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Summary: Introduction: To examine whether within‐person changes in total, regional and organ fat were associated with within‐person changes in type 2 diabetes (T2D)‐related biomarkers following interventions. Methods: A secondary analysis from a randomised trial among Latino youth (30 males, 25 females) aged 12–16 years with obesity. The study sample combined participants randomised to either lifestyle intervention (N = 39) or usual care (N = 16). Total body composition was assessed by DEXA. Hepatic and pancreatic fat fractions were assessed using MRI. T2D risk factors included insulin sensitivity, beta‐cell function and post‐challenge glucose. Results: Significant changes in %body fat, lean mass, insulin sensitivity and 2‐h glucose were observed. Changes in fat mass were associated with changes in insulin sensitivity (β = −0.45, p < 0.001), while changes in lean mass were associated with changes in 2‐h glucose concentrations (β = −0.50, p = 0.02). No association between changes in total, regional, or organ fat and beta cell function were noted. Conclusions: Our study revealed that within‐person changes in fat mass and lean mass were associated with increased insulin sensitivity and reduced 2‐h glucose concentrations, respectively, among high‐risk Latino youth. The impact of reductions in regional and organ fat deposition on T2D risk factors warrants further examination. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). Methods: We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. Results: A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10−11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10−9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Conclusions/interpretation: Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, shows some promise in alleviating beta cell stress and preserving beta cell function in preclinical studies of type 1 diabetes. The aim of this phase 2, placebo-controlled, double-blinded, randomised clinical trial was to investigate the efficacy and safety of fenofibrate in adults and adolescents with newly diagnosed type 1 diabetes. Methods: We enrolled 58 individuals (aged 16 to 40 years old) with newly diagnosed type 1 diabetes and randomised them to daily oral treatment with fenofibrate 160 mg or placebo for 52 weeks (in a block design with a block size of 4, assigned in a 1:1 ratio). Our primary outcome was change in beta cell function after 52 weeks of treatment, assessed by AUC for C-peptide levels following a 2 h mixed-meal tolerance test. Secondary outcomes included glycaemic control (assessed by HbA1c and continuous glucose monitoring), daily insulin use, and proinsulin/C-peptide (PI/C) ratio as a marker of beta cell stress. We assessed outcome measures before and after 4, 12, 26 and 52 weeks of treatment. Blinding was maintained for participants, their healthcare providers and all staff involved in handling outcome samples and assessment. Results: The statistical analyses for the primary outcome included 56 participants (n=27 in the fenofibrate group, after two withdrawals, and n=29 in the placebo group). We found no significant differences between the groups in either 2 h C-peptide levels (mean difference of 0.08 nmol/l [95% CI −0.05, 0.23]), insulin use or glycaemic control after 52 weeks of treatment. On the contrary, the fenofibrate group showed a higher PI/C ratio at week 52 compared with placebo (mean difference of 0.024 [95% CI 0.000, 0.048], p<0.05). Blood lipidome analysis revealed that fenofibrate repressed pathways involved in sphingolipid metabolism and signalling at week 52 compared with placebo. The 52 week intervention evoked few adverse events and no serious adverse events. Follow-up in vitro experiments in human pancreatic islets demonstrated a stress-inducing effect of fenofibrate. Conclusions/interpretation: Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomised, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes. Trial registration: EudraCT number: 2019-004434-41 Funding: This study was funded by the Sehested Hansens Foundation. [ABSTRACT FROM AUTHOR]

Background/Objectives: In this study, the potential effects are evaluated of epigallocatechin gallate (EGCG) on the prognosis of diabetes and insulin resistance. Methods: In an experiment, 35 male Wistar albino rats were used and in the streptozotocin (STZ)-induced diabetic rats, the effects were examined of different doses (50 mg/kg, 100 mg/kg, 200 mg/kg) of EGCG on metabolic parameters associated with diabetes and insulin resistance. Results: The findings show favorable effects of EGCG on fasting blood glucose levels, insulin secretion, insulin resistance, and beta cell function. In this study, it was observed that EGCG was able to significantly lower fasting blood glucose levels, especially at high doses (200 mg/kg), providing the most significant improvement. Furthermore, EGCG has been found to reduce insulin resistance and improve insulin sensitivity by increasing insulin secretion. When the biochemical parameters of increased insulin secretion are evaluated, it is also observed that it creates clinically significant changes. At doses of 100 mg/kg and 200 mg/kg, EGCG has the potential to help control diabetes by most effectively improving insulin resistance and beta cell function. The study results suggest that EGCG, especially at high doses, is an effective component in the treatment of diabetes and the management of insulin resistance. Conclusions: The inclusion of EGCG as a natural flavonoid in medical nutrition therapy may contribute to glycemic control and improve insulin sensitivity in individuals with diabetes. These findings suggest that EGCG may be used as an alternative option in the treatment of diabetes and future studies may further clarify the potential benefits in this area. [ABSTRACT FROM AUTHOR]

Aims In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function. Methods Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months. Results Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P <.05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI:.4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P <.01 and R = 0.19, P <.01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P <.01, R = 0.18, P <.01, respectively). Conclusion The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes. Methods: In this case–control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m2, HbA1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions. Results: PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC0–180 min +261±72 ml min−1 kg−1 × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits. Conclusions: Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. Thirty individuals with T2D (age 18–75 years, BMI 27–50 kg m−2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01). VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Prediabetic pancreatic beta cells can adapt their function to maintain normoglycaemia for a limited period of time, after which diabetes mellitus will manifest upon beta cell exhaustion. Understanding sex-specific beta cell compensatory mechanisms and their failure in prediabetes (impaired glucose tolerance) is crucial for early disease diagnosis and individualised treatment. Our aims were as follows: (1) to determine the key time points of the progression from beta cells' functional adaptations to their failure in vivo; and (2) to mechanistically explain in vivo sex-specific beta cell compensatory mechanisms and their failure in prediabetes. Methods: Islets from male and female transgenic Ins1CreERT2-GCaMP3 mice were transplanted into the anterior chamber of the eye of 10- to 12-week-old sex-matched C57BL/6J mice. Recipient mice were fed either a control diet (CD) or western diet (WD) for a maximum of 4 months. Metabolic variables were evaluated monthly. Beta cell cytoplasmic free calcium concentration ([Ca2+]i) dynamics were monitored in vivo longitudinally by image fluorescence of the GCaMP3 reporter islets. Global islet beta cell [Ca2+]i dynamics in line with single beta cell [Ca2+]i analysis were used for beta cell coordination studies. The glucagon receptor antagonist L-168,049 (4 mmol/l) was applied topically to the transplanted eyes to evaluate in vivo the effect of glucagon on beta cell [Ca2+]idynamics. Human islets from non-diabetic women and men were cultured for 24 h in either a control medium or high-fat/high-glucose medium in the presence or absence of the glucagon receptor antagonist L-168,049. [Ca2+]i dynamics of human islets were evaluated in vitro after 1 h exposure to Fura-10. Results: Mice fed a WD for 1 month displayed increased beta cell [Ca2+]i dynamics linked to enhanced insulin secretion as a functional compensatory mechanism in prediabetes. Recruitment of inactive beta cells in WD-fed mice explained the improved beta cell function adaptation observed in vivo; this occurred in a sex-specific manner. Mechanistically, this was attributable to an intra-islet structural rearrangement involving alpha cells. These sex-dependent cytoarchitecture reorganisations, observed in both mice and humans, induced enhanced paracrine input from adjacent alpha cells, adjusting the glucose setpoint and amplifying the insulin secretion pathway. When WD feeding was prolonged, female mice maintained the adaptive mechanism due to their intrinsically high proportion of alpha cells. In males, [Ca2+]i dynamics progressively declined subsequent to glucose stimulation while insulin secretion continue to increase, suggesting uncoordinated beta cell function as an early sign of diabetes. Conclusions/interpretation: We identified increased coordination of [Ca2+]i dynamics as a beta cell functional adaptation mechanisms in prediabetes. Importantly, we uncovered the mechanisms by which sex-dependent beta cell [Ca2+]i dynamics coordination is orchestrated by an intra-islet structure reorganisation increasing the paracrine input from alpha cells on beta cell function. Moreover, we identified reduced [Ca2+]i dynamics coordination in response to glucose as an early sign of diabetes preceding beta cell secretory dysfunction, with males being more vulnerable. Alterations in coordination capacity of [Ca2+]i dynamics may thus serve as an early marker for beta cell failure in prediabetes. [ABSTRACT FROM AUTHOR]

