Postprandial Plasma Glucose Excursions Research Articles

The role of glucagon-like peptide 1 in the postprandial effects of metformin in type 2 diabetes: a randomized crossover trial.

Although metformin is widely used for treatment of type 2 diabetes (T2D), its glucose-lowering mechanism remains unclear. Using the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) antagonist exendin(9-39)NH2, we tested the hypothesis that postprandial GLP-1-mediated effects contribute to the glucose-lowering potential of metformin in T2D. In a randomized, placebo-controlled, double-blind, crossover study, 15 individuals with T2D (median HbA1c 50 mmol/mol [6.7%], body mass index 30.1 kg/m2, age 71 years) underwent, in randomized order, 14 days of metformin and placebo treatment, respectively. Each treatment period was preceded by 14 days without any glucose-lowering medicine and concluded by two 4 h mixed meal tests performed in randomized order and separated by >24 h with either continuous intravenous exendin(9-39)NH2 or saline infusion. Compared to placebo, metformin treatment lowered fasting plasma glucose (mean of differences [MD] 1.4 mmol/L × min [95% CI 0.8-2.0]) as well as postprandial plasma glucose excursions during both saline infusion (MD 186 mmol/L × min [95% CI 64-307]) and exendin(9-39)NH2 infusion (MD 268 mmol/L × min [95% CI 108-427]). The metformin-induced improvement in postprandial glucose tolerance was unaffected by GLP-1R antagonization (MD 82 mmol/L × min [95% CI -6564-170]). Metformin treatment increased fasting plasma GLP-1 (MD 1.7 pmol/L × min [95% CI 0.39-2.9]) but did not affect postprandial GLP-1 responses (MD 820 pmol/L × min [95% CI -1750-111]). Using GLP-1R antagonization, we could not detect GLP-1-mediated postprandial glucose-lowering effect of metformin in individuals with T2D. We show that 2 weeks of metformin treatment increases fasting plasma GLP-1, which may contribute to metformin's beneficial effect on fasting plasma glucose in T2D. Trial registration: Clinicaltrials.gov NCT03246451.

Empagliflozin Normalizes Fasting Hyperglycemia and Improves Postprandial Glucose Tolerance in Totally Pancreatectomized Patients: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

Insulin remains the only glucose-lowering treatment modality recommended for totally pancreatectomized patients. We investigated the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on fasting and postprandial glucose concentrations in pancreatectomized patients and matched healthy control participants. In a randomized, double-blind, placebo-controlled crossover study, 10 pancreatectomized patients and 10 matched control participants underwent two 3-h liquid mixed meal tests preceded by two doses of 25 mg empagliflozin (administered the night before and in the morning of the meal test) or placebo, respectively. Basal insulin was administered as usual, but bolus insulin was omitted before the meal test during experimental days. Compared with placebo, empagliflozin lowered fasting plasma glucose (5.0 ± 0.4 vs. 7.9 ± 0.9 mmol/L [mean ± SEM], P = 0.007) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under the curve (1,080 [733; 1,231] vs. 1,169 [1,036; 1,417] pmol/L × min [median (25th and 75th percentiles)], P = 0.014) in the pancreatectomized patients. In the control participants, empagliflozin lowered fasting plasma glucose compared with placebo (5.1 ± 0.1 vs. 5.5 ± 0.1 mmol/L, P = 0.008) without affecting postprandial glucose excursions significantly. The pancreatomy group exhibited greater postprandial glucagon excursions compared with the control group on both experimental days (P ≤ 0.015); no within-group differences between days were observed. Empagliflozin administered the day before and immediately before a standardized liquid mixed meal test normalized fasting hyperglycemia and improved postprandial glucose tolerance in pancreatectomized patients.

Signs of a Glucose- and Insulin-Independent Gut-Bone Axis and Aberrant Bone Homeostasis in Type 1 Diabetes.

