Postprandial Glucagon Research Articles

Effect of Dietary Macronutrients on Postprandial Glucagon and Insulin Release in Obese and Normal-Weight Women.

The aim of the study was to assess the effect of dietary macronutrients on circulating glucagon and insulin levels in obese and normal-weight women. Potentially, the impaired release of glucagon may proceed abnormal glucose metabolism in obese patients ahead of overt diabetes. In 20 insulin-sensitive women (11 obese and 9 normal-weight), plasma concentrations of insulin and glucagon levels were assessed before and after 3 different macronutrient test meals. AUCtotal insulin in the obese group was increased after protein and carbohydrates compared to fatty test meal consumption (3981 ± 2171 and 4869 ± 2784 vs. 2349 ± 1004 μIU∗h/m, p < 0.05, respectively), but without a difference between protein and carbohydrates ingestion. However, in the normal-weight group, AUCtotal insulin was increased after carbohydrates compared to fatty test meal ingestion (3929 ± 1719 vs. 2231 ± 509 μIU∗h/ml, p < 0.05) and similar after carbohydrate and protein as well as after fatty and protein test meals (3929 ± 1719 vs. 2231 ± 509 vs. 3046 ± 1406 μIU∗h/ml, respectively). However, AUCtotal insulin was significantly increased in obese compared to normal-weight women only after carbohydrate test meal ingestion (4869 ± 2784 vs. 3929 ± 1719 μIU∗h/ml, p < 0.05). AUCtotal glucagon was similar after carbohydrate, protein, and fatty test meals ingestion in obese and normal-weight women (921 ± 356 vs. 957 ± 368 vs. 926 ± 262 ng∗h/ml and 1196 ± 14 vs. 1360 ± 662 vs. 1792 ± 1176 ng∗h/ml, respectively). AUCtotal glucagon was significantly lower in obese than normal-weight women after a fatty meal (926 ± 262 vs. 1792 ± 1176 ng∗h/ml, p < 0.01). Postprandial glucagon secretion is not related to the macronutrient composition of the meal in normal-weight women since postprandial glucagon concentrations were stable and did not change after carbohydrate, protein, and fatty test meals. Lower glucagon secretion was observed in obese subjects after fatty meal consumption when compared to normal-weight subjects. Postprandial insulin profile was significantly higher after carbohydrate than fatty test meal intake in the obese group and did not differ between obese and normal-weight groups after carbohydrate, protein, and fatty test meals consumption. Impaired glucagon secretion after fatty meat suggests early pancreatic alpha-cell dysfunction, after a carbohydrate meal is a compensatory mechanism.

Effect of tasteless calorie-free gum chewing before meal on postprandial plasma glucose, insulin, glucagon, and gastrointestinal hormones in Japanese men without diagnosed glucose metabolism disorder: a pilot randomized crossover trial.

This pilot study aimed to examine the effect of pre-meal tasteless calorie-free gum chewing on post-meal blood levels of glucose, insulin, glucagon, and gastrointestinal hormones. This was an open-label, randomized, 2-sequence, 3-period, 2-treatment crossover trial with a 1:1 allocation. Sixteen Japanese adult male volunteers aged between 30 and 49years without diagnosed glucose metabolism disorderwere enrolled. Ingestion of 200-g cooked rice after 15-min tasteless calorie-free gum chewing (GUM+ treatment) was compared to that without preceding gum chewing (GUM- treatment). Cooked rice was divided into twelve equally sized portions and consumed by chewing each portion 30 times before swallowing. Treatment sessions were separated by an at least 1-week interval and attended after an overnight fast. Circulating levels of glucose, insulin, glucagon, active glucagon-like peptide (GLP)-1 and ghrelin were measured at baseline (before treatment) and 0, 15, 30, 60, and 120min after completion of the meal ingestion, and the postprandial change from baseline was assessed. As a result, the change in glucose levels at 0min was significantly lower in the GUM+ treatment than in the GUM- treatment (P = 0.004). Furthermore, the GUM+ treatment demonstrated higher incremental insulin levels at 15min (P = 0.041) and higher incremental active GLP-1 levels at 30 and 60min (P = 0.018 and 0.021, respectively); whereas, postprandial glucagon and ghrelin levels were not significantly different. In conclusion, the current pilot study demonstrated that tasteless calorie-free gum chewing before rice eating had a significant but limited impact on the increase of postprandial active GLP-1 levels in male individuals without diagnosed glucose metabolism disorder.