Summary: Background: Postprandial glucose concentration 1-h (1 h-PG) after an oral glucose tolerance test (OGTT) has similar or superior performance to 2 h-PG in predicting type-2 diabetes mellitus (T2DM) in several populations, and is simpler to obtain in clinical practice. However, studies in Asians are scarce. We investigated the utility of elevated baseline 1 h-PG in predicting T2DM incidence within three years, and its relationship with β-cell function in 1250 non-diabetic Asian participants. Methods: Participants underwent an OGTT, an intravenous glucose challenge and a hyperinsulinemic-euglycemic clamp to determine glucose tolerance, acute insulin response (AIR) and insulin sensitivity at baseline. OGTTs were repeated every six months until study completion to monitor T2DM conversion. Findings: The area under the receiver operating characteristic curve of 1 h-PG was not significantly different from 2 h-PG (AUC1h-PG = 0.883 vs. AUC2h-PG = 0.907; ΔAUC = −0.024, P = 0.124) and the optimal 1 h-PG cut-off was ≥10.7 mmol/L. When groups of high/low 1 h-PG and 2 h-PG at baseline were compared, AIR and disposition index were significantly lower in groups with high 1 h-PG, and both had a stronger correlation with 1 h-PG, indicating that impaired β-cell function was more strongly associated with elevated 1 h-PG than 2 h-PG. Interpretation: The ability of 1 h-PG to detect Asians at risk of developing T2DM within three years is on par with 2 h-PG and the optimal cut-off is 10.7 mmol/L. Elevated 1 h-PG is associated with β-cell dysfunction. We conclude that 1 h-PG can be considered as a primary OGTT time point to identify Asians at risk for T2DM, allowing for screening at a reduced time and cost, and with lower patient burden. Funding: National Medical Research Council (NMRC), Ministry of Health (MOH; Singapore) Industry Alignment Fund [NMRC/MOHIAFCat1/0048/2016] and Janssen Pharmaceuticals Inc. (USA).

Background & Objective: Subclinical hypothyroidism (SCH), is defined as an asymptomatic state characterized by a normal serum concentration of free thyroxine and elevated serum concentration of TSH. This study aims to investigate the complex interplay between hyperinsulinism, insulin resistance, beta cell function, and low-grade chronic inflammation in Iranian women with SCH. Methods: Eighty women with SCH and 80 healthy women as controls matched to the patient group for sex, age, and body mass index (BMI), were enrolled in this prospective cross-sectional study. TSH, free T3, free T4, highly sensitive C-reactive protein (hs-CRP), fasting insulin, fasting glucose, total cholesterol, HDL-cholesterol, LDLcholesterol, Triglyceride, HOMA-IR index, Beta cell function (HOMA-B index) and insulin sensitivity were determined. Results: Hs-CRP was not statistically different between the SCH patients and the control group (3.7±3.2 Vs 3.6±4.0, P>0.05). Total cholesterol and LDL-cholesterol were significantly higher; however, triglyceride and HDL-cholesterol were not statistically different in patients with SCH as compared with the control group. Fasting insulin levels and HOMA-IR and Beta cell function (HOMA-B) were significantly higher in SCH women compared to the control group. A positive correlation between HOMA-IR and HOMA-B with TSH levels was found (r=0.324, r=0.191, P<0.05 respectively). A positive correlation between insulin levels and hs-CRP (r=0.22, P<0.05), also between insulin levels and TSH (r=0.312, P<0.05) and LDL-LDL-cholesterol was obtained (r=0.27, P<0.05). Conclusion: Iranian women with SCH may exhibit elevated atherogenic parameters (hyperinsulinemia, LDL-cholesterol, and total cholesterol), HOMA-IR, and HOMA-B. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. Methods: Data were collected from the large INNODIA cohort of individuals (aged 1.0–45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10–17 years; and ≥18 years. Results: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0–382.0) pmol/l (AUC 749.3 [466.2–1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). Conclusions/interpretation: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline. [ABSTRACT FROM AUTHOR]

Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2–7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1–65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6–89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63–0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit. NEW & NOTEWORTHY: If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp. [ABSTRACT FROM AUTHOR]

Teplizumab (TzieldTM, Provention Bio), a monoclonal antibody directed at T-cell marker CD3, is the first medication approved by the FDA to delay progression from stage 2 to stage 3 type 1 diabetes. To date, the overwhelming majority of pediatric endocrinologists do not have experience using immunotherapeutics and seek guidance on the use of teplizumab in clinical practice. To address this need, the Pediatric Endocrine Society (PES) Diabetes Special Interest Group (Diabetes SIG) and Drug and Therapeutics Committee assembled a task force to review clinical trial data and solicit expert recommendations on the approach to teplizumab infusions. We present considerations on all aspects of teplizumab administration, utilizing evidence where possible and providing a spectrum of expert opinions on unknown aspects. We discuss patient selection and prescreening, highlighting the safety and considerations for monitoring and treatment of side effects. We propose a schedule of events, a protocol for administration, and discuss practice management aspects. We advocate for the need for further long-term systematic surveillance studies to continue evaluating the efficacy and safety of teplizumab. [ABSTRACT FROM AUTHOR]