Gut hormones seem to play an important role in postprandial bone turnover, which also may be affected by postprandial plasma glucose excursions and insulin secretion. To investigate the effect of an oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) on bone resorption and formation markers in individuals with type 1 diabetes and healthy controls. This observational case-control study, conducted at the Center for Clinical Metabolic Research, Gentofte Hospital, Hellerup, Denmark, included 9 individuals with C-peptide negative type 1 diabetes and 8 healthy controls matched for gender, age, and body mass index. Subjects underwent an OGTT and a subsequent IIGI. We analyzed changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type I N-terminal propeptide (PINP) concentrations. Baseline CTX and PINP levels were similar in the 2 groups. Both groups exhibited significantly greater suppression of CTX during OGTT than IIGI. PINP levels were unaffected by OGTT and IIGI, respectively, in healthy controls. Participants with type 1 diabetes displayed impaired suppression of CTX-assessed bone resorption and inappropriate suppression of PINP-assessed bone formation during OGTT. Our data suggest the existence of a gut-bone axis reducing bone resorption in response to oral glucose independently of plasma glucose excursions and insulin secretion. Subjects with type 1 diabetes showed impaired suppression of bone resorption and reduced bone formation during OGTT, which may allude to the reduced bone mineral density and increased fracture risk characterizing these individuals.

The glucagon receptor antagonist LY2409021 has no effect on postprandial glucose in type 2 diabetes.

Type 2 diabetes (T2D) pathophysiology includes fasting and postprandial hyperglucagonemia, which has been linked to hyperglycemia via increased endogenous glucose production (EGP). We used a glucagon receptor antagonist (LY2409021) and stable isotope tracer infusions to investigate the consequences of hyperglucagonemia in T2D. A double-blinded, randomized, placebo-controlled crossover study was conducted. Ten patients with T2D and ten matched non-diabetic controls underwent two liquid mixed meal tests preceded by single-dose administration of LY2409021 (100 mg) or placebo. Double-tracer technique was used to quantify EGP. Antagonist selectivity toward related incretin receptors was determined in vitro. Compared to placebo, LY2409021 lowered the fasting plasma glucose (FPG) from 9.1 to 7.1 mmol/L in patients and from 5.6 to 5.0 mmol/L in controls (both P < 0.001) by mechanisms involving reduction of EGP. Postprandial plasma glucose excursions (baseline-subtracted area under the curve) were unaffected by LY2409021 in patients and increased in controls compared to placebo. Glucagon concentrations more than doubled during glucagon receptor antagonism. The antagonist interfered with both glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptors, complicating the interpretation of the postprandial data. LY2409021 lowered FPG concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors.

Postprandial plasma glucose excursion is associated with an atherogenic lipid profile in individuals with type 2 diabetes mellitus: A cross-sectional study.

Coronary heart disease (CHD) is a prevalent complication of type 2 diabetes mellitus (T2DM). The atherogenic low-density lipoprotein (LDL) cholesterol is an established risk factor of cardiovascular disease, and evidence also suggests that postprandial plasma glucose (PPG) levels closely delineate CHD mortality in diabetes. The investigators hypothesized that postprandial plasma glucose excursion (PPGE), defined as the difference between 2-hour PPG and fasting plasma glucose (FPG), may be associated with plasma LDL cholesterol levels in patients with T2DM. This study enrolled diabetic participants for whom FPG and lipid profile were sampled after a 12-hour fast, followed by PPG sampling two hours after consuming a standard meal with 75 grams of carbohydrates. The study enrolled 379 participants who were divided into PPGE tertiles according to the difference between their 2-hour PPG and FPG. Participants in the highest PPGE tertile had considerably greater plasma LDL cholesterol levels than patients in the lowest tertile (126.7 mg/dL vs. 99.5 mg/dL, P <0.001). Linear regression analysis also demonstrated that the PPGE was positively correlated with plasma LDL cholesterol levels (β coefficient: 0.165, P < 0.001). Postprandial glucose excursion positively correlated with plasma LDL cholesterol levels in individuals with T2DM. Participants with raised PPGE harbored greater LDL cholesterol levels than those with lower postprandial glucose fluctuations. Therefore, postprandial glucose excursion is associated with an atherogenic lipid profile and may be a modifiable risk factor of diabetic CHD.

