Incretin Response Research Articles

Effects of miglitol, sitagliptin, and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes. “The MASTER randomized, controlled trial”

To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with α-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D). In this multicenter open-label 24-week trial, Japanese over-weight (BMI ≥ 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated. During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S. In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins.

GLP-1 Plays a Limited Role in Improved Glycemia Shortly After Roux-en-Y Gastric Bypass: A Comparison With Intensive Lifestyle Modification

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin(9–39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.

Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1.

Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1(GCG)) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility. In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender- and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined. Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals. In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

A method for mouse pancreatic islet isolation and intracellular cAMP determination.

Uncontrolled glycemia is a hallmark of diabetes mellitus and promotes morbidities like neuropathy, nephropathy, and retinopathy. With the increasing prevalence of diabetes, both immune-mediated type 1 and obesity-linked type 2, studies aimed at delineating diabetes pathophysiology and therapeutic mechanisms are of critical importance. The β-cells of the pancreatic islets of Langerhans are responsible for appropriately secreting insulin in response to elevated blood glucose concentrations. In addition to glucose and other nutrients, the β-cells are also stimulated by specific hormones, termed incretins, which are secreted from the gut in response to a meal and act on β-cell receptors that increase the production of intracellular cyclic adenosine monophosphate (cAMP). Decreased β-cell function, mass, and incretin responsiveness are well-understood to contribute to the pathophysiology of type 2 diabetes, and are also being increasingly linked with type 1 diabetes. The present mouse islet isolation and cAMP determination protocol can be a tool to help delineate mechanisms promoting disease progression and therapeutic interventions, particularly those that are mediated by the incretin receptors or related receptors that act through modulation of intracellular cAMP production. While only cAMP measurements will be described, the described islet isolation protocol creates a clean preparation that also allows for many other downstream applications, including glucose stimulated insulin secretion, [3(H)]-thymidine incorporation, protein abundance, and mRNA expression.

A Method for Mouse Pancreatic Islet Isolation and Intracellular cAMP Determination

Uncontrolled glycemia is a hallmark of diabetes mellitus and promotes morbidities like neuropathy, nephropathy, and retinopathy. With the increasing prevalence of diabetes, both immune-mediated type 1 and obesity-linked type 2, studies aimed at delineating diabetes pathophysiology and therapeutic mechanisms are of critical importance. The β-cells of the pancreatic islets of Langerhans are responsible for appropriately secreting insulin in response to elevated blood glucose concentrations. In addition to glucose and other nutrients, the β-cells are also stimulated by specific hormones, termed incretins, which are secreted from the gut in response to a meal and act on β-cell receptors that increase the production of intracellular cyclic adenosine monophosphate (cAMP). Decreased β-cell function, mass, and incretin responsiveness are well-understood to contribute to the pathophysiology of type 2 diabetes, and are also being increasingly linked with type 1 diabetes. The present mouse islet isolation and cAMP determination protocol can be a tool to help delineate mechanisms promoting disease progression and therapeutic interventions, particularly those that are mediated by the incretin receptors or related receptors that act through modulation of intracellular cAMP production. While only cAMP measurements will be described, the described islet isolation protocol creates a clean preparation that also allows for many other downstream applications, including glucose stimulated insulin secretion, [3H]-thymidine incorporation, protein abundance, and mRNA expression.

Effects of high-fat diet and the anti-diabetic drug metformin on circulating GLP-1 and the relative number of intestinal L-cells.