Background: Measures of insulin resistance (IR)/sensitivity (IS) are emerging tools to identify metabolic-associated fatty liver disease (MAFLD). However, the comprehensive assessment of the performance of various indicators is limited. Moreover, the utility of measures of IR/IS in detecting liver fibrosis remains unclear. Aims: To evaluate the predictive ability of seventeen IR/IS and two beta cell function indices to identify MAFLD and liver fibrosis. Methods: A cross-sectional study was conducted on individuals aged 25–75 years. Transient elastography was used to estimate liver stiffness and controlled attenuation parameter. The following measures were computed: homeostatic model assessment (HOMA/HOMA2) for IR, IS, and beta cell function; QUICKI; Bennett index; glucose/insulin; FIRI; McAuley index; Reynaud index; SPISE index; TyG; TyG-BMI; TyG-WC; TyG-WHtR; TG/HDL; and METS-IR. Subgroup analyses were performed according to age, gender, diabetes status, and body weight. Results: A total of 644 individuals were included in our analysis. MAFLD and significant liver fibrosis were detected in 320 (49.7%) and 80 (12.4%) of the participants, respectively. All measures of IR/IS identified MAFLD and liver fibrosis. However, TyG-WC, TyG-BMI, and TyG-WHtR were the top three indicators that identified MAFLD. Measures that include insulin level in their mathematical calculation, namely, Raynaud index, HOMA-IR, HOMA 2-IR, FIRI, and QUICKI had the best performance in identifying liver fibrosis in the entire population, as well as among the study subgroups. Conclusions: TyG-WC, TyG-BMI, and TyG-WHtR were the best predictors of MAFLD. Insulin-based measures had better performances in the detection of advanced fibrosis. This was independent of age, gender, obesity, or diabetes status. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission. Methods: Ninety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up. Results: DPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P<0.001). After three months post-SIIT, DPP-4 activity remained stable in the remission group (39.63 ± 8.53 nmol/L) but increased in the nonremission group (42.34 ± 6.64 nmol/L). This resulted in a more pronounced decrease in DPP-4 activity from baseline in the remission group (-3.39 ± 8.90 vs. -1.10 ± 8.95, P = 0.035). Logistic regression analyses showed that patients with greater DPP-4 activity reduction had a higher likelihood of 1-year remission (70% vs. 51.1%, OR: 7.939 [1.829, 34.467], P = 0.006 in the fully adjusted model). A non-linear relationship between DPP-4 and 1-year remission rate was observed, with a clear threshold and saturation effect. Conclusion: Circulating DPP-4 activity significantly decreases after SIIT. The change in circulating DPP-4 activity during the 3-month post-treatment phase has the potential to predict long-term remission. [ABSTRACT FROM AUTHOR]

Introduction: It is still controversial about the efficacy of Diptptidyl peptidase-4 (DPP4) inhibitors in the treatment of autoimmune diabetes, especially it is unclear whether different drugs have different efficacy for different subtypes of autoimmune diabetes. Aims: To evaluated the efficacy and safety of different DPP-4 inhibitors (Sitagliptin or saxagliptin) combined with insulin in the treatment of different subtypes of autoimmune diabetes. Methods: We searched PubMed, Embase, Cochrane library, Web of Science, Wanfang and CNKI databases from inception to August 2022 to identify correlational studies. Then, RevMan 5.4 and Stata 17.0 software were used to make forest plots. Weighted mean difference (WMD) or odds ratio (OR) with 95 %CI to evaluated the outcomes of Saxagliptin or Sitagliptin combined with insulin in the treatment of autoimmune diabetes. Results: 18 studies consisting of 811 patients were included. Our study revealed Sitagliptin or Saxagliptin both have decrease insulin dose without increase the occurrence of hypoglycemia and adverse event, regardless of subtypes of autoimmune diabetes. Saxagliptin did not statistically improve in glucose control and beta cell function in both LADA and T1DM. However, compared with T1DM, Sitagliptin decreased HbA1c and improved islet beta cell function in patients with LADA. Conclusions: Sitagliptin combined with insulin therapy in patients with LADA significantly improve glucose control and beta cell function, decrease insulin dose without increasing the occurrence of hypoglycemia and adverse event. Further research in this field is required. Clinical relevance: DPP-4 inhibitors combined with insulin therapy in patients with autoimmune diabetes significantly reduced blood glycemic, preserve islet beta cell function, decrease insulin dose, BMI and the incidence of hypoglycemia, and do not increase the incidence of adverse events.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00–0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04–0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, −0.07units/kg/day, 95% CI, −0.11 to −0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, −0.11units/kg/day, 95% CI, −0.23 to −0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

To evaluate the association of nonesterified fatty acids (NEFA) with dysglycemia in older adults, NEFA levels were measured among participants in the Cardiovascular Health Study (United States; enrolled 1989-1993). Associations with insulin sensitivity and pancreatic β-cell function, and with incident type 2 diabetes mellitus (DM), were examined. The sample comprised 2,144 participants (aged 77.9 (standard deviation, 4.5) years). Participant data from the Cardiovascular Health Study visit in 1996-1997 was used with prospective follow-up through 2010. Fasting and postload NEFA showed significant associations with lower insulin sensitivity and pancreatic β-cell function, individually and on concurrent adjustment. Over median follow-up of 9.7 years, 236 cases of DM occurred. Postload NEFA were associated with risk of DM (per standard deviation, hazard ratio = 1.18, 95% confidence interval: 1.08, 1.29), but fasting NEFA were not (hazard ratio = 1.12, 95% confidence interval: 0.97, 1.29). The association for postload NEFA persisted after adjustment for putative intermediates, and after adjustment for fasting NEFA. Sex and body mass index modified these associations, which were stronger for fasting NEFA with DM in men but were accentuated for postload NEFA in women and among leaner individuals. Fasting and postload NEFA were related to lower insulin sensitivity and pancreatic β-cell function, but only postload NEFA were associated with increased DM. Additional study into NEFA metabolism could uncover novel potential targets for diabetes prevention in elders.

BackgroundThis study aims to investigate the changes in circulating dipeptidyl peptidase-4 (DPP-4) activity following short-term intensive insulin therapy (SIIT) in newly diagnosed type 2 diabetes (T2D) patients and to assess its potential in predicting long-term remission.MethodsNinety-five patients underwent SIIT for 2-3 weeks to attain and sustain near-normal glycemia. Insulin was then discontinued, and patients were followed for a year to evaluate glycemic outcomes. Biochemical tests, serum DPP-4 activity, and mixed meal tolerance tests were conducted at baseline, post-SIIT, and the 3-month follow-up.ResultsDPP-4 activity decreased from 44.08 ± 9.58 to 40.53 ± 8.83 nmol/min/mL after SIIT (P

