Prenatal air pollution, fetal ß-cell dysfunction and neurodevelopmental delay.

BACKGROUND: Emerging evidence has reported significant associations of prenatal air pollution exposure with neurodevelopmental delay in offspring. Sensitive exposure windows and the modifiable factor remain elusive. OBJECTIVE: We aim to identify sensitive windows of air pollution during pregnancy on neurodevelopmental delay, and examine whether cord blood C-peptide mediates the relationship. METHODS: This study included 7438 mother-newborn pairs in Hefei, China, from 2015 to 2021. Weekly exposure to particulate matter of aerodynamic diameter <2.5 µm, 10 µm (PM2.5, PM10), nitrogen dioxide (NO2) and carbon monoxide (CO) was estimated at regulatory air monitoring stations in Hefei. Denver Developmental Screening Test-II and the Gesell Developmental Schedules were applied to assess the neurodevelopmental delay in children 6-36 mon of age. Distributed lag nonlinear models examined sensitive time windows of prenatal air pollutants exposure. Mediation analysis estimated the mediating role of cord blood C-peptide. RESULTS: The sensitive PM2.5, PM10, NO2, and CO exposure windows associated with neurodevelopmental delay were throughout pregnancy. Weekly air pollutants exposure was related to higher neurodevelopmental delay risks [cumulative odds ratio (OR): 1.40(1.29,1.53) in PM2.5 (per 10 µg/m3), 1.40(1.28,1.53) in PM10 (per 10 µg/m3), 1.41(1.30,1.52) in CO (per 0.1 mg/m3), and 1.49(1.29,1.72) in NO2 (per 5 µg/m3)]. Mediation analysis indicated 18.3 % contributions of cord C-peptide to the relationship [average mediation effect: 0.04(0.01.0.06); average direct effect: 0.15(0.07.0.25)]. CONCLUSIONS: Exposure to air pollution throughout pregnancy is linked to neurodevelopmental delay mediated by poorer fetal ß-cell function. Screening and treatment of abnormal glucose metabolism in infants could benefit the prevention of air pollution-associated neurodevelopment delay.

Teplizumab and ß-Cell Function in Newly Diagnosed Type 1 Diabetes.

BACKGROUND: Teplizumab, a humanized monoclonal antibody to CD3 on T cells, is approved by the Food and Drug Administration to delay the onset of clinical type 1 diabetes (stage 3) in patients 8 years of age or older with preclinical (stage 2) disease. Whether treatment with intravenous teplizumab in patients with newly diagnosed type 1 diabetes can prevent disease progression is unknown. METHODS: In this phase 3, randomized, placebo-controlled trial, we assessed ß-cell preservation, clinical end points, and safety in children and adolescents who were assigned to receive teplizumab or placebo for two 12-day courses. The primary end point was the change from baseline in ß-cell function, as measured by stimulated C-peptide levels at week 78. The key secondary end points were the insulin doses that were required to meet glycemic goals, glycated hemoglobin levels, time in the target glucose range, and clinically important hypoglycemic events. RESULTS: Patients treated with teplizumab (217 patients) had significantly higher stimulated C-peptide levels than patients receiving placebo (111 patients) at week 78 (least-squares mean difference, 0.13 pmol per milliliter; 95% confidence interval [CI], 0.09 to 0.17; P<0.001), and 94.9% (95% CI, 89.5 to 97.6) of patients treated with teplizumab maintained a clinically meaningful peak C-peptide level of 0.2 pmol per milliliter or greater, as compared with 79.2% (95% CI, 67.7 to 87.4) of those receiving placebo. The groups did not differ significantly with regard to the key secondary end points. Adverse events occurred primarily in association with administration of teplizumab or placebo and included headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome. CONCLUSIONS: Two 12-day courses of teplizumab in children and adolescents with newly diagnosed type 1 diabetes showed benefit with respect to the primary end point of preservation of ß-cell function, but no significant differences between the groups were observed with respect to the secondary end points. (Funded by Provention Bio and Sanofi; PROTECT ClinicalTrials.gov number, NCT03875729.).

Maternal 25(OH)D attenuates the relationship between ambient air pollution during pregnancy and fetal hyperinsulinism.

