Second-phase Insulin Secretion Research Articles

Are treatment options used for adult-onset type 2 diabetes mellitus (equally) available and effective for children and adolescents?

Youth-onset type 2 diabetes mellitus (T2DM), influenced by an increase in obesity, is a rising problem worldwide. Pathophysiological mechanisms of this early-onset T2DM include both peripheral and hepatic insulin resistance, along with increased hepatic fasting glucose production accompanied by inadequate first and second-phase insulin secretion. Moreover, the incretin effect is reduced. The initial presentation of type 2 diabetes can be dramatic and symptoms may overlap with those of type 1 diabetes mellitus. Therefore, immediate therapy should address hyperglycemia and associated metabolic derangements irrespective of ultimate diabetes type, while further therapy adjustments are prone to patients’ phenotype. New agents with proven glycemic and beyond glycemia benefits, such as Glucagon-like polypeptide 1 receptor agonists and Sodium-glucose cotransporter-2 inhibitors, used in the adult population of T2DM patients, might become increasingly important in the treatment armamentarium. Moreover, metabolic surgery is an option for markedly obese (body mass index > 35 kg/m2) children and adolescents suffering from T2DM who have uncontrolled glycemia and/or serious comorbidities when lifestyle and pharmacologic interventions fail. In this mini-review, we will discuss the potential of treatment options considering new data available from randomized control trials, including individuals with adult-onset type diabetes mellitus.

Estimating insulin sensitivity and β-cell function from the oral glucose tolerance test: validation of a new insulin sensitivity and secretion (ISS) model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and β-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes (T2D). Existing methods range in sensitivity, input data, and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological than intravenous methods. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic surrogate indices (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new insulin secretion and sensitivity (ISS) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. This model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. This model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including postchallenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts across the lifespan. The new model had a strong correlation with gold-standard estimates from intravenous glucose tolerance tests and insulin clamps. The ISS model has broad applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.NEW & NOTEWORTHY The pathogenesis of type 2 diabetes (T2D) is determined by a balance between insulin sensitivity (SI) and β-cell function (BCF), which can be determined by gold standard direct measurements or estimated by fitting differential equation models to oral glucose tolerance tests (OGTTs). We propose and validate a new differential equation model that is simpler to use than current models and requires less data while maintaining good correlation and agreement with gold standards. Matlab and Python code is freely available.

Association of GLP-1 secretion with parameters of glycemic control in women after gestational diabetes mellitus

IntroductionWomen with a history of gestational diabetes mellitus (GDM) are at high risk of developing type 2 diabetes, while the exact mechanisms underlying its pathophysiology are still unclear. We investigated...

The Potential Weight Loss Benefits Of Tirzepatide: A Double-Edged Sword?

Madam, Tirzepatide, also known as Mounjaro, has become increasingly popular among diabetic patients due to its potential to aid in weight loss. However, with the growing demand for this medication for its weight-loss benefits, there are apprehensions that it may soon become scarce. Tirzepatide, a dual Glucagon-like peptide (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) receptor agonistis an injectable synthetic peptide with glucose-lowering effects.(1) It stimulates first- and second-phase insulin secretion, and reduce glucagon levels. Since its approval by the FDA in late 2021, Tirzepatide has become increasingly popular among diabetic patients as it has reported a mean decrease of 1.53% in patients' HbA1C levels in the first 40 weeks of use, which is higher than other drugs available in the market(1,2). Many patients also reported significant weight loss after starting the medication, which has led to increased demand for the drug. While this drug is yet to be approved by FDA for weight loss, it is expected that it will be approved for weight loss by mid of 2023. Despite that, some doctors already e off-label as a weight loss drug in people not suffering from Diabetes(3). This can lead to an increased demand for the drug as seen earlier in the case of Ozempic (semaglutide) in 2022 leading to an acute shortage (4). Pharmacies are already reporting low supplies of Tirzepatide, and some patients are facing trouble in getting their prescriptions filled(5). For diabetic patients who are relying on Tirzepatide to manage their blood glucose levels and promote weight loss, this shortage could have serious consequences. Patients who are unable to acquire the drug may be forced to switch to other medications or try alternative treatments, which may not be as effective. In conclusion, the recent surge in demand for Tirzepatide has led to concerns about a potential shortage of the medication. While the drug has shown promise in helping diabetic patients improve glycemic control and promote weight loss, patients need to have access to the medication when they need it. To help mitigate the shortage of Tirzepatide, some experts are calling for increased production of the drug and improved distribution channels to ensure that patients can continue to benefit from this promising treatment option.

