Early-phase Insulin Secretion Research Articles

Geriatric nutritional risk index is correlated with islet function but not insulin resistance in elderly patients with type 2 diabetes: A retrospective study.

The geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool that can predict poor prognosis in elderly subjects. The aim of this study was to evaluate the association between GNRI and both islet function and insulin sensitivity in patients with type 2 diabetes mellitus. This research carries significant implications for the integrated treatment and nutritional management of this patient population. A total of 173 patients with type 2 diabetes mellitus, aged 60 years or older, who were hospitalized in the Endocrinology Department at Hebei General Hospital from February 2018 to June 2021, were selected as the research subjects. These subjects were divided into 4 groups according to the quartile of their GNRI values: T1 (GNRI < 99.4, n = 43), T2 (99.4 ≤ GNRI < 103, n = 43), T3 (103 ≤ GNRI < 106.3, n = 43), and T4 (GNRI ≥ 106.3, n = 44). Glucose, insulin, and C-peptide concentrations were tested at 0, 30, 60, 120, and 180 minutes during a 75 g oral glucose tolerance test. The homeostasis model assessment for insulin resistance and the homeostasis model assessment for β cell function index were calculated. As the GNRI value increased, the levels of total protein, albumin, hemoglobin, alanine transaminase, aspartate aminotransferase, and 25-hydroxyvitamin D increased significantly. The area under the curve for blood glucose decreased significantly across the 4 groups, while the AUCs for insulin and C-peptide showed an overall increasing trend. β Cell function index increased significantly with the increase of GNRI; meanwhile, both the early-phase insulin secretion index and the late-phase insulin secretion index increased significantly. Although there was an increasing trend, homeostasis model assessment for insulin resistance did not change significantly among the 4 groups. This study indicates that elderly type 2 diabetes patients with higher nutritional risk have worse islet function, while insulin sensitivity is not associated with nutritional risk.

Early-phase insulin secretion during mixed-meal tolerance testing predicts β-cell function and secretory capacity in cystic fibrosis.

Secondary data analysis of CF-focused prospective studies was performed in PwCF categorized as 1) pancreatic insufficient [PI-CF] or 2) pancreatic sufficient [PS-CF] and in 3) non-CF controls. MMTT: insulin secretory rates (ISR) were derived by parametric deconvolution using 2-compartment model of C-peptide kinetics, and incremental area under the curve (AUC) was calculated for 30, 60 and 180-minutes. GPA: acute insulin (AIR) and C-peptide responses (ACR) were calculated as average post-arginine insulin or C-peptide response minus pre-arginine insulin or C-peptide under fasting (AIRarg and ACRarg), ~230 mg/dL (AIRpot and ACRpot), and ~340 mg/dL (AIRmax and ACRmax) hyperglycemic clamp conditions. Relationships of MMTT to GPA parameters were derived using Pearson's correlation coefficient. Predicted values were generated for MMTT ISR and compared to GPA parameters using Bland Altman analysis to assess degree of concordance. 85 PwCF (45 female; 75 PI-CF and 10 PS-CF) median (range) age 23 (6-56) years with BMI 23 (13-34) kg/m2, HbA1c 5.5 (3.8-10.2)%, and FEV1%-predicted 88 (26-125) and 4 non-CF controls of similar age and BMI were included. ISR AUC30min positively correlated with AIRarg (r=0.55), AIRpot (r=0.62), and AIRmax (r=0.46) and with ACRarg (r=0.59), ACRpot (r=0.60), and ACRmax (r=0.51) (all P<0.001). ISR AUC30min strongly predicted AIRarg (concordance=0.86), AIRpot (concordance=0.89), and AIRmax (concordance=0.76) at lower mean GPA values, but underestimated AIRarg, AIRpot, and AIRmax at higher GPA-defined β-cell secretory capacity. Between test agreement was unaltered by adjustment for study group, OGTT glucose category, and BMI. Early-phase insulin secretion during MMTT can accurately predict GPA-derived measures of β-cell function and secretory capacity when functional β-cell mass is reduced. These data can inform future multicenter studies requiring reliable, standardized, and technically feasible testing mechanisms to quantify β-cell function and secretory capacity.