770-P: The Glucose-Lowering Effect of the Bile Acid Sequestrant Sevelamer Is Not Mediated by Glucagon-Like Peptide-1

Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycemic control in patients with type 2 diabetes (T2D). The mechanism behind the glucose-lowering effect of bile acid sequestrants is unknown but has been proposed to involve glucagon-like peptide 1 (GLP-1) secretion. Using the GLP-1 receptor antagonist exendin(9-39), we investigated the GLP-1-mediated contribution to the glucose-lowering effect of the bile acid sequestrant sevelamer in patients with T2D. In a randomized, double-blind, placebo-controlled, crossover study, patients (9 men/6 women) with T2D (median [interquartile range] age 68 [63-71] years, BMI 30.1 [26.6-33.0] kg/m2, HbA1c 48 [45-61] mmol/mol (6.5 [6.3-7.7]%), on metformin mono-therapy) underwent two 14-day treatment periods with either sevelamer or placebo in a randomized order. After each treatment period, patients participated in two experimental days, each involving a four-hour liquid meal test with concomitant infusion of exendin(9-39) or saline. Compared to placebo, sevelamer lowered both fasting plasma glucose concentrations ((mean ± SEM) 8.7 ± 0.3 vs. 10.2 ± 0.5 mmol/L, P &amp;lt;0.001) and postprandial plasma glucose excursions (baseline-subtracted area under the curve (bsAUC): 456.5 ± 40.3 vs. 620 ± 63.6 mmol/L × min, P &amp;lt;0.001). In both treatment periods, exendin(9-39) increased the glucose bsAUC compared to saline (P &amp;lt;0.001) with no absolute or relative difference between the two treatment periods (∆bsAUC: 365 ± 34.4 mmol/L × min [170 ± 27.6%] (sevelamer) vs. 428 ± 58.2 mmol/L × min [165 ± 40.2%] (placebo treatment), P = 0.17). In conclusion, using the GLP-1 receptor antagonist exendin(9-39), we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer; leaving the mechanism behind the glucose-lowering effect of sevelamer unresolved. Disclosure H. H. Nerild: Employee; Spouse/Partner; Novo Nordisk. A. Brønden: None. D. P. Sonne: 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 &amp; 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.

85-LB: Glucose-Dependent Insulinotropic Polypeptide (GIP) Contributes Substantially to the Improved Beta-Cell Function during Sitagliptin Treatment in Persons with Type 2 Diabetes

In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Using the GIP receptor antagonist GIP(3-30)NH2, we investigated endogenous GIP’s contribution to the insulinotropic effect of DPP-4 inhibition (assessed by insulin secretion rate (ISR) relative to plasma glucose). In a double-blind, placebo-controlled, cross-over study, 12 persons (eight men and four women) with T2D (mean ± SD; BMI 27.4 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% (54 ± 15 mmol/mol)) underwent two randomized 12-13-day treatment courses with DPP-4 inhibitor (sitagliptin 100 mg once-daily) and placebo, respectively, with an interposed 1-3-week washout period. In the end of each treatment period, two randomized 5-hour liquid mixed-meal tests with infusion of GIP(3-30)NH2 (1,200 pmol/kg/min) or saline (placebo) were performed. During placebo treatment, GIP(3-30)NH2 lowered postprandial serum C-peptide (determined as difference in baseline-subtracted area under curve (ΔbsAUC%) ± SEM: −31 ± 9%, P = 0.005) and increased postprandial plasma glucose excursions (ΔAUC% ± SEM: 7.3 ± 2.8%, P = 0.017) compared to saline. Sitagliptin increased concentrations of active GIP(1-42) (ΔAUC% ± SEM: 153 ± 21%, P &amp;lt; 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P &amp;lt; 0.0004), whereas postprandial glucose excursions were unchanged compared to placebo treatment. GIP(3-30)NH2 caused a reduction in AUCISR/AUCglucose ratio equivalent to 37 ± 12% of the increments due to sitagliptin. In conclusion, we demonstrate an insulinotropic and glucose-lowering effect of endogenous GIP in persons with T2D and show that endogenous GIP is responsible for more than one third of the improved beta cell function observed during DPP-4 inhibitor treatment. Disclosure S. Stensen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M. M. Rosenkilde: Board Member; Self; Bainan Biotech, Synklino ApS, Board Member; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Consultant; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Spouse/Partner; Antag Therapeutics, Bainan Biotech. B. Hartmann: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. 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. M. B. Christensen: None. 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 European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (2018); A.P. Møller Foundation

Switching to iGlarLixi versus continuation of a daily or weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) in insufficiently controlled type 2 diabetes: A LixiLan-G trial subgroup analysis by HbA1c and GLP-1 RA use at screening.

