Incretin Response Research Articles

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of β- and α-cell function. Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or β-cell sensitivity to glucose, including for second-phase insulin response, were found. In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.

Foregut Exclusion Enhances Incretin and Insulin Secretion After Roux-en-Y Gastric Bypass in Adults With Type 2 Diabetes.

Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain limited due to the challenges of metabolic evaluation during the early postoperative period. The purpose of this investigation was to determine the role of foregut exclusion in the resolution of type 2 diabetes after RYGB. Patients with type 2 diabetes (n = 15) undergoing RYGB had a gastrostomy tube (G-tube) placed in their gastric remnant at time of surgery. Patients were randomized to receive a mixed meal tolerance test via oral or G-tube feeding immediately prior to and 2 weeks after surgery in a repeated measures crossover design. Plasma glucose, insulin, C-peptide, incretin responses, and indices of meal-stimulated insulin secretion and sensitivity were determined. Body weight, fat mass, fasting glucose and insulin, and circulating lipids were significantly decreased 2 weeks after surgery. The glycemic response to feeding was reduced as a function of total area under the curve but not after adjustment for the reduction in fasting glucose. Oral feeding significantly enhanced insulin and incretin secretion after RYGB, which was entirely ablated by G-tube feeding. Foregut exclusion accounts for the rise in incretin and insulin secretion but may not fully explain the early improvements in glucose metabolism after RYGB surgery.

Normal Versus Slowly Processed Pasta and Post-Prandial Glucose Homeostasis in Healthy Subjects: A Pilot Study.

Nutritional science is gaining increasing attention due to the implicit potential to prevent cardio-metabolic diseases. It is also becoming clear that food-making process might influence the metabolic response to the meal. We have conducted a proof-of-concept study to investigate whether slowly processed pasta might positively impact glucose homeostasis. A total of 14 healthy male volunteers underwent two different mixed-meal tests in a randomized order. One meal was composed of 100 g of normally processed pasta and the other 100 g of slowly processed pasta. Each meal was completed with 10 g of olive oil and 10 g of parmesan cheese. Glucose, insulin, and incretin post-prandial responses were assessed at 15, 30, 60, 90, 120, 150, and 180 min. Glucose tolerance, insulin, and incretin response were unaffected by the two different pasta types. However, a slight difference was evident in the shape of the curve of post-prandial insulin (i.e., mildly delayed with the slowly processed pasta). Despite the common belief of a different impact of normally processed and slowly processed pasta on glucose metabolism, they show a superimposable post-prandial metabolic response after a single meal in male healthy individuals. Further studies are required to confirm these results also in chronic, real-life settings and then to translate them to metabolically impaired individuals.

Postprandial Glucose, Insulin, and Glucagon-Like Peptide-1 Responses in Healthy Adults after Consumption of Chocolate-Products.

Chocolate may affect the glycemic response, which is related the insulin and incretin response. We evaluated the glucose, insulin, and glucagon-like peptide-1 (GLP-1) responses in male adults after consumption of three commonly consumed chocolates. Furthermore, we assessed the glycemic index (GI), insulin index (II), and glycemic load (GL) of the chocolates. The study protocol was adapted from the International Standard Organization recommendations. Test foods were chocolate A (milky chocolate), chocolate B (creamy chocolate), chocolate C (chocolate ball), and reference food (glucose solution). Glucose, insulin, and GLP-1 concentrations were assessed at 0, 15, 30, 45, 60, 90, and 120 min after consumption of the test foods. The glycemic responses of the three chocolates were lower than those of the reference food at 30 and 45 min (P<0.001). However, the insulin and GLP-1 responses did not differ between the three chocolates and the reference food. The GI value of chocolates A, B, and C were 39.2, 47.8, and 33.7, respectively; all GI values were lower than that of the reference food. The II values of all test foods were similar, aside for chocolate B (97.9). All chocolates were classified as low-GL. This study showed that glycemic responses depends on the amount of carbohydrates and the physical properties. Further research is required to examine incretin responses and to determine if the type of chocolate can influence metabolic response beyond glycemia.

Metabolic and Gut Microbiota Responses to Sourdough Pasta Consumption in Overweight and Obese Adults.

