Isoglycemic Intravenous Glucose Infusion Research Articles

Serum osteoglycin is stable during various glycemic challenges in healthy men.

Osteoglycin is hypothesized to be metabolically active and may enhance insulin action. We hypothesized that osteoglycin levels increase during hyperglycemia as a physiological response to enhance the effects of insulin. Eight healthy males were included in a cross-over study consisting of three study days following an 8 h fast. First, we performed an oral glucose tolerance test (OGTT); second, an isoglycemic intravenous glucose infusion (IIGI); and third, a control period consisting of a three hour fast. We analyzed blood samples for circulating osteoglycin levels during the study days. Repeated measures ANOVA was performed to compare levels of s-osteoglycin between OGTT, IIGI, and the fasting control. There were no differences in baseline osteoglycin levels among study days (p > 0.05). We observed no significant changes neither in absolute s-osteoglycin levels by time (p = 0.14) nor over time by study day (p = 0.99). Likewise, we observed no significant changes in percentage s-osteoglycin levels neither by time (p = 0.11) nor over time by study day (p = 0.89). We found that s-osteoglycin levels were stable for three hours during OGTT, IIGI, and fasting in healthy males. Based on the present study, circulating s-osteoglycin levels may be measured independently of fasting or non-fasting conditions. Furthermore, circulating physiological levels of glucose and insulin did not affect s-osteoglycin levels.

Incretin effect determines glucose trajectory and insulin sensitivity in youths with obesity.

In youths with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on β cell function and insulin sensitivity. Youths with obesity and 2-hour glucose level ≥ 120 mg/dL underwent a 3-hour oral glucose-tolerance test (OGTT) and an isoglycemic i.v. glucose infusion to quantify the incretin effect. After 2 years, 30 of 39 participants had a repeated OGTT and were stratified into 3 tertiles according to the baseline incretin effect. The high-incretin effect group demonstrated a longitudinal increase in β cell function (disposition index, minimal model [DIMM]), with greater insulin sensitivity at follow-up and stable insulin secretion (φtotal). A lower incretin effect at baseline was associated with higher 1-hour and 2-hour glucose level at follow-up. The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline, while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin in respect to the high-incretin group. The incretin effect during pubertal transition affected the longitudinal trajectory of β cell function and weight in youths with obesity.

Liraglutide treatment for the prevention of glucose tolerance deterioration in women with prior gestational diabetes mellitus: A 52-week randomized controlled clinical trial.

We investigated the effect of 52-week treatment with liraglutide, a glucagon-like peptide 1 receptor agonist, on glucose tolerance and incretin effect in women with previous gestational diabetes mellitus (pGDM). Women with overweight/obesity and pGDM were randomized to once daily subcutaneous liraglutide 1.8 mg or placebo for 52 weeks. Participants underwent oral glucose tolerance test (OGTT) and isoglycaemic intravenous glucose infusion at baseline and at 52 weeks, and an additional OGTT after the drug wash-out. In total, 104 women [age: mean ± SD, 38 ± 5 years; fasting plasma glucose (FPG): 5.5 ± 0.4 mmol/L; glycated haemoglobin (HbA1c): 33 ± 4 mmol/mol, bodyweight: 88.2 ± 14.8 kg, body mass index: 31.1 ± 4.3 kg/m2 ] were assigned to liraglutide (n = 49) or placebo (n = 55). Estimated treatment difference (ETD) for area under curve during OGTT was -173 (95% confidence interval -250 to -97) mmol/L × min, p < .0001, but after wash-out the difference disappeared [ETD 58 (-30 to 146) mmol/L × min, p = .536]. Liraglutide reduced FPG [ETD -0.2 (-0.4 to -0.1) mmol/L, p = .018], HbA1c [-2.2 (-3.5 to -0.8) mmol/mol, p = .018] and bodyweight [-3.9 (-6.2 to -1.6) kg, p = .012]. No change in the incretin effect was observed. The number of women with prediabetes was reduced from 64% to 10% with liraglutide vs. 50% with placebo [adjusted odds ratio 0.10 (0.03-0.32), p = .002]. Treatment with liraglutide for 52 weeks improved glucose tolerance, FPG, HbA1c and bodyweight in women with overweight/obesity and pGDM. Progression to prediabetes while on drug was markedly reduced, but after a 1-week drug wash-out, the effect was lost.

