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Context: Congenital Hyperinsulinism (CHI) is associated with inappropriately high levels of C-peptide in the context of hypoglycemia., Objective: We aimed to better clarify a diagnostic threshold value of C-peptide for children presenting with CHI., Design: This was a retrospective case-control analysis, examining all hypoglycemia screens, undertaken between 2009 and 2019 at a quaternary paediatrics unit. Plasma C-peptide, insulin, free fatty acid (FFA) and B-hydroxybutyrate (BHOB) concentrations in children diagnosed with CHI were compared with concentrations in children diagnosed with other conditions., Patients: All patients requiring hypoglycaemic screens at the quaternary children's hospital were analysed., Results: Median [C-peptide] were statistically significantly different between CHI (147) and non-CHI (72) patients, p < 0.05. The Youden Index indicated that a [C-peptide] value of 291.5 pmol/L would give the greatest optimization of sensitivity (82%) and specificity (99%) for detecting CHI. Median [insulin] differed significantly between the cohorts with a level of 64 pmol/L for CHI patients compared with 0 pmol/L with non-CHI patients (p < 0.01). Median [BOHB] was 0 μmol/L in CHI patients as compared with 2378 μmol/L for non-CHI patients (p < 0.01). Median [FFA] levels were 1910 μmol/L in the non-CHI cohort, compared with 0 in the CHI cohort (p < 0.01)., Conclusions: This study suggests that a C-peptide concentration greater than 291.5 pmol/L is diagnostic of CHI in children. C-peptide appears to offer the greatest utility as a biochemical diagnostic test for CHI and could be prioritised for laboratory analysis., (© 2024 John Wiley & Sons Ltd.)

Context: Identification of prognostic biomarkers in pediatric diabetes is important for precision medicine., Objective: We assessed whether C-peptide and islet autoantibodies are useful to predict the natural history of children with new-onset diabetes., Methods: We prospectively studied 72 children with new-onset diabetes (median follow-up: 8 months) by applying the Aβ classification system ("A+": islet autoantibody positive, "β+": random serum C-peptide≥1.3 ng/mL at diagnosis). Beta-cell function was assessed longitudinally with 2h post-prandial/stimulated urinary C-peptide-to-creatinine ratio (UCPCR) 3-12 weeks (V1) and 6-12 months after diagnosis (V2). We obtained a type 1 diabetes genetic risk score (T1D GRS2) for each participant, and compared characteristics at baseline, and clinical outcomes at V2., Results: The cohort was 50% male. Racial distribution was 76.4% White, 20.8% Black and 2.8% Asian or other races. A total of 46.5% participants were Hispanic. Median age (Q1-Q3) was 12.4 (8.3-14.5) years. The Aβ subgroup frequencies were 46 A+β-(63.9%), 1 A-β-(1.4%), 4 A+β+(5.6%), and 21 A-β+(29.2%). Baseline serum C-peptide correlated with UCPCR at both V1 (r=0.36, p=0.002) and V2 (r=0.47, p<0.001). There were significant subgroup differences in age, race, frequency of diabetic ketoacidosis and T1D GRS2 (p<0.01). At V2, the two β- subgroups had lower UCPCR and higher HbA1c compared with the two β+ subgroups (p<0.001 and p=0.02, respectively). Thirty-eight percent of A-β+ but none of the other subgroups were insulin-independent at V2 (p<0.001)., Conclusions: C-peptide and islet autoimmunity at diagnosis define distinct phenotypes and predict beta-cell function and insulin dependence 6-12 months later in racially/ethnically diverse children with new-onset diabetes., (Copyright © 2024. Published by Elsevier Inc.)

Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) is a subtype of type 1 diabetes. Although SPIDDM is not rare among Japanese children, there are few reports on endogenous insulin secretory capacity and anti-pancreatic islet autoantibodies in pediatric SPIDDM. We followed the trends in endogenous insulin secretory capacity and anti-pancreatic islet autoantibody titers in two pediatric SPIDDM cases over several years. Case 1 developed insulin deficiency eight months after diabetes diagnosis; as her insulinoma-associated antibody test result was positive, insulin therapy was initiated. Fourteen months after the diagnosis, she tested positive for glutamic acid decarboxylase autoantibodies (GADA) and was diagnosed with SPIDDM. Case 2 was mildly positive for GADA at the onset of diabetes, but became a high titer during the course of the disease. Fourteen months after the diagnosis of diabetes, he became mildly insulin deficient, and insulin therapy was initiated. However, his insulin secretory capacity was preserved for 60 mo after the onset. SPIDDM is generally indistinguishable from type 2 diabetes at diagnosis; therefore, repeated evaluation of the insulin secretory capacity and anti-islet autoantibodies facilitates early diagnosis and appropriate treatment, especially in nonobese children with type 2 diabetes., Competing Interests: The authors have no competing interest to declare., (2024©The Japanese Society for Pediatric Endocrinology.)

Background: Serum C-peptide concentration is often utilized for diagnostic, prognostic, or therapeutic assessment in diabetes mellitus. However, there are limited clinical data regarding diagnostic and predictive value of C-peptide measured during hospitalizations for hyperglycemia. Materials and Methods: Adults admitted to Mayo Clinic inpatient facilities due to an acute hyperglycemic emergency between January 2017 and November 2022 were included in our study. Predictive capacity of C-peptide for discontinuation of therapeutic insulin was examined in the entire cohort and the subgroup of non-autoimmune non-pancreatitis diabetes (NANP-DM). Results: We included 187 patients (63 women) in our study. During hospitalization, patients with type 1 diabetes antibodies displayed diminished serum C-peptide concentration ( P = 0.014), correlating inversely with subsequent hemoglobin A1c% [ r = (-0.22), P = 0.005]. Initial C-peptide concentrations did not differ between patients requiring insulin therapy during follow-up and those who did not ( P = 0.16). C-peptide concentrations showed limited predictive capacity for achieving glycemic control. Subgroup analyses in NANP-DM exhibited similar limited capacity for anticipating therapeutic insulin needs and achieving glycemic controls. Discussion: C-peptide concentration did not exhibit a robust predictive capability for future need of insulin therapy and achieving glycemic control, limiting its utility in clinical practice within inpatient settings.

Aims/hypothesis: The gut microbiome is implicated in the disease process leading to clinical type 1 diabetes, but less is known about potential changes in the gut microbiome after the diagnosis of type 1 diabetes and implications in glucose homeostasis. We aimed to analyse potential associations between the gut microbiome composition and clinical and laboratory data during a 2 year follow-up of people with newly diagnosed type 1 diabetes, recruited to the Innovative approaches to understanding and arresting type 1 diabetes (INNODIA) study. In addition, we analysed the microbiome composition in initially unaffected family members, who progressed to clinical type 1 diabetes during or after their follow-up for 4 years., Methods: We characterised the gut microbiome composition of 98 individuals with newly diagnosed type 1 diabetes (ND cohort) and 194 autoantibody-positive unaffected family members (UFM cohort), representing a subgroup of the INNODIA Natural History Study, using metagenomic sequencing. Participants from the ND cohort attended study visits within 6 weeks from the diagnosis and 3, 6, 12 and 24 months later for stool sample collection and laboratory tests (HbA 1c , C-peptide, diabetes-associated autoantibodies). Participants from the UFM cohort were assessed at baseline and 6, 12, 18, 24 and 36 months later., Results: We observed a longitudinal increase in 21 bacterial species in the ND cohort but not in the UFM cohort. The relative abundance of Faecalibacterium prausnitzii was inversely associated with the HbA 1c levels at diagnosis (p=0.0019). The rate of the subsequent disease progression in the ND cohort, as assessed by change in HbA 1c , C-peptide levels and insulin dose, was associated with the abundance of several bacterial species. Individuals with rapid decrease in C-peptide levels in the ND cohort had the lowest gut microbiome diversity. Nineteen individuals who were diagnosed with type 1 diabetes in the UFM cohort had increased abundance of Sutterella sp. KLE1602 compared with the undiagnosed UFM individuals (p=1.2 × 10 -4 )., Conclusions/interpretation: Our data revealed associations between the gut microbiome composition and the disease progression in individuals with recent-onset type 1 diabetes. Future mechanistic studies as well as animal studies and human trials are needed to further validate the significance and causality of these associations., (© 2024. The Author(s).)

