Twin Pregnancy Complicated by Gestational Diabetes Mellitus: Maternal and Neonatal Outcomes.

Context: The risk of gestational diabetes mellitus (GDM) in twin pregnancies is more than double that of singleton pregnancies. Although twin pregnancies present unique challenges for fetal growth and prenatal management, the approach to GDM diagnosis and treatment is the same regardless of plurality. Data on pregnancy outcomes for individuals with GDM and a twin pregnancy are limited and conflicting. Objective: To describe the maternal characteristics associated with GDM in twin pregnancies and to assess the associated pregnancy outcomes compared to twin pregnancies unaffected by GDM. Methods: A retrospective cohort study was conducted at Mayo Clinic, Rochester, Minnesota, USA, and included predominantly Causasian women aged 18 to 45 years who received prenatal care for a twin pregnancy from 2017-2022. Maternal characteristics and a broad spectrum of pregnancy outcomes were evaluated. Universal GDM screening involved a 50 g oral glucose challenge test +/- a 100 g oral glucose tolerance test. Results: GDM was diagnosed in 23% pregnancies (n = 104/452). Compared to those without, women with GDM had known risk factors including a higher prepregnancy body mass index (31.1vs 26.3 kg/m2; P < .01) and a prior history of GDM (21.7 vs 5.9%; P < .01). There were no differences in maternal pregnancy complications or neonatal outcomes between groups. Attendance at postpartum glucose testing among women with GDM was poor at 27.9% (29/104). Conclusion: These data suggest that women with twin pregnancies share a similar GDM risk profile to those with singleton pregnancies and provide reassuring evidence that current management for GDM twin pregnancies produces similar outcomes to twin pregnancies without GDM.

Inclusion of Rurality and Social Determinants of Health in Documents for the Primary Prevention of Type 2 Diabetes: A Systematic Review.

Purpose: The type 2 diabetes (T2D) burden is disproportionately concentrated in low- and middle-income economies, particularly among rural populations. The purpose of the systematic review was to evaluate the inclusion of rurality and social determinants of health (SDOH) in documents for T2D primary prevention. Methods: This systematic review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched 19 databases, from 2017-2023, for documents on rurality and T2D primary prevention. Furthermore, we searched online for documents from the 216 World Bank economies, categorized by high, upper-middle, lower-middle, and low income status. We extracted data on rurality and the ten World Health Organization SDOH. Two authors independently screened documents and extracted data. Findings: Based on 3318 documents (19 databases and online search), we selected 15 documents for data extraction. The 15 documents applied to 32 economies; 12 of 15 documents were from nongovernment sources, none was from low-income economies, and 10 of 15 documents did not define or describe rurality. Among the SDOH, income and social protection (SDOH 1) and social inclusion and nondiscrimination (SDOH 8) were mentioned in documents for 25 of 29 high-income economies, while food insecurity (SDOH 5) and housing, basic amenities, and the environment (SDOH 6) were mentioned in documents for 1 of 2 lower-middle-income economies. For U.S. documents, none of the authors was from institutions in noncore (most rural) counties. Conclusions: Overall, documents on T2D primary prevention had sparse inclusion of rurality and SDOH, with additional disparity based on economic status. Inclusion of rurality and/or SDOH may improve T2D primary prevention in rural populations.

County Rurality and Incidence and Prevalence of Diagnosed Diabetes in the United States.