BackgroundElevated serum free fatty acids (FFAs) contribute to the pathogenesis of type-2-diabetes (T2D), and lipotoxicity is observed in many cell types. We recently showed that simulated hyperlipidemia induces lipoapoptosis also in GLP-1-secreting L-cells in vitro, while metformin confers lipoprotection.The aim of this study was to determine if a high fat diet (HFD) reduces the number of enteroendocrine L-cells and/or GLP-1 plasma levels in a rodent model, and potential effects thereupon of metformin treatment.MethodsC57/Bl6 mice received control/HFD for 12-weeks, and oral administration of metformin/saline for the last 14 days. Blood glucose, glycosylated hemoglobin and plasma insulin and GLP-1 were determined before and after treatment with metformin using ELISAs. GLP-1-immunopositive cells in intestinal tissue sections were quantified using immunohistochemistry.ResultsA HFD increased blood glucose, glycosylated hemoglobin, and fasting plasma insulin (33%, 15% and 70% increase, respectively), in conjunction with reduced oral glucose tolerance, indicating the manifestation of insulin resistance. Metformin counteracted these adverse effects, while also reducing prandial plasma FFAs. The number of GLP-1-positive cells was indicated to be reduced (55% reduction of the number of GLP-1-positive cells, p = 0.134), while there was a trend toward increased prandial plasma GLP-1 despite reduced food intake following a HFD.ConclusionHFD-fed mice rapidly develop insulin resistance. Metformin exerts beneficial glucose lowering effects, and is indicated to improve the incretin response. Albeit no significant effect, a HFD tends to reduce the number of GLP-1-positive cells. However, considering concurrent normal or increased plasma GLP-1, any reduction in the number of GLP-1-positive cells, probably does not contribute to development of the glucose intolerance, but may contribute to progression of the diabetic state through eventual loss of a functional incretin response.

Rapid gastric and intestinal transit is a major determinant of changes in blood glucose, intestinal hormones, glucose absorption and postprandial symptoms after gastric bypass.

To evaluate the effect of modulating pouch emptying (PE) and SI transit of glucose after Roux-en-Y gastric bypass (RYGB) on blood glucose, incretin hormones, glucose absorption and gastrointestinal (GI) symptoms. Ten RYGB patients were studied twice in random order, receiving either a 150 ml glucose drink (200 kcal) or the same solution infused into the proximal Roux-limb at 4 kcal/min. Data were compared with 10 healthy volunteers who received a 4 kcal/min duodenal infusion. PE, cecal arrival time (CAT), blood glucose, plasma 3-O-methylglucose (3-OMG), insulin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), and GI symptoms were measured. In RYGB subjects, the glucose drink emptied very rapidly (PE t50 = 3 ± 1 min) and intestinal glucose infusion was associated with higher blood glucose and plasma 3-OMG, but lower plasma GLP-1, GIP, insulin, and GI symptoms than oral glucose (all P < 0.001), and comparable to volunteers. In RYGB subjects, CAT correlated inversely with peak GLP-1 (r = -0.73, P = 0.01), and plasma 3-OMG correlated tightly blood glucose (r = 0.94, P < 0.0001). After RYGB, reducing intestinal glucose delivery to 4 kcal/min is associated with higher blood glucose, greater glucose absorption, lower incretin responses, and less GI symptoms, supporting rapid transit contribution to the exaggerated incretin responses and "dumping symptoms".

Tu2012 Impact of a 2-Week Very Low Calorie Diet (VLCD) on Glucose Sensing, Absorption, Transporters, Incretin Hormones and Glycemia in Morbidly Obese Humans