Purpose: We aimed to investigate the predictive potential of plasma connecting peptide (C-peptide) in differentiating type 1 diabetes (T1D) from type 2 diabetes (T2D) and to inform evidence-based diabetes classification criteria., Methods: A retrospective review was performed of all the patients with diabetes visiting an outpatient diabetology, endocrinology, general practice and family medicine tertiary health care center between January 2016 and December 2021., Findings: Two hundred twelve individuals with diabetes were included, 85 (44.8%) with T1D and 127 (55.2%) with T2D. Mean (SD) age at diagnosis was 35.9 (15.1) years, and 112 (52.8%) men. Median (interquartile range [IQR]) duration of diabetes was 3.8 (3.0-4.5) years (T1D, 3.9 [3.5-4.6]; T2D, 3.4 [2.4-4.4]; P = 0.001). Body mass index was <18.5 kg/m 2 in 5 (2.5%) individuals (T1D, 5; T2D, none), 18.5 to <25 kg/m 2 in 57 (28.5%) (T1D, 32; T2D, 25), 25 to <30 kg/m 2 in 58 (29%) (T1D, 28; T2D, 30), and >30 kg/m 2 in 80 (40.0%) (T1D, 20; T2D, 60). Median (IQR) glycosylated hemoglobin was 7.4% (6.7%-8.5%) (T1D, 8.3% [7.2%-9.9%]; T2D, 7% [6.3%-7.6%]; P = 0.0001). Median (IQR) C-peptide concentration was 0.59 nmol/L (0.01-1.14 nmol/L) (T1D, 0.01 nmol/L [0.003-0.05 nmol/L]; T2D, 1.03 nmol/L [0.70-1.44 nmol/L]; P = 0.0001). C-peptide concentration of ≤0.16 nmol/L showed 92.9% sensitivity, 1-specificity of 2.4%, and AUC of 97.2% (CI, 94.7%-99.6%; P = 0.0001) in differentiating T1D from T2D., Implications: To our knowledge, this is the first study in the Middle East and North Africa region highlighting the role of C-peptide in diabetes classification. The estimated cutoff point for C-peptide concentration (≤0.16 nmol/L) will certainly help in accurately classifying the T1D and will rule out the routine clinical judgmental approaches in the region, especially in those scenarios and periods where it is always difficult to diagnose the diabetes type. Quantifying the cutoff for C-peptide is among the vital strengths of this study that will provide a better treatment plan in diabetes care management. Also, we evaluated concomitant glucose levels to rule out the phenomenon of falsely low C-peptide values in the setting of hypoglycemia or severe glucose toxicity. Based on our findings, C-peptide testing could be included in postulating an evidence-based guideline that differentiates T1D from T2D. Despite this, our study has some limitations, including the selection bias due to the retrospective design and low C-peptide levels could be indicative of low pancreatic reserves due to other causes or long-standing T2D, and quantifying these reasons requires additional resources and time., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Multiple daily injection (MDI) insulin therapy is an effective method of glycemic control and appropriate assignment to MDI therapy could minimize the risks of hypoglycemia and weight gain. The aim of the present study was to identify factors associated with indication for MDI therapy in type 2 diabetes (T2DM)., Methods: We recruited 360 participants with T2DM that were admitted to the Endocrinology Department of Peking University People's Hospital between August 2017 and July 2018. They first underwent intensive insulin therapy, then were switched to an optimized, simpler insulin treatment that aimed to maintain fasting blood glucose between 4.4 and 7.2 mmol/L, without episodes of hypoglycemia. The baseline characteristics of groups administering either MDI or basal/premix insulin were compared and multivariable logistic regression analysis was used to determine the odds ratios (ORs) for factors associated with MDI therapy. Receiver operating characteristic (ROC) curves were then used to identify independent predictors of MDI insulin regimen efficacy., Results: The mean age of the participants was 57.6 ± 12.9 years, and diabetes duration was 14.2 ± 8.2 years. Two hundred and sixty-seven participants administered basal/premix insulin and 93 underwent MDI therapy, of whom 61.8% and 46.2% were male, respectively (p = 0.01). The duration of diabetes was significantly longer in the MDI group (13.1 ± 7.7 years vs. 17.3 ± 8.7 years; p < 0.01). Fasting plasma glucose (FPG) was higher in the MDI group than in the basal/premix group (8.3 [6.7, 11.3] mmol/L vs. 7.2 [5.7, 9.3] mmol/L; p < 0.01), while the postprandial C-peptide concentration (PCP) was significantly lower in the MDI group (2.6 [1.8, 3.5] ng/mL) compared to the basal/premix group (3.6 [2.5, 6.2] ng/mL, p < 0.01. Multivariable logistic regression analysis suggested that diabetes duration and FPG were positively associated with MDI therapy: OR (95% confidence interval [CI]) 1.06 (1.02, 1.10) and 1.12 (1.02, 1.24), respectively. In addition, PCP was negatively associated with MDI therapy (0.72 [0.60, 0.86]). ROC analysis suggested that a PCP of < 3.1 ng/mL predicted MDI therapy with 59.6% sensitivity and 72.1% specificity., Conclusion: The results of our study suggest that longer diabetes duration, higher FPG, and lower PCP were associated with necessity for MDI insulin regimen. These findings should assist with the personalization of insulin treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In order to investigate microvascular complications in metabolic diseases, we aimed to investigate cerebral and peripheral microcirculation in relation to peripheral neuropathy and laboratory biomarkers in type 2 diabetes mellitus (T2DM) and obesity., Methods: Based on the degree of neuropathy (NP), study participants (40 T2DM and 30 obese individuals) were classified into no-NP, mild-NP and severe-NP subgroups. After the injection of Technetium-99 m hexamethylpropylene amine oxime, both T2DM and obese participants underwent single-photon emission computed tomography/computed tomography ([99mTc]Tc-HMPAO SPECT/CT) and SPECT-only examinations to assess lower limb and brain perfusion; respectively. Peripheral nerve function was evaluated with a neurometer and glycaemic markers were measured from plasma in both groups., Results: Compared to the obese individuals, lower extremity perfusion was significantly reduced in the diabetic subjects (p < 0.005), while it showed a positive correlation with C-peptide levels and negative association with HbA1c values. A U-shape pattern of peripheral microcirculation was observed between the NP groups, indicating a surprisingly better perfusion in the severe-NP group than in the mild one, with the highest levels in obese patients. Since changes in the C-peptide levels exhibited a similar U-shaped trend across the NP subgroups, we suggest a positive correlation between C-peptide levels and the extent of peripheral perfusion. Although, C-peptide values and cerebral microcirculation correlated positively (rho = 0.27), brain perfusion did not show any differences neither between the diabetic and the obese patients, nor between the NP subgroups (at p < 0.05)., Conclusions: Establishing the link between neuropathy and peripheral microcirculation, C-peptide seems to be a promising biomarker for the prediction of microvascular alterations in metabolic diseases. Of note, the dominance of metabolic factors over microvascular damage in the development of obesity-related neuropathy should be emphasized as well., (© 2024. The Author(s).)

