Postprandial Glucose Tolerance Research Articles

1179-P: Acute Physiological Effects of Gastric Aspiration for the Treatment of Obesity

AspireAssist® allows aspiration of ~30% of an ingested meal through a percutaneous gastrostomy tube thereby reducing caloric uptake. We evaluated the acute effects of aspiration therapy on postprandial glucose tolerance, responses of gluco-regulatory and appetite-regulating gut hormones, appetite sensations and food intake. Seven AspireAssist®-treated persons without diabetes (median [IQR] age 52 [44;54] years; BMI 35.6 [31.5;40.5] kg/m2) underwent two mixed meal tests on separate days with double-blinded aspiration (aspiration visit) and sham aspiration (sham visit), respectively. Seven age and BMI-matched controls (age 43 [42;54]; BMI 34.1 [31.6;38.7] kg/m2) underwent one meal test (control visit). All mixed meal tests were followed by an ad libitum meal for evaluation of food intake. Compared to sham visits, postprandial glucose tolerance was improved on aspiration visits (median [IQR] baseline-subtracted area under the curve (bsAUC) 170 [88;356] vs. 388 [239;456] mmol/L × min, P = 0.025). Postprandial responses (bsAUCs) of C-peptide, cholecystokinin (CCK) and glucose-dependent insulinotropic polypeptide (GIP) were reduced during aspiration vs. sham visits (113 [28;224] vs. 302 [215;433] nmol/L × min, P = 0.014; 223 [59.4;402] vs. 467 [416;546] pmol/L × min, P = 0.005; and 4,634 [1,488;9,044] vs. 15,382 [9,588;18,850] pmol/L × min, P = 0.025). Glucagon, gastrin, ghrelin and peptide YY, respectively, were similar on aspiration and sham visits. Appetite sensations and ad libitum food intake were similar on aspiration and sham visits. Responses of plasma glucose, gut hormones, appetite sensations and food intake were similar on sham and control visits. In this study, aspiration therapy acutely improved postprandial glucose tolerance without causing a compensatory increase in appetite sensations or food intake at a subsequent ad libitum meal; pointing to acute beneficial metabolic effect of aspiration therapy in addition to the long-term bodyweight-lowering effect of this treatment. Disclosure I. Gether: None. M. M. Jensen: None. T. Jorsal: None. C. Nexøe-larsen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L. P. S. Naver: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding Augustinus Fonden

The role of GLP-1 in the postprandial effects of acarbose in type 2 diabetes.

The alpha-glucosidase inhibitor acarbose is believed to reduce plasma glucose by delaying hydrolysis of carbohydrates. Acarbose-induced transfer of carbohydrates to the distal parts of the intestine increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes. In a double-blinded, placebo-controlled, randomized, crossover study, 15 participants with metformin-treated type 2 diabetes (age: 57-85 years, HbA1c: 40-74 mmol/mol) were subjected to two 14-day treatment periods with acarbose or placebo, respectively, separated by a 6-week wash-out period. At the end of each period, two randomized 4-h liquid mixed meal tests with concomitant infusion of exendin(9-39)NH2 and saline, respectively, were performed. Compared to placebo, acarbose increased postprandial GLP-1 concentrations and decreased postprandial glucose. We observed no absolute difference in the exendin(9-39)NH2-induced increase in postprandial glucose excursions between placebo and acarbose periods, but relatively, postprandial glucose was increased by 119 ± 116% (mean ± s.d.) during exendin(9-39)NH2 infusion in the acarbose period vs a 39 ± 27% increase during the placebo period (P = 0.0163). We confirm that acarbose treatment stimulates postprandial GLP-1 secretion in patients with type 2 diabetes. Using exendin(9-39)NH2, we did not see an impact of acarbose-induced GLP-1 secretion on absolute measures of postprandial glucose tolerance, but relatively, the effect of exendin(9-39)NH2 was most pronounced during acarbose treatment.

Nocturnal whey protein ingestion impairs post-prandial glucose tolerance at breakfast.

