Postprandial Incretin Research Articles

Effect of vegetable consumption with chewing on postprandial glucose metabolism in healthy young men: a randomised controlled study

Although thorough chewing lowers postprandial glucose concentrations, research on the effectiveness of chewing vegetables in different forms on postprandial glucose metabolism remains limited. This study examined the effects of vegetables consumed in solid versus puree forms on postprandial glucose metabolism. Nineteen healthy young men completed two 180-min trials on separate days in a random order: the chewing trial involved the consumption of shredded cabbage with chewing and the non-chewing trial involved the consumption of pureed cabbage without chewing. Energy jelly was consumed immediately after the consumption of shredded or puree cabbage. Blood samples were collected at 0, 30, 45, 60, 90, 120 and 180 min. Circulating concentrations of glucose, insulin, total glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) concentrations were measured from the plasma. Although plasma glucose concentrations did not differ between the trials, the plasma insulin and GIP incremental area under the curve values were higher in the chewing than in the non-chewing trial. Postprandial total GLP-1 concentrations were higher in the chewing than in the non-chewing trial at 45, 60 and 90 min. This study demonstrates that consuming shredded cabbage while chewing enhances postprandial incretin secretion but has no effect on postprandial glucose concentration.Trial registration: Clinical trial registration ID.: UMIN000052662, registered 31 October 2023.

OGC P54 Catastrophic dumping after gastrectomy in a patient with absent pituitary treated with octreotide – case report

Abstract Background Gastrectomy results in a profound change in appetite, satiety and response to food. Most people will adapt and manage to maintain adequate enteral nutrition, however severe symptoms can hamper quality of life. Early dumping, defined as noxious symptoms occurring within an hour of food, arises due to a combination of vastly increased satiety gut hormone secretion and fluid shifts. Late dumping (reactive hypoglycaemia) occurs due to enhanced post-prandial incretin hormone secretion. We present a case of severe dumping in a patient with absent pituitary treated with the global counter-regulatory hormone octreotide. Methods A 71-year-old patient with absent pituitary underwent total gastrectomy and oesophago-jejunal anastomosis for a greater curve gastric adenocarcinoma. Post-operatively, the patient developed an overall aversion to eating along with significant nausea and vomiting, diarrhoea, abdominal fullness, and tachycardia. Anti-emetics including droperidol, metoclopramide, and haloperidol yielded limited response. NJ feeding also triggered symptoms and was stopped. Parenteral nutrition was the principal source of diet. A trial of a somatostatin analogue, octreotide, resulted in significant improvement of patient symptoms. A dose increase and then conversion to monthly lanreotide was tolerated well resulting in complete resolution of symptoms and no side effects. Results The pituitary gland and hypothalamus are central to regulating appetite and satiety through complex signalling pathways. Hormone signals, including GLP-1, GIP, PYY and ghrelin act on central circuits within the hypothalamus to modulate intake, gastric emptying, and satiety. With an absent pituitary, these hormonal signalling pathways including somatostatin are disrupted. Octreotide therapy likely works through a combination of central suppression of gut hormone signalling as well as peripheral reduction in gut hormone secretion. Conclusions Dumping syndrome is a multifactorial, quality of life limiting consequence of upper GI resection. In patients with altered central appetite control circuitry the symptoms may be so severe as to prevent any enteral intake, including via NJ tube. Interestingly, considering this an endocrinology problem and acting to suppress all hormonal signalling with octreotide had immediate and enduring success in the presented case. This may represent a route for management of patients with significant dumping symptoms and nutritional compromise after gastrectomy or oesophagectomy.

