Sepsis-induced activation of endogenous GLP-1 system is enhanced in type 2 diabetes.

BACKGROUND: High levels of circulating GLP-1 are associated with severity of sepsis in critically ill nondiabetic patients. Whether patients with type 2 diabetes (T2D) display different activation of the endogenous GLP-1 system during sepsis and whether it is affected by diabetes-related metabolic parameters are not known. METHODS: Serum levels of GLP-1 (total and active forms) and its inhibitor enzyme sDPP-4 were determined by ELISA on admission and after 2 to 4 days in 37 sepsis patients with (n = 13) and without T2D (n = 24) and compared to normal healthy controls (n = 25). Correlations between GLP-1 system activation and clinical, inflammatory, and diabetes-related metabolic parameters were performed. RESULTS: A 5-fold (P < .001) and 2-fold (P < .05) increase in active and total GLP-1 levels, respectively, were found on admission as compared to controls. At 2 to 4 days from admission, the level of active GLP-1 forms in surviving patients were decreased significantly (P < .005), and positively correlated with inflammatory marker CRP (r = 0.33, P = .05). T2D survivors displayed a similar but more enhanced pattern of GLP-1 response than nondiabetic survivors. Nonsurvivors demonstrate an early extreme increase of both total and active GLP-1 forms, 9.5-fold and 5-fold, respectively (P < .05). The initial and late levels of circulating GLP-1 inhibitory enzyme sDPP-4 were twice lower in all studied groups (P < .001), compared with healthy controls. CONCLUSIONS: Taken together, these data indicate that endogenous GLP-1 system is activated during sepsis. Patients with T2D display an enhanced and prolonged activation as compared to nondiabetic patients. Extreme early increased GLP-1 levels during sepsis indicate poor prognosis.

Relationships among Postprandial Plasma Active GLP-1 and GIP Excursions, Skeletal Muscle Mass, and Body Fat Mass in Patients with Type 2 Diabetes Treated with Either Miglitol, Sitagliptin, or Their Combination: A Secondary Analysis of the MASTER Study.

BACKGROUND: We previously conducted a pilot randomized controlled trial "the MASTER study" and demonstrated that alpha-glucosidase inhibitor miglitol and a dipeptidyl peptidase-4 inhibitor sitagliptin modified postprandial plasma excursions of active glucagon-like peptide-1 (aGLP-1) and active gastric inhibitory polypeptide (aGIP), and miglitol treatment decreased body fat mass in patients with type 2 diabetes (T2D). However, the details regarding the relationships among postprandial plasma aGLP-1 and aGIP excursions, skeletal muscle mass, and body fat mass are unclear. METHODS: We conducted a secondary analysis of the relationships among skeletal muscle mass index (SMI), total body fat mass index (TBFMI), and the incremental area under the curves (iAUC) of plasma aGLP-1 and aGIP excursions following mixed meal ingestion at baseline and after 24-week add-on treatment with either miglitol alone, sitagliptin alone, or their combination in T2D patients. RESULTS: SMI was not changed after the 24-week treatment with miglitol and/or sitagliptin. TBFMI was reduced and the rates of aGIP-iAUC change were lowered in the two groups treated with miglitol, although their correlations did not reach statistical significance. We observed a positive correlation between the rates of aGIP-iAUC and TBFMI changes and a negative correlation between the rates of TBFMI and SMI changes in T2D patients treated with sitagliptin alone whose rates of aGIP-iAUC change were elevated. CONCLUSIONS: Collectively, although T2D patients treated with miglitol and/or sitagliptin did not show altered SMI after 24-week treatment, the current study suggests that there are possible interrelationships among postprandial plasma aGIP excursion modified by sitagliptin, skeletal muscle mass, and body fat mass.

Association between habitual sleep duration/quality and appetite markers in individuals with obesity.

STUDY OBJECTIVES: To assess if habitual sleep duration/quality was associated with appetite in individuals with obesity, and if the association was modulated by sex. METHODS: Sleep duration/quality was measured with Pittsburgh Sleep Quality Index score in 95 healthy adults with obesity (BMI: 36.6 ± 4.2 kg/m2). Subjective feelings of appetite were assessed using visual analogue scales, and plasma concentrations of active ghrelin, total peptide YY, active glucagon-like peptide 1, cholecystokinin (CCK) and insulin were measured in fasting and every 30 min up to 2.5 h after a meal. RESULTS: No significant associations were found between sleep duration, or overall quality, and appetite in all participants. However, a worse sleep efficiency was associated with lower postprandial CCK, a shorter habitual sleep was associated with lower postprandial desire to eat and a lower daytime dysfunction was associated with higher prospective food consumption in fasting (P<0.05, for all). In males, a shorter habitual sleep duration and a worse subjective sleep quality were associated with increased basal and postprandial active ghrelin (P<0.05, P<0.01, P<0.01 and P<0.05, respectively). Also, a shorter habitual sleep was associated with lower basal and postprandial insulin (P<0.05 for both) and a worse overall sleep quality with lower postprandial insulin (P<0.05). In females, a worse overall sleep quality was associated with lower postprandial active ghrelin (P<0.05), and short habitual sleep with higher postprandial insulin (P<0.05). CONCLUSION: A worse habitual sleep efficiency is associated with blunted postprandial CCK secretion in individuals with obesity. The association between habitual sleep duration/quality and insulin and active ghrelin seems to be modulated by sex, but more studies are needed to confirm these findings.

