Beta-cell Glucose Sensitivity Research Articles

Low-Dose Sulfonylurea Plus DPP4 Inhibitor Lower Blood Glucose and Enhance Beta-Cell Function Without Hypoglycemia.

Low-dose sulfonylureas (SUs) have been found to augment the classical incretin effect, increase glucose sensitivity and late phase incretin potentiation. To evaluate potential synergy between low-dose SU plus a dipeptidyl peptidase 4 (DPP4) inhibitor. Unblinded randomized crossover study at the Clinical Research Centre, University of Dundee. Thirty participants with T2DM (HbA1c < 64 mmol/mol) were treated with diet or metformin. Participants completed 4, 14-day blocks in a random order: control, gliclazide 20 mg (SU), sitagliptin 100 mg (DPP4 inhibitor [DPP4i]), or combination (SUDPP4i). A mixed meal test was conducted after each intervention. The primary outcome was the effect of treatment on beta-cell glucose sensitivity. Secondary outcomes included frequency of glucose <3 mmol/L on continuous glucose monitoring, subanalyses by genotype (KNCJ11 E23K), gender, and body mass index. SU combination with DPP4i showed additive effect on glucose lowering: mean glucose area under the curve (mean 95% CI) (mmol/L) was control 11.5 (10.7-12.3), DPP4i 10.2 (9.4-11.1), SU 9.7 (8.9-10.5), SUDPP4i 8.7 (7.9-9.5) (P < .001). Glucose sensitivity mirrored the additive effect (pmol min-1 m-2 mM-1): control 71.5 (51.1-91.9), DPP4i 75.9 (55.7-96.0), SU 86.3 (66.1-106.4), SUDPP4i 94.1 (73.9-114.3) (P = .04). The additive effect was seen in men but not women. Glucose time in range <3 mmol/L on continuous glucose monitoring (%) was unaffected: control 1 (2-4), DPP4i 2 (3-6), SU 1 (0-4), SUDPP4i 3 (2-7) (P = .65). Low-dose sulfonylurea plus DPP4i has a potent glucose-lowering effect through augmentation of beta-cell function. A double-blind randomized controlled trial would formalize efficacy and safety of this combination, which may avoid negative aspects of SU.

THU295 The Role Of Imatinib In Pediatric Diabetes

Abstract Disclosure: K. Lavelle: None. C. Chamberlain: None. M.S. Anderson: None. M.S. German: None. A. Nip: None. S.E. Gitelman: None. Background: A growing body of evidence suggests that imatinib may attenuate or even reverse diabetes in both mice and adults. In children, however, this has not been reported yet. Clinical Case: A 14-year-old previously healthy Black male presented to the hospital with a 2-week history of polydipsia, polyuria, and weight loss. He had no family history of diabetes. On admission, he was underweight (weight 45th percentile, Z=-0.11; BMI 1st percentile, Z=-2.33) and was found to be in DKA (serum pH 7.15 [7.31-7.47], glucose 560mg/dL [65-99 mg/dL], HCO3 9.7 mEq/L [20-28 mEq/L], urine ketones 4+, Hgb A1c 12.3%, C-peptide &amp;lt;0.2 ng/mL [1.1-4.4 ng/mL]) as well as COVID-19 positive and G6PD deficient with hyperleukocytosis (WBC 137.8 TH/mm3 [5-10 TH/mm3]). He was requiring 0.6u/kg/day insulin upon discharge and went home on glargine 10 units daily, aspart insulin-to-carbohydrate ratio 1u:10g at breakfast, 1:12 at lunch, and 1:15 at dinner with insulin sensitivity factor 1u:50 mg/dL. After discharge, autoantibodies (GAD-65, IA-2, IAA, ZnT8) returned negative. Oncologic testing returned positive for myeloid neoplasm, and he was readmitted for initiation of imatinib 400mg/day 2 months post-discharge. Over the next 3 months, his Hgb A1c decreased from 6.3% to 4.9%. The following month, he had gained weight (weight 83rd percentile, Z=0.95; BMI 61st percentile, Z=0.27) and was requiring only 0.2u/kg/day insulin on a non-restricted diet. His Hgb A1c was down to 4.6% without hypoglycemia 6 months after starting imatinib. Conclusion: Imatinib is a tyrosine kinase inhibitor first approved for treatment of chronic myeloid leukemia. In vivo studies have demonstrated that it targets anti-diabetic pathways as well: imatinib inhibits c-Abl in pancreatic beta cells, thereby blunting endoplasmic reticulum stress responses and reducing apoptosis. It also inhibits platelet-derived growth factor receptors, thereby increasing adiponectin and improving insulin sensitivity. Mouse studies have shown prevention of Type 1 diabetes (T1D) and reversal of both T1D and Type 2 diabetes with imatinib. A phase 2 trial in adults with new onset T1D treated with imatinib for 6 months showed preservation of beta cell function out to 12 months (Gitelman et al, Lancet Diabetes 2021). While receiving imatinib, participants also saw lower Hgb A1c, less insulin use, higher adiponectin and lower proinsulin:C-peptide, and improved beta cell glucose sensitivity when compared to the placebo group. This case suggests that imatinib might similarly benefit children, as our patient experienced a 1.7-point reduction in Hgb A1c% and a 67% reduction in insulin requirement on therapy. It is the first case to describe imatinib use in an adolescent with diabetes and poses two important questions: what is the etiology of diabetes in this patient, and how might imatinib impact the natural course of disease? Further studies are underway to clarify these issues. Presentation: Thursday, June 15, 2023