Background: Very few studies have assessed the impact of hydroxychloroquine (HCQ) on insulin resistance, beta cell function, and inflammatory markers in diabetics which takes paramount importance in understanding the mechanism of its anti-diabetic effect. Objective: To assess the effect of hydroxychloroquine on beta cell function and insulin resistance and inflammatory markers in type 2 diabetes patients uncontrolled on glimepiride and metformin combination. Study design and method: 30 T2DM patients were inadequately controlled on glimepiride and metformin combination with an HbA1c between 7.5 and 10% (both inclusive) and were given hydroxychloroquine 400 mg in addition to glimepiride and metformin during the 12-week study period. Beta cell function, insulin resistance, high-sensitivity C-reactive protein (hsCRP), adiponectin, interleukin-6 (IL6), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and glycated hemoglobin (HbA1c) were assessed at baseline and at 12 weeks after addition of 400 mg hydroxychloroquine. Results: With addition of HCQ, there was a significant improvement in both beta cell function and insulin resistance (p < 0.001). There was also significant improvement in FPG, PPG, and HbA1c along with significant improvement in IL6, hsCRP, and adiponectin levels post 12 weeks of adjunctive treatment with hydroxychloroquine. The changes in beta cell function and insulin resistance correlated significantly with the changes in IL6, hsCRP, and adiponectin levels. Conclusion: Addition of hydroxychloroquine as an add-on drug in uncontrolled diabetes significantly improves the beta cell function and the insulin resistance, along with significant improvement in adiponectin, hsCRP levels, and IL6 levels. [ABSTRACT FROM AUTHOR]

Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose‐stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes. Materials and Methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high‐fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini‐pumps for 25 days. Glucose tolerance, circulating insulin and C‐peptide levels, and GSIS were assessed. In addition, β‐cells (Min‐6) were used to test the effects of sPIF on GSIS and insulin‐degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets. Results: GSIS was enhanced 2‐fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β‐cell function. Finally, genetic (shRNA‐IDE) or pharmacological (6bK) inactivation of IDE in Min‐6 abolished sPIF‐mediated effects on GSIS, showing that both the protein and its protease activity are required for its action. Conclusions: We conclude that sPIF is a promising secretagogue for the treatment of T2D. [ABSTRACT FROM AUTHOR]

Introduction: This study developed a simple algorithm based on clinical results described in medical literature and which allows one to simplify complex insulin regimes with IdegLira to avoid adverse events related to the complexity of some insulin treatments. Methods: We conducted a systematic review of the literature that allowed us to identify studies that evaluated the clinical result of simplifying complex insulin regimes. The authors reviewed the common factors these simpler regimes had, including the type of patients who used them. Results: We found nine clinical studies published between 2017 and 2022, eight performed in Europe and one in Latin America. The monitoring time of the studies ranged between 3 and 18 months. The size of the study populations was between 61 and 611 patients (the latter was in five countries). In all studies, HbA1c decreased by 0.6–1.7% and the weight decreased by 0.1–3.11 kg. Conclusions: On the basis of the findings of these studies, we made some recommendations for clinical practice to simplify treatment. The results of these studies support an algorithm that simplifies the treatment of complex insulin regimens. [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

Aims: This study characterized incidence, patient profiles, risk factors and outcomes of in‐hospital diabetic ketoacidosis (DKA) in patients with COVID‐19 compared with influenza and pre‐pandemic data. Methods: This study consisted of 13 383 hospitalized patients with COVID‐19 (March 2020‐July 2022), 19 165 hospitalized patients with influenza (January 2018‐July 2022) and 35 000 randomly sampled hospitalized pre‐pandemic patients (January 2017‐December 2019) in Montefiore Health System, Bronx, NY, USA. Primary outcomes were incidence of in‐hospital DKA, in‐hospital mortality, and insulin use at 3 and 6 months post‐infection. Risk factors for developing DKA were identified. Results: The overall incidence of DKA in patients with COVID‐19 and influenza, and pre‐pandemic were 2.1%, 1.4% and 0.5%, respectively (p <.05 pairwise). Patients with COVID‐19 with DKA had worse acute outcomes (p <.05) and higher incidence of new insulin treatment 3 and 6 months post‐infection compared with patients with influenza with DKA (p <.05). The incidence of DKA in patients with COVID‐19 was highest among patients with type 1 diabetes (12.8%), followed by patients with insulin‐dependent type 2 diabetes (T2D; 5.2%), non‐insulin dependent T2D (2.3%) and, lastly, patients without T2D (1.3%). Patients with COVID‐19 with DKA had worse disease severity and higher mortality [odds ratio = 6.178 (4.428‐8.590), p <.0001] compared with those without DKA. Type 1 diabetes, steroid therapy for COVID‐19, COVID‐19 status, black race and male gender were associated with increased risk of DKA. Conclusions: The incidence of DKA was higher in COVID‐19 cohort compared to the influenza and pre‐pandemic cohort. Patients with COVID‐19 with DKA had worse outcomes compared with those without. Many COVID‐19 survivors who developed DKA during hospitalization became insulin dependent. Identification of risk factors for DKA and new insulin‐dependency could enable careful monitoring and timely intervention. [ABSTRACT FROM AUTHOR]

Aim: To determine the kinase activity profiles of human pancreatic beta cells downstream of glucagon‐like peptide‐1 receptor (GLP‐1R) balanced versus biased agonist stimulations. Materials and Methods: This study analysed the kinomic profiles of human EndoC‐βh1 cells following vehicle and GLP‐1R stimulation with the pharmacological agonist exendin‐4, as well as exendin‐4–based biased derivatives exendin‐phe1 and exendin‐asp3 for acute (10‐minute) versus sustained (120‐minute) responses, using PamChip protein tyrosine kinase and serine/threonine kinase assays. The raw data were filtered and normalized using BioNavigator. The kinase analyses were conducted with R, mainly including kinase‐substrate mapping and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Results: The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP‐1R agonist exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP‐1R signalling mediators, constituting potential targets for further research on biased GLP‐1R downstream signalling. Conclusion: The results from this study suggest that differentially biased exendin‐phe1 and exendin‐asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti‐type 2 diabetes therapies with optimized downstream kinomic profiles. [ABSTRACT FROM AUTHOR]

A diet high in advanced glycation endproducts (AGEs) is a potential risk factor for insulin resistance, beta cell dysfunction, and ultimately type 2 diabetes. We investigated associations between habitual intake of dietary AGEs and glucose metabolism in a population-based setting. In 6275 participants of The Maastricht Study (mean ± SD age: 60 ± 9, 15.1% prediabetes and 23.2% type 2 diabetes), we estimated habitual intake of dietary AGEs N ε -(carboxymethyl)lysine (CML), N ε -(1-carboxyethyl)lysine (CEL), and N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) by combining a validated food frequency questionnaire (FFQ) with our mass-spectrometry dietary AGE database. We determined insulin sensitivity (Matsuda- and HOMA-IR index), beta cell function (C-peptidogenic index, glucose sensitivity, potentiation factor, and rate sensitivity), glucose metabolism status, fasting glucose, HbA1c, post-OGTT glucose, and OGTT glucose incremental area under the curve. Cross–sectional associations between habitual AGE intake and these outcomes were investigated using a combination of multiple linear regression and multinomial logistic regression adjusting for several potential confounders (demographic, cardiovascular, and lifestyle factors). Generally, higher habitual intake of AGEs was not associated with worse indices of glucose metabolism, nor with increased presence of prediabetes or type 2 diabetes. Higher dietary MG-H1 was associated with better beta cell glucose sensitivity. The present study does not support an association of dietary AGEs with impaired glucose metabolism. Whether higher intake of dietary AGEs translates to increased incidence of prediabetes or type 2 diabetes on the long term should be investigated in large prospective cohort studies. [ABSTRACT FROM AUTHOR]