Poor post-prandial glucose control is a risk factor for multiple health conditions. The second-meal effect refers to the progressively improved glycaemic control with repeated feedings, an effect which is achievable with protein ingestion at the initial eating occasion. The most pronounced glycaemic response each day therefore typically occurs following breakfast, so the present study investigated whether ingesting protein during the night could improve glucose control at the first meal of the day. In a randomised crossover design, fifteen adults (seven males, eight females; age, 22 (sd 3) years; BMI, 24·0 (sd 2·8) kg/m2; fasting blood glucose, 4·9 (sd 0·5) mmol/l) woke at 04.00 (sd 1) hours to ingest 300 ml water with or without 63 g whey protein. Participants then completed a mixed-macronutrient meal tolerance test (1 g carbohydrate/kg body mass, 2356 (sd 435) kJ), 5 h 39 min following the nocturnal feeding. Nocturnal protein ingestion increased the glycaemic response (incremental AUC) to breakfast by 43·5 (sd 55·5) mmol × 120 min/l (P = 0·009, d = 0·94). Consistent with this effect, individual peak blood glucose concentrations were 0·6 (sd 1·0) mmol/l higher following breakfast when protein had been ingested (P = 0·049, d = 0·50). Immediately prior to breakfast, rates of lipid oxidation were 0·02 (sd 0·03) g/min higher (P = 0·045) in the protein condition, followed by an elevated post-prandial energy expenditure (0·38 (sd 0·50) kJ/min, P = 0·018). Post-prandial appetite and energy intake were similar between conditions. The present study reveals a paradoxical second-meal phenomenon whereby nocturnal whey protein feeding impaired subsequent glucose tolerance, whilst increasing post-prandial energy expenditure.

313-OR: Diurnal Pattern of Meal Tolerance in Type 2 Diabetes

The existence of a diurnal pattern of post prandial glucose tolerance is relevant for management of patients with type 2 diabetes (T2D). We studied 10 healthy (4M) and 9 T2D (6M) subjects matched for age (56±3 vs. 58±3 yrs) and BMI (29±2 vs. 32±2 kg/m2). OGTT was done in healthy subjects to rule out diabetes. Identical mixed meals (8 kcal/kg/meal; 75 gm carb) were ingested during breakfast (B), lunch (L), and dinner (D) at 0700, 1300, and 1900 h in randomized latin square order with one labeled test meal/day on 3 consecutive days. Physical activity was kept same. Postprandial glucose turnover was measured utilizing the triple tracer technique modified with all stable isotopes ([1-13C] Glucose, [2-13C] Glucose and [6, 6-2H2] Glucose). Results shown in Fig 1. Fasting and post-meal glucose were higher while fasting and post-meal insulin and C-peptide concentrations lower in T2D for all three meals compared to healthy. Although meal glucose appearance did not differ between meals in either group, fasting endogenous glucose production (EGP) was higher, percent suppression of EGP lower in T2D and glucose disappearance (corrected for urine glucose loss) lower in T2D than healthy for all meals consumed. This data correlates with lower insulin sensitivity, B-cell responsivity to glucose and disposition index in T2D than healthy throughout the day. Our results suggest an emerging diurnal pattern to glucose tolerance and fluxes in humans, and that the pattern is different in T2D. Disclosure Y.R. Yadav: None. D. Romeres: None. F. Ruchi: None. S. Sawleh: None. R. Carter: None. A. Basu: Consultant; Spouse/Partner; GENFIT. Research Support; Spouse/Partner; AstraZeneca. R. Basu: Consultant; Self; GENFIT. Research Support; Self; AstraZeneca. Funding National Institutes of Health (R01DK029953 to R.B.), (R01DK085516 to A.B.), (DK059637, DK020593)

Early structural and functional neurovascular changes in the retina in the prediabetic stage.

This study was undertaken to investigate the neurovascular changes in the retina of prediabetic subjects. Subjects enroled in a prospective study were separated into prediabetic and normal control groups based on their glycosylated haemoglobin (HbA1C) levels, fasting and postprandial blood sugar levels and glucose tolerance test. All the subjects underwent detailed ophthalmic evaluation, which included fundus examination, fundus photography, optical coherence tomography angiography (OCTA), and multifocal electroretinogram (mfERG). Comparisons were done between the groups using the Wilcoxon signed rank test. The median age was 48 years for the normal controls (n = 40), and 49.5 years for prediabetic subjects (n = 45) (p = 0.306). There was no difference in the vision, contrast sensitivity, thickness of the ganglion cell complex or the foveal avascular zone parameters between the groups. But the central foveal thickness and subfoveal choroidal thickness were significantly reduced in prediabetics (p < 0.01). The mfERG showed significant differences in the amplitude. The average amplitude was 35 ± 12 nv/deg2 in the normals and 29 ± 11 nv/deg2 in the prediabetics (p = 0.003). A weak positive correlation was noted between the mfERG and vascular parameters in the prediabetic group. The prediabetic stage reveals earliest functional neuronal changes in the retina. The neuronal function seems to be affected much earlier than clinically appreciable structural changes in the ganglion cell complex and precedes vascular changes in the retina.

The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial.

Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9kg/m2) and 12 healthy control individuals (age 66.1 ± 7.6years; BMI: 24.0 ± 2.9kg/m2) underwent two 3h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20μg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95mmol/l × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0mmol/l was reached at time point 134 ± 11min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4mmol/l (p = 0.008) at time point 148 ± 13min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4mmol/l was reached at time point 70 ± 13min with placebo, compared with a mean peak concentration of 5.5 ± 0.1mmol/l (p < 0.001) at time point 8 ± 25min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31nmol/l × min, p < 0.001). The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon. ClinicalTrials.gov NCT02640118. This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.