OBJECTIVE: To examine differences in the incidence and prevalence of diagnosed diabetes by county rurality. PATIENTS AND METHODS: This observational, cross-sectional study used US Centers for Disease Control and Prevention data from 2004 through 2019 for county estimates of incidence and prevalence of diagnosed diabetes. County rurality was based on 6 levels (large central metro counties [most urban] to noncore counties [most rural]). Weighted least squares regression was used to relate rurality with diabetes incidence rates (IRs; per 1000 adults) and prevalence (percentage) in adults aged 20 years or older after adjusting for county-level sociodemographic factors (eg, food environment, health care professionals, inactivity, obesity). RESULTS: Overall, in 3148 counties and county equivalents, the crude IR and prevalence of diabetes were highest in noncore counties. In age and sex ratio-adjusted models, the IR of diabetes increased monotonically with increasing rurality (P<.001), whereas prevalence had a weak, nonmonotonic but statistically significant increase (P=.002). Further adjustment for sociodemographic factors including food environment, health care professionals, inactivity, and obesity attenuated differences in incidence across rurality levels, and reversed the pattern for prevalence (prevalence ratios [vs large central metro] ranged from 0.98 [95% CI, 0.97 to 0.99] for large fringe metro to 0.94 [95% CI, 0.93 to 0.96] for noncore). In region-stratified analyses adjusted for sociodemographic factors including inactivity and obesity, increasing rurality was inversely associated with incidence in the Midwest and West only and inversely associated with prevalence in all regions. CONCLUSION: The crude incidence and prevalence of diagnosed diabetes increased with increasing county rurality. After accounting for sociodemographic factors including food environment, health care professionals, inactivity, and obesity, county rurality showed no association with incidence and an inverse association with prevalence. Therefore, interventions targeting modifiable sociodemographic factors may reduce diabetes disparities by region and rurality.

Four weeks SGLT2 inhibition improves beta cell function and glucose tolerance without affecting muscle free fatty acid or glucose uptake in subjects with type 2 diabetes.

AIMS: Sodium glucose co-transporter-2 (SGLT2) inhibition lowers glucose levels independently of insulin, leading to reduced insulin secretion and increased lipolysis, resulting in elevated circulating free fatty acids (FFAs). While SGLT2 inhibition improves tissue insulin sensitivity, the increase in circulating FFAs could reduce insulin sensitivity in skeletal muscle and the liver. We aimed to investigate the effects of SGLT2 inhibition on substrate utilization in skeletal muscle and the liver and to measure beta-cell function and glucose tolerance. METHODS: Thirteen metformin-treated individuals with type 2 diabetes were randomized to once-daily empagliflozin 25 mg or placebo for 4 weeks in a crossover design. Skeletal muscle glucose and FFA uptake together with hepatic tissue FFA uptake were measured using [18F]FDG positron emission tomography/computed tomography (PET/CT) and [11C]palmitate PET/CT. Insulin secretion and action were estimated using the oral minimal model. RESULTS: Empagliflozin did not affect glucose (0.73 ± 0.30 vs. 1.16 ± 0.64, µmol/g/min p = 0.11) or FFA (0.60 ± 0.30 vs. 0.56 ± 0.3, µmol/g/min p = 0.54) uptake in skeletal muscle. FFA uptake in the liver (21.2 ± 10.1 vs. 19 ± 8.8, µmol/100 ml/min p = 0.32) was unaffected. Empagliflozin increased total beta-cell responsivity (20 ± 8 vs. 14 ± 9, 10-9 min-1, p < 0.01) and glucose effectiveness (2.6 × 10-2 ± 0.3 × 10-2 vs. 2.4 × 10-2 ± 0.3 × 10-2, dL/kg/min, p = 0.02). CONCLUSIONS: Despite improved beta-cell function and glucose tolerance, empagliflozin does not appear to affect skeletal muscle FFA or glucose uptake.

Characteristics of Normal Weight Insulin-Resistant Adults with Unfavorable Health Outcomes.

Background: Insulin resistance can be present in otherwise healthy, normal weight adults. Whether there are phenotype/sex-differences between normal weight insulin-resistant (NWIR) and normal weight insulin-sensitive (NWIS) Caucasians and whether there are differences in adverse health outcomes are unknown. Our goal was to define phenotypes and intermediate-term health outcomes of NWIR versus NWIS Caucasian adults. Methods: We analyzed data from 227 healthy volunteers body mass index 18 to <25.0 kg/m2 who underwent insulin clamp studies between January 1987 and January 2017 at Mayo Clinic to identify those in the top (NWIS, n = 56) and bottom (NWIR, n = 56) quartiles of insulin action. We compared the phenotypical characteristics and were able to collect medical records data for 80% of NWIS and 88% of NWIR to identify time to onset of hypertension, hyperglycemia, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and all cause death; the follow-up averaged 11 (4, 20) years. Results: Body fat was significantly greater and peak VO2 was significantly less in both NWIS than NWIR males and females. Only in females was abdominal subcutaneous fat by computed tomography significantly greater in NWIR than NWIS. In NWIR males high-density lipoprotein-cholesterol and fat free mass were significantly less, and fasting insulin was greater than NWIS males. For the entire NWIS population, Kaplan-Meier disease-free survival analysis showed longer times free of hypertension, hyperglycemia, and some cardiovascular diseases than for NWIR. Conclusions: There are sex-specific phenotypes of NWIR in Caucasian adults. NWIR may be associated with accelerated onset of some adverse medical outcomes.