Purpose: To investigate determinants of new onset diabetes after COVID-19 (NODAC) and its recovery at 6 months., Methods: This was an observational follow up study conducted from August, 2020 to July, 2023, recruiting patients with preexisting DM and COVID 19 patients with no history of DM. Multivariate regression analysis was used to determine the factors responsible for severity of COVID 19 infection in preexisting DM group. Clinical, laboratory and glycometabolic parameters were estimated at baseline and 6 months in NODAC and euglycemic group to determine the factors responsible for NODAC and its persistence at 6 months., Results: Of 1310 patients, 855 (65.3%) COVID 19 patients were further divided based on their glycemic status: preexisting DM (19%), NODAC (8.5%) and euglycemia (72.5%). Older age and male gender were independent risk factors for severe COVID 19 disease in patients with preexisting diabetes. Prevalence of NODAC in present study was 8.5%. Patients with NODAC had higher mean fasting blood glucose (FBG), random blood glucose (RBG) and HbA1c at baseline as compared to COVID with euglycemic group with no difference in serum C-peptide levels. Female gender, family history of DM, signs of insulin resistance, higher BMI, WHR, HbA1c, serum insulin levels, FBG and RBG predicted persistence of NODAC at 6 months., Conclusion: Preexisting DM is a risk factor for severe COVID 19 disease. Patients with NODAC have evidence of persistence insulin resistance on follow up, underscoring the need for long term glycemic monitoring., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Mass spectrometry (MS) methods exhibit higher accuracy and comparability in measuring serum C-peptide concentrations than immunoassays. We developed and validated a novel isotope dilution-ultraperformance liquid chromatography-tandem MS (ID-UPLC-MS/MS) assay to measure serum C-peptide concentrations., Methods: Sample pretreatment involved solid-phase extraction, ion-exchange solid-phase extraction, and derivatization with 6-aminoquinolyl-N-hydroxysuccinimidylcarbamate (Cayman Chemical, Ann Arbor, Michigan, USA). We used an ExionLC UPLC system (Sciex, Framingham, MA, USA) and a Sciex Triple Quad 6500 + MS/MS system (Sciex) for electrospray ionization in positive-ion mode with multiple charge states of [M+3H]3+ and multiple reaction monitoring transitions. The total run time was 50 mins, and the flow rate was 0.20 mL/min. We evaluated the precision, trueness, linearity, lower limit of quantitation (LLOQ), carryover, and matrix effects. Method comparison with electrochemiluminescence immunoassay (ECLIA) was performed in 138 clinical specimens., Results: The intra- and inter-run precision coefficients of variation were <5% and the bias values for trueness were <4%, which were all acceptable. The verified linear interval was 0.050-15 ng/mL, and the LLOQ was 0.050 ng/mL. No significant carryover or matrix effects were observed. The correlation between this ID-UPLC-MS/MS method and ECLIA was good (R=0.995, slope=1.564); however, the ECLIA showed a positive bias (51.8%)., Conclusions: The developed ID-UPLC-MS/MS assay shows acceptable performance in measuring serum C-peptide concentrations. This will be useful in situations requiring accurate measurement of serum C-peptide in clinical laboratories.

Objective: The aim of this study was to investigate the association of fasting C-peptide and glucagon with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2DM)., Methods: A comprehensive evaluation was conducted on 797 patients with T2DM to assess the various risk factors affecting DPN. The subjects were categorized into short duration and long duration group according to the duration of diabetes with a threshold of 10 years. Logistic regression analysis was employed to examine the association between DPN and islet function, as well as other parameters. Receiver operating characteristic curve analysis was performed to evaluate the predictive capability of glucagon., Results: The fasting C-peptide levels were significantly lower in the DPN patients with short duration of diabetes, but lost significance in the long duration group. Conversely, a decreased level of glucagon was only observed in DPN patients with long duration of diabetes. For the group with long duration of diabetes, glucagon was the sole risk factor associated with DPN. The receiver operating characteristic curve analysis revealed that glucagon in the long duration group exhibited a moderate area under the curve of 0.706., Conclusions: The serum glucagon levels in T2DM patients with DPN exhibited bidirectional changes based on the duration of diabetes. Decreased glucagon was associated with DPN in T2DM patients with long duration of diabetes., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A comprehensive evaluation, including symptoms, medical history, C-peptide levels, and anti-GAD antibodies, is essential for distinguishing between diabetes' types, particularly in cases of diagnostic uncertainty. While obesity is often associated with T2DM, BMI should be viewed as a factor rather than a criterion for the exclusion of diabetes type., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Pathogenesis of type 2 diabetes mellitus (T2DM) is combined from initial insulin resistance (IR) and subsequent β-cell dysfunction. Insulin therapy can replace β-cell function in advanced stages. However excessive insulin therapy increases IR and may expose the patients to risk of cardiovascular disease. We aim to assess β-cell function and IR in patients with type 2 diabetes on insulin therapy by fasting C-peptide to glucose ratio (FCPGR), and triglyceride glucose (TyG) index respectively to support treatment plans., Method: A cross-sectional study was conducted at the Galiawa Diabetes and Endocrinology Teaching Center in Erbil City, Iraq, from June 2023 to January 2024. A convenient sample of 100 patients with T2DM on insulin-based therapy were included after obtaining informed written consent and excluding conditions such as acute illness, uncertain type of diabetes, etc. Each patient was evaluated for anthropometric parameters and current treatment details. Biochemical tests were then carried out to calculate metabolic syndrome (MetS) index score, FCPGR, and TyG index. Finally, patients were divided into four subgroups according to their FCPGR and TyG index and the data were analyzed statistically., Result: The data showed those patients with sufficient β-cell function were 60 (60%), and patients with high TyG index were 95 (95%). There was a significant negative correlation between FCPGR and hemoglobin A1c (HbA1c) (p-value=0.001), while there was a positive correlation between TyG index and HbA1C (p-value=0.001). None of these markers were correlated with BMI (p-value=0.297, and 0.976), duration of T2DM (p-value=0.258, and 0.458), and dose of insulin therapy (p-value=0.901, and 0.477). Patients with sufficient β-cell function and high TyG index had the lowest HbA1C., Conclusion: The study provides valuable insights into the utility of FCPGR and TyG index as biomarkers for β-cell function and insulin resistance in T2DM patients on insulin therapy. The significant correlation with HbA1C underscores their potential in clinical practice. However, the lack of correlation with BMI, disease duration, and insulin dose suggests that further investigation is needed to fully understand these biomarkers' implications across diverse patient profiles., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethical Committee of Faiha Specialized Diabetes, Endocrine, and Metabolism Center (FDEMC) issued approval Reference 56/35/28 on March 19, 2023. The FDEMC Ethical Committee certified that the research fulfills the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Essa et al.)