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

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

Glucose metabolism, gut-brain hormones, and acromegaly treatment: an explorative single centre descriptive analysis.

Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment options include surgery, medical therapy with somatostatin analogues (SSA) and Pegvisomant (PEG), and irradiation. The objective of the study was to describe the differential effect of various treatment regimens on the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) in patients with acromegaly. 23 surgically treated, non-diabetic patients with acromegaly and 12 healthy controls underwent an oral glucose tolerance test (OGTT) and subsequently isoglycaemic intravenous glucose infusion on a separate day. Baseline hormone concentrations, time-to-peak and area under the curve (AUC) on the OGTT-day and incretin effect were compared according to treatment regimens. The patients treated with SSA (N = 15) had impaired GIP-response (AUC, P = 0.001), and numerical impairment of all other hormone responses (P > 0.3). Patients co-treated with PEG (SSA + PEG, N = 4) had increased secretion of insulin and glucagon compared to patients only treated with SSA (SSA ÷ PEG, N = 11) (insulinAUC mean ± SEM, SSA + PEG 49 ± 8.3nmol/l*min vs SSA ÷ PEG 25 ± 3.4, P = 0.007; glucagonAUC, SSA + PEG 823 ± 194pmol/l*min vs SSA ÷ PEG 332 ± 69, P = 0.009). GIP secretion remained significantly impaired, whereas GLP-1 secretion was numerically increased with PEG (SSA + PEG 3088 ± 366pmol/l*min vs SSA ÷ PEG 2401 ± 239, P = 0.3). No difference was found in patients treated with/without radiotherapy nor substituted or not with hydrocortisone. SSA impaired the insulin, glucagon, and incretin hormone secretions. Co-treatment with PEG seemed to counteract the somatostatinergic inhibition of the glucagon and insulin response to OGTT. We speculate that PEG may exert its action through GH-receptors on pancreatic δ-cells. Clinical trial registration NCT02005978.

A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment

Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6–36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)−1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)−1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (−0.79, 0.002), (−0.73,.007), (−0.86,.0003)) respectively).

342-OR: Low Incretin Effect Is Associated with Longitudinal Decline of Beta-Cell Function and Insulin Sensitivity in Obese Youth

Background: We assessed the longitudinal trajectory of beta-cell function with respect to baseline incretin effect in youth with obesity. Methods: At baseline and two years, youth with obesity and 2-h glucose ≥ 120mg/dL underwent a 3-hour OGTT and isoglycemic intravenous glucose infusion (to quantify the incretin effect) . Participants were stratified into three tertiles based on the baseline incretin effect. The oral minimal model quantified beta cell function (oDI) and insulin sensitivity (SI) . Results: Thirty participants completed the assessments [follow-up: age 18.6±2.4y, 19F; BMI 38.6±7.4 kg/m2, NGT/IGT/T2D 12/17/1]. At 2 years, 2-h glucose improved in the high incretin group (p=0.047) , but was stable in the middle- and low- incretin groups (panel G) . At 2 years, the baseline high-incretin group exhibited a lower 60-min glucose (p=0.026) than the low-incretin group, with similar 120-min glucose (p=0.696) , despite the low-incretin cohort’s relative increase in early insulin secretion (panel D, F) . The low-incretin tertile also exhibited a reduced β cell function (oDI) at follow-up (panel I) (p=0.044) mainly due to lower insulin sensitivity (panel H) (p=0.013) . Conclusion: Low incretin effect is associated with a longitudinal decline of beta cell function and decreased insulin sensitivity, despite greater first-phase insulin secretion. Disclosure A.Galderisi: None. J.O.Lat: None. S.Samuels: None. B.Pierpont: None. M.A.Van name: Research Support; Provention Bio, Inc. N.Santoro: None. S.Caprio: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases/NIH/DHHS (16-004945)

61-OR: Machine Learning Framework Predicts Metabolic Subphenotypes Using Glucose Dynamics during Oral Glucose Tolerance Test