The HNF1A transcription factor, implicated in the regulation of pancreatic beta cells, as well as in glucose and lipid metabolism, is responsible for type 3 maturity-onset diabetes of the young (MODY3). HNF1A is also involved in increased susceptibility to polygenic forms of diabetes, such as type 2 diabetes (T2D) and gestational diabetes (GD), while its possible role in type 1 diabetes (T1D) is not known. In this study, 277 children and adolescents with T1D and 140 healthy controls were recruited. The following SNPs in HNF1A gene were selected: rs1169286, rs1169288, rs7979478, and rs2259816. Through linear or logistic regression analysis, we analyzed their association with T1D susceptibility and related clinical traits, such as insulin dose-adjusted glycated hemoglobin A1c (IDAA1c) and glycated hemoglobin (HbA1c). We found that rs1169286 was associated with IDAA1c and HbA1c values (p-value = 0.0027 and p-value = 0.0075, respectively), while rs1169288 was associated with IDAA1c (p-value = 0.0081). No association between HNF1A SNPs and T1D development emerged. In conclusion, our findings suggest for the first time that HNF1A variants may be a risk factor for beta cell function and glycaemic control in T1D individuals. [ABSTRACT FROM AUTHOR]

Background: Beneficial role of fibroblast growth factor 1 (FGF1) in the regulation of glucose metabolism and adipose tissue remodeling was suggested in rodents. This study aimed to investigate the association between serum FGF1 levels and metabolic parameters in adults with glucose intolerance. Methods: Serum FGF1 levels were examined using an enzyme-linked immunosorbent assay in 153 individuals with glucose intolerance. Associations between serum FGF1 levels and metabolic parameters, including body mass index (BMI), glycated hemoglobin (HbA1c), and 75 g oral glucose tolerance testderived parameters, including insulinogenic index (IGI), Matsuda insulin sensitivity index (ISI), and disposition index (DI), were examined. Results: Serum FGF1 was detected in 35 individuals (22.9%), possibly due to the autocrine/paracrine nature of the peptide. IGI and DI levels were significantly lower in individuals with higher FGF1 levels than in those with lower FGF1 levels or undetectable FGF1 (p=0.006 and 0.005 for IGI and DI, respectively, after adjustment for age, sex, and BMI). Univariable and multivariable analyses using the Tobit regression model also revealed a negative association between FGF1 levels and IGI and DI. The regression coefficients per 1-SD of log-transformed IGI and DI were -0.461 (p=0.013) and -0.467 (p=0.012), respectively, after adjustment for age, sex, and BMI. In contrast, serum FGF1 levels were not significantly associated with ISI, BMI, or HbA1c. Conclusions: The serum concentration of FGF1 was significantly elevated in individuals with low insulin secretion, suggesting a possible interaction between FGF1 and beta cell function in humans. [ABSTRACT FROM AUTHOR]

Background: Osteocalcin (OC), also known as bone Gla (gamma-carboxyglutamic acid) protein, is a marker of bone formation. OC has effect on glucose and fat metabolism. Role of OC in type 2 diabetes mellitus (T2DM) is not well studied in Indian population. Our study aimed to see the relationship between OC and parameters of glucose metabolism in type 2 diabetes mellitus. Methods: This cross-sectional study included 120 subjects with T2DM. In each subject, fasting insulin, serum osteocalcin (measured by ELISA), fasting plasma glucose (FPG), post prandial plasma glucose (PPG), and glycated Hb (HbA1c) were measured. HOMA 2.0 model was used to measure insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Then, serum osteocalcin levels were correlated with HOMA-IR, HOMA-β, FPG, PPG, and HbA1c. Results: Serum OC levels reduced with increase in insulin resistance (HOMA-IR) (r = −0.274, p = 0.004); however, there was no association with the beta cell function. OC had negative association with FPG (r = −0.14, p = 0.12) and PPG (r = −0.123, p = 0.18); however, it was statistically insignificant. Glycated hemoglobin (HbA1c) was significantly reduced in diabetic patients with higher OC levels (r = −0.208, p = 0.025). Conclusion: Serum OC has significant association with insulin resistance and HbA1c in subjects with T2DM, which might suggest possible role of serum OC in glucose metabolism in T2DM. [ABSTRACT FROM AUTHOR]

The shape of the glycemic curve during the oral glucose tolerance test (OGTT), interpreted in the correct context, can predict impaired glucose homeostasis. Our aim was to reveal information inherent in the 3 h glycemic trajectory that is of physiological relevance concerning the disruption of glycoregulation and complications beyond, such as components of metabolic syndrome (MS). Methods: In 1262 subjects (1035 women, 227 men) with a wide range of glucose tolerance, glycemic curves were categorized into four groups: monophasic, biphasic, triphasic, and multiphasic. The groups were then monitored in terms of anthropometry, biochemistry, and timing of the glycemic peak. Results: Most curves were monophasic (50%), then triphasic (28%), biphasic (17.5%), and multiphasic (4.5%). Men had more biphasic curves than women (33 vs. 14%, respectively), while women had more triphasic curves than men (30 vs. 19%, respectively) (p < 0.01). Monophasic curves were more frequent in people with impaired glucose regulation and MS compared to bi-, tri-, and multiphasic ones. Peak delay was the most common in monophasic curves, in which it was also most strongly associated with the deterioration of glucose tolerance and other components of MS. Conclusion: The shape of the glycemic curve is gender dependent. A monophasic curve is associated with an unfavorable metabolic profile, especially when combined with a delayed peak. [ABSTRACT FROM AUTHOR]

Aims/introduction: There have been few reports about the longitudinal changes in pancreas volume (PV) or pancreatic steatosis (PS) in response to obesity. In this longitudinal analysis using health check-up data, we explored changes in PV, PS and glucose metabolic indices that occurred after weight gain in Japanese without diabetes. Materials/methods: Clinical data on 37 Japanese subjects with a ≥1 kg/m2 increase in body mass index between two health check-ups and without diabetes were collected. PV, pancreas attenuation (PA) and splenic attenuation (SA) were evaluated using computed tomography (CT) images. The pancreas area was outlined by hand in multiple images with slice thickness of 2 mm, and the PV was computed by summing these areas. PS was defined as the difference between SA and PA (SA-PA). Medical records were collected, including findings on immunoreactive insulin (IRI), homeostasis model assessment of insulin resistance (HOMA-R) and beta cell function (HOMA-β). Paired t-test and Spearman's correlation coefficient were used in the analyses. Results: The median follow-up period was 21.1 months and the mean BMI was increased from 25.5 ± 3.3 kg/m2 to 27.0 ± 3.3 kg/m2. PV (53.5 ± 15.9 cm3 vs. 56.2 ± 16.4 cm3) and SA-PA (8.7 ± 9.1 HU vs. 13.6 ± 10.9 HU) increased significantly after weight gain (both, P