Increasing consumer interest in fermented products has driven the emergence of a number of novel foods including shelf-stable sourdough pasta. This study comprehensively examined the impact of fermentation on the microbial composition of the culture, pasta, its subsequent effects on glycemic responses and gut microbiota in overweight men and women (>25 kg/m2) compared to a conventional, non-fermented pasta. Two, randomized crossover trials were performed. Study A examined acute feeding responses to each product wherein fasted participants completed a meal tolerance test comprised of 75 g of conventional or sourdough pasta to examine glycemic responses. Results showed enhanced gastric emptying with sourdough, but no difference in overall blood glucose, insulin or satiety hormone responses between the treatments. Study B consisted of three standard oral glucose tolerance tests as well as fecal collection for sequencing at baseline and following each pasta intervention (150 g or 2 serving/d for 5 days) followed by a 2-week washout period. Results showed no differential impact of either pasta treatment on glucose tolerance. Analysis of fecal bacterial and fungal (mycobiome) microbiota showed no change at the individual species or genus levels. However, fungi were adaptive following chronic pasta consumption with decreases in alpha diversity of fungi following sourdough, but not conventional pasta. This was accompanied by reductions in total fecal short chain fatty acid concentrations. In conclusion, sourdough fermentation did not change the overall glycemic properties of the pasta, incretin responses or bacterial gut microbiota, but appears to impact microbiome fungal community structure with chronic consumption.

Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease.

BackgroundIndividuals with Alzheimer’s Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear.MethodsHere, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging.ResultsThe meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions.ConclusionOur findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.

Effect of reversal of the whey protein to casein ratio of cow milk, on insulin and incretin responses in humans

Rationale: Milk proteins have recognised functional properties on insulin and incretin secretion. In head-to-head comparisons, whey proteins (WP) are more efficient than casein (Cas) in hormone stimulation. Nevertheless, milk is a unique milieu, where interaction among proteins may modify their functional effects, and should not be excluded when comparing WP and Cas.

Normal insulin sensitivity, glucose tolerance, gut incretin and pancreatic hormone responses in adults with atopic dermatitis

To examine whether adults with mild to moderate atopic dermatitis (AD) had reduced insulin sensitivity and/or exhibited other gluco-metabolic disturbances compared with carefully matched healthy controls. Sixteen adult, non-obese, non-diabetic patients with mild to moderate AD and 16 gender-, age- and body mass index (BMI)-matched healthy controls underwent a hyperinsulinaemic euglycaemic clamp (insulin infusion rate: 40 mU/m2 /minute) and an oral glucose tolerance test (OGTT) with frequent blood sampling for gut and pancreatic hormones. The two groups were similar in age (33 ± 3 vs. 33 ± 3 years, mean ± standard error of the mean [SEM]), gender (56% women), BMI (24.5 ± 0.7 vs. 24.4 ± 0.7 kg/m2 ), physical activity level, fasting plasma glucose and HbA1c. Patients with AD had a mean Eczema Area and Severity Index score of 8.5 ± 1.0 (moderate disease) and a mean AD duration of 28 ± 3 years. During the OGTT, circulating glucose, insulin, C-peptide, glucagon and glucose-dependent insulinotropic polypeptide, respectively, were similar in the two groups, except glucagon-like peptide-1, which was higher in patients with AD. The clamp showed no differences in insulin sensitivity between groups (M-value 9.2 ± 0.6 vs. 9.8 ± 0.8, P = .541, 95% CI -1.51; 2.60), or circulating insulin, C-peptide and glucagon levels. Using OGTT and the hyperinsulinaemic euglycaemic clamp technique, we found no difference in insulin sensitivity or other gluco-metabolic characteristics between patients with mild to moderate AD and matched healthy controls, suggesting that the inflammatory skin disease AD has little or no influence on glucose metabolism.

The Metabolic Effects of Pre-probiotic Supplementation After Roux-en-Y Gastric Bypass (RYGB) Surgery: a Prospective, Randomized Controlled Study.