Suppression of Endogenous Insulin Secretion by Euglycemic Hyperinsulinemia.

CONTEXT: The impact of insulin, particularly exogenous hyperinsulinemia, on insulin secretion in humans is debated. OBJECTIVE: We assessed the effects of exogenous hyperinsulinemia on insulin secretion and whether the response is altered in insulin resistance associated with obesity. METHODS: Insulin secretion rates (ISRs) during euglycemic hyperinsulinemic clamp studies (52 volunteers) were calculated using a model that employs plasma C-peptide concentrations. One study involved a 2-step insulin clamp and the other study was a single step insulin clamp. For both studies the goal was to achieve plasma glucose concentrations of 95 mg/dL during the clamp irrespective of fasting glucose concentrations. The percent change in ISR from fasting to the end of the insulin clamp interval was the main outcome. Linear regression and analysis of covariance were used to test for the effects of insulin on ISR and to test for group differences. RESULTS: ISR was greater in obese volunteers (P < .001) under fasting and hyperinsulinemic clamp conditions. The change in plasma glucose from baseline to the end of the insulin clamp interval was highly correlated with the change in ISR (r = 0.61, P < .001). From baseline to the end of the clamp we observed a 27% (SD 20) suppression of ISR. The participants who underwent a 2-step insulin clamp had greater suppression of ISR during the second step than the first step (P < .001). The proportional suppression of ISR during euglycemic hyperinsulinemia was not different between nonobese and obese groups (P = .19). CONCLUSION: Hyperinsulinemia suppresses endogenous insulin secretion and the relative change in insulin secretion produced by exogenous insulin did not differ between nonobese and obese people.

Glucagon-like peptide-1 receptor blockade impairs islet secretion and glucose metabolism in humans.

BACKGROUNDProglucagon can be processed to glucagon-like peptide1 (GLP-1) within the islet, but its contribution to islet function in humans remains unknown. We sought to understand whether pancreatic GLP-1 alters islet function in humans and whether this is affected by type 2 diabetes.METHODSWe therefore studied individuals with and without type 2 diabetes on two occasions in random order. On one occasion, exendin 9-39, a competitive antagonist of the GLP-1 Receptor (GLP1R), was infused, while on the other, saline was infused. The tracer dilution technique ([3-3H] glucose) was used to measure glucose turnover during fasting and during a hyperglycemic clamp.RESULTSExendin 9-39 increased fasting glucose concentrations; fasting islet hormone concentrations were unchanged, but inappropriate for the higher fasting glucose observed. In people with type 2 diabetes, fasting glucagon concentrations were markedly elevated and persisted despite hyperglycemia. This impaired suppression of endogenous glucose production by hyperglycemia.CONCLUSIONThese data show that GLP1R blockade impairs islet function, implying that intra-islet GLP1R activation alters islet responses to glucose and does so to a greater degree in people with type 2 diabetes.TRIAL REGISTRATIONThis study was registered at ClinicalTrials.gov NCT04466618.FUNDINGThe study was primarily funded by NIH NIDDK DK126206. AV is supported by DK78646, DK116231 and DK126206. CDM was supported by MIUR (Italian Minister for Education) under the initiative "Departments of Excellence" (Law 232/2016).

International Guidelines for the Diagnosis and Management of Hyperinsulinism.