Habitual intake of advanced glycation endproducts is not associated with worse insulin sensitivity, worse beta cell function, or presence of prediabetes or type 2 diabetes: The Maastricht Study

A diet high in advanced glycation endproducts (AGEs) is a potential risk factor for insulin resistance, beta cell dysfunction, and ultimately type 2 diabetes. We investigated associations between habitual intake of dietary AGEs and glucose metabolism in a population-based setting. In 6275 participants of The Maastricht Study (mean±SD age: 60±9, 15.1% prediabetes and 23.2% type 2 diabetes), we estimated habitual intake of dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) by combining a validated food frequency questionnaire (FFQ) with our mass-spectrometry dietary AGE database. We determined insulin sensitivity (Matsuda- and HOMA-IR index), beta cell function (C-peptidogenic index, glucose sensitivity, potentiation factor, and rate sensitivity), glucose metabolism status, fasting glucose, HbA1c, post-OGTT glucose, and OGTT glucose incremental area under the curve. Cross-sectional associations between habitual AGE intake and these outcomes were investigated using a combination of multiple linear regression and multinomial logistic regression adjusting for several potential confounders (demographic, cardiovascular, and lifestyle factors). Generally, higher habitual intake of AGEs was not associated with worse indices of glucose metabolism, nor with increased presence of prediabetes or type 2 diabetes. Higher dietary MG-H1 was associated with better beta cell glucose sensitivity. The present study does not support an association of dietary AGEs with impaired glucose metabolism. Whether higher intake of dietary AGEs translates to increased incidence of prediabetes or type 2 diabetes on the long term should be investigated in large prospective cohort studies.

Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo—The Maastricht Study

ObjectiveWe investigated, using population-based data, whether worse autonomic function, estimated from lower 24-hour heart rate variability (HRV), was associated with beta cell function, assessed from beta cell response during an oral glucose tolerance test (OGTT).Research design and methodsWe used cross-sectional data from The Maastricht Study, a population-based cohort study (N = 2,007; age, mean ± SD:60 ± 8 years; 52% men; and 24% with type 2 diabetes). We used linear regression analyses with adjustment for potential confounders (demographic, cardiovascular, and lifestyle factors) to study the associations of time- and frequency-domain HRV (composite scores) with overall beta cell response (estimated from a composite score calculated from: C-peptidogenic index, overall insulin secretion, beta cell glucose sensitivity, beta cell potentiation factor, and beta cell rate sensitivity). In addition, we tested for interaction by sex and glucose metabolism status.ResultsAfter full adjustment, lower time- and frequency-domain HRV was significantly associated with lower overall beta cell response composite score (standardized beta, -0.055 [-0.098; -0.011] and − 0.051 [-0.095; -0.007], respectively). These associations were not modified by sex and there was no consistent pattern of interaction by glucose metabolism status.ConclusionThe present etiological study found that worse autonomic function, estimated from lower HRV, was associated with worse beta cell function, estimated from a composite score in a population-based sample which covered the entire spectrum of glucose metabolism. Hence, autonomic dysfunction may contribute to beta cell dysfunction and, ultimately, to the alteration of glucose metabolism status from normal glucose metabolism to prediabetes and type 2 diabetes.