We showed that glucose absorption is accelerated in the proximal intestine of morbidly obese humans, associated with increased expression of sodium dependent glucose co-transporter 1 (SGLT1), an altered incretin profile, hyperinsulinemia and hyperglycemia. This study aimed to examine the effects of energy restriction on glucose absorption, expression of intestinal glucose transporters and sweet taste receptors (STR), incretin hormone responses and glycemia in the morbidly obese. Methods: 10 non-diabetic, morbidly obese subjects (2M:8F; 45±3yrs, BMI: 46±3kg/m2) were studied before and after a 2-week VLCD (750kcal/day). On each occasion, endoscopic duodenal biopsies were collected before and after intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3-OMG, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and insulin were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results After 2 weeks of VLCD, body weight (-5.6±0.5kg, P<0.001), HbA1c (-0.32±0.08%, P=0.001), fasting blood glucose (-0.5±0.1mmol/L, P=0.02) and fasting expression of T1R2 (-54±22%, P=0.03), SGLT1 (-30±7%, P=0.004) and GLUT2 (-50±15%, P=0.008) were lower than at baseline. Prior to VLCD, intra-duodenal glucose had no impact onT1R2, SGLT-1 and GLUT2 expression, but after VLCD, intra-duodenal glucose stimulated increased expression of T1R2 (45±30%, P=0.03) and GLUT2 (57±14%, P=0.003). The blood glucose (P=0.002), plasma GIP (P=0.03) and plasma insulin (P=0.002) responses to intra-duodenal glucose were all reduced after VLCD, while plasma 3-OMG and GLP-1 concentrations were unchanged. CONCLUSIONS: The improvement in glycemic control after short-term VLCD in morbid obesity is most likely mediated by reduced insulin resistance from weight loss, but not via a reduction in intestinal glucose absorption or an increased incretin response. Although VCLD reduces the fasting expression of both STR and glucose transporters, these increase rapidly on exposure to glucose. Further studies with inhibitors of STR and/or glucose transporters are warranted to determine whether the changes in receptor expressional dynamics are responsible for the observed incretin responses.

579 Accelerated Glucose Absorption in Proximal Intestine and Its Relationship to Glucose Transporters, Incretin Hormones and Glycaemia in Morbidly Obese Humans: the “X-Factor” of the Foregut Theory?

Glucose absorption in the small intestine is mediated by sodium dependent glucose cotransporter 1 (SGLT-1) and glucose transporter-2 (GLUT2), and is potentially linked to sweet taste receptor (STR) signaling and incretin hormone secretion. Both glucose absorption and expression of SGLT-1 are increased in obese rats, but human data is lacking. This study aimed to examine intestinal glucose absorption inmorbidly obese humans, and its relationship to glycemia, incretin responses, SGLT-1, GLUT2, and STR expression. Methods: 17 nondiabetic, morbidly obese subjects (5M:12F; 45 ± 3yrs, BMI: 48 ± 4kg/m2) and 11 lean controls (10M:1F; 44 ± 6yrs, BMI: 25 ± 1kg/m2) underwent endoscopic duodenal biopsies prior to intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP1), insulin, and glucagon were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results: Both the rate of glucose absorption, as assessed by the rise in plasma 3-OMG concentrations (P<0.001) and blood glucose concentrations (P<0.0001) were substantially greater in obese than lean subjects (Fig AB Fig C), but not GLUT2 or T1R2, was higher in the obese than lean subjects, and was related to peaked plasma 3OMG (r=0.61, P=0.01). CONCLUSIONS: Glucose absorption in the proximal intestine is (i) accelerated in morbid obesity, (ii) associated with an incretin profile that potentially promotes both hyperinsulinemia and hyperglycemia, and (iii) associated with increased expression of SGLT-1. These novel findings suggest that accelerated glucose absorption in the proximal gutmay be the X-factor accounting for the foregut theory of obesity and diabetes.

580 Ezetimibe Modulates Endogenous LXR Ligands to Regulate Intestinal LDLR Receptors via IDOL

Glucose absorption in the small intestine is mediated by sodium dependent glucose cotransporter 1 (SGLT-1) and glucose transporter-2 (GLUT2), and is potentially linked to sweet taste receptor (STR) signaling and incretin hormone secretion. Both glucose absorption and expression of SGLT-1 are increased in obese rats, but human data is lacking. This study aimed to examine intestinal glucose absorption inmorbidly obese humans, and its relationship to glycemia, incretin responses, SGLT-1, GLUT2, and STR expression. Methods: 17 nondiabetic, morbidly obese subjects (5M:12F; 45 ± 3yrs, BMI: 48 ± 4kg/m2) and 11 lean controls (10M:1F; 44 ± 6yrs, BMI: 25 ± 1kg/m2) underwent endoscopic duodenal biopsies prior to intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP1), insulin, and glucagon were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results: Both the rate of glucose absorption, as assessed by the rise in plasma 3-OMG concentrations (P<0.001) and blood glucose concentrations (P<0.0001) were substantially greater in obese than lean subjects (Fig AB Fig C), but not GLUT2 or T1R2, was higher in the obese than lean subjects, and was related to peaked plasma 3OMG (r=0.61, P=0.01). CONCLUSIONS: Glucose absorption in the proximal intestine is (i) accelerated in morbid obesity, (ii) associated with an incretin profile that potentially promotes both hyperinsulinemia and hyperglycemia, and (iii) associated with increased expression of SGLT-1. These novel findings suggest that accelerated glucose absorption in the proximal gutmay be the X-factor accounting for the foregut theory of obesity and diabetes.