Hyperinsulinism (HI) due to dysregulation of pancreatic beta-cell insulin secretion is the most common and most severe cause of persistent hypoglycemia in infants and children. In the 65 years since HI in children was first described, there has been a dramatic advancement in the diagnostic tools available, including new genetic techniques and novel radiologic imaging for focal HI, however; there have been almost no new therapeutic modalities since the development of diazoxide. Recent advances in neonatal research and genetics have improved our understanding of the pathophysiology of both transient and persistent forms of neonatal hyperinsulinism. Rapid turnaround of genetic test results combined with advanced radiologic imaging can permit identification and localization of surgically-curable focal lesions in a large proportion of children with congenital forms of HI, but are only available in certain centers in 'developed' countries. Diazoxide, the only drug currently approved for treating HI, was recently designated as an "essential medicine" by the World Health Organization but has been approved in only 16% of Latin American countries and remains unavailable in many under-developed areas of the world. Novel treatments for HI are emerging, but they await completion of safety and efficacy trials before being considered for clinical use. This international consensus statement on diagnosis and management of HI was developed in order to assist specialists, general pediatricians, and neonatologists in early recognition and treatment of HI with the ultimate aim of reducing the prevalence of brain injury caused by hypoglycemia. A previous statement on diagnosis and management of HI in Japan was published in 2017. The current document provides an updated guideline for management of infants and children with HI and includes potential accommodations for less-developed regions of the world where resources may be limited.

Effects of acute changes in fasting glucose and free fatty acid concentrations on indices of ß-cell function and glucose metabolism in subjects without diabetes.

Elevated fasting free fatty acids (FFAs) and fasting glucose are additively associated with impaired glucose tolerance (IGT) and decreased ß-cell function [quantified as disposition index (DI)]. We sought to examine how changes in fasting FFA and glucose alter islet function. We studied 10 subjects with normal fasting glucose (NFG) and normal glucose tolerance (NGT) on two occasions. On one occasion, Intralipid and glucose were infused overnight to mimic conditions present in IFG/IGT. In addition, we studied seven subjects with IFG/IGT on two occasions. On one occasion, insulin was infused to lower overnight FFA and glucose concentrations to those observed in people with NFG/NGT. The following morning, a labeled mixed meal was used to measure postprandial glucose metabolism and ß-cell function. Elevation of overnight fasting FFA and glucose in NFG/NGT did not alter peak or integrated glucose concentrations (2.0 ± 0.1 vs. 2.0 ± 0.1 Mol per 5 h, Saline vs. Intralipid/glucose, P = 0.55). Although overall ß-cell function quantified by the Disposition Index was unchanged, the dynamic component of ß-cell responsivity (ϕd) was decreased by Intralipid and glucose infusion (9 ± 1 vs. 16 ± 3 10-9, P = 0.02). In people with IFG/IGT, insulin did not alter postprandial glucose concentrations or indices of ß-cell function. Endogenous glucose production and glucose disappearance were also unchanged in both groups. We conclude that acute, overnight changes in FFA, and glucose concentrations do not alter islet function or glucose metabolism in prediabetes.NEW & NOTEWORTHY This experiment studied the effect of changes in overnight concentrations of free fatty acids (FFAs) and glucose on ß-cell function and glucose metabolism. In response to elevation of these metabolites, the dynamic component of the ß-cell response to glucose was impaired. This suggests that in health overnight hyperglycemia and FFA elevation can deplete preformed insulin granules in the ß-cell.

Guidelines, position statements, and advisories for the primary prevention of type 2 diabetes, hypertension, and cardiovascular disease in rural populations: A systematic review protocol.