Improvement of early-phase insulin secretion is an independent factor for achieving glycaemic control: A pooled analysis of SEED and DAWN study.

To investigate the effect of improving early phase insulin secretion function for glycaemic control in patients with type 2 diabetes mellitus treated with a new class of antidiabetic drug dorzagliatin. Early insulin secretion function was studied in 726 participants of which 414 were treated with dorzagliatin in the SEED and DAWN study. The early insulinogenic index (IGI30min ) and disposition index (DI) were used to assess early-phase insulin secretion function in this study. Logistic regression analysis was performed to verify the importance of IGI30min and DI indices for achieving effective glycaemic control. The reduction in HbA1c has a significant correlation with the improvement of IGI30min for patients that received 24 weeks of dorzagliatin treatment (p < .001), and this correlation was not observed in the placebo group (p = .364). In the dorzagliatin treatment group, the responders showed significant improvements in homeostasis model assessment 2-β, IGI30min and DI compared with the non-responders. Logistic regression analysis revealed that the odds ratio (OR) for achieving glycaemic control was 1.28 (95% CI 1.14-1.43) for baseline IGI30min , and 1.24 (95% CI 1.14-1.35) for the 24-week incremental IGI30min from baseline. The OR for baseline DI and 24-week changes in DI from baseline were 1.39 (95% CI 1.2-1.6) and 1.30 (95% CI 1.19-1.43) respectively. The timing of insulin secretion analysis showed the significant contribution of early-phase insulin secretion, rather than late-phase insulin secretion, to postprandial glucose control with the OR for the incremental IGI30min and IGI2h to postprandial glucose control were 1.3 (95% CI 1.19-1.42) and 1 (95% CI 1-1.01) respectively. Restoring the impaired early-phase insulin secretion function in patients with type 2 diabetes mellitus is a critical factor for improving the glycaemic control by dorzagliatin treatment.

PS-B11-3: THE ROLE OF INTESTINAL NAMPT-MEDIATED NAD+ BIOSYNTHESIS IN WHOLE-BODY ENERGY AND GLUCOSE METABOLISM

The purpose of the present study was to test our hypothesis that intestinal nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) biosynthesis plays a pivotal role in whole-body energy and glucose metabolism. To this end, we generated a new mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. Under regular chow diet, deletion of intestinal epithelial NAMPT did not affect body weight gain, food intake, or whole-body energy expenditure, suggesting that intestinal epithelial NAMPT deficiency had no significant impacts on overall energy intake or expenditure. However, INKO mice displayed reduced early-phase insulin secretion and postprandial hyperglycemia, at least partly due to diminished glucagon-like peptide-1 (GLP-1) production. In addition, we found that diet-induced obese mice had impaired intestinal NAMPT-mediated NAD+ biosynthesis, associated with impaired GLP-1 production and whole-body glucose metabolism, similar to the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide, to INKO and diet-induced obese mice, restored ileal NAD+ levels and obesity-associated metabolic derangements, manifested by an impairment in GLP-1 production as well as postprandial hyperglycemia. Taken together, our study provides a new understanding of the role of intestinal NAMPT-mediated NAD+ biosynthesis in energy and glucose metabolism, and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia (Nagahisa, Yamaguchi et al. Endocrinology. 2022). A future study using INKO mice to investigate if diminished GLP-1 production is involved in obesity-associated hypertension is warranted.