The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes

Aim/hypothesisThe risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear.MethodsBeta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial–Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes.ResultsAmong the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (−13.7 [21.2] vs −11.9 [21.5] pmol min−1 m−2 [mmol/l]−1, median [IQR], p=0.52) or insulin sensitivity (−22 [37] vs −14 [40] ml min−1 m−2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years.Conclusions/interpretationOur data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.Graphical abstract

321-OR: Empagliflozin Improves Beta-Cell Function Independently of Glucose Toxicity in Patients with Type 2 Diabetes

Introduction: SGLT2-inhibitors improve beta-cell glucose sensitivity (BGS) and insulin sensitivity in patients with type 2 diabetes (T2D) . This effect has been attributed to relief of glucotoxicity, but very few studies have controlled for differences in glycemia. Here, we explore the effects of empagliflozin on BGS and secondarily, peripheral insulin sensitivity (IS) , compared to similar glycemic control with insulin treatment. Materials and Methods: 17 subjects with T2D (13 males, 58±3 years (mean±sem) , BMI 32.9±0.9 kg/m2, HbA1c 52.4±2.4 mmol/L, T2D duration 8.9±1.3 years) were treated with empagliflozin (E) and NPH-insulin (I) for 5 weeks in a randomized cross-over study design with 3 weeks of washout. Insulin was titrated to obtain similar glycemic control as with empagliflozin. An OGTT with stable iv and oral glucose tracers was performed prior to and at the end of each treatment. Results: Glycemia was similarly reduced on both treatments (Δfasting glucose: E: -1.3±0.2, p&amp;lt;0.01; I: -0.8±0.2, p&amp;lt;0.01; E vs. I: p=NS) . Fasting insulin concentrations were lower with empagliflozin and higher with insulin (E: 92±12 vs. 180±27 pmol/L, p&amp;lt;0.001) . Fasting hepatic glucose production (HGP) was increased with empagliflozin compared to insulin (19.5±0.8 vs. 16.6±0.6 µmol/kg/min, p&amp;lt;0.001) , but postprandial HGP did not differ between treatments. BGS was greater with empagliflozin compared to insulin (0.82±0.1 vs. 0.59±0.pmol/ (kg·min·mM) , p=0.001) . IS (AUC Glucose Rd, tissue /AUC Insulin) was unchanged with empagliflozin, but decreased with insulin compared to washout (0.09±0.vs. 0.11±0.02 µmol/ (kg FFM·pM·min) , p=0.025) . Fatty tissue insulin resistance (Adipo-IR: fasting FFA x fasting insulin) was lower with empagliflozin compared to insulin (77±vs. 110±17 mmol/L x pmol/L, p=0.012) . Conclusion: Improved beta-cell function during empagliflozin treatment is not a result of reduced glucotoxicity. Peripheral hyperinsulinemia may induce insulin resistance. Disclosure R.Thirumathyam: None. E.A.Richter: None. J.Goetze: Consultant; Novo Nordisk A/S. P.L.Madsen: None. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. S.Madsbad: None. N.B.Jørgensen: Advisory Panel; Novo Nordisk A/S, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Novo Nordisk A/S, Stock/Shareholder; Eli Lilly and Company, Novo Nordisk A/S. Funding Boehringer Ingelheim Gmbh Investigator initiated study grant