Fasting glucagon concentrations are associated with longitudinal decline of β-cell function in non-diabetic humans

PurposeAbnormal glucagon concentrations are a feature of prediabetes but it is uncertain if α-cell dysfunction contributes to a longitudinal decline in β-cell function. We therefore sought to determine if a decline in β-cell function is associated with a higher nadir glucagon in the postprandial period or with higher fasting glucagon. MethodsThis was a longitudinal study in which 73 non-diabetic subjects were studied on 2 occasions 6.6 ± 0.3 years apart using a 2-hour, 7-sample oral glucose tolerance test. Disposition Index (DI) was calculated using the oral minimal model applied to the measurements of glucose, insulin, C-peptide concentrations during the studies. We subsequently examined the relationship of glucagon concentrations at baseline with change in DI (used as a measure of β-cell function) after adjusting for changes in weight and the baseline value of DI. ResultsAfter adjusting for covariates, nadir postprandial glucagon concentrations were not associated with changes in β-cell function as quantified by DI. On the other hand, fasting glucagon concentrations during the baseline study were inversely correlated with longitudinal changes in DI. ConclusionsDefects in α-cell function, manifest as elevated fasting glucagon, are associated with a subsequent decline in β-cell function. It remains to be ascertained if abnormal α-cell function contributes directly to loss of β-cell secretory capacity in the pathogenesis of type 2 diabetes.

Postprandial Lipemia Modulates Pancreatic Alpha-Cell Function in the Prediction of Type 2 Diabetes Development: The CORDIOPREV Study.

Diabetes (T2DM) is a major global health issue, and developing new approaches to its prevention is of paramount importance. We hypothesized that abnormalities in lipid metabolism are involved in alpha-cell deregulation. We therefore studied the metabolic factors underlying alpha-cell dysfunction in T2DM progression after a dietary intervention (Mediterranean and low-fat). Additionally, we evaluated whether postprandial glucagon levels may be considered as a predictive factor of T2DM in cardiovascular patients. Non-T2DM participants from the CORDIOPREV study were categorized by tertiles of the area under the curve (AUC) for triacylglycerols and also by tertiles of AUC for glucagon. Our results showed that patients with higher triacylglycerols levels presented elevated postprandial glucagon (P = 0.009). Moreover, we observed higher risk of T2DM (hazard ratio: 2.65; 95% confidence interval: 1.56-4.53) in subjects with elevated glucagon. In conclusion, high postprandial lipemia may induce alpha-cell dysfunction in cardiovascular patients. Our results also showed that postprandial glucagon levels could be used to predict T2DM development.

Subjects with high fasting insulin also have higher postprandial GLP-1 and glucagon levels than controls with lower insulin