Inflammatory responses have been demonstrated to link air pollution with insulin resistance and type 2 diabetes in adults. However, few studies have focused on the relationship between prenatal air pollution and fetal ß-cell function and the mediating effect of systematic inflammation remains elusive. Whether the anti-inflammatory effect of vitamin D could attenuate the ß-cell dysfunction in early life warrants further investigations. We aimed to determine whether maternal blood 25(OH)D attenuates the associations of ambient air pollution during pregnancy with fetal hyperinsulinism mediated by maternal inflammatory response. A total of 8250 mother-newborn pairs were included between 2015 and 2021 in the Maternal & Infants Health in Hefei study. Weekly mean air pollution exposure to fine particles (PM2.5 and PM10), SO2, and CO was estimated across pregnancy. Maternal serum samples in the third trimester were used to measure the high-sensitivity c-reactive protein (hs-CRP) and 25(OH)D. Cord blood samples at delivery were collected for the measurement of C-peptide. Fetal hyperinsulinism was based on cord C-peptide >90th centile. An increased fetal hyperinsulinism risk was associated with per 10 µg/m3 increase in PM2.5 [odds ratios (OR): 1.45 (95% confidence interval (CI):1.32, 1.59)], per 10 µg/m3 increase in PM10 [OR = 1.49 (95% CI:1.37, 1.63)], per 5 µg/m3 increase in SO2 [OR = 1.91 (95% CI: 1.70, 2.15)], and per 0.1 mg/m3 increase in CO [OR = 1.48 (95% CI:1.37, 1.61)] across pregnancy. Mediation analysis showed a 16.3% contribution of maternal hsCRP to the relationship between air pollution throughout pregnancy and fetal hyperinsulinism. Air pollution-associated higher levels of hsCRP and risk of fetal hyperinsulinism could be attenuated by higher maternal 25(OH)D levels. Prenatal ambient air pollution exposures were associated with an increased fetal hyperinsulinism risk mediated by maternal serum hsCRP. Higher antenatal 25(OH)D levels could attenuate air pollution-induced inflammatory responses and hyperinsulinism risk.

Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes.

AIMS/HYPOTHESIS: Prediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of ß-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. METHODS: We recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, ß-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. RESULTS: Participants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and ß-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in ß-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and ß-cell function revealed a different pattern. CONCLUSIONS: Lower AIR to intravenous glucose and ß-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.

Relationship Between Remnant Pancreatic Volume and Endocrine Function After Pancreaticoduodenectomy.

BACKGROUND: Decreased pancreatic volume (PV) is a predictive factor for diabetes mellitus (DM) after surgery. There are few reports on PV and endocrine function pre- and post-surgery. We investigated the correlation between PV and insulin secretion. METHODS: Seventeen patients underwent pancreaticoduodenectomy (PD) Pre- and post-surgery PV and C-peptide index (CPI) measurements were performed. Additionally, the correlation between PV and CPI was analyzed. RESULTS: The mean preoperative PV (PPV) was 55.1 ± 31.6 mL, postoperative remnant PV (RPV) was 25.3±17.3 mL, and PV reduction was 53%. The mean preoperative C-peptide immunoreactivity (CPR) was 1.39 ± .51 and postoperative CPR was .85±.51. The mean preoperative CPI was 1.29±.72 and postoperative CPI was .73 ± .48. Significant correlations were observed between RPV and post CPR (ρ = .507, P = .03) and post CPI (ρ = .619, P = .008). DISCUSSION: There was a significant correlation between RPV and CPI after PD. A smaller RPV resulted in lower insulin secretion ability, increasing the potential risk of new-onset DM after PD.

Análisis comparativo de respuesta glicémica y de péptido C, tras la ingesta de estevia y D-tagatosa, según habitualidad de consumo de edulcorantes no nutritivos y preferencias alimentarias reportadas por mujeres con resistencia a la insulina / Comparative analysis of glicemic response and c peptide, after comsumption of stevia and d tagatosa, according to regular compsumtion of not nutritive sweeteners andnourish preferences reported by woman with insuline resistance