Tu2013 A Short Bowel Syndrome Rodent Model Mimicking the Human Pathology Results in Increased AgRP/NPY and Decreased POMC/TRH Expression in the Hypothalamus

We showed that glucose absorption is accelerated in the proximal intestine of morbidly obese humans, associated with increased expression of sodium dependent glucose co-transporter 1 (SGLT1), an altered incretin profile, hyperinsulinemia and hyperglycemia. This study aimed to examine the effects of energy restriction on glucose absorption, expression of intestinal glucose transporters and sweet taste receptors (STR), incretin hormone responses and glycemia in the morbidly obese. Methods: 10 non-diabetic, morbidly obese subjects (2M:8F; 45±3yrs, BMI: 46±3kg/m2) were studied before and after a 2-week VLCD (750kcal/day). On each occasion, endoscopic duodenal biopsies were collected before and after intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3-OMG, glucosedependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and insulin were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results After 2 weeks of VLCD, body weight (-5.6±0.5kg, P<0.001), HbA1c (-0.32±0.08%, P=0.001), fasting blood glucose (-0.5±0.1mmol/L, P=0.02) and fasting expression of T1R2 (-54±22%, P=0.03), SGLT1 (-30±7%, P=0.004) and GLUT2 (-50±15%, P=0.008) were lower than at baseline. Prior to VLCD, intra-duodenal glucose had no impact onT1R2, SGLT-1 and GLUT2 expression, but after VLCD, intra-duodenal glucose stimulated increased expression of T1R2 (45±30%, P=0.03) and GLUT2 (57±14%, P=0.003). The blood glucose (P=0.002), plasma GIP (P=0.03) and plasma insulin (P=0.002) responses to intra-duodenal glucose were all reduced after VLCD, while plasma 3-OMG and GLP-1 concentrations were unchanged. CONCLUSIONS: The improvement in glycemic control after short-term VLCD in morbid obesity is most likely mediated by reduced insulin resistance from weight loss, but not via a reduction in intestinal glucose absorption or an increased incretin response. Although VCLD reduces the fasting expression of both STR and glucose transporters, these increase rapidly on exposure to glucose. Further studies with inhibitors of STR and/or glucose transporters are warranted to determine whether the changes in receptor expressional dynamics are responsible for the observed incretin responses.

Incretin Response to Acute Exercise of Differing Intensities in Obese Women

Incretin Response to Acute Exercise of Differing Intensities in Obese Women

Postprandial Metabolite Profiles Reveal Differential Nutrient Handling After Bariatric Surgery Compared With Matched Caloric Restriction