722-P: Tirzepatide Improves Multiple Aspects of Beta-Cell Function

We investigated the effect of tirzepatide (TZP) 15 mg (novel GIP-GLP-1 dual receptor agonist) , placebo and semaglutide 1 mg (SEMA) on beta-cell function using euglycaemic and hyperglycemic glucose clamps (EGC, HGC) and Mixed Meal Tolerance Tests (MMTT) in a 28-week double-blind randomized controlled trial of people with type 2 diabetes. During EGC and HGC, TZP improved insulin sensitivity (M-value) , first and second phase insulin secretion (ISR) and beta-cell glucose sensitivity (ratio of ISR and glucose increments) more than SEMA and placebo (Table; EASD symposium 2021) . During MMTT, both fasting and AUC glucose were reduced more with TZP than with SEMA or placebo, while incremental glucose AUC was reduced with TZP and SEMA vs. placebo similarly. Despite similarly reduced incremental glucose AUC, insulin AUC and incremental insulin AUC were reduced by TZP but not by SEMA. Model-derived beta-cell glucose sensitivity was increased with TZP and SEMA from baseline similarly. In contrast, ISR at 7.2 mmol/L glucose increased more with TZP than with placebo and SEMA (Table) . The glucose-lowering effect of TZP is mediated through improvements in multiple aspects of beta-cell function, including beta-cell glucose sensitivity and ISR, and in insulin sensitivity, resulting in pronounced lowering of fasting and postprandial glucose. These effects help explain the superior improvement in glucose control seen with TZP vs. comparators in clinical trials. Disclosure A. Mari: Consultant; Lilly. Research Support; Lilly. J. Li: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. S. Urva: Employee; Eli Lilly and Company. T. Heise: Advisory Panel; Novo Nordisk A/S. Research Support; ADOCIA, AstraZeneca, Biocon, Boehringer Ingelheim International GmbH, Crinetics Pharmaceuticals, Inc., Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Genova, Nestlé, Neuraly Inc., Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker's Bureau; Eli Lilly and Company, Gan &amp; Lee Pharmaceuticals, Novo Nordisk A/S. J. De Vries: Advisory Panel; ADOCIA, Novo Nordisk A/S, Zealand Pharma A/S. Speaker's Bureau; Novo Nordisk A/S. E.J. Pratt: Employee; Eli Lilly and Company. R.J. Heine: Employee; Eli Lilly and Company. M.K. Thomas: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Z. Milicevic: Employee; Eli Lilly and Company. K.J. Mather: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

1280-P: Use of Machine Learning to Determine the Relative Influence (RI) of Genetic Risk Scores of Glycemic Traits on Myocardial Infarction and Stroke in 409,633 Participants in the UK Biobank

Introduction: Genome-wide association studies have identified numerous glycemic traits-associated SNPs with myocardial infarction (MI) and stroke. However, conventional regression methods combining these large numbers of highly significant SNPs in a weighted genetic risk score (wGRS) have only explained a small proportion of variance in MI and stroke. Therefore, we used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for glycemic traits with MI and stroke in the UK Biobank population. Methods: We identified 4626 SNPs associated with glycemic traits from the NGHRI catalogue for GWAS studies. wGRS were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on prevalent stroke and MI in the UK Biobank population. Results: The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m2. The prevalence rates of MI and stroke were 3.6% and 2.3%. In the GBM model, top wGRS associated with MI were type 2 diabetes (RI=14.6) , blood glucose levels adjusted for fasting time (RI=12.2) and beta-cell glucose sensitivity (RI=10.06) . In contrast, the top wGRS associated with stroke were HbA1c (RI=12.13) and fasting insulin levels (RI=10.31) . The addition of wGRS’s to the model comprising the baseline characteristics slightly improved the AUC for predicting stroke and MI. Conclusion: We showed a differential effect of wGRS for various glycemic traits on the risk of MI and stroke in the UK Biobank population. However, even in machine learning models, these wGRS for various glycemic traits had a limited utility in predicting stroke and MI in the general population. Disclosure H.Deshmukh: None. M.Miles: None. A.Bhaiji: None. N.Shah: None. S.Akbar: None. M.Papageorgiou: None. T.Sathyapalan: n/a. Funding NIHR Clinical Lectureship

357-OR: Improved Glycemic Control in Persons with Type 2 Diabetes Improves Beta-Cell Actions of Endogenous Glucose-Dependent Insulinotropic Polypeptide

The insulinotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) is severely reduced or even absent in persons with type 2 diabetes but may be partly regained following improved glycemic control. Here, we examined the beta cell response to endogenous GIP before and after a period of plasma glucose (PG) normalization. In a randomized, double-blind design, 15 metformin-treated persons with dysregulated type 2 diabetes (HbA1c 8.3±0.3% (67±3 mmol/mol) ([mean±SEM]) were subjected to two 75 g-oral glucose tolerance tests (OGTT) with continuous infusions of GIP receptor antagonist (GIP (3-30) NH2) and placebo (saline) , respectively, before and in the end of a 3-4 week period of PG normalization achieved using administration of empagliflozin and individually dosed insulin based on continuous glucose monitoring (CGM) (fasting PG (FPG) target: 72-1mg/mL (4.0-5.9 mmol/L) ; 2-hour postprandial PG target: &amp;lt;162 mg/mL (&amp;lt;9.0 mmol/L)) . At the end of the PG normalization period, FPG was reduced from 195±mg/mL (10.8±0.6 mmol/L) to 114±4 mg/mL (6.3±0.2 mmol/L) (P&amp;lt;0.001) and area under curve (AUC) for PG during OGTT diminished (3,409±95 vs. 2,428±91 mmol/L×min, P&amp;lt;0.001) . Before the period of PG normalization, GIP (3-30) NH2 did not affect oral glucose tolerance. PG normalization amplified GIP (3-30) NH2-induced lowering of beta cell glucose sensitivity (∆baseline-subtracted AUCplasma C-peptide:PG ratio: 1,579±380 vs. 3,296±617 pmol/mmol×min, P=0.021) and resulted in a significant effect of GIP (3-30) NH2 on oral glucose tolerance (baseline-subtracted AUCPG: 1,146±65 vs. 1,225±58 mmol/L×min, P=0.025) . In persons with dysregulated type 2 diabetes, a period of PG normalization increased beta cell sensitivity to GIP, translating into a detectable contribution of endogenous GIP to oral glucose tolerance. Disclosure B.Hoe: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. M.B.Lynggaard: None. L.S.Gasbjerg: Speaker's Bureau; Eli Lilly and Company, Stock/Shareholder; Antag Therapeutics. M.M.Helsted: None. S.Stensen: Employee; Novo Nordisk A/S. B.Hartmann: Board Member; Bainan Biotech. J.J.Holst: Advisory Panel; Novo Nordisk, Board Member; Antag Therapeutics, Bainan Biotech. M.B.Christensen: None. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. Funding The Novo Nordisk Foundation

Glucagon-like peptide-1 and beta cell glucose sensitivity - a glucose ramp study in mice

The incretin glucagon-like peptide-1 (GLP-1) is a gut hormone but also locally produced in pancreatic islets. We evaluated effects of GLP-1 on the insulin response to a gradual increase in glucose in mice within physiological levels. We initially developed a glucose ramp technique in mice. Glucose levels were slowly increased by 0.2 mmol/l/min for 40 min under control conditions, during intravenous infusion of GLP-1 and in GLP-1 receptor knockout mice. In control mice, glucose levels increased from 8.5 ± 0.3 to 16.1 ± 0.3 mmol/l over the 40 min, i.e., by 0.22 ± 0.01 mmol/l/min. This resulted in a slow increase in insulin levels by 96 ± 38 pmol/l from the baseline of 319 ± 53 pmol/l. GLP-1 at 0.5 nmol/kg as bolus plus 0.3 nmol/kg/min over 40 min progressively increased this insulin response by 100-fold, to 9.5 ± 0.2 nmol/l (P < 0.001). Higher doses of GLP-1 enhanced the insulin response similarly (1.0 or 3.0 nmol/kg bolus followed by 0.4 or 1.2 nmol/kg/min), whereas a lower dose (0.3 nmol/kg bolus plus 0.15 nmol/kg/min) had no significant effect compared to controls. Moreover, there was no significant difference in insulin responses between controls and GLP-1 receptor knockout mice. Since the increase in glucose levels were standardized, there was no significant difference in glucose levels between the experimental groups. We conclude that the glucose ramp technique is a tool for studies on insulin responses to slow changes in circulating glucose levels in mice. We also conclude that GLP-1 is extraordinarily potent in enhancing the insulin response to a slow increase in glucose levels.

Haplotypes of the genes (GCK and G6PC2) underlying the glucose/glucose-6-phosphate cycle are associated with pancreatic beta cell glucose sensitivity in patients with newly diagnosed type 2 diabetes from the VNDS study (VNDS 11).