Type 2 diabetes (T2D) is classically defined by measures of glycemia which do not take into account its physiologic basis, which differs between individuals. Defining the relative contribution of fundamental physiologic processes to glucose dysregulation would facilitate targeted treatment approaches for diabetes prevention and treatment. We propose that muscle insulin resistance, beta cell dysfunction, incretin defect, and hepatic insulin resistance are present to varying degrees in individuals predisposed to T2D, who can be thus classified according to their metabolic subphenotype. While this transformative approach to T2D is appealing, traditional metabolic tests are invasive and unavailable outside research units. We tested the ability of the shape of the glucose response curve during an oral glucose tolerance test (OGTT) to identify metabolic subphenotypes. 32 participants underwent gold-standard metabolic tests including frequently-sampled 3-hour OGTT, isoglycemic intravenous glucose infusion for quantification of incretin effect, steady-state plasma glucose measurement of insulin resistance, and calculated hepatic insulin resistance. We developed a machine learning framework to predict metabolic subphenotypes of an individual using dynamic features of the glucose time series during the OGTT. Metabolic testing revealed extensive inter-individual heterogeneity and the existence of four major metabolic subphenotypes. The features of the glucose time series identified insulin resistance, beta cell deficiency, and incretin deficiency with auROCs of 94%, 76%, and 75%, respectively. These were superior to standard clinical and laboratory measures of metabolic phenotypes. We suggest that identification of distinct metabolic subphenotypes using features of the glucose time series during OGTT may both enhance early identification of at-risk individuals as well as inform targeted therapeutic approaches to prevent and treat T2D. Disclosure A.A.Metwally: None. D.Perelman: None. H.Park: None. A.L.Gloyn: Other Relationship; Genentech, Inc., Roche Pharmaceuticals. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck &amp; Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals. M.Snyder: Stock/Shareholder; January, Inc. Funding National Institutes of Health (R01DK110186-01) National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK105535; U01-DK085545, UM1DK126185)

Insulin clearance and incretin hormones following oral and \u201cisoglycemic\u201d intravenous glucose in type 2 diabetes patients under different antidiabetic treatments

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7–36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

224-LB: A Study to Evaluate the Glucagon and Incretin Responses and Identify the Role of Extrapancreatic Glucagon in Patients with Fibrocalcific Pancreatic Diabetes

Aim: The aim of this study is to evaluate glucagon and incretin responses in patients with FCPD. Methods: Nine FCPD patients and six age- and body mass index-matched healthy controls were subjected to 75 g oral glucose tolerance test (OGTT) followed by isoglycemic intravenous glucose infusion (IIGI). Blood samples were analyzed for incretins and glucagon at nine pre-specified time-points over 3 h and the area under curve was calculated. Results: Glucagon was significantly higher during OGTT compared to IIGI in FCPD patients (98.8 ± 13 pg/ml vs. 63.4 ± 7 pg/ml, P = 0.03) and was also higher when compared to controls (98.8 ± 13 pg/ ml vs. 65.8 ± 18 pg/ml, P = ns). FCPD patients showed very low basal and stimulated c-peptide (0.43 ± 0.14 ng/ml and 1.09 ± 0.3 ng/ ml, respectively) and pancreatic polypeptide (12.3 ± 0.0pg/ml and 12.0 ± 0.6 pg/ml, respectively) levels. Glucagon-like peptide-1 (GLP-1) was significantly higher in cases on OGTT when compared to controls (44.5 ± 9.2 pM vs. 12.8 ± 7.5 pM, P = 0.02). Oxyntomodulin was also insignificantly higher in cases on OGTT when compared to controls (1252 ± 350 pg/ml vs. 859.8 ± 165 pg/ml, P = 0.43). GIP was lower in cases on IIGI when compared to controls (52.9 ± 23.9 pg/ml vs. 144.5 ± 36.1 pg/ml, P = 0.045) and there was blunted response on OGTT as well (106.8 ± 40.3 pg/ml vs. 557.8 ± 96.4 pg/ml, P = 0.003). Discussion: We found hyperglucagonemia in FCPD on OGTT, which was suppressed on IIGI. Increase in L-cell products: GLP-1 and oxyntomodulin and a good correlation between glucagon and GLP-1 during OGTT were suggestive of extrapancreatic glucagon production probably from L-cell. The blunted GIP could probably be due to: inadequate pancreatic enzyme supplements, a selective PC-2 enzyme up-regulation or a negative feedback regulation from extrapancreatic glucagon. Conclusion: Extrapancreatic glucagon does exist in FCPD and may contribute to postprandial hyperglycemia and lower GIP levels. Disclosure A. Shankar: None.

