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 β-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.

Aims/Introduction: Differences in the glucose‐lowering mechanisms of glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been noted. Clarifying these differences could facilitate the choice of optimal drugs for individuals with type 2 diabetes and requires investigation in a clinical setting.Materials and Methods: A single‐arm, prospective, observational study was conducted to evaluate the effects of various GLP‐1RAs on postprandial glucose excursion, secretions of insulin and glucagon as well as on the gastric emptying rate. Participants were subjected to meal tolerance tests before and 2 weeks and 12 weeks after GLP‐1RA initiation. Effects on postprandial secretions of glucose‐dependent insulinotropic polypeptide (GIP) and apolipoprotein B48 were also investigated.Results: Eighteen subjects with type 2 diabetes received one of three GLP‐1RAs, i.e., lixisenatide, n = 7; liraglutide, n = 6; or dulaglutide, n = 5. While 12‐week administration of all of the GLP‐1RAs significantly reduced HbA1c, only lixisenatide and liraglutide, but not dulaglutide, significantly reduced body weight. Postprandial glucose elevation was improved by all of the GLP‐1RAs. Postprandial insulin levels were suppressed by lixisenatide, while insulin levels were enhanced by liraglutide. Postprandial glucagon levels were suppressed by lixisenatide. The gastric emptying rate was significantly delayed by lixisenatide, while liraglutide and dulaglutide had limited effects on gastric emptying. GIP secretion was suppressed by lixisenatide and liraglutide. Apolipoprotein B48 secretion was suppressed by all of the GLP‐1RAs.Conclusions: All of the GLP‐1RAs were found to improve HbA1c in a 12‐week prospective observational study in Japanese individuals with type 2 diabetes. However, differences in the mechanisms of the glucose‐lowering effects and body weight reduction were observed.

Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic β-cells are glucose-responsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K⁺(K_ATP) channel comprising KIR6.2 and sulfonylurea receptor 1. In absorptive epithelial cells and enteroendocrine cells, sodium glucose co-transporter 1 (SGLT1) is also known to play an important role in glucose absorption and glucose-induced incretin secretion. However, the glucose-sensing mechanism in K-cells is not fully understood. In this study, we examined the involvement of SGLT1 (SLC5A1) and the K_ATPchannels in glucose sensing in GIP secretion in both normal and streptozotocin-induced diabetic mice. Glimepiride, a sulfonylurea, did not induce GIP secretion and pretreatment with diazoxide, a K_ATPchannel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking K_ATPchannels (Kir6.2^−/−mice), glucose-induced GIP secretion was enhanced compared with control (Kir6.2^+/+) mice, but was completely blocked by the SGLT1 inhibitor phlorizin. InKir6.2^−/−mice, intestinal glucose absorption through SGLT1 was enhanced compared with that inKir6.2^+/+mice. On the other hand, glucose-induced GIP secretion was enhanced in the diabetic state inKir6.2^+/+mice. This GIP secretion was partially blocked by phlorizin, but was completely blocked by pretreatment with diazoxide in addition to phlorizin administration. These results demonstrate that glucose-induced GIP secretion depends primarily on SGLT1 in the normal state, whereas the K_ATPchannel as well as SGLT1 is involved in GIP secretion in the diabetic statein vivo.

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the incretin hormones secreted from enteroendocrine K‐cells and L‐cells, respectively, by oral ingestion of various nutrients including glucose. K‐cells, L‐cells and pancreatic β‐cells are glucose‐responsive cells with similar glucose‐sensing machinery including glucokinase and an adenosine triphosphate‐sensitive K⁺ channel comprising KIR6.2 and sulfonylurea receptor 1. However, the physiological role of the adenosine triphosphate‐sensitive K⁺ channel in GIP secretion in K‐cells and GLP‐1 secretion in L‐cells is not elucidated. Recently, it was reported that GIP and GLP‐1‐producing cells are present also in pancreatic islets, and islet‐derived GIP and GLP‐1 contribute to glucose‐induced insulin secretion from pancreatic β‐cells. In this short review, we focus on GIP and GLP‐1 secretion by monosaccharides, such as glucose or fructose, and the role of the adenosine triphosphate‐sensitive K⁺ channel in GIP and GLP‐1 secretion.

Adenosine triphosphate‐sensitive K⁺ (K_ATP) channels play an essential role in glucose‐induced insulin secretion from pancreatic β‐cells. It was recently reported that the K_ATP channel is also found in the enteroendocrine K‐cells and L‐cells that secrete glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), respectively. In the present study, we investigated the involvement of the K_ATP channel in fructose‐induced GIP, GLP‐1 and insulin secretion in mice. Fructose stimulated GIP secretion, but pretreatment with diazoxide, a K_ATP channel activator, did not affect fructose‐induced GIP secretion under streptozotocin‐induced hyperglycemic conditions. Fructose significantly stimulated insulin secretion in Kir6.2^+/+ mice, but not in mice lacking K_ATP channels (Kir6.2^−/−), and fructose stimulated GLP‐1 secretion in both Kir6.2^+/+ mice and Kir6.2^−/− mice under the normoglycemic condition. In addition, diazoxide completely blocked fructose‐induced insulin secretion in Kir6.2^+/+ mice and in MIN6‐K8 β‐cells. These results show that fructose‐induced GIP and GLP‐1 secretion is K_ATP channel‐independent and that fructose‐induced insulin secretion is K_ATP channel‐dependent.

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.