SAT661 Bypass-oma Or Medication-oma: A Clinical Dilemma About Hypoglycemia

Abstract Disclosure: C.A. Perez Hernandez: None. M.J. Pesantez Borja: None. Introduction With the ongoing worldwide obesity epidemic, the number of bariatric procedures rises every year. Although complications have decreased in the last 20 years, they can result in significant morbidity and mortality. Hypoglycemia is a complication that usually occurs 1-3 years after a Roux-en-Y gastric bypass, and is caused by increased postprandial incretin secretion. Although reported incidence is 0.1%, it is likely underdiagnosed and underestimated cause of hyper insulinemic hypoglycemia. Clinical Case A 33-year-old male with history of pancreatic cancer status post partial pancreatectomy and Roux-en-Y gastric bypass performed 10 years ago, and type 2 diabetes on insulin was admitted for severe persistent hypoglycemia refractory to treatment. He stopped using insulin 6 months ago after passing out while driving 1-2 hours postprandially. Only 2 hours after starting a 72-hour fasting test, the patient had a venous blood glucose of 39 mg/dl. Laboratory results showed: C-peptide:3.3, Insulin:9.3, cortisol:2.6, BHB: 0.5 and proinsulin:3.7; and negative sulfonylurea screening. Dotatate scan was unremarkable. He has started diazoxide, acarbose, octreotide and Everolimus with no improvement to his symptoms. Plan was to repeat the work up, however, the patient refused to cooperate. He also declined a Calcium stimulation test, endoscopic US and bariatric surgery reversal. Review of his imaging studies which, showed no signs of pancreatic surgery. When re-interrogated, medical history inconsistencies were noticed. Hypoglycemia episodes occurred exclusively after being transferred out of ICU, patient was placed in a one-to-one monitoring. During the night shift, he was found injecting himself an unknown medication via PICC line and several medications were found in his room. After being confronted by staff, the Patient left the AMA only to be readmitted the same day for hypoglycemia at another institution. Conclusion Our patient was diagnosed with Munchausen's syndrome, substance abuse and depressive disorder upon evaluation by psychiatry. It was found that 4 years prior to current admission, he completed a 72-hour fasting test in another hospital, without hypoglycemia episodes. However, due to concerns for insulinoma, his oncology team was contacted who reported never having seen the patient or diagnosing with pancreatic cancer. Also, patient was found self-injecting with an unknown medication, and when confronted, he left AMA just like he did while he was under our care. History of self-harm behavior and inconsistencies in medical history may call for atypical presentations of Post Bariatric Surgery hypoglycemia and should prompt a detailed anamnesis and psychiatric assessment. This case represents a clinical dilemma and illustrates the therapeutic challenges encountered with a patient diagnosed with post bariatric surgery hypoglycemia and Munchausen syndrome. Presentation: Saturday, June 17, 2023

Comparison of Hormonal Response to a Mixed-Meal Challenge in Hypoglycemia After Sleeve Gastrectomy vs Gastric Bypass.

Exaggerated postprandial incretin and insulin responses are well documented in postbariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). We sought to compare meal-stimulated hormonal response in those with PBH after SG vs RYGB. We enrolled 23 post-SG (12 with and 11 without PBH) and 20 post-RYGB (7 with and 13 without PBH) individuals who underwent bariatric surgery at our institution. PBH was defined as plasma glucose less than 60 mg/dL on 4-hour mixed-meal tolerance test (MTT). Islet and incretin hormones were compared across the 4 groups. Participants (N = 43) were on average 5 years post surgery, with a mean age of 48 years, mean preoperative body mass index of 48.4, 81% female, 61% White, and 53% post SG. Regardless of PBH, the SG group showed lower glucose, glucagon, and glucagon-like peptide 1 (GLP-1) responses to MTT and similar insulin and glucose-dependent insulinotropic polypeptide (GIP) responses compared to the RYGB group. Among those with PBH, the SG group following the MTT showed a lower peak glucose (P = .02), a similar peak insulin (90.3 mU/L vs 171mU/L; P = .18), lower glucagon (P < .01), early GLP-1 response (AUC0-60 min; P = .01), and slower time to peak GIP (P = .02) compared to PBH after RYGB. Among individuals with PBH, those who underwent SG were significantly different compared to RYGB in meal-stimulated hormonal responses, including lower glucagon and GLP-1 responses, but similar insulin and GIP responses. Future studies are needed to better understand the differential contribution of insulin and non-insulin-mediated mechanisms behind PBH after SG vs RYGB.