591-P: Glucose Dynamics during OGTT Identify Metabolic Subphenotypes in Individuals with Glucose Dysregulation

Type 2 diabetes (T2D) is a heterogeneous disorder, with a complex physiologic basis. Muscle insulin resistance, beta-cell dysfunction, and impaired incretin effect may be present to differing degrees. Identifying the underlying physiology of glucose dysregulation in a given individual would allow for tailored treatment. We hypothesized that glucose dynamics (i.e., glucotypes) during a frequently-sampled 3-hour OGTT could identify the underlying pathophysiology of glucose dysregulation. If true, glucotypes from OGTT and/or continuous glucose monitoring devices may extend current diagnostic approaches for T2D by defining the dominant metabolic subphenotype. A total of 33 participants underwent gold-standard metabolic tests including: OGTT with blood sampled every 5-10 min for 180 min with c-peptide deconvolution, isoglycemic intravenous glucose infusion (IIGI), and modified insulin suppression test (IST), to quantify beta-cell function, incretin effect, and insulin resistance. Glucotypes were constructed from a time series with glucose values from the OGTT. Missing timepoints were imputed using cubic smoothing splines. Each series was Z-normalized to focus on the shape of the curve rather than the amplitude. Singular value decomposition was performed and the first two principal components were used in cluster analysis, and related to gold-standard metabolic tests. Cluster analysis of glucose dynamics variables revealed 2 separable clusters identifying individuals classified as insulin resistant or sensitive based on IST. Beta-cell dysfunction was also distinguishable by cluster analysis. Although impaired incretin effect status was identified using the deconvolution of the c-peptide from the OGTT and IISI, it was not clearly separable through glucotypes. Glucotypes may be used to identify metabolic subphenotypes in glucose-dysregulated states, with the potential to personalize treatment approaches that address the dominant physiologic defect. Disclosure A. A. Metwally: None. D. Perelman: None. H. Park: None. A. Celli: None. T. Mclaughlin: Board Member; Self; January, Inc. M. Snyder: Research Support; Self; Fitbit, Inc., Stock/Shareholder; Self; January, Inc., Qbio. Funding National Institutes of Health (5R01DK110186-02); Precision Health and Integrated Diagnostics Center at Stanford

Meal Timing-Based Dietary Patterns Are Associated With Glucose Regulation, Insulin Resistance, and Incretin Effect in Individuals at Risk for Type 2 Diabetes

Abstract Objectives Food is an external cue to entrain the circadian rhythm, and when and how to eat may be a crucial factor for glucose homeostasis. This study sought to quantify the impact of meal timing-based dietary habits on glucose homeostasis in prediabetic and normal individuals by using digital monitoring technologies. Methods 35 study participants (56.6 y; prediabetes n = 19 and normoglycemia n = 16) tracked their food intake and timing by a food-logging mobile app for at least two weeks. Gold-standard glucose metabolic tests were performed such as OGTT, insulin suppression test, and isoglycemic intravenous glucose infusion to quantify insulin resistance, beta-cell function, and incretin effects. The energy contribution of six meal timings to the total daily energy intake was determined. Principal component analysis (PCA) was used to group participants in the cohort based on their meal timing patterns. Multivariate linear regression (MLR) models confirmed differences in each meal timing feature by glycemic control groups. Results A total of 2307 meals and 625 days of food logs were collected from study participants. From the PCA plot based on meal timing features, the cohort was clearly separated into two clusters by their HbA1c levels: normoglycemia (HbA1c &amp;lt; 5.7%) vs. prediabetes (5.7%&amp;lt; HbA1c &amp;lt; 6.5%). MLR models further showed that people with prediabetes had lower Meal_4 (2pm-5pm) energy contribution (P = 0.00,697) and higher Meal_5 (5pm-9pm) energy contribution (P = 0.0462) than normal group even after adjustment for age, sex, ethnicity, and BMI. Similarly, insulin resistant and sensitive groups were separated based on meal timing features, as did incretin function. However, beta-cell function groups were not distinguished by meal timing features. Conclusions The data suggest that meal timing-based dietary patterns can be used to predict different types of glucose metabolic dysregulation such as prolonged high blood glucose, insulin resistance, and incretin dysfunction. Funding Sources NIH 2T32HL09804911, NIH 5R01DK110186-02, Stanford PHIND Award.

