Tongzhi Wu

Disordered control of intestinal sweet taste receptor expression and glucose absorption in type 2 diabetes.

We previously established that the intestinal sweet taste receptors (STRs), T1R2 and T1R3, were expressed in distinct epithelial cells in the human proximal intestine and that their transcript levels varied with glycemic status in patients with type 2 diabetes. Here we determined whether STR expression was 1) acutely regulated by changes in luminal and systemic glucose levels, 2) disordered in type 2 diabetes, and 3) linked to glucose absorption. Fourteen healthy subjects and 13 patients with type 2 diabetes were studied twice, at euglycemia (5.2 ± 0.2 mmol/L) or hyperglycemia (12.3 ± 0.2 mmol/L). Endoscopic biopsy specimens were collected from the duodenum at baseline and after a 30-min intraduodenal glucose infusion of 30 g/150 mL water plus 3 g 3-O-methylglucose (3-OMG). STR transcripts were quantified by RT-PCR, and plasma was assayed for 3-OMG concentration. Intestinal STR transcript levels at baseline were unaffected by acute variations in glycemia in healthy subjects and in type 2 diabetic patients. T1R2 transcript levels increased after luminal glucose infusion in both groups during euglycemia (+5.8 × 104 and +5.8 × 104 copies, respectively) but decreased in healthy subjects during hyperglycemia (−1.4 × 104 copies). T1R2 levels increased significantly in type 2 diabetic patients under the same conditions (+6.9 × 105 copies). Plasma 3-OMG concentrations were significantly higher in type 2 diabetic patients than in healthy control subjects during acute hyperglycemia. Intestinal T1R2 expression is reciprocally regulated by luminal glucose in health according to glycemic status but is disordered in type 2 diabetes during acute hyperglycemia. This defect may enhance glucose absorption in type 2 diabetic patients and exacerbate postprandial hyperglycemia.

Effects of rectal administration of taurocholic acid on glucagon‐like peptide‐1 and peptide YY secretion in healthy humans

Glucagon‐like peptide‐1 (GLP‐1) and peptide YY (PYY), secreted by enteroendocrine L‐cells located most densely in the colon and rectum, are of fundamental importance in blood glucose and appetite regulation. In animal models, colonic administration of bile acids can stimulate GLP‐1 and PYY by TGR5 receptor activation. We evaluated the effects of taurocholic acid (TCA), administered as an enema, on plasma GLP‐1 and PYY, as well as gastrointestinal sensations in 10 healthy male subjects, and observed that rectal administration of TCA promptly stimulated secretion of both GLP‐1 and PYY, and increased fullness, in a dose‐dependent manner. These observations confirm that topical application of bile acids to the distal gut may have potential for the management of type 2 diabetes and obesity.

Effects of taurocholic acid on glycemic, glucagon-like peptide-1, and insulin responses to small intestinal glucose infusion in healthy humans.

CONTEXT In vitro and animal studies suggest that bile acids have the capacity to reduce blood glucose by stimulating glucagon-like peptide-1 (GLP-1) and, thereby, insulin. OBJECTIVE This study evaluated the effects of intrajejunal taurocholic acid (TCA) on blood glucose, GLP-1, and insulin responses to jejunal glucose infusion in healthy men. PARTICIPANTS AND DESIGN Ten healthy men were each studied on 2 days in a double-blind, randomized order. After the subjects fasted overnight, a jejunal catheter was positioned and a balloon inflated 30 cm beyond the pylorus with aspiration of endogenous bile. Two grams TCA in saline, or saline control, was infused beyond the balloon over 30 minutes, followed by 2 g TCA or control, together with 60 g glucose, over the next 120 minutes. Blood was sampled frequently for the measurements of blood glucose, total GLP-1, insulin, C-peptide, and glucagon. RESULTS Intrajejunal infusion of TCA alone (t = -30 to 0 minutes) had no effect on blood glucose, GLP-1, insulin, C-peptide, or glucagon concentrations. During intrajejunal glucose infusion (t = 0 to 120 minutes), blood glucose concentrations were lower (P < .001), and plasma GLP-1 (P < .001) and the C-peptide/glucose ratio (P = .008) were both greater, whereas plasma insulin, C-peptide, and glucagon levels were not significantly different after TCA than after control. CONCLUSIONS In healthy humans, small intestinal infusion of TCA potently reduces the glycemic response to small intestinal glucose, associated with an increase in GLP-1 and C-peptide/glucose ratio. These observations indicate the potential for bile acid-based therapy in type 2 diabetes.