Roux-en-Y gastric bypass (RYGB) surgery results in exaggerated postprandial insulin and incretin responses and increased susceptibility to hypoglycemia. We examined whether these features are due to caloric restriction (CR) or altered nutrient handling. We performed comprehensive analysis of postprandial metabolite responses during a 2-hour mixed-meal tolerance (MMT) test in 20 morbidly obese subjects with type 2 diabetes who underwent RYGB surgery or matched CR. Acylcarnitines and amino acids (AAs) were measured using targeted mass spectrometry. A linear mixed model was used to determine the main effect of interventions and interaction term to assess the effect of interventions on postprandial kinetics. Two weeks after these interventions, several gut hormones (insulin, glucose-dependent insulinotropic polypeptide, and glucagon-like peptide 1), glucose, and multiple AAs, including branched-chain and aromatic species, exhibited a more rapid rate of appearance and clearance in RYGB surgery subjects than in CR subjects during the MMT test. In the RYGB surgery group, changes in leucine/isoleucine, methionine, phenylalanine, and glucagon-like peptide 1 response were associated with changes in insulin response. Levels of alanine, pyruvate, and lactate decreased significantly at the later stages of meal challenge in RYGB surgery subjects but increased with CR. RYGB surgery results in improved metabolic flexibility (ie, greater disposal of glucose and AAs and more complete β-oxidation of fatty acids) compared with CR. The changes in the AA kinetics may augment the hormonal responses seen after RYGB surgery. The reduction in key gluconeogenic substrates in the postprandial state may contribute to increased susceptibility to hypoglycemic symptoms in RYGB surgery subjects.

Glucagon Response to Oral Glucose Challenge in Type 1 Diabetes: Lack of Impact of Euglycemia

OBJECTIVE Previous studies have demonstrated aberrant glucagon physiology in the setting of type 1 diabetes (T1D) but have not addressed the potential impact of ambient glycemia on this glucagon response. Thus, our objective was to evaluate the impact of euglycemia versus hyperglycemia on the glucagon response to an oral glucose challenge in T1D. RESEARCH DESIGN AND METHODS Ten adults with T1D (mean age 56.6 ± 9.0 years, duration of diabetes 26.4 ± 7.5 years, HbA1c 7.5% ± 0.77, and BMI 24.1 kg/m(2) [22.6-25.4]) underwent 3-h 50-g oral glucose tolerance tests (OGTTs) on two separate days at least 24 h apart in random order under conditions of pretest euglycemia (plasma glucose [PG] between 4 and 6 mmol/L) and hyperglycemia (PG between 9 and 11 mmol/L), respectively. RESULTS Glycemic excursion on the OGTT was similar between the euglycemic and hyperglycemic tests (P = 0.72 for interaction between time postchallenge and glycemic setting). Interestingly, glucagon levels increased in response to the OGTT under both glycemic conditions (P < 0.001) and there were no differences in glucagon response between the euglycemic and hyperglycemic days (P = 0.40 for interaction between time postchallenge and glycemic setting). In addition, the incretin responses to the OGTT (glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon-like peptide-2) were also not different between the euglycemic and hyperglycemic settings. CONCLUSIONS In patients with T1D, there is a paradoxical increase in glucagon in response to oral glucose that is not reversed when euglycemia is achieved prior to the test. This abnormal glucagon response likely contributes to the postprandial hyperglycemia in T1D irrespective of ambient glycemia.

Effects of consumption of main and side dishes with white rice on postprandial glucose, insulin, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 responses in healthy Japanese men

The co-ingestion of protein, fat and fibre with carbohydrate reportedly affects postprandial glucose, insulin and incretin (glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)) responses. However, the effects of combination dishes with carbohydrate-rich foods at typically eaten amounts remain unclear. The objective of the present study was to evaluate the effects of consuming recommended amounts of side dishes with boiled white rice in the same meal on postprandial plasma glucose, insulin and incretin hormone responses. A total of nine healthy male volunteers consumed four different meals in a random order on separate days. The test meals were as follows: S, white rice; SM, addition of protein-rich main dishes to the S meal; SMF, addition of a fat-rich food item to the SM meal; SMFV, addition of vegetables to the SMF meal. Plasma glucose, GIP and GLP-1 and serum insulin concentrations were determined during a 3h period after consumption of these meals. Postprandial glucose responses were lower after SMFV meal consumption than after consumption of the other meals. The incremental AUC for GIP (0-180min) were largest after consumption of the SMF and SMFV meals, followed by that after SM meal consumption, and was smallest after S meal consumption (P<0·05). Furthermore, we found GIP concentrations to be dose dependently increased by the fat content of meals of ordinary size, despite the amount of additional fat being small. In conclusion, the combination of recommended amounts of main and vegetable side dishes with boiled white rice is beneficial for lowering postprandial glucose concentrations, with an increased incretin response, when compared with white rice alone.