INTRODUCCIÓN: El consumo de edulcorantes no nutritivos (ENN) ha ido en aumento. A pesar de ello, se desconoce el efecto entre el consumo habitual de ENN y las preferencias alimentarias con parámetros bioquímicos en pacientes con resistencia a la insulina. OBJETIVO: Comparar la respuesta glicémica y de péptido C, según habitualidad de consumo de edulcorantes y preferencias alimentarias reportados por mujeres con resistencia a la insulina tras la ingesta de estevia y D-tagatosa. MÉTODOS: Treinta y tres mujeres con RI se sometieron a una encuesta de opción múltiple sobre preferencias alimentarias y ETCC modificada de edulcorantes. Aleatoriamente recibieron una precarga de control o experimental (estevia y D-tagatosa) donde se midió glicemia y péptido C en los tiempos -10, 30, 60, 90, 120, 180. RESULTADOS: Se encontró un ABC de péptido C más alto después de la ingesta de D-tagatosa (p = 0,02) en pacientes que prefieren alimentos ricos en proteínas en comparación con aquellos que prefieren alimentos ricos en grasas o en carbohidratos simples. Se observó un mayor ABC de péptido C (p = 0,04) para la prueba control en quienes prefieren el sabor salado y consumen menor cantidad de ENN, sin diferencias significativas entre quienes prefirieron sabor dulce. CONCLUSIONES: Al comparar las respuestas glicémicas e insulinémicas entre habitualidad de consumo de edulcorantes y preferencias alimentarias reportados por las pacientes tras la ingesta de agua, estevia y D-Tagatosa, no se obtuvieron diferencias significativas. Salvo en quienes preferían alimentos ricos en proteínas tras la ingesta de D- tagatosa y quienes preferían sabor salado con menor consumo habitual de ENN tras ingesta control.

INTRODUCTION: The consumption of non-nutritive sweeteners (NNS) has been increasing. Despite this, the effect between the habitual consumption of ENN and food preferences with biochemical parameters in patients with insulin resistance is unknown. OBJECTIVE: To compare the glycemic and C-peptide response, according to the habitual consumption of sweeteners and food preferences reported by women with insulin resistance after ingesting stevia and D-tagatose. METHODS: Thirty-three women with IR underwent a multiple choice survey on food preferences and modified ETCC for sweeteners. They randomly received a control or experimental preload (stevia and D-tagatose) where glycemia and peptide C were measured at times -10, 30, 60, 90, 120, 180. RESULTS: A higher C-peptide AUC was found after ingestion of D-tagatose (p = 0.02) in patients who prefer foods rich in protein compared to those who prefer foods rich in fat or simple carbohydrates. A higher AUC of peptide C (p = 0.04) is performed for the control test in those who prefer a salty taste and consume a lower amount of ENN, without significant differences between those who prefer a sweet taste. CONCLUSION: When comparing the glycerol and insulin responses between the habitual consumption of sweeteners and the food preferences reported by the patients after the ingestion of water, stevia and D-Tagatose, no significant differences were obtained. Except in those who prefer foods rich in protein after ingesting D-tagatose and those who prefer salty taste with less habitual consumption of NNS after control intake.

Novel Human Insulin Isoforms and Cα-Peptide Product in Islets of Langerhans and Choroid Plexus.

Human insulin (INS) gene diverged from the ancestral genes of invertebrate and mammalian species millions of years ago. We previously found that mouse insulin gene (Ins2) isoforms are expressed in brain choroid plexus (ChP) epithelium cells, where insulin secretion is regulated by serotonin and not by glucose. We further compared human INS isoform expression in postmortem ChP and islets of Langerhans. We uncovered novel INS upstream open reading frame isoforms and their protein products. In addition, we found a novel alternatively spliced isoform that translates to a 74-amino acid (AA) proinsulin containing a shorter 19-AA C-peptide sequence, herein designated Cα-peptide. The middle portion of the conventional C-peptide contains ß-sheet (GQVEL) and hairpin (GGGPG) motifs that are not present in Cα-peptide. Islet amyloid polypeptide (IAPP) is not expressed in ChP, and its amyloid formation was inhibited in vitro more efficiently by Cα-peptide than by C-peptide. Of clinical relevance, the ratio of the 74-AA proinsulin to proconvertase-processed Cα-peptide was significantly increased in islets from type 2 diabetes mellitus autopsy donors. Intriguingly, 100 years after the discovery of insulin, we found that INS isoforms are present in ChP from insulin-deficient autopsy donors.

Increased Prevalence of Beta-Cell Dysfunction despite Normal HbA1c in Youth and Young Adults with Turner Syndrome.