Little is known about postprandial release of serum ghrelin, glucagon, and glucagon-like peptide-1 (GLP-1) in relation with differing fasting insulin levels. We hypothesized that these hormones are affected by insulin resistance, and hence, we compared different postprandial responses of GLP-1, glucagon, and ghrelin in subjects with relatively high (RHI) or relatively low (RLI) fasting insulin levels. The trial was a randomized crossover study with 4 different meal conditions. Fourteen nonobese or obese, healthy, men and 14 women were randomly assigned to the order of supervised intake of a 750 kcal drink with the same protein contents but with 20 energy-percent (E%) or 55 E% from carbohydrates, and the remaining energy from fat. Participants were also randomized to consume the drinks as 1 large beverage or as five 150-kcal portions every 30 minutes. The 28 subjects were divided into 2 equally sized groups based on fasting insulin levels. Statistics were done with general linear mixed model. Fasting insulin levels were 3-fold higher in the group with RHI compared with the RLI group (RHI: 1004 ± 510 pg/mL, RLI: 324 ± 123 pg/mL, P < .0005). Serum GLP-1 was highest in the RHI group after both single meals and after 5 drinks and following high- and low-carbohydrate meals (both P ≤ .002), and this was the case also for glucagon levels (both P ≤ .018), whereas ghrelin levels did not differ between groups. Thus, subjects with RHI displayed both higher postprandial serum GLP-1 and glucagon than the participants with RLI, suggesting that glucagon could play a role in the advent of dysglycemia by insulin resistance.

Concurrent Use of Teneligliptin and Canagliflozin Improves Glycemic Control with Beneficial Effects on Plasma Glucagon and Glucagon-Like Peptide-1: A Single-Arm Study.

IntroductionWe investigated the mechanisms of the glucose-lowering effects of teneligliptin and canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, by monitoring several gastrointestinal peptides using the most appropriate measuring methods during multiple meal tolerance tests (MTTs) and flash glucose monitoring.MethodsTwelve Japanese patients with type 2 diabetes were enrolled in the 14-day study. Subjects were treated with teneligliptin 20 mg/day from day 4, followed by a combination tablet of teneligliptin 20 mg and canagliflozin 100 mg (T/C) per day from day 11. MTTs were conducted on days 3 (premedication; Pre), 10 (teneligliptin; T) and 13 (T/C) to evaluate plasma glucose, C-peptide, glucagon, active glucagon-like peptide-1 (GLP-1), active gastric inhibitory polypeptide (GIP), ghrelin and des-acyl ghrelin.ResultsPlasma glucose was significantly decreased with the progress of treatment intervention, and C-peptide was significantly decreased in T/C compared to the others. Plasma postprandial glucagon was increased for 90 min from fasting in Pre, but only for 30 min in T and T/C. Plasma postprandial active GLP-1 was significantly increased in T compared to Pre, and that of T/C was significantly higher than T. Plasma postprandial active GIP was increased in T and T/C compared to Pre. Plasma ghrelin and des-acyl ghrelin levels did not change during the treatment.ConclusionTeneligliptin increased incretin hormones and suppressed postprandial glucagon secretion as expected. Concurrent use of canagliflozin and teneligliptin improved glycemic control without increasing postprandial glucagon secretion, and increased postprandial GLP-1 secretion and decreased the required amount of postprandial insulin secretion. The underlying mechanisms may involve canagliflozin’s inhibitory activity against not only SGLT2 but also SGLT1.Trial RegistrationUMIN identifier, UMIN000030043.FundingMitsubishi Tanabe Pharma Corporation and a Grant for Clinical Research from Miyazaki University Hospital.Electronic supplementary materialThe online version of this article (10.1007/s13300-019-0666-7) contains supplementary material, which is available to authorized users.

Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery.

After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. The 29-amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry-validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

Association of variants of the TCF7L2 gene at rs7903146(C/T) and rs12255372(G/T) with type 2 diabetes mellitus in Chennai suburban population

Association of variants of the TCF7L2 gene at rs7903146(C/T) and rs12255372(G/T) with type 2 diabetes mellitus in Chennai suburban population - IJCBR- Print ISSN No: - 2394-6369 Online ISSN No:- 2394-6377 Article DOI No:- 10.18231/j.ijcbr.2019.043, International Journal of Clinical Biochemistry and Research-Int J Clin

64-OR: Postprandial Effects of Endogenous Glucose-Dependent Insulinotropic Polypeptide in Type 2 Diabetes

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1). In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients. Disclosure S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: 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 Novo Nordisk Foundation; European Foundation for the Study of Diabetes

1831-P: Delayed Glucagon Suppression Contributes to Postprandial Hyperglycemia Independently of the Degree of Insulin Secretion