Loss of Intestine-Specific FFA3 Has Protective Effects Against Diet-Induced Obesity and Hyperglycemia in Mice on a Western Diet

Free fatty acid receptor 3 (FFA3) is a recently-deorphaned G protein-coupled receptor belonging to the free fatty acid receptor family. Its ligands are short-chain fatty acids (SCFAs), which are key nutrients that play a diverse role in physiological function, including the regulation of metabolic homeostasis and glycemic control. FFA3 is broadly expressed in a multitude of tissues including the intestine, pancreas, and central nervous system, and is thought to contribute to metabolic homeostasis via a summation of its tissue-specific effects. Consequently, FFA3 has been identified as a potential drug target for metabolic diseases including obesity and type-2 diabetes. FFA3 is highly expressed in enteroendocrine cells (EECs) within the intestinal epithelium - the major site of SCFA generation - and is hypothesized to play a role in the secretion of postprandial incretin hormones, which are a group of specialized gut peptides that regulate a variety of metabolic and digestive functions following a meal. However, due to a paucity of data, the role of FFA3 within the intestine and its effects on physiology and metabolism is largely unclear. Previous in vivo studies involving this receptor have largely relied on global knockout mouse models, making it difficult to isolate its effects in EECs. To overcome this challenge, we have generated a novel intestine-specific knockout mouse model for FFA3, utilizing Cre-mediated recombination under the expression of the villin promoter. Here, we report the first in vivo characterization of FFA3 in the intestine and reveal novel insights into receptor function. Following model validation, we conducted a general metabolic assessment of male Villin-Cre-FFA3 mice on normal chow and observed no major congenital or time-dependent defects. Because dietary changes are known to alter gut microbial composition, and thereby SCFA production, a pilot study was performed on male Villin-Cre-FFA3 mice and their littermate controls to probe for a phenotype on a high-fat, high-sugar “western diet.” Mice were placed on either normal chow (NC) or western diet (WD) at 10 weeks of age and metabolically profiled for 25 weeks. Our data reveals that Villin-Cre-FFA3 mice on WD, but not NC, were protected from diet-induced metabolic dysfunction, and displayed significantly lower levels of fat mass as well as modestly improved glycemic control. Our findings suggest a novel role of FFA3 in mediating the metabolic consequences of a western diet - a state of high inflammation, dysbiosis and metabolic stress. Moreover, these data support an intestine-specific role of FFA3 in both glucose and lipid metabolism, and further suggest the receptor’s role in whole-body metabolic homeostasis and in the development of adiposity and hyperglycemia.

GK-rats respond to gastric bypass surgery with improved glycemia despite unaffected insulin secretion and beta cell mass

Roux-en-Y gastric bypass (RYGB) is the most effective treatment for morbid obesity and results in rapid remission of type 2 diabetes (T2D), before significant weight loss occurs. The underlying mechanisms for T2D remission are not fully understood. To gain insight into these mechanisms we used RYGB-operated diabetic GK-rats and Wistar control rats. Twelve adult male Wistar- and twelve adult male GK-rats were subjected to RYGB- or sham-operation. Oral glucose tolerance tests (OGTT) were performed six weeks after surgery. RYGB normalized fasting glucose levels in GK-rats, without affecting fasting insulin levels. In both rat strains, RYGB caused increased postprandial responses in glucose, GLP-1, and GIP. RYGB caused elevated postprandial insulin secretion in Wistar-rats, but had no effect on insulin secretion in GK-rats. In agreement with this, RYGB improved HOMA-IR in GK-rats, but had no effect on HOMA-β. RYGB-operated GK-rats had an increased number of GIP receptor and GLP-1 receptor immunoreactive islet cells, but RYGB had no major effect on beta or alpha cell mass. Furthermore, in RYGB-operated GK-rats, increased Slc5a1, Pck2 and Pfkfb1 and reduced Fasn hepatic mRNA expression was observed. In summary, our data shows that RYGB induces T2D remission and enhanced postprandial incretin hormone secretion in GK-rats, without affecting insulin secretion or beta cell mass. Thus our data question the dogmatic view of how T2D remission is achieved and instead point at improved insulin sensitivity as the main mechanism of remission.