Following Roux-en-Y gastric bypass (RYGB), positive alterations are observed in gut microbiota and intestinal peptides. Previous studies demonstrated similar alterations observed in cases when pre-probiotics are used without surgery. The aim of this trial was to evaluate the effectiveness of early use of pre-probiotics after RYGB. The operation and follow-up of the patients were performed at Istanbul University Medical Faculty. Thirty-two patients who had undergone RYGB were randomized to pre-probiotic group (PreProBG, n = 16; 200g/day yogurt plus 10g/day inulin+oligofructose) and probiotic group (ProBG, n = 16; 200g/day yogurt only) for 6months. Blood samples (glucose, insulin, A1c, GLP-1, PYY), anthropometric measurements, and appetite ratings have been evaluated at baseline and 3 (m3) and 6 (m6) months after RYGB. Initial anthropometric measurements and appetite ratings decreased significantly after surgery and there were no significant differences between the groups. The decrease of area under the curve(insulin) was less and has a positive correlation with the changes in anthropometric measurements in PreProBG. GLP-1 and PYY which increased dramatically after surgery in all patients were higher in PreProBG. But this increase had a negative correlation with the changes in anthropometric measurements during the study. Increased insulin, GLP-1, and PYY secretion was more enhanced by pre-probiotic use in early postoperative period. But this increase not only in anthropometric measurements but also in appetite ratings affects negatively, contrary to expectations. In summary, it should be investigated with new studies that use of pre-probiotics in the late postoperative period may be more effective in patients with weak insulin and incretin response and therefore insufficient weight loss. Trial Registration clinicaltrials.gov Identifier: NCT03517345.

A Reduced Incretin Effect Mediated by the rs7903146 Variant in the TCF7L2 Gene Is an Early Marker of β-Cell Dysfunction in Obese Youth.

The risk genotype for the common variant rs7903146 of the transcription factor 7-like-2 (TCF7L2) gene has been found to affect the incretin response in healthy and obese adults; however, whether a similar functional defect is also present in obese adolescents remains unexplored. Herein, we examined the functional effect of the rs7903146 variant in the TCF7L2 gene on the incretin effect and determined its translational metabolic manifestation by performing deep phenotyping of the incretin system, β-cell function relative to insulin sensitivity, the gastrointestinal-induced glucose disposal (GIGD) in obese youth with normal and impaired glucose tolerance. Thirty-nine obese adolescents without diabetes (median age 15 [25th, 75th percentile 14, 18] years; BMI 37 [33, 43] kg/m2) were genotyped for the rs7903146 variant of TCF7L2 and underwent a 3-h oral glucose tolerance test (OGTT) followed by an isoglycemic intravenous glucose infusion (iso-intravenous glucose tolerance test [IVGTT]) to match the plasma glucose concentrations during the OGTT and a hyperglycemic clamp with arginine stimulation. The incretin effect was measured as 100 * (AUC-SROGTT - AUC-SRiso-IVGTT) / AUC-SROGTT, where AUC-SR = area under the curve of C-peptide secretion rate. Participants were grouped into tertiles according to the percentage incretin effect (high, moderate, and low) to describe their metabolic phenotype. The presence of T risk allele for TCF7L2 was associated with a markedly reduced incretin effect compared with the wild-type genotype (0.3% [-7.2, 14] vs. 37.8% [12.5, 52.4], P < 0.002). When the cohort was stratified by incretin effect, the high, moderate, and low incretin effect groups did not differ with respect to anthropometric features, while the low incretin effect group exhibited higher 1-h glucose (P = 0.015) and a reduced disposition index, insulin sensitivity, and insulin clearance compared with the high incretin effect group. GIGD was reduced in the low incretin effect group (P = 0.001). The three groups did not differ with respect to intravenous glucose-induced insulin secretion and arginine response during the hyperglycemic clamp. A reduced incretin effect and its association with the TCF7L2 variant rs7903146 identify an early metabolic phenotype in obese youth without diabetes, featuring a higher plasma glucose peak at 1 h; lower insulin secretion, sensitivity, and clearance; and GIGD.