No detectable effect of a type 2 diabetes-associated TCF7L2 genotype on the incretin effect.

The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes (T2D), possibly by modulation of incretin action. In this study, we evaluated the effect of the TCF7L2 rs7903146 T allele on the incretin effect and other glucometabolic parameters in normal glucose tolerant individuals (NGT) and participants with T2D. The rs7903146 variant was genotyped in cohorts of 61 NGT individuals (23 were heterozygous (CT) or homozygous (TT) T allele carriers) and 43 participants with T2D (20 with CT/TT). Participants were previously examined by an oral glucose tolerance test (OGTT) and a subsequent isoglycemic intravenous glucose infusion (IIGI). The incretin effect was assessed by quantification of the difference in integrated beta cell secretory responses during the OGTT and IIGI. Glucose and hormonal levels were measured during experimental days, and from these, indices of beta cell function and insulin sensitivity were calculated. No genotype-specific differences in the incretin effect were observed in the NGT group (P = 0.70) or the T2D group (P = 0.68). NGT T allele carriers displayed diminished glucose-dependent insulinotropic polypeptide response during OGTT (P = 0.01) while T allele carriers with T2D were characterized by lower C-peptide AUC after OGTT (P = 0.04) and elevated glucose AUC after OGTT (P = 0.04). In conclusion, our findings do not exclude that this specific TCF7L2 variant increases the risk of developing T2D via diminished incretin effect, but genotype-related defects were not detectable in these cohorts.

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.

Impaired Succinate Response to a Mixed Meal in Obesity and Type 2 Diabetes Is Normalized After Metabolic Surgery.

OBJECTIVETo explore the meal response of circulating succinate in patients with obesity and type 2 diabetes undergoing bariatric surgery and to examine the role of gastrointestinal glucose sensing in succinate dynamics in healthy subjects.RESEARCH DESIGN AND METHODSCohort I comprised 45 patients with morbid obesity and type 2 diabetes (BMI 39.4 ± 1.9 kg/m2) undergoing metabolic surgery. Cohort II was a confirmatory cohort of 13 patients (BMI 39.3 ± 1.4 kg/m2) undergoing gastric bypass surgery. Cohort III comprised 15 healthy subjects (BMI 26.4 ± 0.5 kg/m2). Cohorts I and II completed a 2-h mixed-meal tolerance test (MTT) before the intervention and at 1 year of follow-up, and cohort II also completed a 3-h lipid test (LT). Cohort III underwent a 3-h oral glucose tolerance test (OGTT) and an isoglycemic intravenous glucose infusion (IIGI) study.RESULTSIn cohort I, succinate response to MTT at follow-up was greater than before the intervention (P < 0.0001). This response was confirmed in cohort II with a greater increase after 1 year of surgery (P = 0.009). By contrast, LT did not elicit a succinate response. Changes in succinate response were associated with changes in the area under the curve of glucose (r = 0.417, P < 0.0001) and insulin (r = 0.204, P = 0.002). In cohort III, glycemia, per se, stimulated a plasma succinate response (P = 0.0004), but its response was greater in the OGTT (P = 0.02; OGTT versus IIGI).CONCLUSIONSThe meal-related response of circulating succinate in patients with obesity and type 2 diabetes is recovered after metabolic surgery.

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.

OR23-06 Is the Improved Glucose Homeostasis in Patients with Acromegaly Treated with Pegvisomant Caused by Improved Glucagon Secretion?