Type 2 diabetes (T2DM) is characterized by impaired postprandial insulin secretion and glucagon suppression. Recent work suggests that α-cell dysfunction is independent of β-cell dysfunction. The effect of diabetes-associated variation in TCF7L2 on α-cell function also suggests a direct role in the pathogenesis of T2DM. To quantify the interaction between a lack of glucagon suppression with intact, mildly or moderately impaired insulin secretion we studied 45 nondiabetic subjects with and without suppressed glucagon. On both occasions, an intravenous glucose infusion mimicking the systemic appearance of 50g oral glucose was administered in the presence of a pancreatic clamp. Glucagon was infused at a rate of 0.65ng/kg/min, starting at 0 min or 120 min (non-suppressed vs. suppressed respectively). In one group (100%) a nondiabetic insulin profile was infused; another group received 80% of this profile and the third group received 60% of the insulin infused in the first group. We observed that a lack of glucagon suppression increased peak (p &amp;lt; 0.05) and area above basal (AAB) glucose (p &amp;lt; 0.02) in all groups (1.5 ± 0.1 vs. 1.1 ± 0.1; 1.6 ± 0.1 vs. 1.1 ± 0.1; 1.5 ± 0.1 vs.1.3 ± 0.1 Mol per 5hr, 100%, 80%, 60% respectively). These increases were explained by delayed suppression of endogenous glucose production (EGP) so that EGP at 120 minutes was higher (p &amp;lt; 0.05) in the presence of non-suppressed glucagon (6.6 ± 1.0 vs. 4.2 ± 0.6; 7.2 ± 0.8 vs. 5.1 ± 0.5; 7.7 ± 0.8 vs. 5.9 ± 0.6 μmol/kg/min, 100%, 80%, 60% respectively) as was integrated EGP (p &amp;lt; 0.05) over the postprandial period (-1.9 ± 0.4 vs. -2.1 ± 0.1; -1.8 ± 0.1 vs. -1.9 ± 0.2; -1.6 ± 0.3 vs. -1.8 ± 0.1 mmol/kg per 5hr, 100%, 80%, 60% respectively). These data indicate that impaired postprandial glucagon suppression contributes to postprandial hyperglycemia through increased EGP even when insulin secretion is intact as can occur early in prediabetes. These effects are exacerbated by increasing degrees of insulin deficiency. Disclosure J. Adams: None. M.C. Laurenti: Employee; Self; GlySens Incorporated. R.A. Rizza: Advisory Panel; Self; Lilly Diabetes, Metavention, Novo Nordisk A/S, vTv Therapeutics. A.M. Egan: None. C. Cobelli: None. C. Dalla Man: None. A. Vella: Advisory Panel; Self; vTv Therapeutics. Research Support; Self; Novo Nordisk Inc. Funding National Institutes of Health

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

1214-P: Effect of Short-Term Improvements in Glycemic Control with SGLT2 Inhibitor Therapy on Insulin and Glucagon Secretion: How Does It Differ With or Without Concurrent DPP-4 Inhibitor Therapy

