Christie, Hannah E.

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.

Objective To update, synthesise and provide meta-analytical evidence of the associations between domain-specific physical activity (PA) and mental health and mental ill-health outcomes. Design Systematic review and multilevel meta-analysis. Data sources In March 2024, we systematically searched five databases. Eligibility criteria Methods employed replicated those of a previous review in 2017. All studies examining associations between domain-specific PA and specified mental health outcomes were included. Results 372 studies met inclusion criteria and 361 were included in the meta-analysis. Across the 372 studies (combined sample size of 3 323 711), 338 examined leisure-time PA, 54 work-related PA, 72 transport-related PA, 44 household PA, 5 school sport and 8 physical education. Multilevel meta-analyses showed that leisure-time PA (r=0.205, 95% CI 0.157 to 0.253), transport-related PA (r=0.138, 95% CI 0.042 to 0.231) and household PA (r=0.096, 95% CI 0.025 to 0.165) were positively associated with mental health . Leisure-time PA (r=−0.149, 95% CI −0.189 to –0.11) and school sport (r=−0.096, 95% CI −0.115 to –0.077) were inversely associated with mental ill health . However, work-related PA (r=0.134 95% CI 0.069 to 0.199) was positively associated with mental ill health . Conclusion The direction of the association between PA and mental health/mental ill health is dependent on the domain in which PA occurs. Promoting PA for leisure purposes is likely to yield the greatest benefits for both promoting mental health and preventing mental ill health. As such, leisure-time PA should be prioritised in messaging, guidelines and interventions/programmes designed to support mental health through PA. PROSPERO registration number CRD42024510303.

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.

We describe a method that lowers the limit of quantification of a glucagon immunoassay thereby enhancing the ability to differentiate between normal and abnormal α-cell responsiveness to glucagon.

Abstract Context Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes. Objective To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes. Design The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model. Setting The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN. Participants Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of TCF7L2 genotype at rs7903146 from the Mayo Biobank. Intervention Two-hour, 7-sample OGTT. Main Outcome Measures Fasting, nadir, and integrated glucagon concentrations. Results One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype. Conclusion The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.

Abstract 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 &lt; .01) and a prior history of GDM (21.7 vs 5.9%; P &lt; .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.