INTRODUCTION: Adult women with Turner syndrome (TS) have a high prevalence of diabetes and ß-cell dysfunction that increases morbidity and mortality, but it is unknown if there is ß-cell dysfunction present in youth with TS. This study aimed to determine the prevalence of ß-cell dysfunction in youth with TS and the impact of traditional therapies on insulin sensitivity (SI) and insulin secretion. METHODS: Cross-sectional, observational study recruited 60 girls with TS and 60 healthy controls (HC) matched on pubertal status. Each subject had a history, physical exam, and oral glucose tolerance test (OGTT). Oral glucose and c-peptide minimal modeling was used to determine ß-cell function. RESULTS: Twenty-one TS girls (35%) met criteria for prediabetes. Impaired fasting glucose was present in 18% of girls with TS and 3% HC (p value = 0.02). Impaired glucose tolerance was present in 23% of TS girls and 0% HC (p value <0.001). The hemoglobin A1c was not different between TS and HC (median 5%, p = 0.42). Youth with TS had significant reductions in SI, ß-cell responsivity (Φ), and disposition index (DI) compared to HC. These differences remained significant when controlling for body mass index z-score (p values: 0.0006, 0.002, <0.0001 for SI, Φ total, DI, respectively). CONCLUSIONS: ß-Cell dysfunction is present in youth with TS compared to controls. The presence of both reduced insulin secretion and SI suggest a unique TS-related glycemic phenotype. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in TS youth.

Impact of COVID-19 on new-onset type 1 diabetes mellitus - A one-year prospective study.

OBJECTIVE: A positive relationship between the recently emerged Corona Virus Disease-19 (COVID-19) and diabetes has been inferred, but not confirmed, in children. The aim of the present study was to investigate the possible impact of COVID-19 on new-onset Type-1 Diabetes Mellitus (T1DM) in a pediatric population. PATIENTS AND METHODS: This is a prospective study of all children and adolescents diagnosed with T1DM during the first year of the COVID-19 pandemic (March 2020-February 2021) in Western Greece (population coverage ≈1,000,000). The incidence and severity of T1DM, the age and sex of the participants and HbA1c and c-peptide concentrations at diagnosis were recorded and compared to those of the previous year (pre-COVID-19 year). RESULTS: 21 children aged 8.03±0.90 years old were diagnosed with T1DM in the COVID-19 year and 17, aged 9.44±3.72 years old, in the pre-COVID-19 year. A different seasonality pattern of new onsets was observed during the COVID-19 year compared to the previous year, with increasing trend from spring to winter (spring: 9.5% vs. 23.5%, autumn: 23.8% vs. 29.4%, summer: 19% vs. 11.8%, winter: 47.6% vs. 35.3%). Also, compared to the preceding year, HbA1c was significantly higher (p=0.012) and the incidence and severity of diabetic ketoacidosis greater (p=0.045, p=0.013, respectively). CONCLUSIONS: This is the first study to report a different seasonality pattern and increased severity of new-onset T1DM during the first year of the COVID-19 pandemic. Future research should further investigate the possible role of SARS-CoV-2 and the different pattern of overall infection incidence during the COVID-19 year.

Hsa_circ_0054633 association of C peptide is related to IL-17 and TNF-α in patients with diabetes mellitus receiving insulin treatment.

BACKGROUND: Chronic inflammation damaged the islet and resulted in dysfunction of T2D. Circular RNA is stable and better for biomarker in many diseases. Here, we aimed to identify potential circular RNA hsa_circ_0054633 that can be a biomarkers for the effects of insulin therapy in T2D. METHODS: In this retrospective case-control study, patients were from Li Huili Hospital, Ningbo, China, from February 10, 2019, to August 15, 2019. We included 47 healthy adults, 46 new-onset T2D with insulin resistance, and 51 patients with insulin therapy. Serum inflammation factors were tested by ELISA assays. We selected hsa_circ_0054633 as a candidate biomarker and measured its concentration in serum by qRT-PCR. The Pearson correlation test was used to evaluate the correlation between this circRNA and clinical variables. RESULTS: Clinical data indicated that serum C peptide was increased in T2D treatment with insulin. Serum hsa_circ_0054633 was decreased in insulin treatment group. Hsa_circ_0054633 was negative correlated with C peptide (r = -0.2841, p = 0.0433,). IL-1 and IL-6, IL-17, and TNF-α were higher in T2D patients and decreased after insulin treatment, only IL-17 and TNF-α showed a positive correlation to hsa_circ_0054633 (r = 0.4825, p < 0.0001, and r = 0.6190, p < 0.0001). The area under ROC curve was 0.7432, 0.5839, and 0.7573 for Hsa_circ_0054633, C peptide, and their combination. CONCLUSION: Hsa_circ_0054633 level was lower in T2D with insulin treatment than untreated and was a negative correlation with C peptide, and positively correlated with IL-17 and TNF-α, suggesting that hsa_circ_0054633 may be a potential early indicator of insulin treatment effect to improve inflammation condition.