376-P: Analysis of the Fasting and Postprandial Plasma Metabolome Reveals Metabolic Signatures of Postbariatric Hypoglycemia

One severe complication of gastrointestinal and bariatric surgery is post-bariatric hypoglycemia (PBH). Affected patients may develop severe hypoglycemia, typically 1-3 hours after meals. While exaggerated postprandial incretin hormone and insulin secretion has been implicated, additional contributors to hypoglycemia remain uncertain. We performed untargeted semiquantitative metabolomic analysis of plasma samples collected in the fasting state and at 30 and 120 minutes after a liquid mixed meal (Ensure) in 13 individuals with PBH post-RYGB, 10 asymptomatic post-RYGB, and 8 overweight/obese individuals without history of gastrointestinal surgery. Multiple analytes were reduced in the fasting state in PBH, including 10 amino acids (Leu, Ile, Val, Ala, Phe, Tyr, Met, Trp, Thr, Asn, nominal p&amp;lt;0.05 vs. asymptomatic, FC -1.2 to -1.4), multiple lipid species (C22:6 LPC, C22:6 LPE, C20:4 LPE, C56:7 TAG, C54:5 TAG, C50:5 TAG, p&amp;lt;0.05 vs. asymptomatic,FC -1.3 to -1.5). We also observed robust reduction (2-10 fold, p&amp;lt;0.05) in multiple tryptophan pathway metabolites, including kynurenic acid, xanthurenate, and serotonin. Markers of insulin resistance and T2D risk, such as 2-aminoadipate and alpha-hydroxybutyrate, and multiple B complex vitamins (B3, B5, B6) were also decreased in PBH in the fasting state. By contrast, tricarboxylic acid (TCA) cycle intermediates such as aconitate, isocitrate, succinate and malate and the ketone beta-hydroxybutyrate were all increased in PBH (p&amp;lt;0.05). In summary, we identify several metabolic signatures of PBH including reduction in multiple circulating AA, lipid species, and tryptophan intermediates as well as increased TCA cycle intermediates. Together these could potentially contribute to alterations in glucose metabolic flux in both the fasting and postprandial state in individuals with PBH. Disclosure R. Ferraz-Bannitz: None. C.M. Mulla: None. J. Dreyfuss: None. H. Pan: None. M. Patti: Consultant; Self; Fractyl Laboratories, Inc. Research Support; Self; Dexcom, Inc., Xeris Pharmaceuticals, Inc. Other Relationship; Self; Academy of Nutrition and Dietetics, American Diabetes Association, American Society of Metabolic and Bariatric Surgery, Endocrine Society, Insulet Corporation, King Abdullah International Medical Research Center, SUNY Downstate. Funding National Institutes of Health (R01DK121995, P30DK046200)

755-P: A Plant-Based Meal Stimulates Incretin and Insulin Secretion More than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study

Objective: We tested the effects of two energy- and macronutrient-matched meals: a standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with type 2 diabetes (T2D). Research Design and Methods: A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide -1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120 and 180 minutes. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Results: Postprandial plasma glucose responses were similar after both test meals (p=0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p&amp;lt;0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p&amp;lt;0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p&amp;lt;0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p&amp;lt;0.001) and a decrease in GIP (by -9.4%; 95% CI -17.3 to -0.7%; p=0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Conclusions: Our results indicate an increase in postprandial incretin and insulin secretion, following consumption of a single vegan meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D. Disclosure H. Kahleova: None. A. Tura: None. M. Klementova: None. L. Belinova: None. M. Haluzik: None. R. Pavlovicova: None. M. Hill: None. T. Pelikanova: None. Funding Ministry of Health of the Czech Republic (AZV15-27338A); Institute for Clinical and Experimental Medicine (MZCR00023001)

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

389-P: Comparison of Hormonal Response to a Mixed-Meal Challenge in Individuals with Hypoglycemia after Sleeve Gastrectomy vs. Gastric Bypass