Sleep apnea in men is associated with altered lipid metabolism, glucose tolerance, insulin sensitivity, and body fat percentage

PurposeObstructive sleep apnea (OSA) is associated with obesity and risk for type 2 diabetes. In this community-based study, we thoroughly investigated fatty acid metabolism, incretin response, glucose tolerance, insulin secretion and insulin sensitivity, and autonomic nerve activity in men with or without OSA.MethodsFifteen men without diabetes but with signs of severe OSA, defined as apnea–hypopnea index (AHI) >30, and 15 age- and BMI-matched men without OSA (AHI < 5) were recruited from a community-based cohort. Assessments included clinical and anthropometric measurements, a 2-h oral glucose tolerance test (OGTT), and autonomic nerve activity using heart rate variability (HRV).ResultsMen with OSA had higher body fat % than BMI-matched men without OSA (p = 0.046) and it was associated with markers of insulin resistance. The area under the curve for nonesterified fatty acids (NEFA) during OGTT was higher in men with OSA (p = 0.021) and fasting NEFA levels were numerically higher (p = 0.097). The plasma glucose at fasting and during OGTT was higher in men with OSA (p < 0.001). Incretin response was similar between groups. Fasting and OGTT-derived indices indicated impaired insulin sensitivity in men with OSA. Compared with men without OSA, Matsuda index (p = 0.068) and Gutt index (p < 0.01) were lower in men with OSA. The HRV measures did not differ between groups.ConclusionsOur study suggests that fatty acid handling, glucose tolerance, and insulin sensitivity are impaired in men with severe OSA. This might partly be explained by the increased body fat percentage.

The insulinotropic and incretin response to feeding a milk based protein matrix in healthy young women

Abstract Independent of glucose, ingestion of protein evokes an insulinotropic response due to enterogastric incretin hormones and hyperaminoacidemia. The aim of this study was to characterise insulin and incretin secretion in healthy young women (age 22.0 ± 1.2 y, n = 8) following acute ingestion of a milk based protein matrix (MPM) containing casein, whey protein and whey protein hydrolysates with in vitro dipeptidyl peptidase IV (DPP-IV) inhibitory activity. Following ingestion of 0.33 g protein/kg body mass, plasma insulin, glucose, glucagon, total glucose-dependent insulinotropic polypeptide (GIP), active glucagon-like peptide-1 (GLP-1), DPP-IV activity and amino acids were measured over a 3 h period. These biomarkers were also determined following ingestion of an isocaloric maltodextrin drink (MALT) in order to estimate the equivalent glucose-dependent response. Ingestion of MPM evoked ~50% of the insulin response obtained with MALT without hyperglycaemia. Time-dependent changes in plasma GIP, GLP-1 and amino acid levels indicated these factors were probably regulators of insulin secretion on MPM ingestion.

1324-P: GLP-1 Hypersecretion in Gestational Diabetes

Background and Aims: Incretins are crucial for an adequate insulin secretion in response to ingestions of nutrients. In patients with diabetes, prediabetes or a specific genetic background, this incretin effect is blunted. Data on incretin secretion and action during pregnancy are scarce. Here we investigated the incretin response during an oral glucose tolerance test (OGTT) in pregnant women with and without gestational diabetes. Methods: Pregnant women from the ongoing PREG study underwent 5-point OGTT with 75 g glucose. We measured plasma glucose, insulin and C-peptide at all time points and total GLP-1 at minute 0, 30 and 120. Indices of insulin secretion and GLP-1 increase were calculated from the difference at min 0 and 30. We used linear regression to analyze the relation of GLP-1 and glucose with insulin secretion. Results: We examined 163 women during gestational week 26.8 (±2.0 SD), GDM was present in 30 (18.4%) women. Insulin secretion was significantly lower in women with GDM (p=0.04, adjusted for BMI, age, week of gestation, insulin sensitivity). GLP-1 levels increased after glucose intake with a peak at 30 min. GLP-1 levels at minute 30 and AUCGLP-1 was significantly higher in women with GDM (by ∼20%, both p=0.03, adjusted for age, BMI and week of gestation). The GLP-1 increase was associated with insulin secretion only in GDM, but not in women with normal glucose tolerance. This association remained significant even after adjustment for increase of glucose and basal insulin levels (GDM group: p&amp;lt;0.001, non GDM: p=0.69). Conclusion: Women with GDM had lower insulin secretion despite increased GLP-1 levels during OGTT. The more pronounced GLP-1 increase in women with GDM could be part of a compensatory mechanism counteracting GLP-1 resistance. In addition to incretin resistance, this phenomenon suggests a dysfunction of glucose stimulated insulin secretion. Disclosure L. Fritsche: None. M. Heni: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi. Speaker’s Bureau; Self; Novo Nordisk A/S. S.S. Eckstein: None. M.J. Winzenried: None. J. Hummel: None. A.L. Birkenfeld: None. H. Preissl: None. H. Haering: None. A. Peter: None. A. Fritsche: None. R. Wagner: Advisory Panel; Self; Novo Nordisk A/S. Speaker’s Bureau; Self; Novo Nordisk A/S. Other Relationship; Self; Eli Lilly and Company. Funding German Federal Ministry of Education and Research (01GI0925)