Changes in insul resistance, glucose effectiveness, and first and second phase of insulin secretion in women aged 45-60 years old in Taiwan.

In women after menopause, the incidence of diabetes mellitus increases. Increased insulin resistance (IR), decreased glucose effectiveness (GE), and the first and second phases of insulin secretion (FPIS and SPIS), are the four most important factors that trigger glucose intolerance and diabetes (diabetogenic factor [DF]). In the cross-sectional study, we enrolled non-diabetic women between the ages of 45 and 60 years to observe the changes in DFs during the perimenopausal period and to elucidate the underlying mechanisms of diabetes in menopausal women. We randomly enrolled 4,194 women who underwent health checkups. Using demographic and biochemical data, IR, FPIS, SPIS, and GE were calculated using previously published equations. The relationship between the DFs and age was evaluated using a simple correlation. Body mass index, blood pressure, fasting plasma glucose, low-density lipoprotein-cholesterol, triglyceride, and SPIS were higher, and GE was lower in older women (≥ 52 years old). A significant decrease in GE and increased SPIS were observed with age. However, no changes were observed in IR or FPIS. The IR and FPIS did not change during perimenopause. Increased SPIS may compensate for the decrease in GE, which is probably one of the reasons for the higher incidence of diabetes in menopausal women.

Aging Affects Insulin Resistance, Insulin Secretion, and Glucose Effectiveness in Subjects with Normal Blood Glucose and Body Weight.

Several studies have demonstrated that factors including diabetes, including insulin resistance (IR), glucose effectiveness (GE), and the first and second phase of insulin secretion (FPIS, SPIS) could easily be calculated using basic characteristics and biochemistry profiles. Aging is accompanied by deteriorations of insulin resistance (IR) and insulin secretion. However, little is known about the roles of aging in the different phases of insulin secretion (ISEC), i.e., the first and second phase of insulin secretion (FPIS, SPIS), and glucose effectiveness (GE). In total, 169 individuals (43 men and 126 women) recruited from the data bank of the Meei-Jaw (MJ) Health Screening Center and Cardinal Tien Hospital Data Access Center between 1999 and 2008, with a similar fasting plasma glucose (FPG: 90 mg/dL) and BMI (men: 23 kg/m2, women 22 kg/m2) were enrolled. The IR, FPIS, SPIS, and GE were estimated using our previously developed equations shown below. Pearson correlation analysis was conducted to assess the correlations between age and four diabetes factors (DFs: IR, FPIS, SPIS, and GE). The equations that are used to calculate the DF in the present study were built and published by our group. The age of the participants ranged from 18 to 78 years. Men had higher FPIS but lower HDL-C levels than women (2.067 ± 0.159, 1.950 ± 0.186 μU/min and 1.130 ± 0.306, 1.348 ± 0.357 mmol/dl, accordingly). The results of the Pearson correlation revealed that age was negatively related to the IR and GE in both genders (IR: r = -0.39, p < 0.001 for men, r = -0.24, p < 0.003 for women; GE: r = 0.66, p < 0.001 for men, r = 0.78, p < 0.001 for women). At the same time, the FPIS was also only found to be negatively correlated with age in females (r = -0.238, p = 0.003), but there was no difference in the SPIS and age among both genders. We have found that in Chinese subjects with a normal FPG level (90 mg/dL) and body mass index (men: 23 kg/m2, women: 22: kg/m2), age is negatively related to the IR and GE among both genders. Only the FPIS was found to be negatively related to age in women. The tightness of their relationships, from the highest to the lowest, are GE, FPIS, and IR. These results should be interpreted with caution because of the small sample size.