Objective: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients., Methods: This was a retrospective study in which thirty-two overweight/obese patients with PCOS ( n  = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated., Results: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease., Conclusion: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Purpose: Alpelisib is a PI3K (Phosphoinositide 3-kinases) inhibitor used for breast cancer which develops hyperglycemia based on its action on glucose metabolism regulation. This study aims to identify potential risk factors predicting hyperglycemia development and the need for multiple treatments for hyperglycemia in patients receiving Alpelisib., Methods: Fourteen women diagnosed with metastatic hormone receptor-positive breast cancer carrying PI3K mutations who initiated treatment with Alpelisib were monitored through consultations in the Oncology and Endocrinology departments. Non-parametric ROC curves were generated to assess the need for three or more antidiabetic medications to achieve glycemic control., Results: The study population had a median age of 64 years (range:48-69) with a median body mass index (BMI) of 26.6 kg/m 2 (range: 22.9-29.4). Overweight was observed in 35.7% of the participants and obesity in 21.4%. Fifty percent of the participants had prediabetes, and 85.7% developed hyperglycemia requiring pharmacological treatment, although none of them needed to discontinue treatment for this reason. Baseline C-peptide levels and BMI were associated with the number of antidiabetic drugs used (Spearman's Rho 0.553, p = 0.040; Spearman's Rho 0.581, p = 0.030, respectively). ROC curve analysis showed and area under the curve (AUC) of 0.819 for the variable risk profile (defined as baseline C-peptide >10.5 ng/ml and BMI > 27 kg/m 2 ), whereas AUC values were 0.556 and 0.514 for HbA1c and baseline glucose, respectively, (p = 0.012)., Conclusion: A joint follow-up by an Oncology department and a Diabetes Unit can prevent treatment discontinuation in patients under Alpelisib therapy. Baseline BMI and plasma C-peptide levels can predict an increased need for anti-hyperglycemic treatment., (© 2024. The Author(s).)

Hypoglycaemic unawareness (HU) is more frequently described in relation to diabetics in the literature. We have noted that there is also an increasing reporting of HU in insulinoma cases. We report a hospital presentation for an incidental finding of hypoglycaemic unawareness in a gentleman in his fifties who was eventually diagnosed with insulinoma following biochemical studies, radiologic evaluation and histologic evaluation of an excised lesion between the pancreas and the spleen. We have reviewed existing literature evidence regarding the possible aetiologies and management options for this occurrence. More research studies to identify the epidemiology of this association and the determination of a protocol for increased detection of patients with insulinoma who display HU will need to be done., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alkundi et al.)

Background: Islets of Langerhans beta cells diminish in autoimmune type 1 diabetes mellitus (T1DM). Teplizumab, a humanized anti-CD3 monoclonal antibody, may help T1DM. Its long-term implications on clinical T1DM development, safety, and efficacy are unknown., Aim: To assess the effectiveness and safety of teplizumab as a therapeutic intervention for individuals with T1DM., Methods: A systematic search was conducted using four electronic databases (PubMed, Embase, Scopus, and Cochrane Library) to select publications published in peer-reviewed journals written in English. The odds ratio (OR) and risk ratio (RR) were calculated, along with their 95%CI. We assessed heterogeneity using Cochrane Q and I 2 statistics and the appropriate P value., Results: There were 8 randomized controlled trials (RCTs) in the current meta-analysis with a total of 1908 T1DM patients from diverse age cohorts, with 1361 patients receiving Teplizumab and 547 patients receiving a placebo. Teplizumab was found to have a substantial link with a decrease in insulin consumption, with an OR of 4.13 (95%CI: 1.72 to 9.90). Teplizumab is associated with an improved C-peptide response (OR 2.49; 95%CI: 1.62 to 3.81) and a significant change in Glycated haemoglobin A1c (HbA1c) levels in people with type 1 diabetes [OR 1.75 (95%CI: 1.03 to 2.98)], and it has a RR of 0.71 (95%CI: 0.53 to 0.95)., Conclusion: In type 1 diabetics, teplizumab decreased insulin consumption, improved C-peptide response, and significantly changed HbA1c levels with negligible side effects. Teplizumab appears to improve glycaemic control and diabetes management with good safety and efficacy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Context: Metabolic measures are frequently used to predict type 1 diabetes (T1D) and to understand effects of disease-modifying therapies., Objective: Compare metabolic endpoints for their ability to detect preventive treatment effects and predict T1D., Methods: Six-month changes in metabolic endpoints were assessed for (1) detecting treatment effects by comparing placebo and treatment arms from the randomized controlled teplizumab prevention trial, a multicenter clinical trial investigating 14-day intravenous teplizumab infusion and (2) predicting T1D in the TrialNet Pathway to Prevention natural history study. For each metabolic measure, t-Values from t tests for detecting a treatment effect were compared with chi-square values from proportional hazards regression for predicting T1D. Participants in the teplizumab prevention trial and participants in the Pathway to Prevention study selected with the same inclusion criteria used for the teplizumab trial were studied., Results: Six-month changes in glucose-based endpoints predicted diabetes better than C-peptide-based endpoints, yet the latter were better at detecting a teplizumab effect. Combined measures of glucose and C-peptide were more balanced than measures of glucose alone or C-peptide alone for predicting diabetes and detecting a teplizumab effect., Conclusion: The capacity of a metabolic endpoint to detect a treatment effect does not necessarily correspond to its accuracy for predicting T1D. However, combined glucose and C-peptide endpoints appear to be effective for both predicting diabetes and detecting a response to immunotherapy. These findings suggest that combined glucose and C-peptide endpoints should be incorporated into the design of future T1D prevention trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: This pivotal study aimed to evaluate circulating levels of bone remodeling markers in children and adolescents at the onset of type 1 diabetes (T1D). Additionally, we assessed their correlation with glucose control, residual β-cell function, and the severity of presentation., Methods: In this single-center cross-sectional study, we recruited children and adolescents newly diagnosed with T1D at our tertiary-care Diabetes Centre. Anamnestic, anthropometric, clinical, and biochemical data at T1D diagnosis were collected. Basal and stimulated C-peptide levels were assessed, along with the following bone remodeling biomarkers: osteocalcin (OC), alkaline phosphatase (ALP), parathormone (PTH), 25-OH Vitamin D (25OH-D), and the C-terminal cross-linked telopeptide of type 1 collagen (CTX)., Results: We enrolled 29 individuals newly diagnosed with T1D, with a slight male prevalence (51.7%). The mean age was 8.4 ± 3.7 years. A positive correlation between OC and stimulated C-peptide (R = 0.538; p = 0.026) and between PTH and serum HCO3- (R = 0.544; p = 0.025) was found. No other correlations between bone remodeling biomarkers and clinical variables were detected., Conclusion: Our data showed a positive correlation between OC levels and residual β-cell function in children and adolescents at T1D presentation. Further longitudinal studies evaluating OC levels in pediatric subjects with T1D are needed to better understand the complex interaction between bone and glucose metabolisms., (© 2024. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Aim: To provide updated efficacy and safety information for teplizumab in the treatment of Stage 3 type 1 diabetes mellitus (T1DM)., Materials and Methods: The PubMed, Embase and Cochrane databases were searched for randomized controlled trials (RCTs) comparing teplizumab to placebo for T1DM that reported any of the following outcomes: (1) C-peptide area under the curve (AUC); (2) glycated haemoglobin (HbA1c) levels; (3) insulin requirements; and (4) adverse events. Heterogeneity was examined with I 2 statistics. p values <0.05 were taken to indicate statistical significance. The continuous endpoints were compared through the pooled mean difference (MD) and binary endpoints were assessed using risk ratios, both with 95% confidence intervals (CIs). Statistical analyses were performed using Review Manager Web software., Results: Eight RCTs with 1052 patients (754 receiving teplizumab) were included. Teplizumab significantly increased the AUC of C-peptide levels at 6 (MD 0.10 nmol/L, 95% CI 0.05, 0.16), 12 (MD 0.13 nmol/L, 95% CI 0.06, 0.20), 18 (MD 0.18 nmol/L, 95% CI 0.09, 0.27) and 24 months (MD 0.16 nmol/L, 95% CI 0.02, 0.31), significantly reduced HbA1c levels at 6 (MD -0.57%, 95% CI -1.07, -0.08) and 12 months (MD -0.31%, 95% CI -0.59, -0.02), and significantly reduced insulin requirements at 6 (MD -0.12 U/kg, 95% CI -0.16, -0.08), 12 (MD -0.11 U/kg, 95% CI -0.15, -0.07), 18 (MD -0.17 U/kg, 95% CI -0.26, -0.09) and 24 months (MD -0.11 U/kg, 95% CI -0.22, -0.01)., Conclusion: Teplizumab increases AUC of C-peptide levels and decreases HbA1c levels and insulin use, without raising serious adverse event risk., (© 2024 John Wiley & Sons Ltd.)