Objective. The primary objective was to assess beta-cell function of recently-diagnosed young-onset type 2 diabetes mellitus (T2DM) individuals using basal and stimulated C-peptide levels. The secondary objective was to examine the association between C-peptide with metabolic factors and diabetes complications. Methodology. A cross-sectional study was conducted for young-onset T2DM individuals aged 18-35 years with a disease duration of not more than 5 years. Plasma C-peptide was measured before and after intravenous glucagon injection. Demographic data, medical history and complications were obtained from medical records and clinical assessment. Continuous data were expressed as median and interquartile range (IQR). Categorical variables were described as frequency or percentage. Multivariable linear regression analysis was used to determine factors associated with C-peptide levels. Results. 113 participants with young-onset T2DM with a median (IQR) age of 29.0 (9.5) years and 24 (36) months were included in this study. The median (IQR) basal and stimulated C-peptide was 619 (655) pmol/L and 1231 (1024) pmol/L. Adequate beta-cell function was present in 78-86% of the participants based on the basal and stimulated C-peptide levels. We found hypertension, obesity and diabetic kidney disease (DKD) to be independently associated with higher C–peptide levels. In contrast, females, smokers, those on insulin therapy and with longer duration of disease had lower C–peptide levels. Conclusion. Most recently diagnosed young-onset T2DM have adequate beta-cell function. Elevated C-peptide levels associated with obesity, hypertension and diabetic kidney disease suggest insulin resistance as the key driving factor for complications.

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Antihyperglycemic action of scopoletin needs to be validated before considering it for clinical trials. The present study explored antihyperglycemic action of scopoletin in high-fructose high-fat diet (HFHFD)–induced diabetes in rats. The animal study was performed using 48 rats, 6 in each group. HFHFD was administered for model induction for 74 days. Rats in Group I (normal control [NC]) and group II (experimental control [EC]) received normal saline and HFHFD, respectively, throughout the study. Groups III, IV, V, and VI received oral scopoletin (1 mg/kg [low dose, LD], 5 mg/kg [medium dose, MD], 10 mg/kg [high dose, HD]), and metformin (250 mg/kg; positive control [PC] for efficacy), respectively, once daily from day 60 to 74, in addition to HFHFD. Group VII (10 mg/kg oral scopoletin safety group) and VIII (0.1 mg/kg oral warfarin; PC for safety) were separately used for bleeding time-clotting time (BTCT) assessment on days 60, 68, and 74. Groups I, VII, and VIII rats were studied for safety assessment. Later, animals were sacrificed for histological examination. Scopoletin-treated groups showed a significant decline in glucose levels, especially in the MD (5.18 ± 0.12) and HD group (5.271 ± 0.11) in comparison to the EC (6.37 ± 0.05) on day 74 (P < .05). Two weeks after scopoletin treatment, β-cell function significantly improved (53.073 ± 4.67) in the MD group versus 29.323 ± 8.505 in the NC group (P < .05). A statistically significant difference was observed when the MD group (53.07 ± 4.67) was compared to the metformin-treated group (24.80 ± 3.24; P < .05). The safety assessment in the form of BTCT findings did not observe a difference among groups I, VII, and VIII (P > .05). The study showed that scopoletin dose-independently reversed insulin resistance. Consequently, scopoletin can be a potential candidate for antidiabetic drug development. [ABSTRACT FROM AUTHOR]

Background/aim: Type 2 diabetes mellitus (T2D) is a complex metabolic impairment. Beta cell (BC) failure is the most challenging among its pathogenetic mechanisms. Recognizing reversible contributors to BC failure could guide individualized approach to early T2D treatment. The aim of this study was to compare early short-term insulin treatment vs. glimepiride, both added to metformin, on BC function, glycemic and lipid control, during 12-month follow-up. Patients and methods: Eighty newly diagnosed T2D patients, 30-65 years of age, presenting with HbA1c = 9% were enrolled in the study. They were randomly assigned to single-month initial insulin therapy (INS) added to metformin, or to glimepiride and metformin (OAD) as only treatment. Subjects assigned to initial insulin intervention were thereafter switched to OAD. C-peptide (C-Pep) was analyzed at baseline and 2 hours after standardized test meal (STM). All subjects were STM-retested after 3 and 12 months. HbA1c, serum lipids, BMI, HOMA IR, and HOMA B were assessed over follow-up. Results: HbA1c was lower in INS vs OAD at 3-months: 6.26 ± 0.18% vs 6.78 ± 0.10% (p = 0.016), remaining so by 12 months (p = 0.056). BMI-adjusted ΔC-Pep was greater in INS vs. OAD at 3 months (4.60 ± 0.59 vs. 3.21 ± 0.34 m2/kg; p = 0.044), persisting by 12 months (4.57 ± 0.56 vs. 3.04 ± 0.34 m2/kg; p = 0.023). Average ΔC-Pep improvement from recruitment to 3 months was 100.8% in INS, vs. 51.3% in OAD. Prevalence of STM-ΔC-Pep response greater than 2.4 ng/mL had risen 3.2-fold by 12 months in the INS, vs. 2.4-fold only in the OAD group (p = 0.018). Conclusion: Early short-term insulin intervention in newly diagnosed T2D improves beta cell function more than glimepiride, both added to metformin, resulting in a superior and longer lasting glycemic and lipid control. [ABSTRACT FROM AUTHOR]