1548-P: GLP-1 and GIP Reduce Insulin Clearance in Individuals with Pancreatic-Insufficient Cystic Fibrosis (PI-CF)

PI-CF is characterized by impaired insulin secretion with disruption of the enteroinsular axis and alterations in incretin secretion and action. We have reported augmented glucose-dependent insulin secretion to glucose-potentiated arginine (GPA) testing with GLP-1 infusion but not GIP, with these effects independent of glucose tolerance in PI-CF. We aimed to assess the effect of incretin infusion on insulin clearance during GPA testing and explore its relationship to second-phase insulin response in individuals with PI-CF in a retrospective analysis. Thirty-two individuals with PI-CF and abnormal glucose tolerance underwent GPA testing of islet function following intravenous infusion of incretin or placebo in a randomized cross-over study design. Sixteen individuals were randomized to incretin infusion with GLP-1 and sixteen with GIP. Insulin clearance was assessed by the molar ratio of acute C-peptide to insulin response over the 5-minutes following glucose-potentiation of arginine-induced insulin and C-peptide secretion (target glucose ~230 mg/dL). Insulin clearance was related to second-phase insulin secretion by hyperbolic function (y=P1/(P2 + x) with a reduction in insulin clearance for increasing second-phase insulin secretion (R2=0.20; p&amp;lt;0.001). A reduction in insulin clearance was observed with both GLP-1 vs. placebo (mean±SD 2.7±2.1 vs. 15.5±5.7; p&amp;lt;0.001) and GIP vs. placebo (2.4±0.8 vs. 18.0±10.8; p&amp;lt;0.001). GLP-1 and GIP appear to reduce insulin clearance in individuals with PI-CF presumably through effects at the liver. Reduced insulin clearance is most apparent following GIP infusion where there is no augmentation of second-phase insulin secretion, supporting that the effect of GIP occurs independently of an increase in pre-hepatic insulin secretion. Further work should explore underlying mechanisms of incretin-induced reduction in insulin clearance in PI-CF that could support therapeutic approaches to improve glucose homeostasis. Disclosure A.Flatt: None. A.Doliba: None. A.J.Peleckis: None. R.C.Rubenstein: None. A.Kelly: None. M.R.Rickels: Consultant; Sernova, Corp., Vertex Pharmaceuticals Incorporated, Zealand Pharma A/S, Research Support; Dompé. Funding National Institutes of Health (R01DK97830, UL1TR001878, P30DK19525, T32DK007314); Cystic Fibrosis Foundation (to M.R.R.)

A minimal mathematical model to study insulin synthesis and secretion process

Insulin, secreted from pancreatic β-cells, plays a vital role in maintaining glucose homeostasis in our body. In various pathophysiological conditions like diabetes, cancer, etc., this glucose-insulin relationship is altered. However, the underlying mechanisms behind the β-cell malfunctioning under these pathophysiological conditions remain a research topic. The current study aimed to explore the key factors responsible for impaired insulin secretion from β-cells. We studied insulin synthesis and secretion processes through a minimal mathematical model incorporating insulin mRNA, proinsulin pool, and insulin granules. Defects in the insulin granule trafficking and exocytosis processes hamper first- and second-phase insulin secretion and might be one of the main reasons for β-cell dysfunction in type 2 diabetes. The long-term effect of abnormal insulin synthesis could hamper insulin secretion and make the scenario more critical, causing complete insulin loss inside the β-cells. Besides, uncontrolled insulin synthesis could increase basal insulin secretion and drive toward fasting hypoglycemia. The present study also hypothesizes that regulation of insulin synthesis through targeting transcription and translation is a potential therapeutic strategy for controlling impaired insulin secretion.

Rapid Quantification of First and Second Phase Insulin Secretion Dynamics using an In vitro Platform for Improving Insulin Therapy

High-throughput quantification of the first- and second-phase insulin secretion dynamics is intractable with current methods. The fact that independent secretion phases play distinct roles in metabolism necessitates partitioning them separately and performing high-throughput compound screening to target them individually. We developed an insulin-nanoluc luciferase reporter system to dissect the molecular and cellular pathways involved in the separate phases of insulin secretion. We validated this method through genetic studies, including knockdown and overexpression, as well as small-molecule screening and their effects on insulin secretion. Furthermore, we demonstrated that the results of this method are well correlated with those of single-vesicle exocytosis experiments conducted on live cells, providing a quantitative reference for the approach. Thus, we have developed a robust methodology for screening small molecules and cellular pathways that target specific phases of insulin secretion, resulting in a better understanding of insulin secretion, which in turn will result in a more effective insulin therapy through the stimulation of endogenous glucose-stimulated insulin secretion.

Visceral fat correlates with insulin secretion and sensitivity independent of BMI and subcutaneous fat in Chinese with type 2 diabetes.