Backgruound: We evaluated changes in glycemic status, over 1 year, of coronavirus disease 2019 (COVID-19) survivors with dysglycemia in acute COVID-19., Methods: COVID-19 survivors who had dysglycemia (defined by glycosylated hemoglobin [HbA1c] 5.7% to 6.4% or random glucose ≥10.0 mmol/L) in acute COVID-19 were recruited from a major COVID-19 treatment center from September to October 2020. Matched non-COVID controls were recruited from community. The 75-g oral glucose tolerance test (OGTT) were performed at baseline (6 weeks after acute COVID-19) and 1 year after acute COVID-19, with HbA1c, insulin and C-peptide measurements. Progression in glycemic status was defined by progression from normoglycemia to prediabetes/diabetes, or prediabetes to diabetes., Results: Fifty-two COVID-19 survivors were recruited. Compared with non-COVID controls, they had higher C-peptide (P< 0.001) and trend towards higher homeostasis model assessment of insulin resistance (P=0.065). Forty-three COVID-19 survivors attended 1-year reassessment. HbA1c increased from 5.5%±0.3% to 5.7%±0.2% (P<0.001), with increases in glucose on OGTT at fasting (P=0.089), 30-minute (P=0.126), 1-hour (P=0.014), and 2-hour (P=0.165). At baseline, 19 subjects had normoglycemia, 23 had prediabetes, and one had diabetes. Over 1 year, 10 subjects (23.8%; of 42 non-diabetes subjects at baseline) had progression in glycemic status. C-peptide levels remained unchanged (P=0.835). Matsuda index decreased (P=0.007) and there was a trend of body mass index increase from 24.4±2.7 kg/m2 to 25.6±5.2 (P=0.083). Subjects with progression in glycemic status had more severe COVID-19 illness than non-progressors (P=0.030). Reassessment was not performed in the control group., Conclusion: Subjects who had dysglycemia in acute COVID-19 were characterized by insulin resistance. Over 1 year, a quarter had progression in glycemic status, especially those with more severe COVID-19. Importantly, there was no significant deterioration in insulin secretory capacity.

Background and Objective: The autoimmune mechanism in T1DM causes gradual loss of pancreatic β-cell, which progresses to hyperglycemia and ultimate reliance on consistent insulin therapy. T1DM has been the commonest type of diabetes in children and this study will help in refining indulgent towards the problem and its pathophysiology in our people. The objective was to find out the prevalence of C-peptide and antibody levels (anti GAD, ICA, IAA and IA2) in children and adolescents of Pakistan with T1DM., Methods: We conducted this cross-sectional study at Department of Pediatric Endocrinology, National Institute of Child Health, Karachi between August 2019 to February 2020 and included 98 children who had T1DM for more than one month. Subjects whose GFR was <30ml/min were omitted from the study. Among those registered subjects, C-peptide, human islet cell antibody (ICA), insulin auto antibodies (IAA) and anti-glutamic acid decarboxylase were assessed. Demographical and laboratorial facts were noted on a pre-constructed proforma., Results: There were 77(78.3%) cases who had level of C-peptide <0.8 and anti-GAD was found in 47(48%) subjects. 35(35.7%) cases found positive for IA2 .and 7(7.1%) patients had insulin auto antibodies positive while ICA was negative in total 98(100%) subjects., Conclusion: Children with T1 DM possessed increased levels of anti-GAD antibodies, insulin autoantibodies and anti (IA2) but islet cells antibodies were negligible in our population when checked at a point of time. C-peptide may be normal in some, but its level declines with long duration of diabetes in children., (Copyright: © Pakistan Journal of Medical Sciences.)

Aims/Hypotheses: To investigate the frequency and characteristics of partial remission in Swedish children with type 1 diabetes and whether the insulin delivery method, that is, continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDIs), affects incidence and duration of this period, 2007-2011. Factors that increase the proportion of subjects who enter partial remission and extend this period can improve long-term metabolic control and reduce the risk of severe hypoglycemia, improve quality of life, and, in the long run, reduce late complications. Methods: Longitudinal data from 2007 to 2020 were extracted from the Swedish National Quality Register (SWEDIABKIDS) with all reported newly diagnosed children. Data on C-peptide from the participants in the Better Diabetes Diagnosis study from 2007 to 2010 were used. The definition of partial remission was insulin dose-adjusted HbA1c: HbA1c (%) + [4 × total daily insulin dose (U/kg/day)] ≤9. Results: Of the 3887 patients, 56% were boys. More boys than girls were in partial remission throughout the follow-up period until 24 months after diabetes onset. Fewer children 0-6 years old had partial remission at 3 and 12 months but not at 24 months compared with older age-groups. A larger proportion of patients using CSII at 12 and 24 months remained in partial remission compared with those with MDI (37% vs. 33%, P = 0.02 and 31% vs. 27%, P = 0.01, respectively). The level of C-peptide was higher in the group with partial remission and mean HbA1c was lower (both P < 0.001). Partial remission at 12 months after diabetes onset was associated with CSII (odds ratio [OR]: 1.39, confidence interval [CI]:1.13, 1.71), shorter diabetes duration (OR: 0.80, CI: 0.76, 0.84), and male sex (OR: 1.23, CI: 1.04, 1.46). Conclusions/Interpretation: Insulin through MDI, longer duration of diabetes, and female sex were associated with lower frequency of partial remission. Use of CSII seems to contribute to longer partial remission among Swedish children with type 1 diabetes.

Introduction: Insulin and C-peptide played crucial roles as clinical indicators for diabetes and certain liver diseases. However, there has been limited research on the simultaneous detection of insulin and C-peptide in trace serum. It is necessary to develop a novel method with high sensitivity and specificity for detecting insulin and C-peptide simultaneously., Methods: A core-shell-satellites hierarchical structured nanocomposite was fabricated as SERS biosensor using a simple wet-chemical method, employing 4-MBA and DTNB for recognition and antibodies for specific capture. Gold nanorods (Au NRs) were modified with Raman reporter molecules and silver nanoparticles (Ag NPs), creating SERS tags with high sensitivity for detecting insulin and C-peptide. Antibody-modified commercial carboxylated magnetic bead@antibody served as the capture probes. Target materials were captured by probes and combined with SERS tags, forming a "sandwich" composite structure for subsequent detection., Results: Under optimized conditions, the nanocomposite fabricated could be used to detect simultaneously for insulin and C-peptide with the detection limit of 4.29 × 10 -5 pM and 1.76 × 10 -10 nM in serum. The insulin concentration (4.29 × 10 -5 -4.29 pM) showed a strong linear correlation with the SERS intensity at 1075 cm -1 , with high recoveries (96.4-105.3%) and low RSD (0.8%-10.0%) in detecting human serum samples. Meanwhile, the C-peptide concentration (1.76 × 10 -10 -1.76 × 10 -3 nM) also showed a specific linear correlation with the SERS intensity at 1333 cm -1 , with recoveries 85.4%-105.0% and RSD 1.7%-10.8%., Conclusion: This breakthrough provided a novel, sensitive, convenient and stable approach for clinical diagnosis of diabetes and certain liver diseases. Overall, our findings presented a significant contribution to the field of biomedical research, opening up new possibilities for improved diagnosis and monitoring of diabetes and liver diseases., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Zhang et al.)