MON-660 Hypoglycemia Following OGTT Is More Frequent and Pronounced in CF Compared with Controls

Glucose homeostasis is often abnormal in people with pancreatic insufficient cystic fibrosis (PI-CF). This dysfunction is viewed on a continuum from “normal” glucose tolerance to cystic fibrosis-related diabetes (CFRD), and may also include postprandial and oral glucose tolerance test (OGTT)-related hypoglycemia. This study aimed to delineate the mechanism(s) underlying OGTT-related hypoglycemia. We compared extended OGTT with frequent blood sampling of glucose and insulin in adolescents and young adults with PI-CF [CF(+)] to historical data from a healthy cohort [CF(-)]. We hypothesized that the subset of CF(+) with hypoglycemia would demonstrate 1-hour glucose ≥ 155 mg/dL and impaired early phase insulin secretion (insulin secretion within first 30 min of OGTT). Hypoglycemia [hypo(+)] was defined as plasma glucose <65 mg/dL and was used to assign subjects to exposure groups. We restricted analyses to 180 minutes given available control data. Glucose and insulin incremental areas under the curve (Glc-AUC; Ins-AUC) for 30-minute intervals were calculated. One-hour glucose, nadir glucose, Glc-AUC0-30, and Ins-AUC0-30 and were compared between CF(+) and CF(-) subjects using Student’s t-test or Wilcoxon Rank Sum depending upon normality. Participants were 60.5% male, age: 25.4±4.8 years, with BMI-Z: 0.06±0.96kg/m2 [no differences for CF(+) vs CF(-)]. FEV1%-predicted for CF(+) was 83±21. 69.6% of CF(+) participants self-reported prior episodes of hypoglycemia, 68.7% of whom reported confirmation via glucometer. Hypoglycemia occurred by 180 minutes [hypo(+)] in 15/23 (65%) CF(+) and 5/15 (33.3%) CF(-) subjects (p=0.028). For hypo(+), nadir glucose occurred on average at 180 minutes for both CF(+) and (-). Hypo(+) CF(+) had higher mean 1-hour glucose (197±49mg/dL vs 134±66mg/dL, p=0.035), lower mean glucose nadir (48±7mg/dL vs 61±4mg/dL, p<0.01), and lower early-phase insulin secretion (Ins-AUC0-30: 263±168 versus 650±275 µU/mL, p<0.01) than hypo(+) CF(-). There was no difference in Glc-AUC0-30 for hypo(+) CF(+) vs CF(-). Hypoglycemia is frequent in CF, and is associated with early glucose dysregulation (elevated 1-hour glucose) and compromised early-phase insulin secretion compared to controls with presumed non-pathologic reactive hypoglycemia. The mechanism of hypoglycemia in CF appears to be different than that seen in healthy individuals, and its association with progression to CFRD warrants further evaluation.

390-P: Changes in Glycaemic Variability after RYGB: A One-Year Prospective Study with Comparison to Patients with Post-bariatric Hypoglycaemia

Some patients suffer disabling hypoglycaemia after RYGB, typically post prandially: Post Bariatric Hypoglycaemia (PBH). We hypothesised that these patients have increased glycaemic variability (GV), as assessed by continuous glucose monitoring (CGM). Method: Prospective study of 6 patients undergoing RYGB with mixed meal tests (MMT) and CGM at baseline (BL), at 1 month and at 12 months. This cohort was compared to 15 patients with hypoglycaemia. Results: RYGB leads to improvement in postprandial glucose tolerance at 120 minutes, preceded by an early peak of glucose and insulin at 30 minutes (Figure 1). Compared to pre-surgery, hypoglycaemic patients have significantly elevated peak glucose and insulin levels at 30 minutes followed by hypoglycaemia at 120 minutes. GV increases post RYGB: mean amplitude of glycaemic excursions (MAGE) median (95% CI) at BL 3.1 (2.3-6.8); 1 m 2.8 (2.2-4.2); 12 m 4.5 (3.4-5.5). PBH patients exhibit similar GV: MAGE 4.4 (3.7-6.5). The %time in range (TIR) glucose &amp;lt;3.9 increases post-surgery (BL 0 (0-3.8); 1 m 1.8 (0.5-4.1); 12 m 8.0 (0-25.8) but patients with PBH exhibit similar %TIR&amp;lt;3.9: 6.8 (3.5-11.9). Conclusion: PBH patients exhibit exaggerated early glucose and insulin secretion to MMT. ‘Real-world’ CGM demonstrates that GV and time in hypoglycaemia is not significantly different between RYGB without PBH and patients with PBH. All patients post RYGB are at risk of hypos. Disclosure G. Tharakan: None. I.I. Ilesanmi: None. P. Behary: None. K. Alexiadou: None. C.S. Doyle: None. H. Chahal: None. S. Purkayastha: None. A. Miras: None. N. Oliver: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Dexcom, Inc., Roche Diabetes Care. Speaker's Bureau; Self; Dexcom, Inc., Sanofi. A. Ahmed: None. S. Bloom: None. T.M. Tan: Other Relationship; Self; Novo Nordisk A/S. Funding Medical Research Council UK