The International Diabetes Federation (IDF) has recently recommended determination of 1-hour plasma glucose (1-hPG) during an oral glucose tolerance test (OGTT) to diagnose intermediate hyperglycemia (IH) and type 2 diabetes (T2DM). Herein, we investigated the cardiometabolic characteristics of individuals with IH and T2DM according to IDF criteria. We studied 3086 individuals stratified on the basis of fasting, 1-hPG and 2-hPG in four groups: 1) normal glucose tolerance (NGT), 2) isolated impaired fasting glucose (iIFG,), 3) IH (fasting glucose < 126 mg/dL, 1-hPG 155–208 mg/dL, and/or 2-hPG 140–199 mg/dL, and 4) newly diagnosed T2DM (fasting glucose, 1-hPG and/or 2-hPG≥126 mg/dL, 209 mg/dL and 200 mg/dL, respectively). Individuals with IH and T2DM exhibited higher adiposity, blood pressure, uric acid, a worse lipid and inflammatory profile and a progressive reduction in Matsuda index of insulin sensitivity, insulinogenic index, and disposition index as compared to the NGT group. Moreover, individuals with IH and T2DM exhibited lower Matsuda, insulinogenic, and disposition indexes as compared to the iIFG group. 1-h PG-based criteria for diagnosis of IH and diabetes identify individuals having an unfavorable cardiometabolic risk profile with a progressive reduction in insulin sensitivity associated with impaired β cell function. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes. Methods: This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210). Results: We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient –0.35; 95% CI –0.44, –0.25) and men (coefficient –0.09; 95% CI –0.15, –0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men. Conclusions/interpretation: We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Sub-Saharan Africa (SSA) is the region with the highest projected rates of increase in type 2 diabetes (129% by 2045), which will exacerbate the already high prevalence of type 2 diabetes complications and comorbidities in SSA. In addition, SSA is grappling with poverty-related health problems and infectious diseases and is also undergoing the most rapid rates of urbanisation globally. These socioenvironmental and lifestyle factors may interact with genetic factors to alter the pathophysiological sequence leading to type 2 diabetes in sub-Saharan African populations. Indeed, current evidence from SSA and the diaspora suggests that the pathophysiology of type 2 diabetes in Black Africans is different from that in their European counterparts. Studies from the diaspora suggest that insulin clearance is the primary defect underlying the development of type 2 diabetes. We propose that, among Black Africans from SSA, hyperinsulinaemia due to a combination of both increased insulin secretion and reduced hepatic insulin clearance is the primary defect, which promotes obesity and insulin resistance, exacerbating the hyperinsulinaemia and eventually leading to beta cell failure and type 2 diabetes. Nonetheless, the current understanding of the pathogenesis of type 2 diabetes and the clinical guidelines for preventing and managing the disease are largely based on studies including participants of predominately White European ancestry. In this review, we summarise the existing knowledge base and data from the only non-pharmacological intervention that explores the pathophysiology of type 2 diabetes in SSA. We also highlight factors that may influence the pathogenesis of type 2 diabetes in SSA, such as social determinants, infectious diseases and genetic and epigenetic influences. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Improvements in glycemic control following acute exercise are typically attributed to improved post-exercise insulin sensitivity (IS) with comparatively little known about how acute exercise impacts beta cell function, especially in post-menopausal females. We determined how two high-intensity interval training (HIIT) protocols, matched for total estimated energy expenditure, impact beta cell function in post-menopausal females with type 2 diabetes. Methods: Thirteen post-menopausal females (70 ± 5 years; 12 ± 7 years since diagnosis, 80.9 ± 13.8 kg, 32.4 ± 5.6 kg*m 2 ; HbA1c - 49.8 ± 10.3 mmol/mol [6.7 ± 1.0]) living with type 2 diabetes were included in this semi-randomized crossover trial. The trial involved an initial resting control condition followed by two HIIT conditions [4 X 4-minute HIIT (HIIT4) and 10 X 1-minute HIIT (HIIT10)] completed in a randomized order 2-4 days apart. Beta cell function (glucose sensitivity) and insulin sensitivity were determined from a 2 h mixed-meal tolerance test performed 2 hours after rest or HIIT. Results: Both HIIT4 and HIIT 10 significantly improved beta cell glucose sensitivity compared to control (15 pmol*min -1 *m -2 [mmol/L] -1 , [95% CI 6, 23]; p= 0.002 and 16 pmol*min -1 *m -2 [mmol/L] -1 , [95% CI 7, 25]; p= 0.002, respectively), with no difference between HIIT protocols (1 [-8, 10], P = 0.79). There were no significant differences in IS metrics (Matsuda index, OGIS, Stumvoli, and QUICKI) between the conditions. Conclusions/interpretation: An acute bout of 4 X 4-minute or 10 X 1-minute HIIT improves beta cell glucose sensitivity in post-menopausal females living with type 2 diabetes.

Aims/hypothesis: Postprandial hypoglycaemia (PPHG) is a frequent late complication of Roux-en-Y gastric bypass (RYGB) in people without diabetes. We aimed to examine the pathogenetic mechanisms of PPHG and its clinical consequences in people with a history of type 2 diabetes., Methods: In this case-control study, 24 participants with type 2 diabetes treated with RYGB (14 women; median [IQR] age 53.5 [13.8] years, BMI 29.3 [6.3] kg/m 2 , HbA 1c 36.0 [6.2] mmol/mol [5.4% (0.6%)]) underwent a dual-tracer, frequently sampled, 300 min, 75 g OGTT for the diagnosis of PPHG (glucose nadir <3.0 mmol/l, or <3.3 mmol/l with symptoms). Plasma glucose, glucose tracers, insulin, C-peptide, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon, adrenaline (epinephrine), noradrenaline (norepinephrine), cortisol and NEFAs were measured. Mathematical models were implemented to estimate glucose metabolic fluxes and beta cell function. ECG recordings, cognitive testing and hypoglycaemia awareness assessments were repeated during the OGTT. Glycaemic levels and dietary habits were assessed under free-living conditions., Results: PPHG occurred in 12 (50%) participants, mostly without symptoms, due to excessive tracer-derived glucose clearance (mean group difference ± SE in AUC 0-180 min +261±72 ml min -1 kg -1 × min) driven by higher whole-body insulin sensitivity and early glucose-stimulated hyperinsulinaemia, the latter depending on lower insulin clearance and enhanced beta cell function, regardless of incretin hormones. PPHG participants also had defective counterregulatory hormone responses to hypoglycaemia, preventing a physiological increase in endogenous glucose production and the appearance of symptoms and signs of sympathetic cardiovascular activation and neuroglycopenia. PPHG was associated with more frequent and prolonged hypoglycaemia on 14 day continuous glucose monitoring and alterations in free-living dietary habits., Conclusions: Our results demonstrate that post-bypass PPHG occurs frequently in individuals with a history of type 2 diabetes, often without warning symptoms, and expose its complex pathogenetic mechanisms, revealing potential therapeutic targets., Competing Interests: Acknowledgements: We are deeply grateful to all participants for their consent and willingness to participate in this study. We gratefully acknowledge S. Amiel (Department of Diabetes, King’s College of London, London, UK) for her constructive comments and insightful discussion on the research questions and study design. Preliminary data were presented as an abstract at the 60th Annual Meeting of the EASD in 2024. Data availability: The data that support the study findings are available from the corresponding author on request. Funding: This research was funded by the European Foundation for the Study of Diabetes (EFSD Rising Star Fellowship supported by EFSD/Novo Nordisk to DT) and by the European Society for Clinical Nutrition and Metabolism (ESPEN Research Fellowship to DT). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: DT designed the study protocol, conducted experiments, acquired and analysed data and wrote the manuscript. LS, ER, NC, MC and LN conducted experiments and acquired data. GN revised and analysed the self-reported food diaries. DM and GD recruited participants and provided substantial contributions to the interpretation of data. SB, SF and MTS conducted experiments and analysed blood samples. AM performed glucose tracer and beta cell function modelling. MN and AN revised the study protocol, recruited participants, supervised the study and share last authorship. All authors commented on and approved the final version of the manuscript. DT and AN are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract Background Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown. Methods We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-β, a marker of beta cell function. Results Median (IQR) arsenic concentration was 0.45 (0.67) μg/g in toenails and 2.0 (6.5) μg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (− 3.13, 3.37) higher and HOMA-β was 0.96% (− 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null. Conclusions Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.