Association between osteocalcin, a pivotal marker of bone metabolism, and secretory function of islet beta cells and alpha cells in Chinese patients with type 2 diabetes mellitus: an observational study

BackgroundSeveral recent studies have found that Osteocalcin (OCN), a multifunctional protein secreted exclusively by osteoblasts, is beneficial to glucose metabolism and type 2 diabetes mellitus (T2DM). However, the effects of OCN on islets function especially islet ɑ cells function in patients with type 2 diabetes mellitus characterized by a bi-hormonal disease are still unclear. The purpose of this cross-sectional study was to investigate the relationship between serum OCN and the secretion of islet β cells and ɑ cells in Chinese patients with type 2 diabetes mellitus.Methods204 patients with T2DM were enrolled. Blood glucose (FBG, PBG0.5h, PBG1h, PBG2h, PBG3h), insulin (FINS, INS0.5h, INS1h, INS2h, INS3h), C-peptide (FCP, CP0.5h, CP1h, CP2h, CP3h), and glucagon (GLA0, GLA0.5 h, GLA1h, GLA2h, GLA3h) levels were measured on 0 h, 0.5 h, 1 h, 2 h, and 3 h after a 100 g standard bread meal load. Early postprandial secretion function of islet β cells was calculated as Δcp0.5h = CP0.5-FCP. The patients were divided into low, medium and high groups (T1, T2 and T3) according to tertiles of OCN. Comparison of parameters among three groups was studied. Correlation analysis confirmed the relationship between OCN and pancreatic secretion. Multiple regression analysis showed independent contributors to pancreatic secretion.Main resultsFBG, and PBG2h were the lowest while Δcp0.5h was the highest in the highest tertile group (respectively, p < 0.05). INS3h, area under the curve of insulin (AUCins3h) in T3 Group were significantly lower than T1 Group (respectively, p < 0.05). GLA1h in T3 group was lower than T1 group (p < 0.05), and GLA0.5 h in T3 group was lower than T2 and T1 groups (p < 0.05). Correlation analysis showed OCN was inversely correlated with Homeostatic model of insulin resistance (HOMA-IR), INS3h, AUCins3h (p < 0.05), and was still inversely correlated with FCP, GLA0.5 h, GLA1h, area under the curve of glucagon (AUCgla3h) (respectively, p < 0.05) after adjustment for body mass index (BMI) and alanine aminotransferase (ALT). The multiple regression analysis showed that OCN was independent contributor to Δcp0.5h, GLA0.5h and GLA1h (respectively, p < 0.05).ConclusionsHigher serum OCN level is closely related to better blood glucose control, higher insulin sensitivity, increased early-phase insulin secretion of islet β cells and appropriate inhibition of postprandial glucagon secretion of islet ɑ cells in adult patients with type 2 diabetes mellitus.

Age-related adiposity and beta-cell function: impact on prediabetes and diabetes prevalence in middle-aged and older Han Chinese adults.

To investigate the effect of aging on the prevalence of prediabetes and diabetes, and the influence of aging on the associations among adipose mass, redistribution, β cell function, and the prevalence of hyperglycaemia. This urban-based cross-sectional study included 1033 Chinese Han people, aged 40-65years. The abdominal subcutaneous fat area (SFA) and visceral fat area (VFA) were determined by magnetic resonance imaging. The prevalence rates of prediabetes and diabetes were analyzed according to age group (40-49, 50-59, and 60-65years). The effects of aging on abdominal fat mass, adipose distribution, insulin action indexes were also assessed. Prediabetes and diabetes prevalence gradually increased with age. Both SFA and VFA increased, while SFA/VFA decreased, in the 50-59 and 60-65years age groups compared to the 40-49years group. Homeostatic model assessment of insulin resistance (HOMA-IR) increased with fat mass. Homeostatic model assessment of beta-cell function (HOMA-β) and early-phase insulin secretion (∆I30/∆G30) were decreased in the 60-65years group compared to the younger age groups. Increased age, VFA, and HOMA-IR, as well as decreased HOMA-β, were risk factors for the development of prediabetes and diabetes. The associations between central obesity and the development of prediabetes and diabetes, but not the associations of SFA/VFA, HOMA-IR, and HOMA-β with hyperglycaemia prevalence, weakened with age. The prevalence of prediabetes and diabetes increased with age. Central obesity may be related stronger to the development of hyperglycaemia in younger people.