Insulin autoimmune syndrome (IAS) is a rare cause of spontaneous hypoglycaemia. We discuss a 91-year-old Caucasian lady who presented with syncope and episodic adrenergic and neuroglycopenic symptoms. Despite significantly elevated insulin, C-peptide, and proinsulin levels with the presence of anti-insulin antibodies, a pancreatic mass was not identified. Serum immunoelectrophoresis demonstrated monoclonal gammopathy of undetermined significance (MGUS). Treatment involved high-dose steroids, diazoxide, corn starch and acarbose, however the patient passed away four months later due to worsening co-morbidities. The management of IAS in the setting of MGUS is challenging., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press.)

Impaired insulin secretory capacity is associated with high glycemic variability in patients with type 2 diabetes (T2DM). However, there are no existing reports on the association between insulin secretory capacity and time in range (TIR). This retrospective study involved 330 T2DM admitted for diabetes education who underwent intermittently scanned continuous glucose monitoring (isCGM) and had their fasting serum C-peptide immunoreactivity (S-CPR) measured within 5 days of admission. The baseline characteristics were as follows: age, 60.2 years; glycated hemoglobin (HbA1c), 9.2%; S-CPR, 2.2 ng/mL; S-CPR index (S-CPR [ng/mL]/fasting plasma glucose [mg/dL] × 100), 1.6; and TIR, 60.3%. TIR correlated significantly with the S-CPR index, which was confirmed by multivariate analysis that included various factors such as HbA1c. Receiver operating characteristic (ROC) analysis showed that 1.88 was the optimal S-CPR index level to predict TIR ≥ 70%. In addition to HbA1c and biguanide use, the S-CPR index was a significant factor associated with TIR > 70%. S-CPR index values of ≥ 1.88 also correlated significantly with TIR > 70%. In conclusion, insulin secretory capacity is associated with TIR in Japanese T2DM, suggesting that the S-CPR index might be a potentially useful biomarker insulin secretory capacity, in association with TIR.Trial registration UMIN0000254333., (© 2024. The Author(s).)

Background: Laparoscopic sleeve gastrectomy (LSG) has emerged as a valuable treatment for various metabolic disorders, including metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with obesity. Consequently, there is a pressing need to develop noninvasive biomarkers for diagnosing and monitoring disease progression., Objectives: This study aimed to evaluate specific biomarkers, including Cytokeratin-18 (CK-18), C-peptide, monocyte to HDL cholesterol ratio (MHR), and MACK-3, in patients with obesity with MAFLD undergoing LSG., Design: A prospective cohort study on patients with obesity before and 6 months after the LSG procedure., Methods: 70 patients with obesity with confirmed MAFLD, determined by Transient Elastography (TE), were pre- and 6 months postoperatively tested. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), lipid profile, ghrelin, leptin, peptide YY, GLP-1, and liver fibrosis scores, including AST/ALT ratio (AAR), Fibrosis-4 index (FIB-4), and BARD Score were tested., Results: BMI significantly decreased in all participants, with a % excess weight loss of 62.0% ± 15.4%. TE measurements revealed a significant postoperative reduction from 100% to 87.1% ( P  = .006). All selected biomarkers showed significant postoperative improvement-a significant association of CK-18 with MAFLD markers, including AAR, FIB-4, and BARD score, were found. MACK-3 had positive associations with FIB-4. C-peptide and MHR showed no association with MAFLD markers. Furthermore, there was a positive correlation between CK-18 and MACK-3 tests and between C-peptide and CK-18 and MACK-3. Additionally, a receiver operating characteristic (ROC) curve was constructed, with CK-18 performing the best, with an estimated area under the curve of 0.863., Conclusion: Serum CK-18 outperformed other selected biomarkers in predicting and monitoring MAFLD in patients with obesity, suggesting its prospective utility in clinical practice. Further studies are needed to validate the accuracy of the MACK-3 test., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Backgruound: The Korean Endocrine Hormone Reference Standard Data Center (KEHRS DC) has created reference standards (RSs) for endocrine hormones since 2020. This study is the first of its kind, wherein the KEHRS DC established RSs for serum Cpeptide levels in a healthy Korean population., Methods: Healthy Korean adults were recruited from May 2021 to September 2023. After excluding participants according to our criteria, serum samples were collected; each participant could then choose between fasting glucose only or fasting glucose plus an oral glucose tolerance test (OGTT). If their sample showed high glucose (≥100 mg/dL) or hemoglobin A1c (HbA1c) (≥5.70%), their C-peptide levels were excluded from analyzing the RSs., Results: A total of 1,532 participants were recruited; however, only the data of 1,050 participants were analyzed after excluding those whose samples showed hyperglycemia or high HbA1c. Post-30-minute OGTT data from 342 subjects and post-120-minute OGTT data from 351 subjects were used. The means±2 standard deviations and expanded uncertainties of fasting, post-30-minute and 120-minute OGTT C-peptide levels were 1.26±0.82 and 0.34-3.18, 4.74±3.57 and 1.14-8.33, and 4.85±3.58 and 1.25-8.34 ng/mL, respectively. Serum C-peptide levels correlated with obesity, serum glucose levels, and HbA1c levels., Conclusion: The RSs for serum C-peptide levels established in this study are expected to be useful in both clinical and related fields.

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, HbA 1c 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. HbA 1c 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., (© 2024. The Author(s).)

Objective: We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis., Methods: We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis., Results: Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β=-0.11, P=0.002) and multivariate (β=-0.06, P=0.018) analyses., Conclusions: The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD., Methods: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed., Results: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders., Conclusion: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background : Since metabolic diseases and atherosclerotic vascular events are firmly associated, herein we investigate changes in central microcirculation and atherosclerosis-related body fat distribution in patients with type 2 diabetes mellitus and obesity. Methods: Resting brain perfusion single-photon emission computed tomography (SPECT) imaging with Technetium-99m hexamethylpropylene amine oxime ([ 99m Tc]Tc-HMPAO SPECT) was performed, and the breath-holding index (BHI) and carotid intima-media thickness (cIMT) were measured to characterise central microcirculation. Besides CT-based abdominal fat tissue segmentation, C-peptide level, glycaemic and anthropometric parameters were registered to search for correlations with cerebral blood flow and vasoreactivity. Results : Although no significant difference was found between the resting cerebral perfusion of the two patient cohorts, a greater blood flow increase was experienced in the obese after the breath-holding test than in the diabetics ( p < 0.05). A significant positive correlation was encountered between resting and provocation-triggered brain perfusion and C-peptide levels ( p < 0.005). BMI and cIMT were negatively correlated (rho = -0.27 and -0.23 for maximum and mean cIMT, respectively), while BMI and BHI showed a positive association (rho = 0.31 and rho = 0.29 for maximum and mean BHI, respectively), which could be explained by BMI-dependent changes in fat tissue distribution. cIMT demonstrated a disproportional relationship with increasing age, and higher cIMT values were observed for the men. Conclusions: Overall, C-peptide levels and circulatory parameters seem to be strong applicants to predict brain microvascular alterations and related cognitive decline in such patient populations.