Objective: Exaggerated post-prandial incretin and insulin responses are well-documented in post-bariatric surgery hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). However, less is known about PBH after sleeve gastrectomy (SG). Thus, we sought to compare meal-stimulated hormonal response in those with PBH after SG vs. RYGB. Methods: We enrolled 20 RYGB (7 with and 13 without PBH) and 23 SG (12 with and 11 without PBH) who underwent bariatric surgery at our institution. PBH was defined as a postprandial interstitial or plasma glucose &amp;lt;55 mg/dl on continuous glucose monitor (5-days as outpatient, Dexcom) or 4-hour mixed meal tolerance test (MTT). Plasma samples from MTT were used to measure glucose, insulin, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). We used Kruskal Wallis Test to compare the difference in glucose or hormones across 4 groups (with and without PBH after SG or RYGB). Results: Participants (N=43) were on average 5 years since surgery, with mean age of 50 years, mean preoperative BMI of 48 kg/m2, 81% female, 61% Caucasian, 53% post SG. There were no differences in fasting glucose (p=0.38) or fasting insulin (p=0.34) across the 4 groups. Among those with PBH, the SG group showed a lower peak glucose (131.8 mg/dl, p&amp;lt;0.01), similar nadir glucose (59.6 mg/dl, p=0.18), peak insulin (68.7 mU/L, p&amp;lt;0.01) and peak GLP-1 (15.3 pM, p&amp;lt;0.01) and differed in overall hormonal response (AUC 0-240min) with lower insulin (3956.1 mU/L/min, p&amp;lt;0.01), lower GLP-1 (2498.9 pM/min, p&amp;lt;0.01) and higher GIP (51335.4 pM/min, p=0.05) compared to RYGB with PBH group. Conclusion: Among those with PBH, the SG group showed less glycemic excursion and different hormonal profiles including lower insulin, GLP-1 and higher GIP responses to MTT compared to the RYGB group. Future studies are needed to better understand the differential contribution of insulin and non-insulin mediated mechanisms behind PBH after SG vs. RYGB. Disclosure C. Lee: Consultant; Self; XOMA Corporation. Research Support; Self; Eiger BioPharmaceuticals. T. Brown: None. M. Schweitzer: Consultant; Self; Ethicon, Inc. T. Magnuson: None. J. Clark: None. Funding National Institutes of Health

A Plant-Based Meal Stimulates Incretin and Insulin Secretion More Than an Energy- and Macronutrient-Matched Standard Meal in Type 2 Diabetes: A Randomized Crossover Study.

Diminished postprandial secretion of incretins and insulin represents one of the key pathophysiological mechanisms behind type 2 diabetes (T2D). We tested the effects of two energy- and macronutrient-matched meals: A standard meat (M-meal) and a vegan (V-meal) on postprandial incretin and insulin secretion in participants with T2D. A randomized crossover design was used in 20 participants with T2D. Plasma concentrations of glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), amylin, and gastric inhibitory peptide (GIP) were determined at 0, 30, 60, 120, and 180 min. Beta-cell function was assessed with a mathematical model, using C-peptide deconvolution. Repeated-measures ANOVA was used for statistical analysis. Postprandial plasma glucose responses were similar after both test meals (p = 0.64). An increase in the stimulated secretion of insulin (by 30.5%; 95% CI 21.2 to 40.7%; p < 0.001), C-peptide (by 7.1%; 95% CI 4.1 to 9.9%; p < 0.001), and amylin (by 15.7%; 95% CI 11.8 to 19.7%; p < 0.001) was observed following consumption of the V-meal. An increase in stimulated secretion of GLP-1 (by 19.2%; 95% CI 12.4 to 26.7%; p < 0.001) and a decrease in GIP (by −9.4%; 95% CI −17.3 to −0.7%; p = 0.02) were observed after the V-meal. Several parameters of beta-cell function increased after the V-meal, particularly insulin secretion at a fixed glucose value 5 mmol/L, rate sensitivity, and the potentiation factor. Our results showed an increase in postprandial incretin and insulin secretion, after consumption of a V-meal, suggesting a therapeutic potential of plant-based meals for improving beta-cell function in T2D.

Impaired Beta-Cell Compensation and Glucose Effectiveness in Insulin Resistant, Nondiabetic South Asians