Administration of resveratrol for 5 wk has no effect on glucagon-like peptide 1 secretion, gastric emptying, or glycemic control in type 2 diabetes: a randomized controlled trial

BACKGROUND Resveratrol has been reported to lower glycemia in rodent models of type 2 diabetes associated with the stimulation of glucagon-like peptide 1 (GLP-1), which is known to slow gastric emptying, stimulate insulin secretion, and suppress glucagon secretion and energy intake. OBJECTIVE We evaluated the effects of 5 wk of resveratrol treatment on GLP-1 secretion, gastric emptying, and glycemic control in type 2 diabetes. DESIGN Fourteen patients with diet-controlled type-2 diabetes [mean ± SEM glycated hemoglobin (HbA1c): 6.4 ± 0.2% (46.4 ± 2.2 mmol/mol)] received resveratrol (500 mg twice daily) or a placebo over two 5-wk intervention periods with a 5-wk washout period in between in a double-blind, randomized, crossover design. Before and after each intervention period (4 visits), body weight and HbA1c were measured, and patients were evaluated after an overnight fast with a standardized mashed-potato meal labeled with 100 μg (13)C-octanoic acid to measure blood glucose and plasma GLP-1 concentrations and gastric emptying (breath test) over 240 min. Daily energy intake was estimated from 3-d food diaries during the week before each visit. RESULTS Fasting and postprandial blood glucose and plasma total GLP-1 as well as gastric emptying were similar at each assessment, and the change in each variable from weeks 0 to 5 did not differ between resveratrol and placebo groups. Similarly, changes in HbA1c, daily energy intake, and body weight after 5 wk did not differ between the 2 treatments. CONCLUSIONS In patients with diet-controlled type 2 diabetes, 5 wk of twice-daily 500 mg-resveratrol supplementation had no effect on GLP-1 secretion, glycemic control, gastric emptying, body weight, or energy intake. Our observations do not support the use of resveratrol for improving glycemic control. This trial was registered at www.anzctr.org.au as ACTRN12613000717752.

Effects of a D-xylose preload with or without sitagliptin on gastric emptying, glucagon-like peptide-1, and postprandial glycemia in type 2 diabetes.

OBJECTIVE Macronutrient “preloads” can reduce postprandial glycemia by slowing gastric emptying and stimulating glucagon-like peptide-1 (GLP-1) secretion. An ideal preload would entail minimal additional energy intake and might be optimized by concurrent inhibition of dipeptidyl peptidase-4 (DPP-4). We evaluated the effects of a low-energy d-xylose preload, with or without sitagliptin, on gastric emptying, plasma intact GLP-1 concentrations, and postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS Twelve type 2 diabetic patients were studied on four occasions each. After 100 mg sitagliptin (S) or placebo (P) and an overnight fast, patients consumed a preload drink containing either 50 g d-xylose (X) or 80 mg sucralose (control [C]), followed after 40 min by a mashed potato meal labeled with 13C-octanoate. Blood was sampled at intervals. Gastric emptying was determined. RESULTS Both peak blood glucose and the amplitude of glycemic excursion were lower after PX and SC than PC (P < 0.01 for each) and were lowest after SX (P < 0.05 for each), while overall blood glucose was lower after SX than PC (P < 0.05). The postprandial insulin-to-glucose ratio was attenuated (P < 0.05) and gastric emptying was slower (P < 0.01) after d-xylose, without any effect of sitagliptin. Plasma GLP-1 concentrations were higher after d-xylose than control only before the meal (P < 0.05) but were sustained postprandially when combined with sitagliptin (P < 0.05). CONCLUSIONS In type 2 diabetes, acute administration of a d-xylose preload reduces postprandial glycemia and enhances the effect of a DPP-4 inhibitor.