Elevated fasting plasma glucose has been associated with increased risk for development of type 2 diabetes (T2D). The balance between glucokinase (GCK) and glucose-6-phosphate catalytic subunit 2 (G6PC2) activity are involved in glucose homeostasis through glycolytic flux, and subsequent insulin secretion. In this study, we evaluated the association between the genetic variability of G6PC2 and GCK genes and T2D-related quantitative traits. In 794 drug-naïve, GADA-negative, newly diagnosed T2D patients (VNDS; NTC01526720) we performed: genotyping of 6 independent tag-SNPs within GCK gene and 5 tag-SNPs within G6PC2 gene; euglycaemic insulin clamp to assess insulin sensitivity; OGTT to estimate beta-cell function (derivative and proportional control; DC, PC) by mathematical modeling. Genetic association analysis has been conducted using Plink software. Two SNPs within GCK gene (rs882019 and rs1303722) were associated to DC in opposite way (both p < 0.004). Two G6PC2 variants (rs13387347 and rs560887) were associated to both parameters of insulin secretion (DC and PC) and to fasting C-peptide levels (all p < 0.038). Moreover, subjects carrying the A allele of rs560887 showed higher values of 2h-plasma glucose (2hPG) (p = 0.033). Haplotype analysis revealed that GCK (AACAAA) haplotype was associated to decreased fasting C-peptide levels, whereas, the most frequent haplotype of G6PC2 (GGAAG) was associated with higher fasting C-peptide levels (p = 0.001), higher PC (β = 6.87, p = 0.022) and the lower 2hPG (p = 0.012). Our findings confirmed the role of GCK and G6PC2 in regulating the pulsatility in insulin secretion thereby influencing insulin-signaling and leading to a gradual modulation in glucose levels in Italian patients with newly diagnosed T2D.

170-OR: Hypothalamic Gliosis Predicts Decline in Insulin Sensitivity over One Year in People with Obesity

Studies demonstrate evidence of gliosis in the mediobasal hypothalamus (MBH) of people with obesity and T2D or impaired glucose tolerance (IGT), but whether MBH gliosis predicts worsening glucose homeostasis is unknown. The study evaluated 38 subjects with obesity (68% female, 76% White). Mean age was 47±11 y and BMI was 35±3.9 kg/m2. MRI, DXA, and 75 g OGTT were performed at baseline and DXA and OGTT repeated at 1y. Mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions was measured as a marker of gliosis. Serial blood samples from OGTT were used to calculate glucose area under the curve (incremental [iAUC] and total [totalAUC]) and to model insulin sensitivity (OGIS) and beta-cell function (beta-cell glucose sensitivity). Generalized estimating equations tested associations and interactions by region. On average, measures of glucose tolerance (iAUC and totalAUC), OGIS, and beta-cell glucose sensitivity were stable over 1 y. Baseline bilateral mean MBH T2 relaxation time was not associated with changes in glucose tolerance (Δ iAUC β: -5.8 ms, 95% CI -21.0, 9.4, P=0.45; Δ totalAUC β: 1.3 ms, 95% CI -33.5, 36.0, P=0.94, adjusted for sex, age) or change in glucose sensitivity (β: 0.3 ms, 95% CI -1.0, 1.6, P=0.66) nor were interactions present. Change in OGIS over 1y was significantly negatively associated with bilateral mean MBH T2 relaxation time at baseline (β: -0.94 ms, 95% CI -1.7, -0.2, P=0.02, adjusted for sex, age); subjects with longer MBH T2 relaxation times at baseline reduced OGIS over 1 y. A formal interaction by region was not significant (chi2(7)=7.11, Pint=0.42). The relationship within the MBH was attenuated when also adjusted for change in fat mass (β: -0.70 ms 95% CI -1.4, 0.02, P=0.056). Subjects with greater radiologic evidence for MBH gliosis exhibited declines in insulin sensitivity over 1 y which were not fully accounted for by changes in adiposity. These longitudinal findings are consistent with a role for MBH gliosis in T2D pathogenesis in people with obesity. Disclosure J. L. Rosenbaum: None. S. Schoen: None. S. J. Melhorn: None. M. De leon: None. M. Webb: None. K. Utzschneider: None. E. Schur: None. Funding American Diabetes Association (1-17-ICTS-085 to E.S.)

Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Randomised Blinded Phase 2 Trial

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site. The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test). In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping. Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes. Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975. Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk and Pfizer, and is co-founder and chief medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.

Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans

Aims/hypothesisType 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the “disappearance” of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. MethodsUsing immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. ResultsThe islets of diabetic subjects were 3 times more innervated than controls (0.91 ± 0.21 vs 0.32 ± 0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = −0.84; p = 0.01), incremental second-phase insulin secretion (r = −0.84, p = 0.03) and arginine-stimulated insulin secretion (r = −0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). Conclusions/interpretationNoradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Corrigendum to: "Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity".

Corrigendum to: "Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity".

Serum sclerostin and glucose homeostasis: No association in healthy men. Cross-sectional and prospective data from the EGIR-RISC study.

Sclerostin, an inhibitor of bone formation, has emerged as a potential negative regulator of glucose homeostasis. We aimed to investigate if serum sclerostin associates with insulin sensitivity, beta cell function, prediabetes or metabolic syndrome in healthy men. Serum sclerostin was measured in basal and insulin-stimulated samples from 526 men without diabetes from the RISC cohort study. An OGTT was performed at baseline and after 3years. An IVGTT and a hyperinsulinaemic-euglycaemic clamp were performed at baseline. Insulin sensitivity was estimated by the oral glucose sensitivity index (OGIS) and the M-value relative to insulin levels. Beta cell function was assessed by the acute and total insulin secretion (ISRtot) and by beta cell glucose sensitivity. Serum sclerostin levels correlated positively with age but were similar in individuals with (n=69) and without (n=457) prediabetes or the metabolic syndrome. Serum sclerostin was associated with measures of neither insulin sensitivity nor beta cell function at baseline in age-adjusted analyses including all participants. However, baseline serum sclerostin correlated inversely with OGIS at follow-up in men without prediabetes (B: -0.29 (-0.57, -0.01) p=0.045), and inversely with beta cell glucose sensitivity in men with prediabetes (B: -13.3 (-26.3, -0.2) p=0.046). Associations between serum sclerostin and 3-year changes in measures of glucose homeostasis were not observed. Acute hyperinsulinemia suppressed serum sclerostin (p=0.02), and this reduction correlated with OGIS and ISRtot. Overall, serum sclerostin was not associated with prediabetes, insulin sensitivity or insulin secretion in healthy men. The inverse relationship between serum sclerostin and insulin sensitivity at follow-up was weak and likely not of clinical relevance. The ability of insulin to reduce sclerostin, possibly promoting bone formation, needs to be clarified.

Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity

ContextPancreatic beta-cell glucose sensitivity is the slope of the plasma glucose-insulin secretion relationship and is a key predictor of deteriorating glucose tolerance and development of type 2 diabetes. However, there are no large-scale studies looking at the genetic determinants of beta-cell glucose sensitivity.ObjectiveTo understand the genetic determinants of pancreatic beta-cell glucose sensitivity using genome-wide meta-analysis and candidate gene studies.DesignWe performed a genome-wide meta-analysis for beta-cell glucose sensitivity in subjects with type 2 diabetes and nondiabetic subjects from 6 independent cohorts (n = 5706). Beta-cell glucose sensitivity was calculated from mixed meal and oral glucose tolerance tests, and its associations between known glycemia-related single nucleotide polymorphisms (SNPs) and genome-wide association study (GWAS) SNPs were estimated using linear regression models.ResultsBeta-cell glucose sensitivity was moderately heritable (h2 ranged from 34% to 55%) using SNP and family-based analyses. GWAS meta-analysis identified multiple correlated SNPs in the CDKAL1 gene and GIPR-QPCTL gene loci that reached genome-wide significance, with SNP rs2238691 in GIPR-QPCTL (P value = 2.64 × 10−9) and rs9368219 in the CDKAL1 (P value = 3.15 × 10−9) showing the strongest association with beta-cell glucose sensitivity. These loci surpassed genome-wide significance when the GWAS meta-analysis was repeated after exclusion of the diabetic subjects. After correction for multiple testing, glycemia-associated SNPs in or near the HHEX and IGF2B2 loci were also associated with beta-cell glucose sensitivity.ConclusionWe show that, variation at the GIPR-QPCTL and CDKAL1 loci are key determinants of pancreatic beta-cell glucose sensitivity.