Aim: To evaluate the ability of ladarixin (LDX, 400 mg twice‐daily for three cycles of 14 days on/14 days off), an inhibitor of the CXCR1/2 chemokine receptors, to maintain C‐peptide production in adult patients with newly diagnosed type 1 diabetes. Materials and Methods: A double‐blind, randomized (2:1), placebo‐controlled study was conducted in 45 males and 31 females (aged 18‐46 years) within 100 days of the first insulin administration. The primary endpoint was the area under the curve (AUC) for C‐peptide in response to a 2‐hour mixed meal tolerance test (AUC[0‐120 min]) at week 13 ± 1. Secondary endpoints included C‐peptide AUC(15‐120 min), HbA1c, daily insulin requirement, severe hypoglycaemic events (SHE), the proportion of subjects achieving HbA1c less than 7.0% without SHE and maintaining a residual beta cell function. Follow‐up assessments were scheduled at weeks 13 ± 1, 26 ± 2 and 52 ± 2. Results: In total, 26/26 (100%, placebo) and 49/50 (98%, LDX) patients completed week 13. The mean change from baseline to week 13 in C‐peptide AUC(0‐120 min) was −0.144 ± 0.449 nmol/L with placebo and 0.003 ±.322 nmol/L with LDX. The difference was not significant (0.149 nmol/L, 95% CI −0.04 to 0.33; P =.122). At week 26, the proportion of patients with HbA1c less than 7.0% without SHE was transiently higher in the LDX group (81% vs. 54%, P =.024). Otherwise, no significant secondary endpoint differences were noted. Transient metabolic benefit was seen at week 26 in favour of the LDX group in the prespecified subpopulation with fasting C‐peptide less than the median value at screening. Conclusions: In newly diagnosed patients with type 1 diabetes, short‐term LDX treatment had no appreciable effect on preserving residual beta cell function. [ABSTRACT FROM AUTHOR]

B APPENDIX SENSITIVITY ANALYSIS 2 B.1 Using the Quantitative Response (QR) metric to quantify C-peptide treatment effect In order to assess the robustness of the findings regardless of analytical model, we repeated the analysis of the C-peptide effect using a modified version of the QR metric suggested by Krischer and Bundy (Endocrinol Diabetes Metab 2020, PMID 32704564). In brief, the original QR metric quantifies the treatment effect on C-peptide preservation as the difference between the observed C-peptide and the predicted C-peptide after 12 months in recent-onset T1D patients. The association between the treatment effect has not been reported for other investigational treatments, such as for other antigen-specific therapies or immunosuppressive treatments. Keywords: antidiabetic drug; beta cell function; clinical trial; meta-analysis; type 1 diabetes EN antidiabetic drug beta cell function clinical trial meta-analysis type 1 diabetes 1647 1655 9 07/11/22 20220801 NES 220801 BACKGROUND Preservation of insulin secretion in type 1 diabetes (T1D) lowers the risk of complications such as retinopathy and severe hypoglycaemia.1-3 C-peptide preservation - a biomarker for endogenous insulin secretion - is used as a surrogate endpoint in clinical trials assessing beta cell-preserving therapies. [Extracted from the article]

The HNF1A transcription factor, implicated in the regulation of pancreatic beta cells, as well as in glucose and lipid metabolism, is responsible for type 3 maturity-onset diabetes of the young (MODY3). HNF1A is also involved in increased susceptibility to polygenic forms of diabetes, such as type 2 diabetes (T2D) and gestational diabetes (GD), while its possible role in type 1 diabetes (T1D) is not known. In this study, 277 children and adolescents with T1D and 140 healthy controls were recruited. The following SNPs in HNF1A gene were selected: rs1169286, rs1169288, rs7979478, and rs2259816. Through linear or logistic regression analysis, we analyzed their association with T1D susceptibility and related clinical traits, such as insulin dose-adjusted glycated hemoglobin A1c (IDAA1c) and glycated hemoglobin (HbA1c). We found that rs1169286 was associated with IDAA1c and HbA1c values (p-value = 0.0027 and p-value = 0.0075, respectively), while rs1169288 was associated with IDAA1c (p-value = 0.0081). No association between HNF1A SNPs and T1D development emerged. In conclusion, our findings suggest for the first time that HNF1A variants may be a risk factor for beta cell function and glycaemic control in T1D individuals.

To explore parameters that may determine the improvement in C-peptide levels in patients with type 2 diabetes (T2D) receiving continuous subcutaneous insulin infusion (CSII) therapy. The trial included a lead-in period for collecting baseline parameters and correcting hyperglycemia, a 4-day CGM period, and a 2–3 weeks treatment period. After screening, patients were hospitalized and randomized to the metformin add-on NovoRapid group or the Prandilin group. Once the glycemic target was reached, all patients underwent a 4-day CGM, with treatments maintained for 2–3 weeks. OGTTs were performed at baseline and endpoint. The primary endpoint was identifying factors contributing to better β-cell function recovery after CSII therapy. A total of 99 recruited patients were admitted as inpatients and achieved glycemic control within 3.8 ± 1.1 days. Of these, 83 (84 %) patients showed improvement in C-peptide levels, while 16 (16 %) did not show any change in C-peptide levels at the endpoint. Pearson analysis showed a negative correlation between the incremental AUC of glucose concentration (from 0700 to 1000) and the increase in incremental AUC of C-peptide levels (r = −0.199, P < 0.05). Drug-naïve T2D patients with lower postprandial glucose concentration during CSII therapy exhibit better β-cell function recovery. [ABSTRACT FROM AUTHOR]

Background: Gestational diabetes mellitus (GDM) is a pregnancy complication characterized by second trimester hyperglycemia. Untreated, GDM is related to an increased risk for adverse pregnancy outcomes. Both beta cell dysfunction and insulin resistance underlie impaired glucose tolerance. Understanding the dominant mechanism predisposing to GDM may be important to provide effective treatment in order to improve perinatal outcomes. We hypothesize that insulin resistance rather that beta cell dysfunction predisposes to GDM. Methods: A 75g oral glucose tolerance test (OGTT) was performed on 2112 second-trimester pregnant women to determine the relationship between insulin resistance (HOMA-IR), beta cell function (HOMA-β), and the prevalence of abnormal glucose handling. Results: High insulin resistance raised the risk of GDM (relative risk (RR) 6.1, 95% confidence interval (CI) (4.4–8.5)), as did beta cell dysfunction (RR 3.8, 95% CI (2.7–5.4)). High insulin resistance, but not beta cell function, enhances the necessity for additional glucose lowering medication on top of a low carbohydrate diet in women diagnosed with GDM. Conclusions: Both high insulin resistance and beta cell dysfunction increase the risk of GDM. As increased insulin resistance, rather than beta cell function, is related to an insufficient response to a low carbohydrate diet, we speculate that insulin sensitizers rather than insulin therapy may be the most targeted therapeutic modality in diet-insensitive GDM. [ABSTRACT FROM AUTHOR]