INTRODUCTION: Globally, noncommunicable diseases (NCDs), which include type 2 diabetes (T2D), hypertension, and cardiovascular disease (CVD), are associated with a high burden of morbidity and mortality. Health disparities exacerbate the burden of NCDs. Notably, rural, compared with urban, populations face greater disparities in access to preventive care, management, and treatment of NCDs. However, there is sparse information and no known literature synthesis on the inclusion of rural populations in documents (i.e., guidelines, position statements, and advisories) pertaining to the prevention of T2D, hypertension, and CVD. To address this gap, we are conducting a systematic review to assess the inclusion of rural populations in documents on the primary prevention of T2D, hypertension, and CVD. METHODS AND ANALYSIS: This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched 19 databases including EMBASE, MEDLINE, and Scopus, from January 2017 through October 2022, on the primary prevention of T2D, hypertension, and CVD. We conducted separate Google® searches for each of the 216 World Bank economies. For primary screening, titles and/or abstracts were screened independently by two authors (databases) or one author (Google®). Documents meeting selection criteria will undergo full-text review (secondary screening) using predetermined criteria, and data extraction using a standardized form. The definition of rurality varies, and we will report the description provided in each document. We will also describe the social determinants of health (based on the World Health Organization) that may be associated with rurality. ETHICS AND DISSEMINATION: To our knowledge, this will be the first systematic review on the inclusion of rurality in documents on the primary prevention of T2D, hypertension, and CVD. Ethics approval is not required since we are not using patient-level data. Patients are not involved in the study design or analysis. We will present the results at conferences and in peer-reviewed publication(s). TRIAL REGISTRATION: PROSPERO Registration Number: CRD42022369815.

Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD).

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Nonlinear Mixed Effects Modeling of Glucagon Kinetics in Healthy Subjects.

OBJECTIVE: To date, the lack of a model of glucagon kinetics precluded the possibility of estimating and studying glucagon secretion in vivo, e.g., using deconvolution, as done for other hormones like insulin and C-peptide. Here, we used a nonlinear mixed effects technique to develop a robust population model of glucagon kinetics, able to describe both the typical population kinetics (TPK) and the between-subject variability (BSV), and relate this last to easily measurable subject characteristics. METHODS: Thirty-four models of increasing complexity (variably including covariates and correlations among random effects) were identified on glucagon profiles obtained from 53 healthy subjects, who received a constant infusion of somatostatin to suppress endogenous glucagon production, followed by a continuous infusion of glucagon (65 ng/kg/min). Model selection was performed based on its ability to fit the data, provide precise parameter estimates, and parsimony criteria. RESULTS: A two-compartment model was the most parsimonious. The model was able to accurately describe both the TPK and the BSV of model parameters as function of body mass and body surface area. Parameters were precisely estimated, with central volume of distribution V1 = 5.46 L and peripheral volume of distribution V2 = 5.51 L. The introduction of covariates resulted in a significant shrinkage of the unexplained BSV and considerably improved the model fit. CONCLUSION: We developed a robust population model of glucagon kinetics. SIGNIFICANCE: This model provides a deeper understanding of glucagon kinetics and is usable to estimate glucagon secretion in vivo by deconvolution of plasma glucagon concentration data.

Interventional vs surgical procedures in localized/nonmetastatic insulinomas (ablation vs surgery).

Localized insulinoma is an uncommon entity that can result in substantial morbidity due to the associated hypoglycemia. Recent studies have suggested an increase in the incidence of insulinoma in recent decades that may possibly be secondary to increased awareness, incidental diagnoses, and better diagnostic methods. Diagnosing and localizing insulinoma within the pancreas can be challenging, but advances in nuclear imaging may improve diagnostic accuracy. Delays in diagnosis are common, but once a localized insulinoma is diagnosed and appropriately treated, the long-term prognosis is excellent. Surgical resection is considered the standard of care management option for localized insulinoma, but tumor ablation with endoscopic ultrasound guidance has also been shown to be an effective and safe method for therapy.

Predictors of Metformin Failure: Repurposing Electronic Health Record Data to Identify High-Risk Patients.