1980-P: A Characterization of Postprandial Glucose Metabolism and Incretin Hormone Responses in Patients with Bile Acid Malabsorption

Bile acid malabsorption (BAM) is characterized by an excessive spill-over of bile acids to the colon leading to bile acid-induced diarrhea; the condition is usually treated with bile acid sequestrants. Bile acids have been demonstrated to modulate the secretion of the incretin hormone glucagon-like peptide 1 (GLP-1) and the aim of this study was to characterize postprandial glucose metabolism and incretin hormone responses in patients with BAM. Twelve patients with BAM (6 women; mean age 39.1 (SD 13.2); mean BMI 28.4 kg/m2 (SD 1.2); HbA1c 31.4 (SD 3.7)) and 12 healthy gender, age, BMI and HbA1c-matched controls (6 women; mean age 39.3 (SD 15.6); mean BMI 29,1 kg/m2 (SD 1.1); HbA1c 31.0 (SD 2.8)) were subjected to two 4-hour standardized liquid meal tests with double-blinded single-dose administration of the bile acid sequestrant colesevelam (3.75 g) and placebo, respectively, performed on separate days, and in randomized order. Fasting and postprandial plasma GIP and GLP-1 concentrations were comparable among patients with BAM and control subjects and unaffected by colesevelam administration. Peak plasma glucose concentrations were higher in BAM patients vs. control subjects, but area under curve for plasma glucose did not differ between the two groups. Patients with BAM exhibited significantly higher postprandial serum C-peptide concentrations and hyperglucagonemia compared to controls. Single-dose colesevelam had no effect on postprandial glucose or glucagon excursions in any of the groups but decreased the postprandial C-peptide response in BAM patients. Patients with BAM are characterized by elevated serum C-peptide concentrations and hyperglucagonemia whereas postprandial glucose tolerance and GLP-1 and GIP responses are similar to healthy controls. Disclosure M.L. Kårhus: None. D.P. Sonne: None. M.L. Thomasen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. A. Brønden: Other Relationship; Self; AstraZeneca. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation

Effects of Cinnamon Spice on Postprandial Plasma Levels of Glucose and Insulin in Healthy Participant with Normal Weight (FS15-04-19)

ObjectivesThe objective of this study is to investigate the effect of one time intake of cinnamon spice on the postprandial glucose tolerance and insulin secretion following consumption of a high glycemic index meal in normal weight and glucose tolerance individuals. MethodsSixteen healthy controls (BMI = 18.5–24.9 kg/m2 and fasting blood glucose (BG) < 100 mg/dL) aging 20–50 years, who typically consume a low fiber/polyphenol diet (beige diet) were recruited for this study. Recruitment of overweight/obese, prediabetic participants is not completed (no data presented). Participants consume a typical American breakfast containing 50 g of carbohydrates (1/3 cup of oatmeal and 1 cup 2% milk) with or without cinnamon (6 g) followed by 1-week washout and crossover to the opposite intervention. The blood samples were taken at fasting state and at 30, 60, 90, 120, 150 and 180 minutes after the meal. The main outcome measures included BG and insulin. The secondary outcome measures were C-peptide and glucagon. Cinnamon spice (Indonesia) was purchased at the local grocery store (McCormick®) and contains 3.9% proanthocyanin. The statistical significance was set at P < 0.05 using SPSS. ResultsConsumingcinnamon spice with the oatmeal significantly decreased the rate of glucose change from fasting state at 60 and 90 minutes after the meal by 37% and 31%, respectively. The peak postprandial BG and the areas under the curve (AUC) of glucose were also lowered by cinnamon compared to oatmeal alone but did not reach the significant levels. There was a trend towards significant decrease (21%, P = 0.08) in plasma insulin concentrations and a significant decrease in plasma C-peptide levels 30 minutes after ingestion of the meal with cinnamon. Cinnamon ingestion compared to oatmeal alone also significantly decreased plasma glucagon levels at 90 minutes after the meal test. ConclusionsOur results suggest that one time intake of cinnamon spice lowers the mean rate of glucose change following a high glycemic index meal in healthy individuals. Cinnamon also decreased plasma levels of insulin, C-peptide, and glucagon. Funding SourcesUCLA Center for Human Nutrition.