AimIn people with type 2 diabetes (T2D) requiring intensification beyond glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and oral antihyperglycaemic drugs (OADs), switching to iGlarLixi was shown to be efficacious and well‐tolerated in the LixiLan‐G trial. This exploratory analysis of LixiLan‐G assessed the efficacy and safety of switching to iGlarLixi versus continuing GLP‐1 RA therapy, stratified by screening HbA1c level (≥7.0 to ≤7.5 %; >7.5 to ≤8.0 %; >8.0 to ≤9.0 % [≥53 to ≤58 mmol/mol; >58 to ≤64 mmol/mol; >64 to ≤75 mmol/mol]) and previous GLP‐1 RA regimen at screening (once/twice daily or once weekly).Materials and MethodsEndpoints for all subgroups included: change in HbA1c, achievement of HbA1c <7 % and hypoglycaemia events. Adverse events and changes in fasting plasma glucose (FPG), 2‐hour postprandial plasma glucose (PPG), 2‐hour PPG excursion and weight were analysed according to previous GLP‐1 RA regimen.ResultsSwitching to iGlarLixi in all subgroups resulted in significantly greater reductions in HbA1c and proportions of participants reaching HbA1c <7 % (including with no documented hypoglycaemia) at Week 26 compared with continued GLP‐1 RA treatment. Switching to iGlarLixi also led to significantly greater reductions in FPG, 2‐hour PPG, and 2‐hour PPG excursion, irrespective of previous GLP‐1 RA regimen. Rates of hypoglycaemia were low, but slightly higher in those who switched to iGlarLixi for all subgroups. Modest weight gain was seen with iGlarLixi, irrespective of previous GLP‐1 RA regimen.ConclusionsSwitching to iGlarLixi improved glycaemic control, regardless of screening HbA1c or previous GLP‐1 RA type, offering a simple, efficacious and well‐tolerated treatment intensification option for people with T2D inadequately controlled by GLP‐1 RAs and OADs.

Comparative effects of insulin glulisine and lispro on postprandial plasma glucose and lipid profile in Japanese patients with type 2 diabetes mellitus

The control of postprandial plasma glucose (PPG) excursions is critical in the prevention of diabetic complications. Controversy remains on the differences in postprandial actions of insulin glulisine and lispro. The aim of this study was to define the differences in the efficacy of these two insulin analogues on PPG. The study subjects were 20 in-hospital patients with type 2 diabetes mellitus (T2DM). Plasma glucose (PG) was tightly controlled with basal insulin and insulin glulisine or lispro, and then glulisine or lispro were switched to the other insulin analog every other day for 6 study days. PG was measured before breakfast and 0.5-, 1-, and 2h-postprandial during the study. Postprandial plasma C-peptide and lipids were analyzed in the first 2days of the study. Postprandial increments in each parameter were compared between glulisine and lispro. Whereas the median value of 0.5h-Δ-PPG was comparable in glulisine and lispro, the 1h-Δ-PPG was significantly lower with lispro than with glulisine (41 vs 53mg/dl, respectively, p = 0.03). Similarly, the 2h-Δ-PPG with lispro was 10mg/dl lower than that with glulisine (35 vs 45mg/dl, respectively, p = 0.05). In parallel with PPG, Δ-C-peptide at 1- and 2h-postprandial were significantly lower with lispro than glulisine (0.50 vs 0.75ng/ml, respectively, and 0.55 vs 0.75ng/ml, respectively). The increment in LDL-C and HDL-C was significantly lower with lispro than with glulisine at 0.5h-postprandial. Insulin lispro seems superior to glulisine in the control of PPG in Japanese patients with T2DM.

The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition.