Insulinogenic index and early phase insulin secretion predict increased risk of worsening glucose tolerance and of cystic fibrosis-related diabetes

ObjectiveMeasures of stimulated insulin secretion are emerging as important predictors of diabetes mellitus in at-risk populations. We analyzed the utility of clinical estimates of insulin secretion in a prospective cohort at risk for cystic fibrosis-related diabetes (CFRD). MethodsWe divided the profiles of 189 people with CF (pwCF) followed longitudinally in the Montreal CF cohort (mean follow up 6.6 ± 1.2 years) according to quartiles of the insulinogenic index (IGI; (I30-I0)/(G30-G0)); area under the curve for insulin normalized for glucose (AUCins/glu), and HOMA-B at baseline to compare clinical characteristics and risk of CFRD according to quartiles for each measure. We also compared characteristics of 40 pwCF found to have de novo CFRD at baseline. ResultsAt baseline, IGI and AUCins/glu were lower in subjects with de novo CFRD and those who later developed CFRD than those who never developed CFRD (p < 0.0001 for each). Subjects with the lowest quartiles of IGI, AUCins/glu, and AUCins/glu 0–30 had increased risk of developing CFRD by Kaplan-Meier analysis (p = 0.0244, p = 0.0024, and p = 0.0338, respectively). There was no significant difference in risk between quartiles of HOMA-B. Subjects in the lowest quartile of IGI showed a significant increase in 2-hour OGTT glucose and AUCglu between the initial and final study visits (p = 0.0027 and p = 0.0044, respectively). ConclusionIGI is easily measured in a clinical setting and needs to be validated in prospective studies as a potential tool to improve risk stratification in CFRD with direct relevance to pathogenesis.

Reversal of Diabesity: Normalization of Insulin Release Curve in Association with Reversal of Non-Alcoholic Fatty Liver Disease

Objective: Type 2 diabetes with obesity is regarded as an incurable, progressive disease with many complications. The hypothesis was tested that glycated haemoglobin (HbA1c) and the insulin release curve can be restored by traceable systematic methods. Methods: 122 people with diabesity were investigated before and after three and 6 months of traceable systematic management methods. Basal body mass index (BMI), fatty liver, HbA1c, and insulin release curve were measured. Results: After 3 months of traceable systematic management, BMI decreased from 30.76 ± 0.48 to 21.86 ± 0.09 kg/m2 (p < 0.001) and remained stable during the last 3 months (21.82 ± 0.09 kg/m2 at 6 months). Colour Doppler ultrasound showed non-alcoholic fatty liver disease (NAFLD) in all diabesity participants at baseline. At 3 months, only one participant had low-grade fatty liver, and fatty liver was reversed in other participants (p < 0.001). The number and grade of fatty liver at 6 months were the same as at 3 months. Fasting plasma glucose decreased and continued to decrease thereafter (p < 0.001). Two-hour postprandial plasma glucose decreased and continued to decline until 6 months (p < 0.001). HbA1c also decreased and maintained this level at 6 months. At baseline, the peak value of insulin release was 1,141.09 ± 43.02 pmol/L at 2 h after meals, and the early phase of insulin secretion was lost. After 3 months of management, the insulin concentration was 621.62 ± 19.32 pmol/L at 2 h after meals. After 6 months, the value decreased, and the early phase of insulin secretion recovered. Conclusions: Normalization of the insulin release curve in type 2 diabetes was achieved by traceable systematic methods. This was associated with recovery from NAFLD. Diabesity is reversible by traceable systematic management.