South Asians (SA) are insulin-resistant (IR) and are at increased risk for developing type 2 diabetes mellitus (T2DM) when compared with Caucasians (CA). However, the changes in pancreatic β-cell responsivity, glucose effectiveness (Sg), and insulin clearance in SA are not well characterized. Healthy SA (n=30) and CA (n=30) matched for age, sex, and BMI and with no history of T2DM were evaluated in the Clinical Center. A frequently sampled intravenous glucose tolerance test (FSIVGTT) and a mixed meal test (MMT) were used for minimal modeling (MM). Insulin sensitivity, beta-cell function, and glucose effectiveness were calculated. Tissue-specific surrogate indices of insulin sensitivity and post-prandial incretin levels were also measured. SA were less insulin-sensitive (SI: 3.30±2.72 vs. 7.31±4.89, minutes-1/µU/mL, p&amp;lt;0.001; Matsuda index: 4.34±3.69 vs. 13.26±7.17, p&amp;lt;0.05). Tissue specific IR surrogate indices (hepatic IR index and adipocyte IR index) were higher and muscle insulin sensitivity index was lower in SA. Sg derived from an FSIVGTT was lower in SA (0.025 ± 0.033 vs. 0.012 ± 0.006, minutes-1, p&amp;lt;0.001). Beta-cell responsivity indices estimated by the C-peptide MM [phi (dynamic), phi (static), and phi (total)] were not different between the groups, but the disposition indices were significantly lower in SA. Post-prandial GIP but not GLP-1 levels were higher in SA than in CA. Insulin clearance at baseline and following MMT was also significantly lower in SA. Thus, when compared with age-, sex-, and BMI-matched CA, SA exhibit reduced overall insulin sensitivity in the muscle, liver, and adipose tissue. Despite similar β-cell responsivity to glucose, the disposition indices in SA were lower, suggesting diminished beta-cell compensation. In addition to defects in insulin-mediated glucose disposal and impaired beta-cell compensation, normoglycemic SA have reduced glucose effectiveness. These results suggest different approaches to prevent and treat T2DM in SA. Disclosure

Evolution of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are a class of antidiabetic drugs developed over the past 15 years. GLP-1, a gastrointestinal peptide hormone that contributes to the postprandial incretin effect, stimulates glucose-dependent insulin secretion. The incretin effect is greatly diminished in type 2 diabetes, but can be restored by GLP-1RAs. These drugs also exert other GLP-1 effects, including reducing glucagon secretion, delaying gastric emptying, reducing food intake, improving cardiac ventricular function, and lowering blood pressure. Short-acting GLP-1RAs are administered once daily (lixisenatide) or twice daily (exenatide); long-acting GLP 1RAs are administered once daily (liraglutide) or once weekly (slow-release exenatide, dulaglutide, albiglutide). All GLP-1RAs significantly reduce glycated hemoglobin (HbA1c) in patients with type 2 diabetes whose glycemic control is inadequate with oral antidiabetic drugs. Compared with other antidiabetic medications, GLP-1RAs provide better glycemic control with the additional benefit of weight loss. Within this class, long-acting GLP-1RAs are more efficacious than short-acting GLP-1RAs, with similar or lower risk of hypoglycemia and lower incidence of gastrointestinal adverse effects. Head-to-head trials and a network meta-analysis suggest that once daily liraglutide is the most effective GLP-1RA in reducing HbA1c. Dulaglutide is the only once-weekly GLP 1RA demonstrated to be noninferior to liraglutide. The once-weekly GLP-1RAs offer additional advantages to patients, including fewer injections and easy-to-use, single-dose pen devices. Despite the relatively recent development of GLP-1RAs, international diabetes guidelines recognize the benefits of this class of drugs and recommend them as a treatment option for patients with type 2 diabetes.

Effects of a high-fat meal on postprandial incretin responses, appetite scores and ad libitum energy intake in women with obesity.

Considering the possible role of triglycerides (TG), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the regulation of appetite, this study aimed to compare high fat meal-induced response of GIP and GLP-1, appetite scores and ad libitum energy intake in women with obesity, according to postprandial increment in triglyceridemia (∆TG). Methods: Thirty-three no-diabetic women (BMI = 35.0 ± 3.2 kg.m-2) were divided into two groups: Group with ∆TG ≤ median were called "Low TG change -LTG" and ∆TG > median, "High TG change - HTG". Plasma concentrations of GIP, GLP-1 and appetite sensations were measured prior to, and every 30 min for 180 min after ingestion of a high-fat breakfast. An ad libitum lunch was served 3 h after the test meal. The AUC incrementalGIP were significant lower in HTG vs. LTG group (p = 0.03). The same was observed for GIP levels at 150 min (p = 0.03) and at 180 min (p < 0.01). Satiety was lower in HTG at 120 min (p = 0.03) and 150 min (p < 0.01). The AUC totalGLP1 were similar between groups and there were no between-group differences for the GLP-1 at each time point. Ad libitum food intake were also similar between groups. The HTG group exhibited differences in satiety scores and lower postprandial secretion of GIP, however with no impact on ad libitum food intake in short term.