Background and Aims: Bariatric surgery is effective for treating type 2 diabetes (T2D) in patients with obesity, although a significant proportion of these patients do not achieve diabetes remission after the surgery even after significant weight loss and metabolic improvement. C-peptide is a valuable marker of beta cell function and insulin secretion, but renal function must be considered when interpreting measurements in patients with T2D. The study aims to investigate the association of serum levels of C-peptide adjusted for creatinine with diabetes remission and glycemic target achievement after bariatric surgery in patients with obesity and T2D., Methods and Results: Prospective data from a cohort of 84 patients with obesity and T2D submitted to Roux-en-Y gastric bypass (RYGB) were collected at baseline and at least a 6-month follow up. A multivariate binomial regression model showed that Ln(C-peptide/creatinine) and age were significantly associated with 6-month T2D remission. The area under the curve for the receiver operating characteristic analysis (AUROC) to predict remission was 0.87, and more accurate than the AUROC based on C-peptide levels alone (0.75). The same model was also able to predict achieving an HbA1c target of 7 % (53 mmol/mol) (AUROC 0.96)., Conclusion: In conclusion, Ln(C-peptide/creatinine) ratio could be a useful tool in predicting T2D remission and target achievement after RYGB surgery, providing a more accurate reflection of beta cell function in bariatric patients., Competing Interests: Declaration of competing interest The authors declare no potential conflict of interests with the present study., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: To compare the efficacy and safety of saxagliptin/dapagliflozin and insulin glargine in people with latent autoimmune diabetes in adults (LADA)., Methods: In this phase 2b multicentre, open-label, comparator-controlled, parallel-group, non-inferiority study, we randomly assigned 33 people with LADA who had a fasting C-peptide concentration ≥0.2 nmol/L (0.6 ng/mL) to receive 1-year daily treatment with either the combination of saxagliptin (5 mg) plus dapagliflozin (10 mg) or insulin glargine (starting dose: 10 IU), both on top of metformin. The primary outcome was the 2-h mixed meal-stimulated C-peptide area under the curve (AUC), measured 12 months after randomization. Secondary outcomes were glycated haemoglobin (HbA1c) levels, change in body mass index (BMI), and hypoglycaemic events., Results: In the modified intention-to-treat analysis, the primary outcome was similar in participants assigned to saxagliptin/dapagliflozin or to insulin glargine (median C-peptide AUC: 152.0 ng*min/mL [95% confidence interval {CI} 68.2; 357.4] vs. 122.2 ng*min/mL [95% CI 84.3; 255.8]; p for noninferiority = 0.0087). Participants randomized to saxagliptin/dapagliflozin lost more weight than those randomized to insulin glargine (median BMI change at the end of the study: -0.4 kg/m 2 [95% CI -1.6; -0.3] vs. +0.4 kg/m 2 [95% CI -0.3; +1.1]; p = 0.0076). No differences in HbA1c or in the number of participants experiencing hypoglycaemic events were found., Conclusions: Saxagliptin/dapagliflozin was non-inferior to glargine in terms of β-cell function in this 12-month, small, phase 2b study, enrolling people with LADA with still viable endogenous insulin production. Weight loss was greater with saxagliptin/dapagliflozin, with no differences in glycaemic control or hypoglycaemic risk., (© 2024 John Wiley & Sons Ltd.)

Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule peptides are detectable within murine and human islets. The 2.5HIP (C-peptide-chromogranin A [CgA] HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in the nonobese diabetic mouse. However, the relevance of this epitope in human disease is currently unclear. A recent study probed T-cell reactivity toward HIPs in patients with type 1 diabetes, documenting responses in one-third of the patients and isolating several HIP-reactive T-cell clones. In this study, we isolated a novel T-cell clone and showed that it responds vigorously to the human equivalent of the 2.5HIP (designated HIP9). Although the responding patient carried the risk-associated DRB1*04:01/DQ8 haplotype, the response was restricted by DRB1*11:03 (DR11). HLA class II tetramer staining revealed higher frequencies of HIP9-reactive T cells in individuals with diabetes than in control participants. Furthermore, in DR11+ participants carrying the DRB4 allele, HIP9-reactive T-cell frequencies were higher than observed frequencies for the immunodominant proinsulin 9-28 epitope. Finally, there was a negative correlation between HIP9-reactive T-cell frequency and age at diagnosis. These results provide direct evidence that this C-peptide-CgA HIP is relevant in human type 1 diabetes and suggest a mechanism by which nonrisk HLA haplotypes may contribute to the development of β-cell autoimmunity., (© 2024 by the American Diabetes Association.)

Aims: Alström syndrome (AS) is a rare recessive disorder characterised by diabetes, obesity, insulin resistance (IR), and visual and hearing impairments. Mutations in the ALMS1 gene have been identified as the causative agents of AS. This study aimed to explore the relationship between rare ALMS1 variants and clinical features in Chinese patients with early-onset type 2 diabetes (age at diagnosis ≤40 years; EOD)., Materials and Methods: ALMS1 gene sequencing was performed in 611 Chinese individuals with EOD, 36 with postprandial hyperinsulinemia, and 47 with pre-diabetes and fasting IR. In-silico prediction algorithm and the American College of Medical Genetics Guidelines (ACMG) were used to evaluate the deleteriousness and pathogenicity of the variants., Results: Sixty-two rare ALMS1 variants (frequency <0.005) were identified in 82 patients with EOD. Nineteen variants were predicted to be deleterious (pD). Patients with EOD carrying pD variants had higher fasting C-peptide, postprandial C-peptide, and HOMA2-IR levels than those without variants. The frequency of ALMS1 pD variants in the subgroup with more insulin-resistant EOD was higher than that in other EOD subgroups. Two patients with EOD, obesity, and IR who carried one heterozygous pathogenic/likely pathogenic rare variant of ALMS1 according to ACMG were identified. Moreover, rare heterozygous pD variants of ALMS1 were found in participants from cohorts of postprandial hyperinsulinemia as well as in pre-diabetes with fasting IR., Conclusions: ALMS1 rare pD variants are enriched in the populations with significant IR, which is a major hallmark of diabetes pathogenesis. Accordingly, our exploratory study provides insights and hypotheses for further studies of gene function., (© 2024 John Wiley & Sons Ltd.)