Effects of sitagliptin on glycemia, incretin hormones, and antropyloroduodenal motility in response to intraduodenal glucose infusion in healthy lean and obese humans, and patients with type 2 diabetes treated with or without metformin

The impact of variations in gastric emptying, which influence the magnitude of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) secretion, on glucose lowering by dipeptidyl peptidase-4 (DPP-4) inhibitors is unclear. We evaluated responses to intraduodenal glucose infusion (60 g over 120 min [i.e., 2 kcal/min], a rate that predominantly stimulates GIP but not GLP-1) after sitagliptin versus control in 12 healthy lean, 12 obese, and 12 type 2 diabetic subjects taking metformin 850 mg b.i.d. versus placebo. As expected, sitagliptin augmented plasma-intact GIP substantially and intact GLP-1 modestly. Sitagliptin attenuated glycemic excursions in healthy lean and obese but not type 2 diabetic subjects, without affecting glucagon or energy intake. In contrast, metformin reduced fasting and glucose-stimulated glycemia, suppressed energy intake, and augmented total and intact GLP-1, total GIP, and glucagon in type 2 diabetic subjects, with no additional glucose lowering when combined with sitagliptin. These observations indicate that in type 2 diabetes, 1) the capacity of endogenous GIP to lower blood glucose is impaired; 2) the effect of DPP-4 inhibition on glycemia is likely to depend on adequate endogenous GLP-1 release, requiring gastric emptying >2 kcal/min; and 3) the action of metformin to lower blood glucose is not predominantly by way of the incretin axis.

Artificial Sweeteners Have No Effect on Gastric Emptying, Glucagon-Like Peptide-1, or Glycemia After Oral Glucose in Healthy Humans

Intestinal exposure to glucose stimulates the release of glucagon-like peptide-1 (GLP-1), slows subsequent gastric emptying, and reduces appetite. These responses are signaled, at least in part, by intestinal “sweet taste receptors” (STRs), including taste receptor type 1 members 2 and 3 (T1R2, T1R3), and their cellular signaling partners α-gustducin and transient receptor potential cation channel subfamily M member 5 (TRPM5) (1). A recent study by Brown et al. (2) in healthy humans reported that oral ingestion of “diet soda,” containing both sucralose (46 mg) and acesulfame potassium (AceK) (26 mg), augmented GLP-1 release by more than one-third after an oral glucose load given 10 min later compared with carbonated water, suggesting a potential synergy between artificial sweeteners and glucose in stimulating GLP-1 secretion. The design of that study was, however, suboptimal, as the diet soda contained a number of substances (including caramel color, gum acacia, natural flavors, citric acid, potassium benzoate, phosphoric acid, and potassium citrate) that were not controlled for. Therefore, we evaluated whether oral administration of sucralose and AceK in doses comparable with those used by Brown et al. (2) would augment the GLP-1 response to oral glucose and modulate gastric emptying or glycemia …

Mechanism of increase in plasma intact GLP-1 by metformin in type 2 diabetes: Stimulation of GLP-1 secretion or reduction in plasma DPP-4 activity?

Metformin was reported to increase plasma intact glucagon-like peptide-1 (GLP-1) concentrations in type 2 diabetes. This is, at least partly, attributable to stimulation of GLP-1 secretion. A reduction in soluble dipeptidyl peptidase-4 activity may also make a modest contribution.

Effects of Intraduodenal Glutamine on Incretin Hormone and Insulin Release, the Glycemic Response to an Intraduodenal Glucose Infusion, and Antropyloroduodenal Motility in Health and Type 2 Diabetes

OBJECTIVE Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying. RESEARCH DESIGN AND METHODS Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline. RESULTS ID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5). CONCLUSIONS Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes

OBJECTIVE Nutrient “preloads” given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. RESEARCH DESIGN AND METHODS Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a 13C-octanoate–labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. RESULTS Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each). CONCLUSIONS In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.