Context: Active acromegaly is associated with impaired glucose metabolism, which improves upon treatment. Treatment with first generation somatostatin analogues (SSA) has a detrimental effect on insulin secretion, but the effect on glucose homeostasis is neutralized by the reduction in growth hormone (GH) and Insulin-like growth factor-1 (IGF-1). Treatment with GH receptor antagonists has a more favorable effect on glucose homeostasis. Objective: To describe the secretion of glucose, insulin, glucagon, glucagon-like peptide-1 (GLP1), and glucose-dependent insulinotropic polypeptide (GIP) in surgically treated patients with acromegaly treated or not with somatostatin analogues, either as monotherapy (SSA) or in co-treatment with pegvisomant (SSA+PEG), respectively, compared to healthy controls. Methods: Descriptive study of data from 23 surgically treated, non-diabetic patients with acromegaly and 6 healthy controls. After an overnight fast, all participants underwent a three-hour 75 g oral glucose tolerance test (OGTT) and subsequently a three-hour isoglycaemic intravenous glucose infusion on a separate day. Analysis: Baseline hormone concentrations, time to peak and area under the curve (AUC) on the OGTT-day, and the incretin effect in the patient groups and controls were compared using analysis of variance with post-hoc analysis. Results: The total group of patients treated with somatostatin analogues (N=15) had numerically impaired glucose, insulin, GLP1 and glucagon responses (AUC, P>0.05 respectively), and an impaired GIP-response (AUC, P=0.007) during OGTT as compared to patients not treated with somatostatin analogues and healthy controls. Similarly, the incretin effect was numerically impaired.Patients co-treated with pegvisomant (SSA+PEG, N=4) had a numerically increased secretion of insulin and glucagon compared to patients on SSA (N=11) during OGTT (insulin AUC mean (SEM), SSA+PEG 49 nmol/l*min (8.3) vs SSA 25 (3.4), P>0.05) [healthy controls 62 (13.6)]; glucagon AUC, SSA+PEG 823 pmol/l*min (194) vs SSA 332 (69), P>0.05) [healthy controls 946 (233)]). GIP secretion remained significantly impaired, whereas GLP1 secretion was numerically increased with PEG (SSA+PEG 3088 pmol/l*min (366) vs SSA 2401 (239), P>0.05) [healthy controls 3972 (451)] but remained without a glucose-dependant increase as in SSA. The incretin effect numerically increased in SSA+PEG compared to SSA (SSA+PEG 49.9% (13.9) vs SSA 33.6% (47.4), P>0.05) [healthy controls 55.5% (7.7)]. Conclusion: Somatostatin analogues impaired the secretion of both insulin, glucagon and incretin hormones secretion. Co-treatment with pegvisomant seemed to counteract the somatostatinergic inhibition of the glucagon secretion and improved the insulin response to OGTT. We speculate that pegvisomant exerts its action via GH-receptors on pancreatic δ-cells.

1721-P: Effect of the TCF7L2 Variant rs7903146 T Allele on the Incretin Effect in Individuals with Normal Glucose Tolerance or Type 2 Diabetes

Background and Aim: The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes. The mechanisms underlying this association are not fully understood, but diminished incretin-induced insulin secretion has been suggested. We undertook this study to evaluate the effect of the TCF7L2 rs7903146 T allele on the incretin effect in normal glucose tolerant individuals and patients with type 2 diabetes. Methods: The incretin effect was assessed by relating the difference in integrated beta cell secretory responses to oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) to the response during OGTT in 36 normal glucose tolerant individuals (of whom 12 had the risk-conferring variant rs7903146 (TC/TT)) and 20 patients with type 2 diabetes (10 with TC/TT). Homeostatic model assessment (HOMA) was used to estimate insulin resistance. Results: No differences in incretin effect estimates between risk allele carriers and non-carriers in the two groups were observed. Normal glucose tolerant individuals with rs7903146 displayed higher C-peptide levels in the fasting state (P=0.029) as well as during OGTT (P=0.029) and IIGI (P=0.015) compared to normal glucose tolerant non-carriers. Normal glucose tolerant risk allele carriers were more insulin resistant compared to normal glucose tolerant non-carriers (P=0.042). No detectable differences in glucose metabolism were found between risk allele carriers and non-carriers in the type 2 diabetes group. Conclusions: The TCF7L2 rs7903146 T allele was not associated with reduced incretin effect in these relatively small cohorts of normal glucose tolerant individuals and patients with type 2 diabetes. Insulin resistance rather than beta cell secretory defects distinguished the normal glucose tolerant risk allele carriers examined here, from the normal glucose tolerant non-carriers. Disclosure D.S. Mathiesen: None. A.B. Lund: None. K.B. Hansen: None. A. Junker: None. T. Idorn: Employee; Self; Novo Nordisk A/S. M. Hornum: None. A. Jonsson: None. T. Hansen: None. T. Vilsbøll: None. J.I. Bagger: 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 (NNF17OC0029370)