Model-Based Assessment of C-Peptide Secretion and Kinetics in Post Gastric Bypass Individuals Experiencing Postprandial Hyperinsulinemic Hypoglycemia.

Assessment of insulin secretion is key to diagnose postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized complication following bariatric surgery. To this end, the Oral C-peptide Minimal Model (OCMM) can be used. This usually requires fixing C-peptide (CP) kinetics to the ones derived from the Van Cauter population model (VCPM), which has never been validated in PHH individuals. The objective of this work was to test the validity of the OCMM coupled with the VCPM in PHH subjects and propose a method to overcome the observed limitations. Two cohorts of adults with PHH after gastric bypass (GB) underwent either a 75 g oral glucose (9F/3M; age=42±9 y; BMI=28.3±6.9 kg/m2) or a 60 g mixed-meal (7F/3M; age = 43 ± 11 y; BMI=27.5±4.2 kg/m2) tolerance test. The OCMM was identified on CP concentration data with CP kinetics fixed to VCPM (VC approach). In both groups, the VC approach underestimated CP-peak and overestimated CP-tail suggesting CP kinetics predicted by VCPM to be inaccurate in this population. Thus, the OCMM was identified using CP kinetics estimated from the data (DB approach) using a Bayesian Maximum a Posteriori estimator. CP data were well predicted in all the subjects using the DB approach, highlighting a significantly faster CP kinetics in patients with PHH compared to the one predicted by VCPM. Finally, a simulation study was used to validate the proposed approach. The present findings question the applicability of the VCPM in patients with PHH after GB and call for CP bolus experiments to develop a reliable CP kinetic model in this population.

Impact of endogenous insulin secretion on the improvement of glucose variability in Japanese patients with type 2 diabetes treated with canagliflozin plus teneligliptin.

AIMS/INTRODUCTION: To identify the effect of combination therapy with a dipeptidyl peptidase-4 inhibitor and a sodium-glucose cotransporter 2 inhibitor compared with switching from a dipeptidyl peptidase-4 inhibitor to a sodium-glucose cotransporter 2 inhibitor on improving the glucose variability in patients with or without impaired endogenous insulin secretion. MATERIALS AND METHODS: A secondary analysis regarding the relationship between endogenous insulin secretion and the change in mean amplitude of glycemic excursions (ΔMAGE) was carried out in a multicenter, prospective, randomized, parallel-group comparison trial that enrolled patients with type 2 diabetes who had been taking teneligliptin and were treated by switching to canagliflozin (SWITCH) or adding canagliflozin (COMB). Participants were categorized into the following four subgroups: SWITCH or COMB and high or low fasting C-peptide (CPR) divided at baseline by the median. RESULTS: ΔMAGE in the COMB group was greatly improved independent of a high or low CPR (-29.2 ± 28.3 vs -20.0 ± 24.6, respectively; P = 0.60). However, ΔMAGE was not ameliorated in the low CPR SWITCH group, and the ΔMAGE was significantly smaller than that in the high CPR COMB group (P < 0.01). CONCLUSIONS: COMB would be a better protocol rather than switching teneligliptin to canagliflozin to improve daily glucose variability in patients with impaired endogenous insulin secretion.

The utility of assessing C-peptide in patients with insulin-treated type 2 diabetes: a cross-sectional study.