OR14-02 Circadian Regulation of Chromatin State Mediates Pancreatic Islet Incretin Response

The circadian clock is programmed by an autoregulatory transcription feedback loop present in brain and peripheral tissues that coordinates metabolism with nutritional state and the sleep-wake cycle. Epidemiologic and genetic studies indicate circadian disruption as a risk factor in the development of diabetes. We have demonstrated that conditional ablation of the β cell clock in adult life leads to hypoinsulinemic diabetes, and through mRNA-sequencing in mouse and human islets we revealed clock control of gene networks involved in insulin secretion, nutrient sensing, and exocytosis. A remaining question is: How does the core molecular clock modulate time-of-day dependent chromatin state to regulate pancreatic islet response to glucose and insulin secretagogues? Here we report that loss of the pancreatic β cell molecular clock results in closed chromatin at cAMP-responsive gene regulatory elements and dysregulated cAMP-dependent coregulator recruitment following cAMP agonism, consistent with a role for the molecular clock in mediating cell response to environmental stimuli. Further, tandem analyses of ATAC- and ChIP-sequencing in synchronized islets revealed dynamic chromatin accessibility across the 24-hour cycle at genes regulating insulin secretion and at genomic regions enriched for signal-inducible and circadian transcription factor motifs. Our genome-wide sequencing reveals a new role for the clock in global chromatin remodeling underlying the incretin response in pancreatic β cells.

SAT-617 Potential Utility of the Mixed Meal Test for Differential Diagnosis of Partial Lipodystrophy from Common Type 2 Diabetes and Truncal Obesity

Background: Better clinical tools are needed to improve the differential diagnosis of partial lipodystrophy (PL) from type 2 diabetes (DM) with truncal obesity. Here, we investigated differences in metabolic parameters during a mixed meal test in PL and DM patients to determine if this test may have a role in this regard. Methods: We retrospectively evaluated data collected from 17 PL patients (4M/13F, ages 12-64) and 20 DM patients (13F/7M, ages 24-72) with truncal obesity, who also had nonalcoholic fatty liver disease. All patients underwent a Mixed Meal Test (MMT) with 474 ml of Optifast (320 kcal, 50% carbs, 15% fat, and 35% protein). Blood was collected before and at 30, 60, 90, 120, and 180 minutes post-meal to measure glucose, insulin, free fatty acids (FFA), triglycerides, inflammatory markers, GIP, GLP-1, PYY, and Ghrelin. All samples of the same cohort were run at the same time in duplicates and results were averaged. Mixed linear models were constructed to compare PL and DM cohorts taking into account within-subject effects. Data were controlled for BMI, sex and age, and glucose when necessary. Results: Patients with PL had higher glucose and triglyceride levels throughout the MMT at all-time points (p < 0.05). While the glucose levels showed an increase and subsequent decrease, the triglyceride levels remained flat throughout the test in both groups. Free fatty acid levels were suppressed compared to baseline during the test, but PL patients had significantly higher FFA from time 30 to time 180 (p < 0.05) and tended to suppress less. While controlling for the differences in glucose levels, GIP levels displayed a large peak at time 30 min in both groups but were significantly higher over the course of the test in the PL group (AUC: 32542, pg/mL x min (20528-57728) vs. 3343 pg/mL x min (1728-4498), p < 0.05). In contrast, GLP-1 levels (also peaking at time 30 min in both groups), were significantly lower in PL throughout the test (AUC: 3017 pg/mL x min (2309-6051) vs. 28387 pg/mL x min (20422-36045), p < 0.05). Ghrelin and PPY levels did not differ significantly between the two groups. Interpretation/Conclusion: PL patients displayed more profound hyperglycemia and impaired suppression of FFAs. Interestingly, PL patients did not show substantial increases in triglyceride levels during MMT. There was a striking difference in the incretin responses between the two populations despite controlling for glucose, suggesting that MMT may have a role in differential diagnosis PL. Also, altered incretin response should be investigated as a contributor to metabolic perturbations and pathophysiology of PL.

