantly decreased glucose consumption, glucose analog uptake, and lactate production in L6 cells, in either the presence or absence of insulin. In contrast, S100B had no effect on glycogen accumulation and insulin signaling. Metabolome analysis revealed that S100B increased the concentration of glycolytic intermediates upstream of GAPDH. S100B impaired GAPDH activity and increased poly(ADP-ribosyl)ated GAPDH proteins. The effects of S100B on glucose metabolism were mostly canceled by a poly(ADP-ribose) polymerase inhibitor. Similar results were obtained in C2C12 myotube cells. We conclude that S100B as a humoral factor may impair glycolysis in muscle cells independent of insulin action, and the effect may be attributed to the inhibition of GAPDH activity from enhanced poly(ADP-ribosyl)ation of the enzyme.