AIMS: We aimed at evaluating residual ß-cell function in insulin-treated patients with type 2 diabetes (T2D) while determining for the first time the difference in C-peptide level between patients on basal-bolus compared to those on the basal insulin scheme, considered as an early stage of insulin treatment, together with assessing its correlation with the presence of complications. METHODS: A total of 93 candidates with T2D were enrolled in this cross-sectional study and were categorized into two groups based on the insulin regimen: Basal-Bolus (BB) if on both basal and rapid acting insulin, and Basal (B) if on basal insulin only, without rapid acting injections. HbA1c, fasting C-peptide concentration and other metabolic parameters were recorded, as well as the patient medical history. RESULTS: The average fasting C-peptide was 1.81 ± 0.15 ng/mL, and its levels showed a significant inverse correlation with the duration of diabetes (r = -0.24, p = 0.03). Despite similar disease duration and metabolic control, BB participants displayed lower fasting C-peptide (p < 0.005) and higher fasting glucose (P = 0.01) compared with B patients. Concentrations below 1.09 ng/mL could predict the adoption of a basal-bolus treatment (Area 0.64, 95%CI:0.521-0.759, p = 0.038, sensitivity 45% and specificity 81%). CONCLUSIONS: Insulin-treated patients with long-standing T2D showed detectable level of fasting C-peptide. Measuring the ß-cell function may therefore guide toward effective therapeutic options when oral hypoglycemic agents prove unsuccessful.

Impact of glucagon response on early postprandial glucose excursions irrespective of residual ß-cell function in type 1 diabetes: A cross-sectional study using a mixed meal tolerance test.

AIMS/INTRODUCTION: Controlling postprandial glucose levels in patients with type 1 diabetes is challenging even under the adequate treatment of insulin injection. Recent studies showed that dysregulated glucagon secretion exacerbates hyperglycemia in type 2 diabetes patients, but little is known in type 1 diabetes patients. We investigated whether the glucagon response to a meal ingestion could influence the postprandial glucose excursion in patients with type 1 diabetes. MATERIALS AND METHODS: We enrolled 34 patients with type 1 diabetes and 23 patients with type 2 diabetes as controls. All patients underwent a liquid mixed meal tolerance test. We measured levels of plasma glucose, C-peptide and glucagon at fasting (0 min), and 30, 60 and 120 min after meal ingestion. All type 1 diabetes patients received their usual basal insulin and two-thirds of the necessary dose of the premeal bolus insulin. RESULTS: The levels of plasma glucagon were elevated and peaked 30 min after the mixed meal ingestion in both type 1 diabetes and type 2 diabetes patients. The glucagon increments from fasting to each time point (30, 60 and 120 min) in type 1 diabetes patients were comparable to those in type 2 diabetes patients. Among the type 1 diabetes patients, the glucagon response showed no differences between the subgroups based on diabetes duration (<5 vs ≥5 years) and fasting C-peptide levels (<0.10 vs ≥0.10 nmol/L). The changes in plasma glucose from fasting to 30 min were positively correlated with those in glucagon, but not C-peptide, irrespective of diabetes duration and fasting C-peptide levels in patients with type 1 diabetes. CONCLUSIONS: The dysregulated glucagon likely contributes to postprandial hyperglycemia independent of the residual ß-cell functions during the progression of type 1 diabetes.

Predictors of neonatal adiposity and associations by fetal sex in women with gestational diabetes mellitus and normal glucose-tolerant women.

AIMS: To determine predictors of neonatal adiposity and differences in associations by fetal sex in women with gestational diabetes mellitus (GDM), normal-weight and overweight (BMI ≥ 25 kg/m2) normal glucose-tolerant women (NGT). METHODS: Skinfold thickness was measured in 576 newborns, and cord blood leptin, c-peptide and lipids in 327 newborns in a multi-centric prospective cohort study. RESULTS: Compared to neonates of normal-weight NGT women (327), neonates of women with GDM (97) were more often large-for-gestational age (LGA) (16.5% vs 8.6%, p = 0.024) ,but the macrosomia rate (8.2% vs 5.8%, p = 0.388), sum of skinfolds (13.9 mm ± 2.9 vs 13.3 mm ± 2.6, p = 0.067), neonatal fat mass (1333.0 g ± 166.8 vs 1307.3 g ± 160.9, p = 0.356), and cord blood biomarkers were not significantly different. Compared to neonates of normal-weight NGT women, neonates of overweight NGT women (152) had higher rates of macrosomia (12.5% vs 5.8%, p = 0.012), LGA (17.1% vs 8.6%, p = 0.006), higher sum of skinfolds (14.3 mm ± 2.6 vs 13.2 mm ± 2.6, p < 0.001), neonatal fat mass (1386.0 g ± 168.6 vs 1307.3 g ± 160.9, p < 0.001), % neonatal fat mass > 90th percentile (15.2% vs 7.1%, p < 0.001), without significant differences in cord blood biomarkers. Maternal BMI, fasting glycemia, triglycerides, gestational weight gain, cord blood leptin ,and cord blood triglycerides were independent predictors for neonatal adiposity. Gestational weight gain was positively associated with adiposity in boys only. CONCLUSION: Compared to neonates of normal-weight NGT women, neonates of GDM women have higher LGA rates but similar adiposity, while neonates of overweight NGT women have increased adiposity. Limiting gestational weight gain might be especially important in the male fetus to reduce neonatal adiposity.