729-P: Post-Breakfast Physical Activity Is Most Optimal for Improving Postprandial Glycemic Control in Healthy Adults

Purposeful and deliberate exercise improves postprandial glucose control. However, there is less information concerning the effects of simple physical activities (standing, walking, circuit exercise) that can easily be integrated into a person’s day. Furthermore, the optimal timing between such an activity and a meal that elicits the most optimal glucose control is completely unknown. Three groups of 16 healthy adults volunteered to participate in three separate interventions: Stand (30-minutes standing still; RPE = 6±1), Walk (30-min treadmill walk at a self-selected brisk pace; RPE = 11±2, 5.6±0.8 kph), and Circuit (three sets of 10 squats, 10 push-ups, 10 lunges, 10 sit-ups; RPE = 11±2, 7.1±1.8 minutes to complete). In each intervention, participants completed four trials during which they drank a mixed-nutrient breakfast shake containing 500 kcals. Interstitial glucose responses were measured by continuous glucose monitoring (Dexcom G5). Postprandial glucose tolerance was quantified during the 2-hours period after meal ingestion. In each trial, the physical activity was completed either 2-hours after (trial A; control), immediately before (trial B), immediate after (trial C), or 30-minutes after (trial D) the meal. While trials B and D showed some improvement in postprandial glucose control compared to trial A, this was not statistically significant. Trial C, however, showed a significant improvement in mean glucose, standard deviation for glucose, and the area under the glucose curve in all three interventions (P&amp;lt;0.05), when compared to trial A. Energy intake (diet records) and energy expenditure (Actigraph) were consistent throughout the studies and did not influence the findings. In conclusion, low to moderate-intensity physical activity (either standing, walking, or body-weight circuit exercise) is best implemented soon after a meal to induce the greatest improvement in blood glucose control, in young healthy adults. Disclosure T.P. Solomon: None. E. Tarry: None. C.O. Hudson: None. A.I. Fitt: None. M. Laye: None. Funding Physiological Society

1145-P: Acarbose-Induced Glucagon-Like Peptide-1 Secretion Contributes to the Glucose-Lowering Effect of Acarbose

The glucose-lowering alpha-glucosidase inhibitor acarbose, is believed to act by delaying digestion and absorption of dietary carbohydrates. It has been shown that acarbose increases circulating glucagon-like peptide 1 (GLP-1). Using the GLP-1 receptor antagonist exendin(9-39)NH2, we investigated the effect of acarbose-induced GLP-1 secretion on postprandial glucose metabolism in patients with type 2 diabetes (T2D). In a double-blinded, placebo-controlled, randomized, cross-over study, 15 participants with metformin-treated T2D (age 57-85 years, BMI 23.6-34.6 kg/m2, HbA1c 40-74 mmol/mol (5.8-8.9%)) were subjected to two 14-day treatment periods with acarbose (uptitrated to 100 mg TID) and placebo treatment, respectively, with an interposed 6-week wash-out period. At the end of each treatment period, we performed two randomized 4-hour mixed meal tests (including acetaminophen for evaluation of gastric emptying) with concomitant infusion of exendin(9-39)NH2 (1000 pmol/kg/min for 20 min followed by 450 pmol/kg/min for 240 min) and saline, respectively. Acarbose treatment lowered fasting plasma glucose (P&amp;lt;0.0001) and postprandial plasma glucose excursions (P&amp;lt;0.0001) compared to placebo. Furthermore, acarbose almost doubled the postprandial GLP-1 response (P=0.0032), reduced postprandial glucose-dependent insulinotropic polypeptide (P&amp;lt;0.0001) and delayed gastric emptying (P=0.0395). No absolute difference was seen in exendin(9-39)NH2-induced postprandial plasma glucose changes between treatment periods (P=0.54), but relative to postprandial glucose tolerance during exendin(9-39)NH2 infusions, the change (i.e., contribution of GLP-1) was significantly higher during acarbose (56±26%) compared to placebo treatment (37±15%) (P=0.042). We conclude that acarbose treatment robustly stimulates GLP-1 secretion in patients with T2D and that acarbose-induced GLP-1 secretion contributes to the glucose-lowering effect of acarbose. Disclosure N.B. Dalsgaard: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Hansen: None. N.L. Hansen: None. S. Stensen: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

23-OR: The Effect of 14-Day Atorvastatin Treatment on Postprandial Glucose Metabolism in Healthy Males—A Link to Why Statin Therapy Increases the Risk of Type 2 Diabetes?