Inter-regulation of gastric emptying and incretin hormone secretion: implications for postprandial glycemic control.

The GI tract is central to the regulation of postprandial glycemia, with the rate of gastric emptying and the secretion of the incretin hormones, glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1, being key determinants. Gastric emptying exhibits a large interindividual variation; the latter not only accounts for differences in postprandial glycemia but also determines postprandial incretin profiles. Accordingly, the rate of gastric emptying may affect the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors. In contrast, glucagon-like peptide-1 receptor agonists lower postprandial glycemia predominantly by their action to slow gastric emptying. This review discusses the inter-relationship between gastric emptying and the incretin axis in the context of changes in blood glucose, with an emphasis on the relevant clinical implications.

Soya milk exerts different effects on plasma amino acid responses and incretin hormone secretion compared with cows’ milk in healthy, young men

Apart from the well-known action of insulin, the mechanism by which soya and cows' milk improve postprandial glycaemia control was examined. In total, twelve healthy, young, Chinese men were studied on three separate occasions, in random order with isovolumetric (322 ml) control water, soya milk and cows' milk. Plasma total amino acid concentrations increased 30 min after test meals consumption and were higher after soya milk (230 %) and cow milk (240 %) consumption compared with water. Cows' milk ingestion induced higher branched-chain amino acids (BCAA) (40 %) than soya milk. Postprandial incretin concentrations increased after meal consumption. Cows' milk meal was accompanied by higher incremental AUC (iAUC) (170 %) for glucagon-like peptide-1 (GLP-1) compared with soya milk and control (P=0·06). However, glucose-dependent insulinotropic polypeptide (GIP) concentrations increased to significantly greater levels after soya milk consumption (iAUC 60 % higher) compared with cows' milk and control. Consumption of both soya and cows' milk with carbohydrates induced a similar reduction in glycaemic response through a different mechanism, beyond insulin action. Plasma amino acids (alanine and arginine), and incretins in particular (GIP was stimulated), may be involved in the hyperinsulinaemia after soya milk meals. However, BCAA and GLP-1 release may be responsible for the reduced glycaemia after cows' milk consumption by delaying gastric emptying. This could be the result of different milk protein/amino acid composition, but also differences in milk carbohydrate composition (i.e. lactose v. sucrose). It can be concluded that soya milk is a good alternative to cows' milk with regard to glycaemic regulation, with different mechanisms involved.

DPP-4 Inhibitors and Heart Failure: Some Reassurance, Some Uncertainty.

The American Diabetes Association’s Standards of Medical Care in Diabetes—2016 recommends the use of dipeptidyl peptidase 4 (DPP-4) inhibitors in combination with metformin as a second- or third-line treatment for type 2 diabetes (1). Owing to their relatively high costs, many jurisdictions restrict their use to patients whose glycemia remains poorly controlled on metformin–sulfonylurea combination therapy. By inhibiting DPP-4 activity, these agents increase postprandial incretin concentrations, thereby increasing insulin secretion and decreasing glucagon secretion (1). With intermediate efficacy, a low risk of hypoglycemia, neutral effects on body weight, and relatively rare adverse effects (1), their use has increased considerably since their 2006 entry into the U.S. market (2). Nevertheless, concerns remain regarding their potential association with serious adverse effects including acute pancreatitis (3), pancreatic cancer (3), and heart failure (HF) (4). The potential increased risk of HF with DPP-4 inhibitors was reported in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, which randomized 16,492 patients with type 2 diabetes and either a history of cardiovascular disease (CVD) or multiple CVD risk factors to saxagliptin (Onglyza) or placebo (5) (Table 1). Patients randomly assigned to saxagliptin unexpectedly had a significantly higher risk of hospitalization for HF (hazard ratio [HR] 1.27 [95% CI 1.07–1.51]), a prespecified component of the secondary composite end point. This increased risk was clustered in the first year of follow-up (HR 1.46 [95% CI 1.15–1.88]) with no increase thereafter (6). View this table: Table 1 Data from randomized placebo-controlled trials of DPP-4 inhibitors and the risk of HF The increased HF risk in SAVOR-TIMI 53 was not observed in subsequent trials (Table 1). In the Examination …

Effects of meal composition on postprandial incretin, glucose and insulin responses after surgical and medical weight loss.