Assessment of individual and standardized glucagon kinetics in healthy humans.

Impaired glucose tolerance arises out of impaired postprandial insulin secretion and delayed suppression of glucagon. These defects occur early and independently in the pathogenesis of prediabetes. Quantification of the contribution of α-cell dysfunction to glucose tolerance has been lacking because knowledge of glucagon kinetics in humans is limited. Therefore, in a series of experiments examining the interaction of glucagon suppression with insulin secretion we studied 51 nondiabetic subjects (age = 54 ± 13 yr, BMI = 28 ± 4 kg/m2). Glucose was infused to mimic the systemic appearance of an oral challenge. Somatostatin was used to inhibit endogenous hormone secretion. 120 min after the start of the experiment, glucagon was infused at 0.65 ng/kg/min. The rise in glucagon concentrations was used to estimate its kinetic parameters [volume of distribution (Vd), half-life (t1/2), and clearance rate (CL)]. A single-exponential model provided the best fit for the data, and individualized kinetic parameters were estimated: Vd = 8.2 ± 2.7 L, t1/2 = 4 ± 1.1 min, CL = 1.4 ± 0.33 L/min. Stepwise linear regression was used to correlate Vd with BMI and sex (R2adj = 0.44), whereas CL similarly correlated with lean body mass or BSA (both R2 = 0.28). This enabled the development of a population-based model using anthropometric characteristics to predict Vd and CL. These data demonstrate that it is feasible to derive glucagon kinetic parameters from anthropometric characteristics, thereby enabling quantitation of the rate of glucagon appearance in the systemic circulation in large populations.NEW & NOTEWORTHY State-of-the-art measurement of insulin secretion in humans is accomplished by deconvolution of peripheral C-peptide concentrations using population-derived parameters of C-peptide kinetics. In contrast, knowledge of the kinetic parameters of glucagon in humans is lacking so that measurement of glucagon secretion to date is largely qualitative. This series of experiments enabled measurement of glucagon kinetics in 51 subjects, and subsequently, stepwise linear regression was used to correlate these parameters with anthropometric characteristics. This enabled the development of a population-based model using anthropometric characteristics to predict the volume of distribution and the rate of clearance. This is a necessary first step in the development of a model to quantitate of glucagon secretion and action (and its contribution to glucose tolerance) in large populations.

Vitamin D3 deficiency is associated with more severe insulin resistance and metformin use in patients with type 2 diabetes.

BACKGROUND: Vitamin D3 (vit. D3) deficiency is considered as one of the main factors involved in the development of type 2 diabetes (T2D). We assessed insulin resistance (IR), ß-cell functional activity and metabolic profile according to 25(OH) vit. D3 status in patients with T2D. METHODS: The study included 109 patients with T2D, divided in 3 groups: group 1 (N.=11) with normal levels of vit. D3 (>30 ng/mL); group 2 (N.=38) with vit. D3 insufficiency (21-29 ng/mL); and group 3 (N.=60) with vit. D3 deficiency (<20 ng/mL). IR and ß-cell functional activity were assessed as change in C-peptide concentration and homeostasis model assessment-estimated (HOMA) ß-cell function which was calculated using HOMA2 calculator. RESULTS: Patients with vit. D3 deficiency presented significantly higher C-peptide concentration compared to other groups. HOMA2 (3.29±1.89 vs. 2.12±0.71; P=0.049) and hemoglobin (H8b)A1c (9.11±1.63 vs. 7.75±1.06; P=0.016) levels changed significantly only in patients with vit. D3 deficiency compared to diabetics with normal vit. D3 levels. Furthermore, in univariate Pearson's correlation analysis, we observed significant association between vit. D3 levels and C-peptide, insulin sensitivity, HOMA2, triglyceride-glucose index, HbA1c and Body Mass Index, only in the vit. D3 deficiency group. In multivariate logistic regression analysis, poor glycemic control, as defined by HbA1c levels, was independent from metformin use while high density lipoprotein-cholesterol levels were associated with vit. D3 deficiency. CONCLUSIONS: Our study demonstrated that vit. D3 deficiency in patients with T2D was associated with more severe IR, poor glycemic control and obesity compared to normal status or vit. D3 insufficiency.