Background and Aim: Statins are LDL cholesterol-lowering drugs that are highly effective in the prevention of cardiovascular disease and death. Recently, it has become known that statin therapy increases the risk of type 2 diabetes, but the mechanism behind this phenomenon remains obscure. We evaluated the gluco-metabolic effects of statin therapy in healthy male individuals. Methods: In a placebo-controlled, double-blinded, randomized, cross-over study, we investigated the effect of 14 days of treatment with atorvastatin (40 mg once-daily for one week and 80 mg once-daily the second week) on fasting and postprandial concentrations of glucose, gluco-regulatory hormones and bile acid profiles in 15 healthy male individuals (age 25.6±3.8 years; BMI 24.7±2.8 kg/m2; glycated hemoglobin A1c 4.8±0.2% (mean±SD)). Four-hour mixed meal tests were performed following each of the two 14-day treatment periods with placebo or atorvastatin, respectively. Results: Treatment with atorvastatin did not affect postprandial plasma glucose or insulin concentrations, but basal as well as postprandial concentrations of glucagon were increased compared to placebo. Postprandial plasma concentrations of the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 were increased after atorvastatin treatment compared to placebo. Also, postprandial concentrations of taurine-conjugated primary bile acids increased, whereas glycine-conjugated secondary bile acids decreased. Conclusion: In healthy male individuals, 14 days of atorvastatin treatment did not affect postprandial glucose tolerance or insulin concentrations. Fasting and postprandial glucagon concentrations were increased by atorvastatin treatment, which may point to hyperglucagonemia as a possible link between statin treatment and type 2 diabetes. Disclosure M.L. Thomasen: None. D.P. Sonne: None. M.L. Kårhus: None. A. Brønden: Other Relationship; Self; AstraZeneca. B. Staels: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. T. Vilsbøll: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Augustinus Fonden

MON-184 Hypoglycemia During Mixed Meal Tolerance Testing and Early Glucose Dysregulation in Cystic Fibrosis

Post-prandial and oral glucose tolerance test (OGTT)-related hypoglycemia is common in cystic fibrosis (CF). The mechanisms underlying this “reactive” hypoglycemia are unclear. We hypothesized that late hypoglycemia would be associated with higher peak plasma glucose, impaired early-phase insulin secretion compared to PI-NGT, and augmentation of late insulin secretion. To understand these relationships, we performed standardized mixed-meal tolerance tests (MMTT) with timed blood sampling for determination of plasma glucose, insulin and C-peptide in non-diabetic adolescents and young adults with pancreatic insufficient CF (PI-CF). Glucose tolerance was defined by OGTT as: normal (NGT; 1-hour glucose <155 and 2-hour glucose <140mg/dL, n=13), or abnormal (AGT; 1-hour glucose ≥155 or 2-hour glucose ≥140 mg/dL and <200 mg/dL, n=21). Hypoglycemia was defined as plasma glucose <70mg/dL during MMTT and used to assign subjects to exposure groups for analysis. Insulin secretory rates (ISRs) were derived by parametric deconvolution of C-peptide kinetics using a two-compartment model. Glucose and ISR incremental areas under curve (Glc-AUC; ISR-AUC) were calculated. Peak plasma glucose and ISR-AUCinterval were compared between hypoglycemia groups [hypo(+) vs hypo(-)] using Student’s t-test and Mann Whitney U Tests, respectively. Linear regression was performed to explore whether ISR AUC was different in hypo(+) vs hypo(-) after adjustment for Glc-AUC. 34 subjects with PI-CF were evaluated. Participants were 50% female, aged 25±8.7 years, with FEV-1 % predicted 81±19, HbA1c 5.5±0.4%, and BMI z-score 0.17±1. Hypoglycemia occurred in 9 subjects (2 NGT, 7 AGT) at 163±30 min following the start of the meal. No group differences in gender, age, lung function, HbA1c, or BMI z-score were found. Peak plasma glucose was higher in hypo(+) vs hypo(-) (215±21 vs 168±33 mg/dL, p=0.0004). Moreover, early-phase ISR-AUC15-45 min was lower in hypo(+) vs hypo(-) PI-NGT (609±190 vs 1313±850 µU/mL, p=0.03), including the 2 NGT-hypo(+): 430mg/dL and 548mg/dL, respectively. ISR-AUC120-180 min was not different in hypo(+) than hypo(-) PI-AGT (2528 ±1723 vs 2219±1072 µU/mL, p=0.85); however, glc-AUC120-180 min was lower in hypo(+) than hypo(-) PI-AGT (-785±1288mg·min/dL vs 750±1115 mg·min/dL, p=0.015). After adjusting for glc-AUC over this interval, hypo(+) tended to have higher late insulin secretion than hypo(-) PI-AGT (p=0.089). Meal-related hypoglycemia in CF is common and not only seen following the glucose load of an OGTT. Hypoglycemia is associated with early glucose dysregulation (higher peak plasma glucose), loss of early-phase insulin secretion (lower ISR AUC15-45 min), and possible late compensatory hyperinsulinemia (higher ISR AUC120-180 min relative to glucose). Whether hypoglycemia may predict progression to CFRD in individuals with PI-CF requires further study.