Objective: We investigated the effect of short-term improvements in glycemic control with SGLT2i therapy on insulin and glucagon secretion with or without concurrent DPP-4 inhibitor (DPP-4i) therapy. Patients and Methods: 78 type 2 diabetic patients admitted for glycemic control and subjected to meal tolerance tests (MTT) on the next day after admission and immediately before discharge using the same diabetes diet while off treatment were subjected to retrospective analysis. Of these, 41 patients were found to have received SGLT2i after admission, with 15 of these also found to have received concurrent DPP-4i. The patients were divided into those not receiving SGLT2i (n=37), those receiving SGLT2i without concurrent DPP-4i (n=26) and those receiving SGLT2i with DPP-4i (n=15) and were compared for changes in postprandial insulin and glucagon secretion. All patients were evaluated at admission and discharge for insulin secretion in terms of ΔCPR/ΔPG 0-30 min and AUC-CPR 0-2h, and as well as for glucagon (G) secretion in terms of ΔG/ΔPG 0-30 min and AUC-G 0-2h during the MTT. Results: There was no significant difference between the 3 groups in their HbA1c, C-peptide index, and urinary CPR excretion at admission. With improvements in glycemic control, ΔCPR/ΔPG 0-30min and AUC-CPR 0-2h were significantly increased, and AUC-PG 0-2h were significantly decreased, in all groups. Again, with improvements in glycemic control, AUC-G 0-2h was significantly decreased in those not receiving SGLT2i, increased in those receiving SGLT2i without DPP-4i, and decreased in those receiving both SGLT2i and DPP-4i. Conclusions: Postprandial insulin secretion was shown to be restored after short-term improvements in glycemic control irrespective of SGLT2i or concurrent DPP-4i, while glucagon secretion was shown to be increased with SGLT2i without DPP-4i but decreased with combined SGLT2i and DPP-4i. Disclosure M. Matsui: None. H. Takahashi: None. S. Sawano: None. Y. Mori: None. K. Utsunomiya: None.

344-LB: A Highly Specific Chemiluminescent Assay That Accurately Measures Human and Rodent Glucagon

Glucagon is a hormone generated as a result of post translational modifications during proglucagon processing. The hormone's amino acid sequence is found in several proglucagon peptides, including the hormones glicentin and oxyntomodulin. In addition, glucagon’s sequence is similar to incretin hormones such as glucagon-like peptide-1 (GLP-1). The similar sequence homology between glucagon and these peptide hormones has created challenges in specifically measuring glucagon concentrations. Current commercially available glucagon assays have been proven to cross-react with oxyntomodulin, glicentin, and other proglucagon peptides. In addition, researchers often report higher cross-reactivity values than the manufacturers, which further complicates accurately measuring glucagon levels. To address this need, ALPCO has developed the STELLUX® Chemi Glucagon ELISA for the quantitative determination of glucagon in EDTA plasma and cell culture samples. This assay has an excellent sensitivity and is capable of measuring post-prandial glucagon levels in both rodents and humans. Most importantly, this assay specifically measures glucagon without any cross-reactivity to other proglucagon peptides including glicentin and oxyntomodulin. In the current study, ALPCO’s ELISA was compared to competitor A’s ELISA to further investigate how differences in specificity contribute to final calculated concentrations of the analyte. A panel of 16 samples of human, mouse, and rat EDTA plasma were assayed on both products and an overall R2 of 0.988 and slope of 1.337 was shown. The consistently higher recovery in values using the competitor ELISA may be explained through its known cross-reactivity with oxyntomodulin and/or glicentin. However, the correlation between the two assays would allow for a seamless transition from the competitor ELISA to the ALPCO ELISA within or between projects. Disclosure C. Caillouette: Employee; Self; Alpco. B.K. McDermott: None. J.M. Cacicedo: Employee; Self; Alpco. B. Bell: Employee; Self; Alpco. C. Wisherd: Employee; Self; Alpco.

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

Transitioning to Fixed-Ratio Combination Therapy: Five Frequently Asked Questions Health Care Providers Should Anticipate From Their Patients.