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on 4 separate days, a liquid mixed-meal test preceded by single-dose administration of either 1) placebo, 2) the SGLT2i empagliflozin (25 mg), 3) the glucagon receptor antagonist LY2409021 (300 mg), or 4) the combination empagliflozin + LY2409021. Empagliflozin and LY2409021 individually lowered fasting PG compared with placebo, and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG through increased urinary glucose excretion. LY2409021 reduced EGP significantly but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin + LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition.

The intestinal microbiome is a co-determinant of the postprandial plasma glucose response.

Elevated postprandial plasma glucose is a risk factor for development of type 2 diabetes and cardiovascular disease. We hypothesized that the inter-individual postprandial plasma glucose response varies partly depending on the intestinal microbiome composition and function. We analyzed data from Danish adults (n = 106), who were self-reported healthy and attended the baseline visit of two previously reported randomized controlled cross-over trials within the Gut, Grain and Greens project. Plasma glucose concentrations at five time points were measured before and during three hours after a standardized breakfast. Based on these data, we devised machine learning algorithms integrating bio-clinical, as well as shotgun-sequencing-derived taxa and functional potentials of the intestinal microbiome to predict individual postprandial glucose excursions. In this post hoc study, we found microbial and clinical features, which predicted up to 48% of the inter-individual variance of postprandial plasma glucose responses (Pearson correlation coefficient of measured vs. predicted values, R = 0.69, 95% CI: 0.45 to 0.84, p<0.001). The features were age, fasting serum triglycerides, systolic blood pressure, BMI, fasting total serum cholesterol, abundance of Bifidobacterium genus, richness of metagenomics species and abundance of a metagenomic species annotated to Clostridiales at order level. A model based only on microbial features predicted up to 14% of the variance in postprandial plasma glucose excursions (R = 0.37, 95% CI: 0.02 to 0.64, p = 0.04). Adding fasting glycaemic measures to the model including microbial and bio-clinical features increased the predictive power to R = 0.78 (95% CI: 0.59 to 0.89, p<0.001), explaining more than 60% of the inter-individual variance of postprandial plasma glucose concentrations. The outcome of the study points to a potential role of the taxa and functional potentials of the intestinal microbiome. If validated in larger studies our findings may be included in future algorithms attempting to develop personalized nutrition, especially for prediction of individual blood glucose excursions in dys-glycaemic individuals.

1140-P: Empagliflozin Attenuates Fasting and Postprandial Hyperglycemia in Totally Pancreatectomized Patients: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial

Insulin remains the only glucose-lowering treatment modality recommended in totally pancreatectomized (PX) patients. We investigated the effects of the sodium glucose transporter 2 (SGLT2) inhibitor empagliflozin on fasting and postprandial glucose concentrations in PX patients. In a randomized, double-blinded, placebo-controlled crossover study, 10 PX patients (age 65.7±6.4 [mean±SD] years; BMI 23.8±4.3 kg/m2) and 10 CTRLs (age 65±7.8 years; BMI 24.3±3.5 kg/m2) underwent a 3-hour liquid mixed meal test (MMT) preceded by two doses of 25 mg empagliflozin (administered the night before and on the morning of the MMT) and placebo, respectively. Basal insulin was administered as usual; no bolus insulin was administered during study days. Empagliflozin lowered fasting plasma glucose compared to placebo (5.0±0.5 vs. 7.9±0.9 mmol/l [mean±SEM], P=0.029) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under curve (999±96 vs. 1,235±69 min×pmol/l, P=0.034) in the PX patients. In CTRLs, empagliflozin lowered fasting plasma glucose compared to placebo (5.2±0.1 vs. 5.5±0.1 mmol/l, P=0.021) without affecting postprandial glucose excursions significantly. Empagliflozin acutely and effectively decreases fasting plasma glucose and attenuates postprandial hyperglycemia in PX patients. Disclosure M. Baekdal: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S.W. Nielsen: None. J.H. Storkholm: None. C. Hansen: None. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S.