Association of postprandial triglyceride responses with insulin resistance among rotational night shift healthcare workers.

What is the central question of this study? Does long-term rotational night shift work among healthcare workers alter postprandial triglyceride metabolism, and are the postprandial triglyceride responses associated with insulin resistance? What is the main finding and its importance? Rotational night shift duties in healthcare workers might have a negative impact on postprandial triglyceride responses and insulin sensitivity. This is the first study in which postprandial triglyceride responses among shift workers exposed to long-term night shifts have been studied. Studies on the postprandial period demonstrate that in experimental conditions, abrupt or acute changes in sleep timing and work are followed by significantly altered postprandial glucose, insulin secretion and lipid tolerance. Whether shift work results in altered postprandial triglyceride (PPTG) metabolism in the long term is not known. In the present study, we aimed to ascertain the association between PPTG and shift work in relationship to cardiometabolic risks and to compare the PPTG response among healthcare workers with and without night shift duties. Twenty healthcare workers with rotational night shifts (group2) and 20 age- and sex-matched healthcare workers who had not done night shift duty in the past 1year or ever (group1) were recruited. Only subjects with normal glucose tolerance were recruited. A standardized fat challenge test was done in all study subjects. The postprandial triglyceride area under the curve (PPTG AUC) showed overall (n=40) a significant positive correlation with fasting insulin and homeostatic model assessment of insulin resistance (HOMA-IR) (r=0.40, P=0.01 and r=0.37, P=0.01, respectively) and in group2 (r=0.49, P=0.02 and r=0.44, P=0.042, respectively). The PPTG peak also showed a significant positive correlation with fasting insulin and HOMA-IR in group2 (r=0.52, P=0.01 and r=0.47, P=0.03, respectively). No significant correlation was found in group1. The PPTG AUC and PPTG peak were, however, comparable between both groups. The findings of this pilot study suggest that rotational night shift duties in healthcare workers might have a negative impact on metabolic parameters, including postprandial triglyceride responses and insulin sensitivity.

Antidiabetic Effects of Hispidulin in Streptozotocin‐Induced Insulin Deficient Mice

In both Type 1 and type 2 diabetes, pancreatic beta‐cell failure plays an important role in the deterioration of glycemic control. In this study, we investigated whether hispidulin, a naturally occurring flavone, can be used to ameliorate diabetes in an animal model of insulin deficiency. Here, we report that oral administration of hispidulin (20 mg/kg) alleviates streptozotocin‐induced hyperglycemia in C57/BL6 male mice. Hispidulin effectively mitigates postprandial and fasting hyperglycemia and glucose tolerance, which was associated with higher circulating plasma insulin concentrations and improved glucose stimulated‐insulin secretion (GSIS). In addition, treatment with hispidulin reduced expression of pyruvate carboxylase and glucose 6‐phosphatase in the livers. In vitro, hispidulin suppressed glucose production in mouse primary hepatocytes, but potentiated GSIS in insulin‐secreting cells and mouse islets. These findings suggest that hispidulin could be a dual action, natural compound that exerts antidiabetic action via promoting beta‐cell function and suppressing hepatic glucose production.Support or Funding InformationThe work was supported by grants from NCCIH of NIH (1R01AT007077, 1R01AT007566)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Inactivity induces resistance to the metabolic benefits following acute exercise.

Acute exercise improves postprandial lipemia, glucose tolerance, and insulin sensitivity, all of which are risk factors for cardiovascular disease. However, recent research suggests that prolonged sedentary behavior might abolish these healthy metabolic benefits. Accordingly, this study aimed to elucidate the impact of an acute bout of exercise on postprandial plasma triglyceride, glucose, and insulin concentrations after 4 days of prolonged sitting (~13.5 h/day). Ten untrained to recreationally active men (n = 5) and women (n = 5) completed a counterbalanced, crossover study. Four days of prolonged sitting without exercise (SIT) were compared with 4 days of prolonged sitting with a 1-h bout of treadmill exercise (SIT + EX; 63.1 ± 5.2% V̇o2max) on the evening of the fourth day. The following morning, participants completed a high-fat/glucose tolerance test (HFGTT), during which plasma was collected over a 6-h period and analyzed for triglycerides, glucose, and insulin. No differences between trials (P > 0.05) were found in the overall plasma triglyceride, glucose, or insulin responses during the HFGTT. This lack of difference between trials comes with similarly low physical activity (~3,500-4,000 steps/day) on each day except for the 1-h bout of exercise during SIT + EX the day before the HFGTT. These data indicate that physical inactivity (e.g., sitting ~13.5 h/day and <4,000 steps/day) creates a condition whereby people become "resistant" to the metabolic improvements that are typically derived from an acute bout of aerobic exercise (i.e., exercise resistance). NEW & NOTEWORTHY In people who are physically inactive and sitting for a majority of the day, a 1-h bout of vigorous exercise failed to improve lipid, glucose, and insulin metabolism measured the next day. It seems that something inherent to inactivity and/or prolonged sitting makes the body resistant to the 1 h of exercise preventing the normally derived metabolic improvements following exercise.