A patient who is overweight with type 2 diabetes and takes multiple oral antihyperglycemic agents has been informed that the current treatment plan is not providing adequate glycemic control and that adding insulin therapy is recommended. However, the patient is concerned about insulin causing weight gain or leading to hypoglycemia and is looking for a treatment that will avoid or reduce these issues. Taking all of these considerations into account, the health care provider recommends that the patient start insulin and a glucagon-like peptide 1 (GLP-1) receptor agonist given as fixed-ratio combination (FRC) therapy administered with a prefilled pen device that allows for both basal insulin and a GLP-1 receptor agonist to be delivered in a single daily injection. Basal insulin and GLP-1 receptor agonists have different but complementary modes of action. Basal insulin predominantly regulates blood glucose between widely spaced meals and overnight (1) through the movement of glucose from blood into certain cells of the body (including skeletal muscle) and the suppression of hepatic glucose production (2); GLP-1 receptor agonists affect glucose control through glucose-dependent insulin secretion, slowing gastric emptying, inducing satiety, and suppressing excess postprandial glucagon release (3). FRC therapies that contain both a basal insulin and a GLP-1 receptor agonist have been shown to improve glycemic control with a risk of hypoglycemia that is similar to that associated with the use of basal insulin alone (4,5). In addition, FRC therapies have been shown to mitigate insulin-induced weight gain and to reduce the likelihood of the gastrointestinal (GI) adverse events that are associated with the use of GLP-1 receptor agonists. This effect is the result of slower up-titration of the GLP-1 receptor agonist component of an FRC compared with the titration schedule recommended when a GLP-1 receptor agonist is used alone (6–8). …

Postprandial levels of GLP-1, GIP and glucagon after 2 years of weight loss with a Paleolithic diet: a randomised controlled trial in healthy obese women.

ObjectiveTo investigate how weight loss by different diets impacts postprandial levels of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon.MethodsIn this single-centre, parallel group 2-year trial, 70 healthy postmenopausal obese women were randomised to the Paleolithic diet or a healthy control diet based on Nordic Nutrition Recommendations. Both diets were without calorie restriction. The primary outcome was the change in fat mass. Here, secondary analyses on GLP-1, GIP and glucagon measured during an OGTT are described.ResultsIn the Paleolithic diet group, mean weight loss compared to baseline was 11% at 6 months and 10% at 24 months. In the control diet group, mean weight loss was 6% after 6 and 24 months (P = 0.0001 and P = 0.049 for the comparison between groups at 6 and 24 months respectively). Compared to baseline, the mean incremental area under the curve (iAUC) for GLP-1 increased by 34 and 45% after 6 and 24 months in the Paleolithic diet group and increased by 59% after 24 months in the control diet group. The mean iAUC for GIP increased only in the Paleolithic diet group. The area under the curve (AUC) for glucagon increased during the first 6 months in both groups. The fasting glucagon increase correlated with the β-hydroxybutyrate increase.ConclusionsWeight loss caused an increase in postprandial GLP-1 levels and a further rise occurred during weight maintenance. Postprandial GIP levels increased only after the Paleolithic diet. Reduced postprandial glucagon suppression may be caused by a catabolic state.

Profile of semaglutide in the management of type 2 diabetes: design, development, and place in therapy.

Type 2 diabetes mellitus (T2DM) has become one of the leading causes of morbidity and mortality in developed countries. Low efficacy, weight gain, and hypoglycemia are the main pitfalls of previous treatments for T2DM. New therapies have been designed with the aim of improving the results in efficacy and quality of life. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RA) increase glucose-dependent insulin secretion, decrease gastric emptying, and reduce postprandial glucagon secretion. The last GLP-1 RA approved by the US Food and Drug Administration and European Medicines Agency was semaglutide. This review describes its pharmacology, core clinical data coming from the randomized controlled trials included in the development program, proven cardiovascular benefits, safety issues, and precautions for the use of semaglutide in special populations. Additionally, an overview of the positioning of semaglutide in T2DM therapy and practical issues regarding semaglutide initiation are offered.

Roux-en-Y Gastric Bypass Is Associated With Hyperinsulinemia But Not Increased Maximal β-Cell Function.