Clinical heterogeneity exists in overall obesity and abdominal obesity in terms of insulin secretion and sensitivity. Further, the impact of visceral fat (VF) on the first- and second-phase insulin secretion (FPIS and SPIS) is controversial. We aim to investigate insulin secretion and sensitivity in Chinese patients with T2DM according to different BMI and VF levels. This study enrolled 300 participants. A dual bioelectrical impedance analyzer was used to assess the visceral and subcutaneous fat area (VFA and SFA). VF levels were categorized as normal or high, with the cutoff value of 100 cm2. FPIS and SPIS were evaluated by arginine stimulation test and standardized steamed bread meal tolerance test, respectively. β-cell function (HOMA2-β), insulin resistance (HOMA2-IR), and Gutt's insulin sensitivity index (Gutt-ISI) were also calculated. Spearman's correlation analysis and multivariate linear regression analysis were adopted for statistical analysis. Participants were categorized into four groups: normal weight-normal VF, normal weight-high VF, overweight/obese-normal VF and overweight/obese-high VF. Multivariate linear regression showed that both VFA and SFA were correlated with FPIS, HOMA2-IR and Gutt-ISI after controlling for gender and diabetes duration. After further adjustment for BMI and VFA, some associations of SFA with insulin secretion and sensitivity disappeared. After adjustment for gender, diabetes duration, BMI and SFA, VFA was positively correlated with FPIS, SPIS and HOMA2-IR. Subjects with overweight/obese-high VF were more likely to have higher FPIS, HOMA2-IR and lower Gutt-ISI (all p < 0.05). VF affects both FPIS and SPIS, and worsens insulin sensitivity independent of BMI and subcutaneous fat in Chinese patients with T2DM. http://www.chictr.org.cn, identifier ChiCTR2200062884.

Circulating spexin levels are influenced by the glycemic status and correlated with pancreatic β-cell function in Chinese subjects.

Spexin plays a role in regulating glucose metabolism. This study investigated the spexin levels in different glycemic status and its association with insulin secretion in humans. A total of 462 subjects were recruited in this study, including 52 healthy subjects, 106 first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM), 115 impaired glucose regulation (IGR), 80 newly diagnosed T2DM, and 106 established T2DM. Serum spexin was measured using ELISA. The homeostasis model assessment of insulin resistance (HOMA2-IR) and β-cell function (HOMA2-β), and Stumvoll index estimating first- and second-phase insulin secretion were calculated. Spexin levels were higher in FDRs [235.53pg/ml (185.28, 293.95)] and IGR [239.79pg/ml (191.52, 301.69)], comparable in newly diagnosed T2DM [224.68pg/ml (187.37, 279.74)], and lower in established T2DM [100.11pg/ml (78.50, 137.34)], compared with healthy subjects [200.23pg/ml (160.32, 275.65)]. Spexin levels were negatively correlated with fasting plasma glucose (FPG) (r = - 0.355, P < 0.001), hemoglobin A1C (HbA1c) (r = - 0.379, P < 0.001), and HOMA2-IR (r = - 0.225, P < 0.001), and positively correlated with HOMA2-β (r = 0.245, P < 0.001) after adjusting for age, sex, and BMI. Multivariate linear regression analysis showed that established T2DM and HOMA2-β were independently associated with serum spexin levels. Serum spexin levels represented as a bell-shaped curve along the glycemic continuum and is closely related with insulin secretion in humans.

Estimating causal effects of physical activity and sedentary behaviours on the development of type 2 diabetes in at-risk children from childhood to late adolescence: an analysis of the QUALITY cohort