The Measurement of Insulin Clearance.

Insulin clearance has recently been highlighted as a fundamental aspect of glucose metabolism, as it has been hypothesized that its impairment could be related to an increased risk of developing type 2 diabetes. This review focuses on methods used to calculate insulin clearance: from the early surrogate indices employing C-peptide:insulin molar ratio, to direct measurement methods used in animal models, to modeling-based techniques to estimate the components of insulin clearance (hepatic versus extrahepatic). The methods are explored and interpreted by critically highlighting advantages and limitations.

Association between 1,5-Anhydroglucitol and Acute C Peptide Response to Arginine among Patients with Type 2 Diabetes.

OBJECTIVE: The aim of this study was to explore the association of 1,5-anhydroglucitol with acute C peptide response (ACPR) to arginine among patients with type 2 diabetes. METHODS: Patients with type 2 diabetes were enrolled from the Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital. ACPR was assessed using arginine stimulation test. Decreased ß-cell function was defined as ACPR < 2.1. Multivariable logistic regression models were used to demonstrate the association between 1,5-anhydroglucitol and decreased ß-cell function. RESULTS: Finally, 623 patients with type 2 diabetes were enrolled into the analysis. Multivariable-adjusted odds ratios for decreased ß-cell function across quartiles of 1,5-anhydroglucitol were 1.00, 0.47 (95% confidence interval (CI) 0.23-0.99), 0.41 (95% CI 0.20-0.84), and 0.27 (95% CI 0.13-0.57) (P trend = 0.042), respectively. When 1,5-anhydroglucitol was considered as a continuous variable after logarithm, the corresponding odds ratio was 0.40 (95% CI 0.23-0.71). CONCLUSIONS: We demonstrated a dose-response linear association between 1,5-anhydroglucitol and ACPR. 1,5-Anhydroglucitol was likely to be associated with ß-cell function. Further analysis with large sample size and prospective study design is warranted to validate our findings.

Energetics at the urban edge: Environmental and individual predictors of urinary C-peptide levels in wild chacma baboons (Papio ursinus).

As human-modified landscapes encroach into natural habitats, wildlife face a reduction in natural food sources but also gain access to calorie-rich, human-derived foods. However, research into the energetics of wildlife living within and adjacent to urban and rural landscapes is lacking. C-peptide - a proxy for insulin production and a diagnostic tool for assessing pancreatic function in humans and domestic animals - can be quantified non-invasively from urine (uCP) and may provide a way to investigate the energetic correlates of living in human-altered landscapes. UCP is increasingly used in studies of primate energetics, and here we examine predictors of variation in uCP levels in n = 17 wild chacma baboons (Papio ursinus) living at the urban edge on the Cape Peninsula, South Africa. We find that uCP was positively associated with food provisioning and negatively with night fasting. UCP levels were comparable between winter and summer but significantly lower during spring, possibly driven by consumption of energy-rich seeds during summer and more human-derived foods during winter. UCP was elevated in pregnant females and similar for lactating and cycling females. We find no effect of dominance rank on uCP. Samples collected with synthetic Salivettes had significantly lower uCP levels than directly pipetted samples. Overall, our results indicate that uCP is a reliable, non-invasive measure of energy balance and intake in baboons, and suggest potential energetic benefits of living at the urban edge. More broadly, studies of uCP may offer unique insight into the environmental control of hormone-behaviour relationships in species crossing natural and urban environments.