314-OR: Synaptotagmin-9 Regulates Early Phase Insulin Secretion by Regulating Tomosyn-1

Insulin secretion from pancreatic β-cells occurs in a biphasic manner. The loss of insulin secretion, entailing the inability of insulin granules to fuse with the plasma membrane (PM) via the formation of the SNARE complex, is a key determinant in impaired glucose tolerance and development of type 2 diabetes (T2D) . Synaptotagmins (Syt) are calcium sensors that regulate insulin-containing granule fusion to the PM for insulin secretion. Syt9 is highly expressed in β-cells; however, its role in insulin secretion is not well-characterized. Our goal is to determine how Syt9 affects insulin secretion from pancreatic β-cells. Mice lacking Syt9 (Syt9-/-) have improved glucose clearance with no change in insulin action than wild-type control mice. Interestingly, Syt9-/- mice showed increased plasma insulin levels at 5 min and 15 min post-glucose challenge. Similarly, islets isolated from Syt9-/- mice demonstrate increased stimulation of insulin secretion in response to the early phase insulin secretagogues (KCl and tolbutamide) compared to WT control islets. Similarly, siRNA-mediated knockdown of Syt9 in INS1 cells increased KCL-stimulated insulin secretion at 5 min and min. Altogether, these data suggest that Syt9 regulates the early phase of insulin secretion from β-cells. Strikingly, Syt9-/- mouse islets have reduced Tomosyn-1 levels (∼50%) without altering the levels of other key SNARE proteins (Stx1A, Stx4A, SNAP25) . Tomosyn-1, an inhibitor of insulin secretion whose increased protein abundance is associated with reduced insulin secretion, binds, cofractionates, and colocalizes with Syt9 and Stx1A. The knockdown of Tomosyn-1 in INS1 β-cells treated with KCL prevents the localization of Syt9 with Stx1A. Further, the knockdown of Syt9 or Tomosyn-1 increases the SNARE complex formation. In sum, these data demonstrate the identification of a novel Stx1A-Tomosyn-1-Syt9 molecular complex that regulates the fusion of insulin granules in the early phase. Disclosure M.Rahman: None. H.Alsharif: n/a. S.Bhatnagar: None. Funding R01DK120684-01

115-LB: Dorzagliatin Showed Sustained Remission in an Observational Study after Discontinuation of Treatment in T2D Patients Who Achieved Good Glycemic Control with Dorzagliatin Monotherapy

Diabetes remission is the optimal goal for treating T2D. While most remission studies focused on metabolic surgery, lifestyle interventions, and intensive insulin therapy, little evidence was found with oral antidiabetic drugs. Dorzagliatin is an oral dual-acting glucokinase activator which has shown effective glycemic control with significant improvements in early-phase insulin secretion and β-cell function. DREAM was an observational, non-pharmacological, non-interventional diabetes remission study, an extension study of a phase 3 monotherapy trial (SEED) with dorzagliatin. Initiated by investigators from 5 in 40 study sites in SEED, DREAM aimed to observe whether patients who had completed SEED and achieved good glycemic control were able to achieve diabetes remission without any antidiabetic medication. In total, 69 subjects previously with drug-naïve T2D and treated with dorzagliatin for 28 or 52 weeks in SEED were enrolled. The primary endpoint was the diabetes remission rate after 52 weeks of dorzagliatin withdrawal, estimated by the Kaplan-Meier method. At week 52, 36 subjects maintained stable glycemic control and the remission rate was 65.2% (95% CI, 53.4 to 77.0) . These 36 patients had shown improvement of early-phase insulin secretion (C30/G30) after dorzagliatin treatment in SEED. Improvements of β-cell function and insulin resistance were sustained during DREAM (indicated by HOMA2-β of 43.8 at baseline and 56.6 at week 52, HOMA2-IR of 1.58 at baseline and 1.46 at week 52) . According to a consensus released in Aug 2021 by ADA, diabetes remission was defined as HbA1c&amp;lt;6.5% measured at least 3 months after cessation of glucose-lowering pharmacotherapy. Based on this definition, the remission rate was 52.0% (95% CI, 31.2 to 69.2) . DREAM observed sustained glycemic control in a high proportion of subjects after withdrawal of dorzagliatin monotherapy, indicating that improvements of early-phase insulin secretion and β-cell function may be a potential mechanism for diabetes remission. Disclosure J. Zeng: None. S. Gan: None. X. Dong: None. Y. Liu: None. X. Su: None. J. Luo: None. J. Ma: None.