CONTEXT: Metformin is the first-line drug for treating diabetes but has a high failure rate. OBJECTIVE: To identify demographic and clinical factors available in the electronic health record (EHR) that predict metformin failure. METHODS: A cohort of patients with at least 1 abnormal diabetes screening test that initiated metformin was identified at 3 sites (Arizona, Mississippi, and Minnesota). We identified 22 047 metformin initiators (48% female, mean age of 57 ± 14 years) including 2141 African Americans, 440 Asians, 962 Other/Multiracial, 1539 Hispanics, and 16 764 non-Hispanic White people. We defined metformin failure as either the lack of a target glycated hemoglobin (HbA1c) (<7%) within 18 months of index or the start of dual therapy. We used tree-based extreme gradient boosting (XGBoost) models to assess overall risk prediction performance and relative contribution of individual factors when using EHR data for risk of metformin failure. RESULTS: In this large diverse population, we observed a high rate of metformin failure (43%). The XGBoost model that included baseline HbA1c, age, sex, and race/ethnicity corresponded to high discrimination performance (C-index of 0.731; 95% CI 0.722, 0.740) for risk of metformin failure. Baseline HbA1c corresponded to the largest feature performance with higher levels associated with metformin failure. The addition of other clinical factors improved model performance (0.745; 95% CI 0.737, 0.754, P < .0001). CONCLUSION: Baseline HbA1c was the strongest predictor of metformin failure and additional factors substantially improved performance suggesting that routinely available clinical data could be used to identify patients at high risk of metformin failure who might benefit from closer monitoring and earlier treatment intensification.

The Effect of Glucagon-Like Peptide 1 Receptor Blockade on Glucagon-Induced Stimulation of Insulin Secretion.

Data from transgenic rodent models suggest that glucagon acts as an insulin secretagogue by signaling through the glucagon-like peptide 1 receptor (GLP-1R) present on ß-cells. However, its net contribution to physiologic insulin secretion in humans is unknown. To address this question, we studied individuals without diabetes in two separate experiments. Each subject was studied on two occasions in random order. In the first experiment, during a hyperglycemic clamp, glucagon was infused at 0.4 ng/kg/min, increasing by 0.2 ng/kg/min every hour for 5 h. On one day, exendin-9,39 (300 pmol/kg/min) was infused to block GLP-1R, while on the other, saline was infused. The insulin secretion rate (ISR) was calculated by nonparametric deconvolution from plasma concentrations of C-peptide. Endogenous glucose production and glucose disappearance were measured using the tracer-dilution technique. Glucagon concentrations, by design, did not differ between study days. Integrated ISR was lower during exendin-9,39 infusion (213 ± 26 vs. 191 ± 22 nmol/5 h, saline vs. exendin-9,39, respectively; P = 0.02). In the separate experiment, exendin-9,39 infusion, compared with saline infusion, also decreased the ß-cell secretory response to a 1-mg glucagon bolus. These data show that, in humans without diabetes, glucagon partially stimulates the ß-cell through GLP-1R.

Differential contribution of alpha and beta cell dysfunction to impaired fasting glucose and impaired glucose tolerance.

AIMS/HYPOTHESIS: People with isolated impaired fasting glucose (IFG) have normal beta cell function. We hypothesised that an increased glucose threshold for beta cell secretion explains IFG. METHODS: We used graded glucose infusion to examine the relationship of insulin secretion rate (ISR) and glucagon secretion rate (GSR) with rising glucose. We studied 39 non-diabetic individuals (53 ± 2 years, BMI 30 ± 1 kg/m2), categorised by fasting glucose and glucose tolerance status. After an overnight fast, a variable insulin infusion was used to maintain glucose at ~4.44 mmol/l (07:00 to 08:30 hours). At 09:00 hours, graded glucose infusion commenced at 1 mg kg-1 min-1 and doubled every 60 min until 13:00 hours. GSR and ISR were calculated by nonparametric deconvolution from concentrations of glucagon and C-peptide, respectively. RESULTS: The relationship of ISR with glucose was linear and the threshold for insulin secretion in isolated IFG did not differ from that in people with normal fasting glucose and normal glucose tolerance. GSR exhibited a single-exponential relationship with glucose that could be characterised by G50, the change in glucose necessary to suppress GSR by 50%. G50 was increased in IFG compared with normal fasting glucose regardless of the presence of impaired or normal glucose tolerance. CONCLUSIONS/INTERPRETATION: These data show that, in non-diabetic humans, alpha cell dysfunction contributes to the pathogenesis of IFG independently of defects in insulin secretion. We also describe a new index that quantifies the suppression of glucagon secretion by glucose.