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.

Sustained Improvements in Glucose Metabolism Late After Roux-En-Y Gastric Bypass Surgery in Patients with and Without Preoperative Diabetes

To describe glucose metabolism in the late, weight stable phase after Roux-en-Y Gastric Bypass (RYGB) in patients with and without preoperative type 2 diabetes we invited 55 RYGB-operated persons from two existing cohorts to participate in a late follow-up study. 44 (24 with normal glucose tolerance (NGT)/20 with type 2 diabetes (T2D) before surgery) accepted the invitation (median follow-up 2.7 [Range 2.2–5.0 years]). Subjects were examined during an oral glucose stimulus and results compared to preoperative and 1-year (1 y) post RYGB results. Glucose tolerance, insulin resistance, beta-cell function and incretin hormone secretion were evaluated. 1 y weight loss was maintained late after surgery. Glycemic control, insulin resistance, beta-cell function and GLP-1 remained improved late after surgery in both groups. In NGT subjects, nadir glucose decreased 1 y after RYGB, but did not change further. In T2D patients, relative change in weight from 1 y to late after RYGB correlated with relative change in fasting glucose and HbA1c, whereas relative changes in glucose-stimulated insulin release correlated inversely with relative changes in postprandial glucose excursions. In NGT subjects, relative changes in postprandial nadir glucose correlated with changes in beta-cell glucose sensitivity. Thus, effects of RYGB on weight and glucose metabolism are maintained late after surgery in patients with and without preoperative T2D. Weight loss and improved beta-cell function both contribute to maintenance of long-term glycemic control in patients with type 2 diabetes, and increased glucose stimulated insulin secretion may contribute to postprandial hypoglycemia in NGT subjects.

1827-P: Higher Glucagon-Like Peptide-1 Response and Lower Beta-Cell Glucose Sensitivity Are Associated with Increased Glycemic Variability among Individuals with Prediabetes

Background: Increased glycemic variability (GV) is thought to represent abnormalities of glucose homeostasis in the progression from prediabetes to diabetes. We evaluated the association between GV, beta-cell function and glucagon-like peptide 1 (GLP-1) response among individuals with prediabetes. Methods: 61 individuals with prediabetes (age Mean±SD 56±9 years, 31 male) each wore a blinded continuous glucose monitor (Medtronic iPro2) for 72 hours. Standard deviation (SD) and coefficient of variation (CV) were calculated from CGM glucose. Participants underwent a 2-hour mixed-meal tolerance test with measurement of insulin, C-peptide, GLP-1 for modelling of beta-cell function. Results: Early and late GLP-1/glucose ratio were positively correlated with CGM sensor glucose SD (r = 0.29, p=0.02 and r= 0.28 p = 0.048 respectively). Beta-cell glucose sensitivity (βCGS) was negatively correlated with SD (r = -0.28, p = 0.03). In multivariate analyses, only βCGS and GLP-1 response were significant predictors of SD, while early phase insulin and insulin secretion rate predicted average sensor glucose but not indices of GV. Conclusions: Higher GLP-1 response and reduced βCGS are associated with greater glucose fluctuations in the prediabetic range. Disclosure E. Chow: Research Support; Self; Powder Pharmaceuticals Inc., Sanofi-Aventis. A. Luk: None. J. Ling: None. A.P. Kong: Advisory Panel; Self; Lilly Diabetes. Research Support; Self; AstraZeneca, Lilly Diabetes. Speaker's Bureau; Self; Abbott. Other Relationship; Self; AstraZeneca, Novartis Pharmaceuticals Corporation, Sanofi. R.C. Ma: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Research Support; Self; AstraZeneca, Bayer AG, Pfizer Inc. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; AstraZeneca. E. Ferrannini: None. J.C. Chan: Board Member; Self; Asia Diabetes Foundation. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Merck Sharp &amp; Dohme Corp., Sanofi-Aventis. Research Support; Self; Amgen Inc., AstraZeneca, Lee Powder, Lilly Diabetes, Pfizer Inc., Sanofi-Aventis. Speaker's Bureau; Self; Ascensia Diabetes Care. Stock/Shareholder; Self; GemVCare.