117-LB: Glucokinase Activator Restores Glucose Sensitivity and Early-Phase Insulin Secretion in T2DM Patient—A Post Hoc Analysis of Dorzagliatin

Background: Insulinogenic index (IGI) and disposition index (DI) measures patient’s early phase insulin secretion ability and glucose sensitivity. Pervious clinical trials of dorzagliatin have showed excellent effect on glycemic control and good safety profile in Chinese T2DM patients. This post-hoc analysis was focused on evaluating the correlation between glycemic control and the restoration effect of glucokinase activator on β-cell function. Method: The analysis has involved two phase III clinical trials of dorzagliatin, monotherapy (SEED) (NCT03173391) and metformin add-on (DAWN) (NCT03141073) , respectively. The change of HOMA2-IR, IGI and DI from baseline to 24 weeks were analyzed. Correlation between glycemic control status and patient’s early phase insulin secretion ability as well as glucose sensitivity were further demonstrated by logistic regression analysis with IGI, DI, HOMA2-IR and other characteristics. Results: Totally 726 patients were included in the final analysis set, with 241 patients from SEED cohort and 485 patients from DAWN. After 24 weeks treatment, two cohorts showed the consistent result of IGI and DI improvement. Nevertheless, The improvement of IGI and DI for HbA1c controlled group (HbA1c &amp;lt;7%) were significantly higher than HbA1c uncontrolled group (HbA1c ≥ 7%) . The result was also consistent across different disease course groups in DAWN cohort considering the relatively longer disease course. Logistic regression analysis revealed that both the improvement of IGI and DI were independent influential factor of patient’s HbA1c controlled status after treatment of dorzagliatin. Conclusion: The post hoc analysis demonstrated the beneficial effect of dorzagliatin on early insulin secretion ability and glucose sensitivity on T2DM patients. The HbA1c control status were significantly affected by improvement of early insulin secretion ability and glucose sensitivity both for drug naïve patients and metformin tolerated patient. Disclosure L. Feng: Employee; Hua Medicine. Q. Guo: None. C. Chen: Employee; Hua Medicine. X. Liu: Employee; Hua Medicine. L. Chen: Employee; Hua Medicine. W. Yang: Advisory Panel; Hua Medicine. Funding Hua Medicine

Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice.

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

Prevalence of Post–Glucose Challenge Hypoglycemia in Adult Patients With Cystic Fibrosis and Relevance to the Risk of Cystic Fibrosis–Related Diabetes