MON-599 Post-Bariatric Hypoglycemia: A Clinical Vignette on an Increasingly Recognized Disease

Introduction: Previously referred to as late dumping syndrome, post-bariatric hypoglycemia (PBH) is thought to represent at least 1% of all hospitalizations for hypoglycemia and 10% of all clinically recognized hypoglycemia cases. However, through the advent of CGM and more strict criteria over the last decade these numbers are likely an underestimate. As obesity continues to remain prevalent and with rising bariatric centers to help deal with this epidemic, endocrinologists will play an increasing role in managing PBH patients.Clinical Case: A 39-year female with a PMH of hypothyroidism and bariatric surgery (BS) in 2009 presented to our ER for a seizure. She has been having seizures nearly every 2 weeks for one year. Neurology started her on Keppra; however, no etiology was identified. EMS had documented a blood glucose of 40 mg/dL; the patient was given an amp of D50 with resolution of neuroglycopenic symptoms. TSH and cortisol levels were within normal range. A sulfonylurea panel in the ED was negative. The patient states the symptoms can occur while fasting but also mainly post-prandial. A 72-hr fast was conducted with the patient nadir POC glucose of 77. Subsequently, the patient had a mixed meal tolerance performed and after 2 hours had a seizure and was found to have a BG of 50 mg/dL with an insulin level of 49 uIU/mL and a c-peptide of 18.8 ng/mL. The patient was diagnosed with PBH, and was discharged with a CGM, started on acarbose and was seen by nutrition to discuss dietary modifications. She is now seen in our clinic with control of her symptoms with the addition of diazoxide.Conclusion: Altered anatomy after bariatric surgery, particularly after gastric bypass and sleeve gastrectomy is thought to play a major role in developing PBH. By bypassing normal anatomy, gastric emptying is increased 2–3 x, which leads to a higher and more rapid appearance of glucose in the distal foregut. This subsequently leads to an amplified incretin response leading to a hyperinsulinemic response in patients who have had bariatric surgery; however, for unclear reasons some patients develop an even more amplified hyperinsulinemic response that leads to subsequent hypoglycemia. History of neuroglycopenic symptoms 1–3 hours after eating in a patient who had a gastric bypass > 6–12 months and with relief of symptoms with carbohydrates should raise an endocrinologist’s suspicion of PBH. Fasting hypoglycemia is an atypical feature that should raise one’s suspicion of a broader differential. Altered nutrition habits is the cornerstone of therapy with which the primary aim is to reduce post-prandial glucose spikes in these patients after they eat carbohydrates. These spikes in turn lead to hyperinsulinism leading to subsequent hypoglycemia. Primary diet modifications include controlled carbohydrate consumption of less than 30g per meal, avoiding high glycemic carbs, and always taking in ample fat and proteins with every meal.

SAT-650 Novel Insights into the Entero-Insular Axis in Fibrocalcific Pancreatic Diabetes: An Isoglycemic Intravenous Glucose Infusion (IIGI) Study from India