1052-P: Investigation of the Extrapancreatic Effects of the DPP-4 Inhibitor Sitagliptin: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial in Totally Pancreatectomized Patients

Dipeptidyl peptidase 4 (DPP-4) inhibitors increase circulating concentrations of the insulinotropic and glucagon-modulating gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). The multiorgan distribution of GIP and GLP-1 receptors suggests pleiotropic extrapancreatic effects of these hormones (and thus DPP-4 inhibition), but these have been difficult to disentangle from their potent effects on the endocrine pancreas. Here, we investigated postprandial effects of the DPP-4 inhibitor sitagliptin in totally pancreatectomized (PX) patients as compared to matched healthy controls (CTRLs). In a randomized, double-blinded, placebo-controlled crossover study, 10 PX patients (age 65.7±6.4 [mean±SD] years; BMI 23.8±4.3 kg/m2) and 10 CTRLs (age 65±7.8 years; BMI 24.3±3.5 kg/m2) underwent a 3-hour liquid mixed meal test (MMT) after two doses of 150 mg sitagliptin (administered the night before and on the morning of the MMT) and placebo, respectively. Basal insulin was administered as usual; no bolus insulin was administered during study days. Blood samples were drawn throughout the experimental days. Sitagliptin did not affect fasting plasma glucose compared to placebo in CTRLs (5.4±0.2 vs. 5.5±0.1 mmol/l, P=0.6) nor in PX patients (7.7±1.0 vs. 7.9±0.9 mmol/l, P=0.88). Also, sitagliptin did not affect postprandial plasma glucose excursions as assessed by peak values, time to peak values or area under the curve in any of the groups. In conclusion, the DPP-4 inhibitor sitagliptin has no effect on fasting plasma glucose or postprandial plasma glucose excursions in PX patients; suggesting that no or little extrapancreatic effects of GIP and GLP-1 are involved in the glucose-lowering action of DPP-4 inhibition in patients with diabetes. Disclosure M. Baekdal: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S.W. Nielsen: None. C. Hansen: None. J.H. Storkholm: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S.

89-LB: The Effect of GIP on Plasma Glucose in a Setting of Prandial Insulin Overdose and Physical Activity after Meal Intake in Patients with Type 1 Diabetes

Gluco-regulatory effects of the insulinotropic and glucagonotropic gut hormone glucose-dependent insulinotropic polypeptide (GIP) in type 1 diabetes (T1D) are unclear. We evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of prandial insulin over-dose and physical activity after meal ingestion. In a randomized, placebo-controlled, double-blinded, crossover study, 12 men with T1D (age [mean±SD]: 26±6.6 years; BMI: 23±2.3 kg/m2; HbA1c: 6.5±2.7% (48.4±6.3 mmol/mol); diabetes duration: 11.3±5.5 years; plasma C-peptide &amp;lt;200 pmol/L) underwent three separate study days involving a liquid mixed meal test with 125% of regular prandial insulin dose, 30 minutes of intermediate bicycling (60 minutes after mixed-meal), and 270 minute infusions of GIP, the GIP receptor antagonist GIP(3-30)NH2 and placebo, respectively. The GIP infusion attenuated postprandial plasma glucose excursions (Cmax-Cmin) by [mean±SEM] 1.5±0.5 mmol/L and 0.92±0.56 mmol/L compared to GIP(3-30)NH2 and placebo, respectively (P=0.03). Infused glucose needed to avoid plasma glucose &amp;lt;2.5 mmol/L was similar on all 3 study days (P=0.13). In conclusion, GIP infusion seems to attenuate postprandial plasma glucose excursions without significantly increasing the need of glucose to avoid hypoglycemia in patients with T1D. Disclosure B. Hoe: None. S.M. Nguyen Heimbürger: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.B. Lynggaard: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp &amp; Dohme Corp., Sanofi. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S. Engberg: None. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp &amp; Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

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.

GIP and GLP-1 Receptor Antagonism During a Meal in Healthy Individuals.