Uncertainty remains regarding the causal effect of physical activity and sedentary behaviours on the development of type 2 diabetes in children. We aimed to estimate average treatment effects of physical activity and sedentary behaviours on risk of type 2 diabetes in individuals who are at risk during childhood and adolescence. We used data from the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) cohort of children of western European descent (white non-Hispanic race or ethnicity) with a parental history of obesity (defined as a BMI of 30 kg/m2 or more, or a waist circumference of more than 102 cm in men and 88 cm in women) evaluated at the ages of 8-10 years (baseline), 10-12 years (first follow-up cycle), and 15-17 years (second follow-up cycle) in Québec, Canada. We measured moderate-to-vigorous physical activity (MVPA) and sedentary time by accelerometry, and leisure screen time by questionnaire at each cycle. Outcomes included fasting and 2 h post-load glycaemia and validated indices of insulin sensitivity and insulin secretion. We estimated average treatment effects of MVPA, sedentary time, and screen time on markers of type 2 diabetes using longitudinal marginal structural models with time-varying exposures, outcomes, and confounders from the ages of 8-10 to 15-17 years and inverse probability of treatment and censoring weighting. We considered both the current and cumulative effects of exposures on outcomes. 630 children were evaluated at baseline (age 8-10 years) between July, 2005, and December, 2008, 564 were evaluated at the first follow-up (age 10-12 years) between July, 2007, and March, 2011, and 377 were evaluated at the second follow-up (age 15-17 years) between September, 2012, and May, 2016. Based on cumulative exposure results, estimated average treatment effects for MVPA were 5·6% (95% CI 2·8 to 8·5) on insulin sensitivity and -3·8% (-7·1 to -0·5) on second-phase insulin secretion per 10 min daily increment from the ages of 8-10 years to age 15-17 years. Average treatment effects for sedentary time and reported screen time resulted in reduced insulin sensitivity (-8·2% [-12·3 to -3·9] and -6·4% [-10·1 to -2·5], respectively), increased second-phase insulin secretion (5·9% [1·9 to 10·1] and 7·0% [-0·1 to 14·7], respectively), and higher fasting glycaemia (0·03 mmol/L [0·003 to 0·05] and 0·02 mmol/L [0·01 to 0·03], respectively) per additional daily hour from the ages of 8-10 years to 15-17 years. Using modern causal inference approaches strengthened the evidence of MVPA and sedentary behaviours as key drivers of development of type 2 diabetes in at-risk children and adolescents, and should be considered as key targets for prevention. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, and Fonds de Recherche du Québec-Santé. For the French translation of the abstract see Supplementary Materials section.

Differences in Insulin Sensitivity, Secretion, and the Metabolic Clearance Rate of Glucose in Newly Diagnosed Type 2 Diabetes Mellitus Patients: The Influences of Body Mass Index and Fatty Liver.

Background: Obesity and nonalcoholic fatty liver disease are strongly associated with type 2 diabetes mellitus (T2DM), affecting insulin sensitivity and β-cell function. They interact, exacerbating the development of hyperinsulinemia to T2DM. Methods: Through oral glucose tolerance and insulin secretion tests, the relationships between insulin sensitivity and secretion, glucose clearance, body mass index (BMI), and fatty liver were studied in newly diagnosed T2DM patients. The homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-β), insulin sensitivity index (ISI), and metabolic clearance rate (MCR) of glucose were calculated to analyze insulin sensitivity and β-cell function. Results: There were no differences in HOMA-IR, HOMA-β, first-phase insulin secretion (1st PH), second-phase insulin secretion (2nd PH), ISI, or MCR between lean fatty liver and lean nonfatty liver patients. Both overweight/obesity (ow/ob) and patients with fatty liver increased HOMA-IR, and decreased ISI and MCR. In the ow/ob subgroup, patients with fatty liver had severe insulin resistance but greater HOMA-β, 1st PH, and 2nd PH than individuals with nonfatty liver. The difference in MCR between fatty liver and nonfatty liver groups was not significant. Conclusion: BMI and hepatic steatosis are independent determinants of increased insulin resistance and decreased MCR. However, it is steatosis, not BMI, related to the increase in insulin secretion.

Elevated alanine aminotransferase is associated with biphasic insulin secretion in the healthy elderly Han Chinese population.

ObjectiveTo evaluate the relationship between alanine transaminase (ALT) level and biphasic insulin secretion (BPIS) in healthy elderly Han Chinese individuals.MethodsThis cross-sectional study enrolled healthy elderly participants aged ≥60 years that were part of a health examination programme. In order to explore the correlation and severity of the clinical condition, those with any possible confounding factors known to affect insulin secretion or liver function were excluded from the study. BPIS was calculated using an equation developed previously by this research team.ResultsThis study enrolled 39 845 healthy elderly individuals (19 058 males and 20 787 females). Participants were stratified into four quartile groups according to their ALT level. In both males and females, the increasing ALT quartiles (ordinal variable) were associated with greater values of log-transformed first-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS). The correlation and the linear regression model showed that increasing ALT level was significantly correlated with higher log-transformed FPIS and SPIS.ConclusionsALT was positively correlated with BPIS in a healthy elderly population in both men and women. Elevated ALT may serve as an indicating factor for developing metabolic syndrome and type 2 diabetes mellitus in healthy elderly individuals.

Impact of CFTR Modulators on Beta-Cell Function in Children and Young Adults with Cystic Fibrosis.