1186-P: Lean Women with Polycystic Ovary Syndrome and Insulin Resistance Have Normal Incretin Effect, which Is Unaffected by Metformin Therapy

Polycystic ovary syndrome (PCOS) is associated with insulin resistance (IR) and a high risk of type 2 diabetes. We investigated the incretin effect (IE) and gastrointestinal-mediated glucose disposal (GIGD) in lean women with PCOS and IR, but normal fasting plasma glucose, and whether metformin affects the IE and GIGD in these women. Ten normoglucose-tolerant, lean women with PCOS and IR (homeostatic model assessment (HOMA-IR) &amp;gt; 1.5) were randomly allocated to receive metformin (500 mg bid) or placebo for 12 weeks interposed by a 6-week wash-out period in a double-blind, cross-over design. The women underwent an OGTT and an isoglycemic intravenous glucose infusion (IIGI) at baseline and at the end of each treatment period. Ten healthy, lean women without PCOS served as controls and underwent one OGTT and one IIGI. At baseline, the control group and the PCOS group had similar age (25±3 vs. 25±4 years (mean±SD), P=0.91), BMI (22±2 vs. 23±2 kg/m2, P=0.42), fasting plasma glucose (4.8±0.3 vs. 5.0±0.2 mmol/l, P=0.11), GIGD (58±15 vs. 59±12%, P=0.84) and IE (56±15 vs. 51±13%, P=0.45); the PCOS group had higher HOMA-IR (1.8±0.4 vs. 1.0±0.3, P&amp;lt;0.0001) and lower Matsuda index (6±3 vs. 9±2, P=0.03). Compared to placebo, 12 weeks’ metformin treatment had no effect on BMI (P=0.42), fasting plasma glucose (P=0.71), HOMA-IR (P=0.95) and Matsuda index (P=0.52). Compared to baseline, metformin treatment lowered the IE in the PCOS group (-9.2% [-17.8;-0.6] (mean [95% CI])), but the change was not different from the change observed after placebo treatment (0.9% [-8.2;10.1], P=0.11) and metformin treatment tended to lower the GIGD (-9.7 [-21.3; 1.9] vs. 1.9% [-10.6; 14.5], P=0.05). We conclude that the studied lean women with PCOS and IR have similar IE and GIGD as matched, insulin-sensitive controls and, surprisingly, we observed no effect of metformin on IR, IE or GIGD in these women. Disclosure L. Vedtofte: None. S. Foghsgaard: None. L. Zierau: None. 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 Foundation; A.P. Møller Foundation

Glucose Tolerance Tests and Osteocalcin Responses in Healthy People.

Aim: Osteocalcin and undercarboxylated osteocalcin are suggested to be endocrine messengers from the bones and have been shown to stimulate insulin secretion from pancreatic β-cells. Insulin is hypothesized to increase the osteoblastic production of osteocalcin. The aim of the study was to investigate whether the route of glucose administration influence the circulating levels of osteocalcin and undercarboxylated osteocalcin.Methods: Twelve healthy males were enrolled in an acute cross-over study where they underwent an oral glucose tolerance test (OGTT), an isoglycemic intravenous glucose infusion (IIGI) and a fasting period (control). Blood samples were collected throughout 180 min and analyzed for osteocalcin and undercarboxylated osteocalcin and compared to insulin, glucose, and gastro-intestinal hormone responses.Results: Neither osteocalcin levels nor undercarboxylated osteocalcin levels over time differed between the OGTT, IIGI, and fasting. Baseline insulin levels and glucose levels were not associated with osteocalcin or undercarboxylated osteocalcin levels. Increases in insulin and glucose levels were neither associated with altered osteocalcin nor undercarboxylated osteocalcin levels.Conclusion: The route of glucose administration does not influence the circulating levels of osteocalcin and undercarboxylated osteocalcin despite the differential insulin and incretin responses. In the acute setting this suggests that insulin does not increase osteoblastic production of osteocalcin in healthy human males.