ContextRoux-en-Y gastric bypass (RYGB) is associated with postprandial hyperinsulinemia.ObjectiveThis study assessed whether increased blood insulin levels may be due to an increase in maximal β-cell function.Design, Setting, and ParticipantsWe performed a cross-sectional study at Columbia University Medical Center, New York, New York. Subjects without a history of diabetes were studied after surgery (n = 12) and were compared with nonsurgical controls (n = 10) who were mean matched for body mass index, insulin sensitivity, and hemoglobin A1c and with nonobese controls (n = 8).MethodsSubjects underwent a mixed-meal tolerance test and on a separate day an intravenous glucose tolerance test followed by a hyperglycemic clamp (450 mg/dL; 25 mM blood glucose) and arginine stimulation. The main outcome measure was maximal insulin secretion quantified after arginine stimulation (AinsRmax).ResultsThe RYGB group exhibited greater peak postprandial glucose levels and fourfold greater peak insulin levels than control groups; however, there were no significant differences in insulinogenic index or AinsRmax. Another finding was significantly greater postprandial glucagon levels in the RYGB group compared with controls.ConclusionsOur results suggest that after RYGB, the increase in postprandial levels of insulin are not due to changes in maximal β-cell function but appear to be an appropriate response to altered nutrient flow and absorption.

Gastrointestinal effects of extra-virgin olive oil associated with lower postprandial glycemia in type 1 diabetes

To explore the possible mechanisms behind the lower glycemic response observed when extra-virgin olive oil (EVOO) is added to a high-glycemic index meal in patients with type 1 diabetes (T1D). According to a randomized cross-over design, eleven T1D patients (6 women, 5 men) on insulin pump consumed in the metabolic ward, one week apart, three high-glycemic index meals differing only for amount and quality of fat: high-monounsaturated fat (EVOO), high-saturated fat (Butter), and low-fat (LF). Before and after the meals, blood glucose (continuous glucose monitoring), gastric emptying rate (ultrasound technique), and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide GIP (ELISA), glucagon (RIA), and lipids (colorimetric assays) were evaluated. Blood glucose iAUC (mmol/lx360min) was lower after the EVOO (690±431) than after the Butter (1320±600) and LF meals (1007±990) (M±SD, p=0.041 by repeated measures ANOVA). Gastric antrum volume was significantly larger in the early (60-90min) postprandial phase (106±21 vs. 90±16ml, p=0.048) and significantly smaller in the late phase (330-360min) (46±10 vs. 57±22ml, p=0.045) after the EVOO than after Butter meal. EVOO significantly increased postprandial GLP-1 iAUC (261±311) compared to Butter (189±349) (pmol/Lx180min, p=0.009). Postprandial GIP and glucagon responses were not significantly different between EVOO and Butter. Postprandial triglyceride iAUC was significantly higher after EVOO (100±53) than after Butter (65±60) (mmol/l×360min, p=0.048). Changes in gastric emptying and GLP-1 secretion and reduced glucose absorption through glucose-lipid competition may contribute to lower glycemia after a high-glycemic index meal with EVOO in T1D patients. NCT02330939.

Postprandial Plasma Glucagon Kinetics in Type 2 Diabetes Mellitus: Comparison of Immunoassay and Mass Spectrometry.

ContextAccurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes.ObjectiveTo evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus.Design and ParticipantsTwenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks. Blood samples were taken serially after the meal, and glucagon levels were measured using both ELISA and LC-HRMS. We compared the change from baseline to 4 weeks (Δ0–4W) using the area under the curve for plasma glucagon during the meal test [area under the curve (AUC)0–3h] measured using ELISA and LC-HRMS.ResultsELISA-based glucagon AUC0–3h was higher than LC-HRMS–based AUC0–3h at baseline and 4 weeks. However, differences in Δ0–4W-AUC0–3h measured using ELISA and LC-HRMS were not statistically significant. Additionally, Δ0–4W-AUC0–3h measured using ELISA and LC-HRMS were strongly correlated (r = 0.87, P < 0.001).ConclusionsPlasma glucagon levels during a meal test in patients with type 2 diabetes measured using ELISA were consistently higher than those measured using LC-HRMS. However, given that the changes in glucagon levels measured using ELISA before and after dipeptidyl peptidase-4 inhibitor therapy were similar to those based on LC-HRMS, this ELISA seems to be useful for evaluating the effect of the drug interventions on postprandial glucagon levels.