ObjectivesThe clinical relevance of fasting and postprandial hypoglycemia in patients with cystic fibrosis (CF) is poorly characterized. Our aim in this study was to characterize the prevalence of hypoglycemia in adult patients during oral glucose tolerance test (OGTT) screening and determine its impact on the risk of developing CF-related diabetes (CFRD). MethodsWe analyzed 2 cohorts of pancreatic insufficient patients with CF exposed to comparable treatment recommendations in France (Lyon CF cohort [DIAMUCO]) and Canada (Montréal CF cohort [MCFC]). Patients were classified into 3 groups based on hypoglycemia absence or presence as well as its severity at baseline. We defined the groups as follows: level 2 hypoglycemia (L2H; plasma glucose [PG]<3.0 mmol/L), level 1 hypoglycemia (L1H; PG 3.0 to <4.0 mmol/L) and no hypoglycemia (NH) during an OGTT. ResultsA total of 153 MCFC and 114 DIAMUCO subjects were included in the study. In total, 22% of the patients experienced hypoglycemia, with 5% having it on 2 or more OGTTs. The L1H and L2H groups tended to have a lower 2-hour glucose and higher early-phase insulin secretion (insulin area under the curve at 0 to 30 minutes) compared with NH patients. In both cohorts, a greater proportion of men and patients with normal glucose tolerance had hypoglycemia. Over a 5-year period, there were no cases of CFRD in the L2H group, whereas 4 subjects in the L1H group and 36 in the NH group developed CFRD. ConclusionsPatients with hypoglycemia were at lower risk of developing CFRD, but at higher risk of early-phase insulin secretion and unsuppressed insulin secretion. This could potentially lead to further hypoglycemia after the 2-hour OGTT, suggesting high clinical relevance.

Insulinogenic Index and Early Phase Insulin Secretion Predict Increased Risk of Worsening Glucose Tolerance and of Cystic Fibrosis-Related Diabetes

Determine whether clinical estimates of insulin secretion derived from oral glucose tolerance test (OGTT) might improve cystic fibrosis-related diabetes (CFRD) risk prediction.

125-OR: Synaptotagmin 9 Regulates Tomosyn-2 Protein Abundance to Affect Early Phase of Insulin Secretion

Insulin secretion from pancreatic β-cells occurs in a biphasic manner. The loss of the early phase of insulin secretion, which occurs due to the inability of insulin granules to fuse with the plasma membrane (PM) via the formation of the SNARE complex, acts as a key determinant in impaired glucose tolerance and development of type 2 diabetes (T2D). Thus, it is critical to elucidate molecular mechanisms underlying early-phase insulin secretion. Tomosyn-2 binds to Stx1A, a key component of the SNARE complex, and functions as an endogenous inhibitor of insulin secretion. The mechanism by which Tomosyn-2 regulates the fusion of insulin granules is not completely understood. Our preliminary data show that Tomosyn-2 binds, colocalizes, and co-fractionates with synaptotagmin-9 (Syt9) at high glucose; Syt9 protein is present in the insulin granule membrane, and its role in insulin secretion remains poorly defined. Our data show that mice lacking Syt9 (Syt9-/-) have improved glucose clearance, increased in vivo early-phase insulin secretion at 5 min and 15 min post-glucose challenge with no change in insulin tolerance vs. the wild type control mice, suggesting that Syt9 regulates the early phase of insulin secretion from β-cells. Strikingly, Syt9-/- mouse islets have reduced Tomosyn-2 levels (∼50%) without altering the levels of other key SNARE proteins. The knockdown of Tomosyn in INS1 β-cells treated with KCL prevents the localization of Syt9 with Stx1A. These results show that Syt9 binding stabilizes Tomosyn-2 protein in a non-fusogenic complex by potentially blocking insulin granules’ access to the PM-Stx1A for membrane fusion and insulin secretion. In summary, our data reveal a novel molecular complex in Stx1A-Tomosyn-2-Syt-9 to regulate the early-phase insulin secretion. Disclosure A. Pathak: None. H. Alsharif: None. J. E. Trombley: None. M. Rahman: None. S. Bhatnagar: None. Funding National Institutes of Health (R01DK120684-01)

Time to the Peak, Shape of the Curve and Combination of These Glucose Response Characteristics During Oral Glucose Tolerance Test as Indicators of Early Beta-cell Dysfunction in Obese Adolescents

Objective:Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT).Methods:Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/≥60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI).Results:Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001].Conclusion:Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.

Saliva 1,5-anhydroglucitol is associated with early-phase insulin secretion in Chinese patients with type 2 diabetes

IntroductionSaliva collection is a non-invasive test and is convenient. 1,5-anhydroglucitol (1,5-AG) is a new indicator reflecting short-term blood glucose levels. This study aimed to explore the relationship between saliva 1,5-AG...