In tropical countries including India, one of the common causes for young onset diabetes mellitus (DM) is “Fibro Calcific Pancreatic Diabetes” (FCPD) characterized by progressive pancreatic destruction. Despite this, glucagon has been found to be elevated in FCPD (1,2). The L-Cells in gut produce glucagon like peptide- 1 (GLP-1) and oxyntomodulin which are products of glucagon gene, thus raising probability of extra-pancreatic glucagon in FCPD. To test this hypothesis we performed 75grams oral glucose tolerance test (OGTT) followed by IIGI on separate days on nine FCPD and six healthy subjects. The latter procedure ensured matched glucose levels achieved during OGTT. Glucagon and incretins were measured at nine pre-specified time points. We found an increase in L-Cell products: GLP-1 (44.5±9.2pM vs. 12.4±4.5pM, p=0.02) and Oxyntomodulin (1252±350pg/ml vs. 859.8±165pg/ml, p=0.43) along with significant rise in glucagon during OGTT (98.8±13pg/ml vs. 63.4±7pg/ml, p=0.03) despite flat basal & stimulated C-peptide (0.43±0.14ng/ml and 1.09±0.3ng/ml, respectively) and Pancreatic polypeptide (12.3±0.0pg/ml and 14.7±1.7pg/ml, respectively) levels.Paradoxically, gastric inhibitory polypeptide (GIP) levels were low in FCPD (106.8±40.3pg/ml vs. 557.8±96.4pg/ml, p=0.003). We speculate that the hyperglucagonemia is extra-pancreatic (L-Cell) in origin and may also contribute to the dichotomous incretin response in FCPD.

Loss of β‐cell Gαz protects against high‐fat diet induced glucose intolerance by preserving incretin responsiveness and enhancing insulin secretion

Cyclic‐adenosine monophosphate (cAMP) is an important secondary messenger in the insulin‐secreting pancreatic β‐cells. Intracellular production of cAMP is augmented by stimulatory heterotrimeric G proteins (Gs) and blocked by inhibitory heterotrimeric G proteins (Gi). Pancreatic expression of the unique Gi family member, Gαz, is restricted to the islet, which contains β‐cells and other endocrine cell types, including glucagon/GLP‐1‐secreting alpha cells and somatostatin‐secreting delta cells. We have previously shown that full body Gαz‐null mice are protected from hyperglycemia in several diabetes model systems. Here, we use a high fat diet (HFD) model of obesity and insulin resistance to explore the impact of loss of beta‐cell Gαz on the type 2 diabetes (T2D) phenotype of male C57BL/6J mice. We hypothesized that loss of beta‐cell Gαz in the context of HFD feeding would enhance insulin secretion, protecting mice from HFD‐induced glucose intolerance. To generate beta‐cell specific Gαz‐null and control mice, we bred Gαz flox/flox mice with rat insulin promoter RIP‐Creherr mice. At 12 weeks of age, transgenic Gαz‐null mice were fed a diet containing 45 kcal% fat or a 10 kcal% fat control diet for 26 weeks. At study end, mice were metabolically phenotyped and sacrificed for whole pancreas and islet phenotyping. Beta‐cell‐specific Gαz loss protected mice from HFD induced glucose intolerance due to a selective effect on islet insulin secretion, particularly in concert with a stable agonist of the Gs‐coupled GLP‐1 receptor. This protective effect was independent of changes in Gαz‐coupled EP3 receptor signaling, as neither EP3 expression nor production of its endogenous ligand, PGE2, were enhanced in islets from HFD‐fed mice. This protective effect was also beta‐cell autonomous, as both full‐body and beta‐cell‐specific Gαz‐null mice had enhanced GLP‐1‐positive alpha‐cells, albeit with no changes in active GLP‐1 secretion. Finally, gene microarray results confirm that Gαz loss and HFD feeding synergize to differentially regulate islet gene expression, specifically up‐regulating secretion‐centric genes, many of which are related to cAMP signaling. This study presents a novel inhibitory mechanism of receptor‐independent G‐protein signaling that may hold promise for developing beta‐cell targeted diabetes therapeutics.

Role of fasting duration and weekday in incretin and glucose regulation.

Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.

Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis.

The aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF). A 3h 75g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3mmol/l with or without symptoms or glucose <3.9mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed. The two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3mmol/l at 180min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1mlmin-1m-2, p = 0.074 based on values until 120min [n = 14]; 512 ± 18.9 vs 438 ± 15.5mlmin-1m-2, p = 0.006 based on values until 180min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9pmolmin-1m-2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5pmolmin-1m-2 [mmol/l]-1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2mmol/l, respectively. Hypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.