Background: To date, no consistent data are available on the possible impact of CFTR modulators on glucose metabolism. The aim of this study was to test the hypothesis that treatment with CFTR modulators is associated with an improvement in the key direct determinants of glucose regulation in children and young adults affected by Cystic Fibrosis (CF). Methods: In this study, 21 CF patients aged 10–25 underwent oral glucose tolerance test (OGTT) before and after 12–18 months of treatment with Lumacaftor/Ivacaftor or Elexacaftor-Ivacaftor-Tezacaftor. β-cell function (i.e., first and second phase of insulin secretion measured as derivative and proportional control, respectively) and insulin clearance were estimated by OGTT mathematical modelling. Insulin sensitivity was estimated by the Oral Glucose Sensitivity Index (OGIS). The dynamic interplay between β-cell function, insulin clearance and insulin sensitivity was analysed by vector plots of glucose-stimulated insulin bioavailability vs. insulin sensitivity. Results: No changes in glucose tolerance occurred after either treatment, whereas a significant improvement in pulmonary function and chronic bacterial infection was observed. Beta cell function and insulin clearance did not change in both treatment groups. Insulin sensitivity worsened in the Lumacaftor/Ivacaftor group. The analysis of vector plots confirmed that glucose regulation was stable in both groups. Conclusions: Treatment of CF patients with CFTR modulators does not significantly ameliorate glucose homeostasis and/or any of its direct determinants.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Isoform-specific Roles of Prolyl Hydroxylases in the Regulation of Pancreatic β-Cell Function.

Pancreatic β-cells can secrete insulin via 2 pathways characterized as KATP channel -dependent and -independent. The KATP channel–independent pathway is characterized by a rise in several potential metabolic signaling molecules, including the NADPH/NADP+ ratio and α-ketoglutarate (αKG). Prolyl hydroxylases (PHDs), which belong to the αKG-dependent dioxygenase superfamily, are known to regulate the stability of hypoxia-inducible factor α. In the current study, we assess the role of PHDs in vivo using the pharmacological inhibitor dimethyloxalylglycine (DMOG) and generated β-cell-specific knockout (KO) mice for all 3 isoforms of PHD (β-PHD1 KO, β-PHD2 KO, and β-PHD3 KO mice). DMOG inhibited in vivo insulin secretion in response to glucose challenge and inhibited the first phase of insulin secretion but enhanced the second phase of insulin secretion in isolated islets. None of the β-PHD KO mice showed any significant in vivo defects associated with glucose tolerance and insulin resistance except for β-PHD2 KO mice which had significantly increased plasma insulin during a glucose challenge. Islets from both β-PHD1 KO and β-PHD3 KO had elevated β-cell apoptosis and reduced β-cell mass. Isolated islets from β-PHD1 KO and β-PHD3 KO had impaired glucose-stimulated insulin secretion and glucose-stimulated increases in the ATP/ADP and NADPH/NADP+ ratio. All 3 PHD isoforms are expressed in β-cells, with PHD3 showing the most distinct expression pattern. The lack of each PHD protein did not significantly impair in vivo glucose homeostasis. However, β-PHD1 KO and β-PHD3 KO mice had defective β-cell mass and islet insulin secretion, suggesting that these mice may be predisposed to developing diabetes.

Ovarian insufficiency impairs glucose-stimulated insulin secretion through activation of hypothalamic de novo ceramide synthesis

Oestrogens regulate body weight through their action on hypothalamus to modulate food intake and energy expenditure. Hypothalamic de novo ceramide synthesis plays a central role on obesity induced by oestrogen deficiency. Depletion in oestrogens is also known to be associated with glucose intolerance, which favours type 2 diabetes (T2D). However, the implication of hypothalamic ceramide in the regulation of glucose homeostasis by oestrogen is unknown. Here, we studied glucose homeostasis and insulin secretion in ovariectomized (OVX) female rats. OVX induces body weight gain associated with a hypothalamic inflammation and impaired glucose homeostasis. Genetic blockade of ceramide synthesis in the ventromedial nucleus of the hypothalamus (VMH) reverses hypothalamic inflammation and partly restored glucose tolerance induced by OVX. Furthermore, glucose-stimulated insulin secretion (GSIS) is increased in OVX rats due to a raise of insulin secretion second phase, a characteristic of early stage of T2D. In contrast, GSIS from isolated islets of OVX rats is totally blunted. Inhibition of ceramide synthesis in the VMH restores GSIS from isolated OVX islets and represses the second phase of insulin secretion. Stimulation of oestrogen receptor α (ERα) by oestradiol (E2) down-regulates ceramide synthesis in hypothalamic neuronal GT1–7 cells but no in microglial SIM-A9 cells. In contrast, genetic inactivation of ERα in VMH upregulates ceramide synthesis. These results indicate that hypothalamic neuronal de novo ceramide synthesis triggers the OVX-dependent impairment of glucose homeostasis which is partly mediated by a dysregulation of GSIS.