The Incretin Response After Successful Islet Transplantation

The Incretin Response After Successful Islet Transplantation

GLP-1 Responses Are Heritable and Blunted in Acquired Obesity With High Liver Fat and Insulin Resistance

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.

Microbial Modulation of Energy Availability in the Colon Regulates Intestinal Transit

Gut microbiota contribute to host metabolic efficiency by increasing energy availability through the fermentation of dietary fiber and production of short-chain fatty acids (SCFAs) in the colon. SCFAs are proposed to stimulate secretion of the proglucagon (Gcg)-derived incretin hormone GLP-1, which stimulates insulin secretion (incretin response) and inhibits gastric emptying. We find that germ-free (GF) and antibiotic-treated mice, which have severely reduced SCFA levels, have increased basal GLP-1 levels in the plasma and increased Gcg expression in the colon. Increasing energy supply, either through colonization with polysaccharide-fermenting bacteria or through diet, suppressed colonic Gcg expression in GF mice. Increased GLP-1 levels in GF mice did not improve the incretin response but instead slowed intestinal transit. Thus, microbiota regulate the basal levels of GLP-1, and increasing these levels may be an adaptive response to insufficient energy availability in the colon that slows intestinal transit and allows for greater nutrient absorption.

Effects of breads of varying carbohydrate quality on postprandial glycaemic, incretin and lipidaemic response after first and second meals in adults with diet-controlled type 2 diabetes

Bread formulations of sprouted grain, whole grain and sourdough fermentation can influence metabolism. Postprandial carbohydrate and lipid metabolism in type 2 diabetes (T2D) is aberrant, rationalising identification of breads to improve these responses. The effect of breads of varying carbohydrate quality on postprandial glycaemic and lipid parameters was examined before and after a first and second meal. Twelve adults with diet-controlled T2D consumed 50g of available carbohydrate from 4 breads (3-grain sprouted sourdough (SPR), whole-grain sourdough (WG), white sourdough (SD), control white (WB)), in a randomised crossover design. Blood glucose incremental area-under-the-curve (iAUC) was significantly lower after SPR compared to all breads. Second meal plasma insulin iAUC was significantly lower after SPR compared to SD and WB; serum apolipoprotein B-100 iAUC was lower with SD compared to WB; but no other significant differences were found. Bread made from sprouted grains can improve postprandial glycaemic responses in adults with T2D.

Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes primarily by increasing plasma active glucagon-like peptide-1 (GLP-1) levels. While various combination therapies based on DPP-4 inhibitors have been proposed for treatment of type 2 diabetes, the effects of combination therapy of DPP-4 inhibitors and alpha-glucosidase inhibitors on β-cell function are less characterized. We evaluated the effects of long-term treatment with vildagliptin, a DPP-4 inhibitor, on metabolic parameters and β-cell function, in combination with miglitol, an alpha-glucosidase inhibitor, in diet-controlled db/db mice. In this study, 6-week-old male db/db mice were provided with standard chow twice a day for 6weeks. Meal tolerance tests and glucose tolerance tests showed that the combination therapy of vildagliptin with miglitol, but not each alone, suppressed postprandial glycemic excursion, enhanced postprandial active GLP-1 levels and prevented deterioration of glucose tolerance in the db/db mice. The combination treatment did not alter β-cell mass, but resulted in preserved expression of glucose transporter 2, Zinc transporter 8 and MafA and reduced the number of α cells. These results suggest that the combination of vildagliptin and miglitol prevents the development of overt diabetes in diet-controlled pre-diabetic db/db mice by normalizing postprandial glucose and incretin response, and by preserving β-cell structure and the expression of factors essential for β-cell function.