Amelioration of Diabetes mellitus by modulation of GLP-1 via targeting alpha-glucosidase using Acacia tortilis polysaccharide in Streptozotocin-Nicotinamide induced diabetes in rats.

BACKGROUND: Polysaccharides decrease the glucose level by inhibiting α-glucosidase enzyme which further increases the level of GLP-1 (Glucagon-like peptide 1) to increase the insulin level as per earlier reports. OBJECTIVE: Similar hypothesis was designed in present study to investigate the α-glucosidase enzyme inhibition and involvement of GLP-1 in antidiabetic mechanism of Acacia tortilis polysaccharides (AEATP) in diabetic rats. Isolated polysaccharides were analyzed for their chemical nature by using HPLC and FTIR method. MATERIALS AND METHODS: Male albino wistar rats were divided into control, diabetic, diabetic + voglibose, diabetic + glimepiride, diabetic+250, 500, 1000 mg/kg of AEATP, diabetic + glimepiride + voglibose, diabetic + glimepiride+ 250, 500 and 1000 mg/kg AEATP, diabetic + GLP-1 antagonist+250, 500 and 1000 mg/kg AEATP. Plasma glucose, insulin and active GLP-1 levels were measured 15 min after OGTT. Fasting blood glucose, Plasma triglycerides, glycated hemoglobin (HbA1c), Fasting insulin, pancreatic insulin content, ileum and colon GLP-1 content were assessed at 5th week. Association of alpha-glucosidase was also assessed with GLP-1 and insulin. RESULTS: AEATP significantly attenuated hyperglycemia by increasing insulin level in plasma and pancreas and increased active GLP-1 as well as insulin level in diabetic rats after OGTT. GLP-1 content was significantly increased in ileum and colon by inhibiting alpha-glucosidase. Involvement of GLP-1 in antihyperglycemic effect of AEATP was confirmed by using GLP-1 antagonist. Moreover, AEATP significantly improved dyslipidemia in diabetic rats. HPLC analysis of A. tortilis polysaccharide comprised four specific monosaccharides (Rhamnose, Glucuronic acid, glucose and galactose) and FTIR spectrum shown band at 3430.6 cm-1 (O-H stretching), 2940.3 cm-1 (C-H linkage), 1630.4 cm-1 (carbonyl stretching), 1410 cm-1 (uronic acid) and 1030.5 cm-1 (glycosidic linkage). CONCLUSION: It can be concluded that antidiabetic effect of AEATP is through the modulation of GLP-1 level in plasma and intestinal tissue via alpha glucosidase inhibition.

The effect of the artificial sweeteners on glucose metabolism in healthy adults: a randomized, double-blinded, crossover clinical trial.

This study aimed to determine the effect of pure forms of sucralose and aspartame, in doses reflective of common consumption, on glucose metabolism. Healthy participants consumed pure forms of a non-nutritive sweetener (NNS) that were mixed with water and standardized to doses of 14% (0.425 g) of the acceptable daily intake (ADI) for aspartame and 20% (0.136 g) of the ADI for sucralose every day for 2 weeks. Blood samples were collected and analyzed for glucose, insulin, active glucagon-like peptide-1 (GLP-1), and leptin. Seventeen participants (10 females and 7 males; age, 24 ± 6.8 years; body mass index, 22.9 ± 2.5 kg/m2) participated in the study. The total area under the curve values of glucose, insulin, active GLP-1 and leptin were similar for the aspartame and sucralose treatment groups compared with the baseline values in healthy participants. There was no change in insulin sensitivity after NNS treatment compared with the baseline values. These findings suggest that daily repeated consumption of pure sucralose or aspartame for 2 weeks had no effect on glucose metabolism among normoglycaemic adults. However, these results need to be tested in studies with longer durations. Novelty Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on glucose metabolism. Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on insulin sensitivity among healthy adults.

Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance.

The effect of peptide tyrosine-tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato-portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient-stimulated glucose tolerance.