The actions of both endogenous incretin hormones during a meal have not previously been characterized. Using specific receptor antagonists, we investigated the individual and combined contributions of endogenous glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) to postprandial glucose metabolism, energy expenditure, and gallbladder motility. Randomized, double-blinded, placebo-controlled, crossover design. On four separate days, four liquid mixed meal tests (1894 kJ) over 270 minutes (min). Twelve healthy male volunteers. Infusions of the GIP receptor antagonist GIP(3-30)NH2 (800 pmol/kg/min), the GLP-1 receptor antagonist exendin(9-39)NH2 (0-20 min: 1000 pmol/kg/min; 20-270 min: 450 pmol/kg/min), GIP(3-30)NH2+exendin(9-39)NH2, or placebo/saline. Baseline-subtracted area under the curve (bsAUC) of C-peptide. Infusion of GIP(3-30)NH2+exendin(9-39)NH2 significantly increased plasma glucose excursions (bsAUC: 261 ± 142 mmol/L × min) during the liquid mixed meals compared with GIP(3-30)NH2 (180 ± 141 mmol/L × min; P = 0.048), exendin(9-39)NH2 (171 ± 114 mmol/L × min; P = 0.046), and placebo (116 ± 154 mmol/L × min; P = 0.015). Correspondingly, C-peptide:glucose ratios during GIP(3-30)NH2+exendin(9-39)NH2 infusion were significantly lower than during GIP(3-30)NH2 (P = 0.0057), exendin(9-39)NH2 (P = 0.0038), and placebo infusion (P = 0.014). GIP(3-30)NH2 resulted in significantly lower AUCs for glucagon than exendin(9-39)NH2 (P = 0.0417). Gallbladder ejection fraction was higher during GIP(3-30)NH2 compared with placebo (P = 0.004). For all interventions, energy expenditure and respiratory quotient were similar. Endogenous GIP and GLP-1 lower postprandial plasma glucose excursions and stimulate insulin secretion but only endogenous GIP affects gallbladder motility. The two incretin hormones potentiate each other's effects in the control of postprandial glycemia in healthy men.

The continuing quest for better subcutaneously administered prandial insulins: a review of recent developments and potential clinical implications.

The class of rapid‐acting insulin analogues were introduced more than 20 years ago to control postprandial plasma glucose (PPG) excursions better than unmodified regular human insulin. Insulins, lispro, aspart and glulisine all achieved an earlier onset of action, greater peak effect and shorter duration of action resulting in lower PPG levels and a reduced risk of late postprandial hypoglycaemia. However, the subcutaneous absorption rate of these analogues still fails to match the physiological profile of insulin in the systemic circulation following a meal. Recent reformulations of aspart and lispro have generated a second generation of more rapid‐acting insulin analogue candidates, including fast‐acting aspart (faster aspart), ultra‐rapid lispro and BioChaperone Lispro. These modifications have the potential to mimic physiological prandial insulin secretion better with an even earlier onset of action with improved PPG control, shorter duration of effect and reduced risk of hypoglycaemia. Recent phase 3 trials in type 1 and type 2 diabetes show that faster aspart and ultra‐rapid lispro compared with conventional aspart and lispro, achieved fewer PPG excursions with a small increase in post‐meal hypoglycaemia but similar or marginally superior glycated haemoglobin levels, and suggest the need for parallel optimization of basal insulin replacement. Phase 1 trials for BioChaperone Lispro are equally encouraging with phase 3 trials yet to be initiated. Comparative analysis of the clinical and pharmacological evidence for these new prandial insulin candidates in the treatment of type 1 and type 2 diabetes is the main focus of this review.

Biliopancreatic Diversion Induces Greater Metabolic Improvement Than Roux-en-Y Gastric Bypass

Diabetes remission is greater after biliopancreatic diversion (BPD) than Roux-en-Y gastric bypass (RYGB) surgery. We used a mixed-meal test with ingested and infused glucose tracers and the hyperinsulinemic-euglycemic clamp procedure with glucose tracer infusion to assess the effect of 20% weight loss induced by either RYGB or BPD on glucoregulation in people with obesity (ClinicalTrials.gov number: NCT03111953). The rate of appearance of ingested glucose into the circulation was much slower, and the postprandial increases in plasma glucose and insulin concentrations were markedly blunted after BPD compared to after RYGB. Insulin sensitivity, assessed as glucose disposal rate during insulin infusion, was ∼45% greater after BPD than RYGB, whereas β cell function was not different between groups. These results demonstrate thatcompared with matched-percentage weight loss induced by RYGB, BPD has unique beneficial effects on glycemic control, manifested by slower postprandial glucose absorption, blunted postprandial plasma glucose and insulin excursions, and greater improvement in insulin sensitivity.

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.

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.