SummaryBackgroundMeal tolerance tests are frequently used to study dynamic incretin and insulin responses in the postprandial state; however, the optimal meal that is best tolerated and suited for hormonal response following surgical and medical weight loss has yet to be determined.ObjectiveTo evaluate the tolerability and effectiveness of different test meals in inducing detectable changes in markers of glucose metabolism in individuals who have undergone a weight loss intervention.MethodsSix individuals who underwent surgical or medical weight loss (two Roux‐en‐Y gastric bypass, two sleeve gastrectomy and two medical weight loss) each completed three meal tolerance tests using liquid‐mixed, solid‐mixed and high‐fat test meals. The tolerability of each test meal, as determined by the total amount consumed and palatability, as well as fasting and meal‐stimulated glucagon‐like peptide, glucose‐dependent insulinotropic polypeptide, insulin and glucose were measured.ResultsAmong the six individuals, the liquid‐mixed meal was better and more uniformly tolerated with a median meal completion rate of 99%. Among the four bariatric surgical patients, liquid‐mixed meal stimulated on average a higher glucagon‐like peptide (percent difference: 83.7, 89), insulin secretion (percent difference: 155.1, 158.7) and glucose‐dependent insulinotropic polypeptide (percent difference: 113.5, 34.3) compared with solid‐mixed and high‐fat meals.ConclusionsThe liquid‐mixed meal was better tolerated with higher incretin and insulin response compared with the high‐fat and solid‐mixed meals and is best suited for the evaluation of stimulated glucose homeostasis.

Gastrointestinal traits: individualizing therapy for obesity with drugs and devices

The aims of this article were to review the discrepancy between numbers of people requiring weight loss treatment and results and to assess the potential effects of pharmacologic treatments (recently approved for obesity) and endoscopically deployed devices on quantitative GI traits in development for obesity treatment. We conducted a review of relevant literature to achieve our objectives. The 2013 guidelines increased the number of adults recommended for weight loss treatment by 20.9%(116.0 million to 140.2 million). There is an imbalance between efficacy and costs of commercial weight loss programs and drug therapy (average weight loss about 5 kg). The number of bariatric procedures performed in the United States has doubled in the past decade. The efficacy of bariatric surgery is attributed to reduction in the volume of the stomach, nutrient malabsorption with some types of surgery, increased postprandial incretin responses, and activation of farnesoid X receptor mechanisms. These GI and behavioral traits identify sub-phenotypes of obesity, based on recent research. The mechanisms or traits targeted by drug and device treatments include centrally mediated alterations of appetite or satiation, diversion of nutrients, and alteration of stomach capacity, gastric emptying, or incretin hormones. Future treatment may be individualized based on quantitative GI and behavioral traits measured in obese patients.

Comparative effect of intraduodenal and intrajejunal glucose infusion on the gut-incretin axis response in healthy males.

The region of enteral nutrient exposure may be an important determinant of postprandial incretin hormone secretion and blood glucose homoeostasis. We compared responses of plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin and glucagon, and blood glucose to a standardised glucose infusion into the proximal jejunum and duodenum in healthy humans. Ten healthy males were evaluated during a standardised glucose infusion (2 kcal min−1 over 120 min) into the proximal jejunum (50 cm post pylorus) and were compared with another 10 healthy males matched for ethnicity, age and body mass index who received an identical glucose infusion into the duodenum (12 cm post pylorus). Blood was sampled frequently for measurements of blood glucose and plasma hormones. Plasma GLP-1, GIP and insulin responses, as well as the insulin:glucose ratio and the insulinogenic index 1 (IGI1) were greater (P<0.05 for each) after intrajejunal (i.j.) than intraduodenal glucose infusion, without a significant difference in blood glucose or plasma glucagon. Pooled analyses revealed direct relationships between IGI1 and the responses of GLP-1 and GIP (r=0.48 and 0.56, respectively, P<0.05 each), and between glucagon and GLP-1 (r=0.70, P<0.001). In conclusion, i.j. glucose elicits greater incretin hormone and insulin secretion than intraduodenal glucose in healthy humans, suggesting regional specificity of the gut–incretin axis.