Vella, Adrian

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

OBJECTIVE Genetic variation in the glucagon-like peptide 1 receptor (GLP1R) has been implicated in type 2 diabetes (T2D) risk and treatment response. We investigated whether GLP1R R131Q, which was previously reported as a T2D-protective variant in genome-wide association studies, alters receptor signaling, β-cell function, and response to glucagon-like peptide 1 receptor agonists (GLP-1RAs). RESEARCH DESIGN AND METHODS Trajectory of β-cell function was evaluated in a 20-year community-based prospective cohort in Korea (n = 6,373), where participants underwent biennial 2-h 75-g oral glucose tolerance tests, and disposition index was used as surrogate marker. Pharmacogenetic response to GLP-1RAs was assessed in a hospital-based T2D cohort in Korea (n = 177). Hyperglycemic clamp studies (n = 17), human islet experiments (n = 21), and in vitro assays were conducted to characterize GLP1R R131Q effects on receptor signaling and islet function. RESULTS GLP1R R131Q was associated with slower decline in disposition index in individuals without T2D, with reductions from baseline of 30% in homozygous carriers, 35% in heterozygotes, and 37% in wild-type individuals. In people with T2D, each allele conferred an additional 0.53% or 5.8 mmol/mol reduction in HbA1c after 6 months of GLP-1RA treatment (P = 5.8 × 10−4). Hyperglycemic clamp and human islet experiments demonstrated allele-dependent enhancement of GLP-1RA–stimulated insulin secretion (P = 0.050 and P = 0.037, respectively). In vitro, GLP1R R131Q increased GLP-1RA–stimulated cAMP production with directional observations consistent with pathway bias. CONCLUSIONS GLP1R R131Q is a gain-of-function variant associated with preservation of β-cell function and enhanced glycemic response to GLP-1RA treatment, supporting further investigation as a candidate pharmacogenetic marker for precision diabetes care.

In this study, we propose two new mathematical models able to quantify glucagon secretion during a graded glucose infusion, in the presence and absence of amino acids. The models provide an index of α-cell responsivity, G 50 , i.e., the glucose increase required to suppress glucose secretion rate (GSR) by 50%. Results show that the presence of amino acids reduced α-cell responsivity to glucose.

The model can be used to quantify hepatic glucagon and insulin sensitivity, accounting also for glucagon evanescence over time. The ability to quantify glucagon effects on postprandial glucose metabolism will further our understanding of its role in the onset and progression of type 2 diabetes. These findings can also be used in the design of novel glucagon-based therapies where accurate modeling of glucagon action is required to meet efficacy and safety standards.

Background: Increasing maternal body mass index (BMI) represents a risk factor for Gestational Diabetes Mellitus (GDM) and adverse obstetrical and perinatal outcomes. Objective: To stratify clinical outcomes for pregnancies affected by GDM according to maternal BMI. Methods: Retrospective cohort study including individuals ≥18 years of age who were diagnosed with GDM from 2018 to 2022. Universal GDM screening was employed with a 50 g oral glucose challenge test ± a 100 g oral glucose tolerance test. Maternal demographics, preexisting medical conditions, and selected obstetric and neonatal morbidities were evaluated. Results: A total of 2193 pregnancies in 2110 women affected by GDM were identified. This included 506 (23.0%) with normal baseline maternal BMI, 596 (27.2%) with overweight, and 1091 (49.7%) with obese BMI. Adverse maternal outcomes were more frequent in the obese compared to overweight or normal BMI categories (cesarean delivery: normal 26.9% vs. overweight 28.5% vs. obese 40.9%; p < 0.001; hypertensive disorders of pregnancy: normal 8.7% vs. overweight 12.1% vs. obese 16.8%; p < 0.001). Postpartum glucose intolerance was higher in women with obesity (normal 7.3% vs. overweight 5.9% vs. obese 14.9%; p < 0.001). Infants born to mothers with obesity had higher birthweights (normal 3.3 kg vs. overweight 3.4 kg vs. obese 3.5 kg; p < 0.001), were more likely to have neonatal hypoglycemia (normal 29.4% vs. overweight 24.3% vs. obese 41.9%; p < 0.001) and require intensive care unit admission (normal 8.1% vs. overweight 5.9% vs. obese 11.9%; p < 0.001). Conclusions: Patients with GDM and baseline BMI in the obese range experienced the highest rate of adverse outcomes, while those with overweight BMI had similar outcomes to individuals who had normal BMI at baseline.

The advent of continuous glucose monitoring (CGM) in non-insulin-treated individuals raises the possibility of quantifying disposition index (DI), a key metric of β-cell function usually assessed in research settings, in outpatients. A method for DI estimation from postprandial glucose data only (DI G ) was developed and validated against a reference. DI G can be used to assess therapy effectiveness and degree of glucose tolerance in non-insulin-treated individuals, paving the way for its quantification in real-life conditions from CGM devices.

In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P &lt; .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.