GRK2 regulates GLP-1R-mediated early phase insulin secretion in vivo

BackgroundInsulin secretion from the pancreatic β-cell is finely modulated by different signals to allow an adequate control of glucose homeostasis. Incretin hormones such as glucagon-like peptide-1 (GLP-1) act as key physiological potentiators of insulin release through binding to the G protein-coupled receptor GLP-1R. Another key regulator of insulin signaling is the Ser/Thr kinase G protein-coupled receptor kinase 2 (GRK2). However, whether GRK2 affects insulin secretion or if GRK2 can control incretin actions in vivo remains to be analyzed.ResultsUsing GRK2 hemizygous mice, isolated pancreatic islets, and model β-cell lines, we have uncovered a relevant physiological role for GRK2 as a regulator of incretin-mediated insulin secretion in vivo. Feeding, oral glucose gavage, or administration of GLP-1R agonists in animals with reduced GRK2 levels (GRK2+/− mice) resulted in enhanced early phase insulin release without affecting late phase secretion. In contrast, intraperitoneal glucose-induced insulin release was not affected. This effect was recapitulated in isolated islets and correlated with the increased size or priming efficacy of the readily releasable pool (RRP) of insulin granules that was observed in GRK2+/− mice. Using nanoBRET in β-cell lines, we found that stimulation of GLP-1R promoted GRK2 association to this receptor and that GRK2 protein and kinase activity were required for subsequent β-arrestin recruitment.ConclusionsOverall, our data suggest that GRK2 is an important negative modulator of GLP-1R-mediated insulin secretion and that GRK2-interfering strategies may favor β-cell insulin secretion specifically during the early phase, an effect that may carry interesting therapeutic applications.

Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women.

In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women. In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

Reduced Birth Weight, Decreased Early-Phase Insulin Secretion, and Increased Glucose Concentrations after Oral Glucose Tolerance Test in Japanese Women Aged 20 Years with Family History of Type 2 Diabetes

Introduction We tested the hypothesis that family history of type 2 diabetes (FHD) is associated with reduced birth weight and reduced insulin secretion later in life. Materials and Methods Birth weight, body composition by whole-body dual-energy X-ray absorptiometry, and homeostasis model assessment-insulin resistance were compared between Japanese women aged 20 years with positive (n = 73) and negative (n = 258) FHD. A subsample of 153 women (57 with positive FHD) underwent a 75 g oral glucose tolerance test. Multivariate logistic regression analyses were used to identify the most important determinants of FHD. Results Women with positive as compared with negative FHD had lower birth weight (3132 ± 364 vs. 3238 ± 418 g, p = 0.04). However, the current fat mass index and trunk/leg fat ratio, sophisticated measures of general and abdominal fat accumulation, respectively, did not differ. Women with positive FHD had a lower insulinogenic index (2.4 ± 7.3 vs. 6.2 ± 16, p = 0.007) and higher area under the glucose curve (217 ± 47 vs. 198 ± 36 mg/dL/2 h, p = 0.006). However, fasting and postload insulinemia, homeostasis model assessment-insulin resistance, and Matsuda index did not differ. In multivariate logistic regression analysis, birth weight was marginally associated with FHD (odds ratio, 0.999; 95% confidential interval, 0.98-1.00000; p = 0.0509). Conclusions FHD was associated not only with reduced birth weight but also with decreased early-phase insulin secretion and increased postload glucose concentrations in Japanese women aged 20 years. These findings may be in keeping with the fetal insulin hypothesis and provide some evidence that FHD can alter size at birth, probably through genetic and shared environmental components, which consequently resulted in decreased early-phase insulin secretion and increased glucose excursion in the early twenties. FHD was not related to sophisticated measures of general and abdominal adiposity and insulin resistance/sensitivity.