Citations

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.

Background: Pregnancy in teenagers and emerging adults is associated with an increased risk of adverse outcomes. Similarly, pregnancies complicated by pregestational and gestational diabetes mellitus (GDM) carry a higher risk of complications. However, limited data exist on the intersection of these two high-risk conditions. Our objective was to establish the prevalence of teenage and emerging adult pregnancies complicated by diabetes in a population-based cohort and compare outcomes to pregnancies uncomplicated by diabetes, noting a background prevalence of GDM of 8.1% and pregestational diabetes of 1.2% across all age groups in the United States. Methods: This is a retrospective cohort study conducted in Olmsted County, Minnesota, USA. It includes female residents aged ≤21 years with a pregnancy ICD-10 code between January 1, 2013, and December 31, 2022. The main outcome measures assessed include maternal characteristics and maternal and fetal pregnancy outcomes. Results: A total of 1491 pregnancies in 1379 individuals were identified and included. In total, 68 (4.6%) pregnancies were complicated by diabetes: 51 (3.4%) with GDM and 17 (1.1%) with pregestational diabetes. In this study, pregnancies with diabetes had higher rates of adverse outcomes including cesarean delivery (GDM 29.4% vs. pregestational 60.0% vs. no diabetes 17.0%, P < 0.001), preeclampsia (GDM 15.7% vs. pregestational 40.0% vs. no diabetes 7.3%, P < 0.001), large-for-gestational-age neonates (GDM 13.7% vs. pre-existing 50.0% vs. no diabetes 5.8%, P < 0.001), and neonatal hypoglycemia (GDM 42.6% vs. pregestational 60.0% vs. no diabetes 13.3%, P < 0.001). Conclusions: The prevalence of pregestational diabetes in our teenage and emerging adult population is similar to that of the general pregnancy population; however, the prevalence of GDM is significantly lower. Overall, diabetes in teenage pregnancy is associated with an elevated risk of adverse maternal and neonatal outcomes. Future research should evaluate interventions aimed at reducing adverse pregnancy outcomes in this vulnerable population.

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.

Abstract Malignant insulinomas are rare pancreatic neuroendocrine tumors characterized by excessive insulin secretion and a high propensity for metastasis, leading to challenging management. This study retrospectively analyzed 57 patients treated for malignant insulinoma at Mayo Clinic sites between 1992 and 2024, focusing on the efficacy of systemic therapies in improving hypoglycemic control and survival outcomes. The most commonly used therapies included somatostatin analogs (SSA), everolimus, capecitabine-temozolomide (CAPTEM), and peptide receptor radionuclide therapy (PRRT). PRRT demonstrated the highest efficacy in controlling hypoglycemia (93%), followed by CAPTEM (68%) and everolimus (62%). SSA, chemotherapy, and streptozocin were less effective, with hypoglycemic improvement seen in 37.5, 33.3, and 28.6% of patients, respectively. Overall survival (OS) was longest with SSA at 84.67 months, followed by CAPTEM at 81.67 months and everolimus at 74.07 months. PRRT demonstrated a median OS of 49.73 months. In contrast, chemotherapy and streptozocin-based therapies had significantly shorter OS times of 15.23 and 8.35 months, respectively. These findings highlight significant variability in systemic therapy efficacy for malignant insulinoma, with PRRT emerging as a promising treatment for refractory hypoglycemia and long survival. Cox regression analysis identified primary tumor resection and a history of benign insulinoma as associated with longer OS. Optimal sequencing of therapies remains unclear, and individualized treatment plans based on hypoglycemic burden and tumor characteristics are critical for improving survival and quality of life in these patients.