Separate and Combined Glucometabolic Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide and Glucagon-like Peptide 1 in Healthy Individuals.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2 During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0-20 min: 1,000 pmol/kg/min; 20-240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.

Effects of feeding frequency of an elevated plane of milk replacer and calf age on behavior, and glucose and insulin kinetics in male Holstein calves

Optimizing feeding regimens in early life to maximize lifelong growth and production are essential in the dairy industry. This study investigated the effects of milk replacer (MR) feeding frequency and calf age on behavior, and glucose and insulin kinetics of pre- and post-weaned calves fed an elevated plane of MR. Ten male Holstein calves (42.2±1.8 kg BW) were blocked by BW and randomly assigned to two treatments offering 8 l MR/day (150 g/l) in two (2×; meal size 4 l) or four (4×; meal size 2 l) feedings via an automated calf feeder. Milk replacer was gradually stepped down by 1 l/day during week 8, with calves being weaned by week 9. Water and pelleted calf starter were offered ad libitum. Individual intake of MR and starter were recorded daily, and BW was recorded weekly. The number of visits to the MR feeder (rewarded and unrewarded), and behaviors such as lying, cross-sucking, non-nutritive sucking and occupancy time in the feeder were recorded for individual calves from weeks 4 to 10. Jugular catheters were placed on weeks 4, 7 and 10 to facilitate postprandial blood sampling and glucose tolerance tests. Statistical analysis was conducted using the PROC GLIMMIX procedure (SAS) for behavioral observations, and the MIXED procedure (SAS) with repeated measures for BW, intake, plasma glucose and plasma insulin data. Final BW, starter and MR intake did not differ between treatments. There were no differences in observed calf behaviors; with the exception that 2× calves visited the MR feeder more often (P<0.01; total: unrewarded and rewarded). Baseline concentrations (mmol/l) and the maximum change in glucose (delta, mmol/l) were greater and lower (P=0.02) in 4×compared to 2×calves, respectively. Postprandial insulin AUC240 tended (P=0.09) to be greater in 2×calves, compared to 4×calves at week 7. Similarly, Tmax (min), AUC240 and delta values (µU/ml) were greater (P⩽0.05) in 2×calves, compared to 4×calves. No treatment ×age interactions were observed for glucose or insulin during the glucose tolerance tests. Therefore, we conclude that feeding an elevated plane of MR (8 l/day) at a lower frequency (2× v. 4×) increased feeder visits, but not other hunger-related behaviors, and while postprandial glucose and insulin parameters varied, insulin sensitivity remained stable in Holstein dairy calves up to 10 weeks of age in calves consuming similar levels of calf starter.

Contribution of endogenous glucagon-like peptide-1 to changes in glucose metabolism and islet function in people with type 2 diabetes four weeks after Roux-en-Y gastric bypass (RYGB)

Glucagon-Like Peptide-1 (GLP-1) is an insulin secretagogue which is elevated after Roux-en-Y Gastric Bypass (RYGB). However, its contribution to glucose metabolism after RYGB remains uncertain. AimsWe tested the hypothesis that GLP-1 lowers postprandial glucose concentrations and improves β-cell function after RYGB. Materials and MethodsTo address these questions we used a labeled mixed meal to assess glucose metabolism and islet function in 12 obese subjects with type 2 diabetes studied before and four weeks after RYGB. During the post-RYGB study subjects were randomly assigned to receive an infusion of either saline or Exendin-9,39 a competitive antagonist of GLP-1 at its receptor. Exendin-9,39 was infused at 300 pmol/kg/min for 6 h. All subjects underwent RYGB for medically-complicated obesity. ResultsExendin-9,39 resulted in increased integrated incremental postprandial glucose concentrations (181 ± 154 vs. 582 ± 129 mmol per 6 h, p = 0.02). In contrast, this was unchanged in the presence of saline (275 ± 88 vs. 315 ± 66 mmol per 6 h, p = 0.56) after RYGB. Exendin-9,39 also impaired β-cell responsivity to glucose but did not alter Disposition Index (DI). ConclusionsThese data indicate that the elevated GLP-1 concentrations that occur early after RYGB improve postprandial glucose tolerance by enhancing postprandial insulin secretion.