The Shape of the Oral Glucose Tolerance Test-Glucose Response Curve in Islet Cell Antibody-Positive vs. -Negative Obese Youth Clinically Diagnosed with Type 2 Diabetes.

BackgroundThe oral glucose tolerance test (OGTT)-glucose response curves (GRCs; incessant increase, monophasic, and biphasic) reflect insulin sensitivity and β-cell function, being worse in the former and superior in the latter. Here, we examined if the OGTT-GRC pattern is worse in obese antibody (glutamic acid decarboxylase 65-kDa [GAD65] and insulinoma-associated protein-2 [IA-2])-positive (Ab+) vs. –negative (Ab–) youth clinically diagnosed with type 2 diabetes (CDX-T2D).MethodsForty-seven obese youth, 15 Ab+ and 32 Ab–, were divided into three OGTT-GRC groups: incessant increase, monophasic, and biphasic. The prevalence of OGTT-GRC, clamp-measured insulin sensitivity, and β-cell function was compared.ResultsIncessant increase OGTT-GRC is the most frequent curve type and is three-fold higher in Ab+ vs. Ab– youth CDX-T2D. In Ab+ youth, there was up to 40% lower second-phase insulin secretion in the incessant increase group vs. the other two groups combined (monophasic and biphasic). In Ab– youth, while first- and second-phase insulin secretion was significantly lower in the incessant increase vs. the other two groups combined, overall β-cell function was less impaired than in Ab+ youth. In neither Ab– or Ab+ youth was OGTT-GRC related to hepatic or peripheral insulin sensitivity.ConclusionSevere insulin deficiency, a characteristic of type 1 diabetes, seems to be related to higher prevalence of incessant increase in Ab+ vs. Ab– obese youth.

1162-P: Proinsulin as a Biomarker for Beta-Cell Function in a Diverse Cohort

Declining beta-cell function is a key component in the development of type 2 diabetes (T2D). Early in disease progression, first-phase insulin secretion deteriorates, precipitating impaired glucose tolerance. Markers for early beta-cell decline could assist in identifying individuals at risk for disease progression, particularly among demographic groups at elevated risk for T2D. This study was designed to test the hypothesis that proinsulin concentrations would be inversely associated with first-phase beta-cell function, as reflected in the Disposition Index (DI), in a diverse cohort of young individuals without T2D. Participants were 117 men and women of African-American and European-American descent aged 19-45 years with normal glucose tolerance. An oral-glucose tolerance test (OGTT) was used to measure proinsulin concentrations and assess beta-cell function. Mathematical modeling was used to estimate insulin sensitivity (Si) and indices of beta-cell function specific to basal, first-phase, second-phase, and total insulin secretion (PhiB, PhiD, PhiS, PhiTot, respectively). First-phase DI (DId) was calculated as Si x PhiD and second-phase DI (DIs) as Si x PhiS. Proinsulin concentrations were normalized for C-peptide. Fasting and 2-h proinsulin concentrations were inversely associated with DId (r=-0.21, p=0.02 and r=-0.22, p=0.01, respectively). Neither fasting nor 2-h proinsulin concentrations were significantly associated with DIs. African-Americans, who as a group have an elevated prevalence of T2D, had 25% higher concentrations of fasting proinsulin and 18% higher concentrations of 2-h proinsulin compared to EA (p=0.001 and p=0.01, respectively). Proinsulin may be a practical biomarker for first-phase beta-cell function that could assist in identification of individuals at risk for T2D who would benefit from interventions to prevent deterioration of glucose metabolism. Disclosure C. Couch: None. B. Gower: Advisory Panel; Self; Abbott. F. Piccinini: Employee; Self; Medtronic. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK096388); Nutrition Obesity Research Center (P30DK056336); Diabetes Research Center (P30DK079626); National Heart, Lung, and Blood Institute (T32HL105349)