Background: Epidemiological evidence for the association between heavy metals exposure during pregnancy and gestational diabetes mellitus (GDM) is still inconsistent. Additionally, that is poorly understood about the potential cause behind the association, for instance, whether heavy metal exposure is related to the change of insulin secretion phase is unknown., Objectives: We aimed to explore the relationships of blood levels of arsenic (As), lead (Pb), thallium (Tl), nickel (Ni), cadmium (Cd), cobalt (Co), barium (Ba), chromium (Cr), mercury (Hg) and copper (Cu) during early pregnancy with the odds of GDM, either as an individual or a mixture, as well as the association of the metals with insulin secretion phase after glucose stimulation., Methods: We performed a nested case-control study consisting of 302 pregnant women with GDM and 302 controls at the First Affiliated Hospital of Anhui Medical University in Hefei, China. Around the 12th week of pregnancy, blood samples of pregnant women were collected and levels of As, Pb, Tl, Ni, Cd, Co, Ba, Cr, Hg and Cu in blood were measured. An oral glucose tolerance test (OGTT) was done in each pregnant woman during the 24-28th week of pregnancy to diagnose GDM and C-peptide (CP) levels during OGTT were measured simultaneously. The four metals (As, Pb, Tl and Ni) with the highest effect on odds of GDM were selected for the subsequent analyses via the random forest model. Conditional logistic regression models were performed to analyze the relationships of blood As, Pb, Tl and Ni levels with the odds of GDM. The weighted quantile sum (WQS) regression and bayesian kernel machine regression (BKMR) were used to assess the joint effects of levels of As, Pb, Tl and Ni on the odds of GDM as well as to evaluate which metal level contributed most to the association. Latent profile analysis (LPA) was conducted to identify profiles of glycemic and C-peptide levels at different time points. Multiple linear regression models were employed to explore the relationships of metals with glycaemia-related indices (fasting blood glucose (FBG), 1-hour blood glucose (1h BG), 2-hour blood glucose (2h BG), fasting C-peptide (FCP), 1-hour C-peptide (1h CP), 2-hour C-peptide (2h CP), FCP/FBG, 1h CP/1h BG, 2h CP/2h BG, area under the curve of C-peptide (AUCP), area under the curve of glucose (AUCG), AUCP/AUCG and profiles of BGs and CPs, respectively. Mixed-effects models with repeated measures data were used to explore the relationship between As (the ultimately selected metal) level and glucose-stimulated insulin secretion phase. The mediation effects of AUCP and AUCG on the association of As exposure with odds of GDM were investigated using mediation models., Results: The odds of GDM in pregnant women increased with every ln unit increase in blood As concentration (odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.04-2.05). The joint effects of As, Pb, Tl and Ni levels on the odds of GDM was statistically significant when blood levels of four metals were exceeded their 50th percentile, with As level being a major contributor. Blood As level was positively associated with AUCG and the category of glucose latent profile, the values of AUCG were much higher in GDM group than those in non-GDM group, which suggested that As exposure associated with the odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance among pregnant women. The significant and positive relationships of As level with AUCP, CP latent profile category, 2h CP and 2h CP/2h BG were observed, respectively; and the values of 1h CP/1h BG and AUCP/AUCG were much lower in GDM group than those in non-GDM group, which suggested that As exposure may not relate to the impairment of insulin secretion (pancreatic β-cell function) among pregnant women. The relationships between As level and 2h CP as well as 2h CP/2h BG were positive and significant; additionally, the values of 2h CP/2h BG in GDM group were comparable with those in non-GDM group; the peak value of CP occurred at 2h in GDM group, as well as the values of 2h CP/2h BG in high As exposure group were much higher than those in low As exposure group, which suggested that As exposure associated with the increased odds of GDM may be due to that As exposure was related to the change of insulin secretion phase (delayment of the peak of insulin secretion) among pregnant women. In addition, AUCP mediated 11% (p < 0.05) and AUCG mediated 43% (p < 0.05) of the association between As exposure and the odds of GDM., Conclusion: Our results suggested that joint exposure to As, Pb, Tl and Ni during early pregnancy was positively associated with the odds of GDM, As was a major contributor; and the association of environmental As exposure with the increased odds of GDM may be due to that As exposure was related to the impairment of glucose tolerance and change of insulin secretion phase after glucose stimulation (delayment of the peak of insulin secretion) among pregnant women., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest Linong Ji has received fees for lecture presentations and for consulting from AstraZeneca, Merck, Metabasis, MSD, Novartis, Eli Lilly, Roche, Sanofi-Aventis and Takeda. No other support from any organization for the submitted work other than that described above. All other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Teplizumab has emerged as a potential disease-modifying drug in type 1 diabetes (T1D). This meta-analysis sought to summarize the therapeutic effect of teplizumab in newly diagnosed patients with T1D., Methods: Randomized controlled trials involving patients with T1D receiving teplizumab in the intervention arm and placebo (or no active intervention) in the control arm were searched throughout the electronic databases. The primary outcome was the change in area under the curve of C-peptide levels from baseline., Results: Seven reports from 6 studies involving 834 subjects met the inclusion criteria. Compared to teplizumab, greater reductions in area under the curve of C-peptide from the baseline values were observed in the control group after 6 months (mean difference [MD] 0.07 nmol/L [0.01, 0.13], P = .02), after 12 months (MD 0.07 nmol/L [0.04, 0.11], P = .0001), after 18 months (MD 0.10 nmol/L [0.06, 0.14], P < .00001), and after 24 months (MD 0.07 nmol/L [0.01, 0.14], P = .03) of interventions. Moreover, fewer patients treated with teplizumab had a decreased C-peptide response after 6 months (odds ratio [OR] 0.21), after 12 months (OR 0.17), after 18 months (OR 0.30), and after 24 months (OR 0.12) of treatment. The preservation of endogenous insulin production was supported by reduced use of exogenous insulin with maintenance of comparable glycemic control for up to 18 months post-treatment. Teplizumab imparted higher risks of grade 3 or higher adverse events, adverse events leading to study medication discontinuation, nausea, rash, and lymphopenia., Conclusion: The results of the meta-analysis support teplizumab as a promising disease-modifying therapy for newly diagnosed T1D., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: People with type 2 diabetes are heterogeneous in their disease trajectory, with some progressing more quickly to insulin initiation than others. Although classical biomarkers such as age, HbA 1c and diabetes duration are associated with glycaemic progression, it is unclear how well such variables predict insulin initiation or requirement and whether newly identified markers have added predictive value., Methods: In two prospective cohort studies as part of IMI-RHAPSODY, we investigated whether clinical variables and three types of molecular markers (metabolites, lipids, proteins) can predict time to insulin requirement using different machine learning approaches (lasso, ridge, GRridge, random forest). Clinical variables included age, sex, HbA 1c , HDL-cholesterol and C-peptide. Models were run with unpenalised clinical variables (i.e. always included in the model without weights) or penalised clinical variables, or without clinical variables. Model development was performed in one cohort and the model was applied in a second cohort. Model performance was evaluated using Harrel's C statistic., Results: Of the 585 individuals from the Hoorn Diabetes Care System (DCS) cohort, 69 required insulin during follow-up (1.0-11.4 years); of the 571 individuals in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) cohort, 175 required insulin during follow-up (0.3-11.8 years). Overall, the clinical variables and proteins were selected in the different models most often, followed by the metabolites. The most frequently selected clinical variables were HbA 1c (18 of the 36 models, 50%), age (15 models, 41.2%) and C-peptide (15 models, 41.2%). Base models (age, sex, BMI, HbA 1c ) including only clinical variables performed moderately in both the DCS discovery cohort (C statistic 0.71 [95% CI 0.64, 0.79]) and the GoDARTS replication cohort (C 0.71 [95% CI 0.69, 0.75]). A more extensive model including HDL-cholesterol and C-peptide performed better in both cohorts (DCS, C 0.74 [95% CI 0.67, 0.81]; GoDARTS, C 0.73 [95% CI 0.69, 0.77]). Two proteins, lactadherin and proto-oncogene tyrosine-protein kinase receptor, were most consistently selected and slightly improved model performance., Conclusions/interpretation: Using machine learning approaches, we show that insulin requirement risk can be modestly well predicted by predominantly clinical variables. Inclusion of molecular markers improves the prognostic performance beyond that of clinical variables by up to 5%. Such prognostic models could be useful for identifying people with diabetes at high risk of progressing quickly to treatment intensification., Data Availability: Summary statistics of lipidomic, proteomic and metabolomic data are available from a Shiny dashboard at https://rhapdata-app.vital-it.ch ., (© 2024. The Author(s).)

Currently, a paradigm change occurs in type 1 diabetes from insulin substitution to the treatment of the underlying autoimmune disease. Teplizumab, a humanized monoclonal anti-CD3 antibody, is the first FDA-approved disease-modifying treatment of preclinical stage 2 diabetes. Research of drugs like golimumab, a monoclonal antibody specific for TNF alpha, baricitinib, a tyrosine kinase inhibitor, or frexalimab, a monoclonal antibody against the CD40 ligand, is still ongoing. Repurposing drugs that have been used in other indications like the calcium channel blocker verapamil, antithymocyte globulin (ATG), an antibody preparation used in solid organ transplantation, glucagon-like peptide-1 agonists utilized in type 2 diabetes and obesity, or the antiviral drugs pleconaril and ribavirin have shown positive effects in preserving beta-cell function. While new therapies to halt autoimmunity and restore beta cells in stages one to three are being developed, replacing beta-cell function via inducible pluripotent stem cells have shown glucose control and insulin independence in long-standing type 1 diabetes, albeit with concomitant immunosuppression. Multicenter multinational initiatives developing a clinical trial network like INNODIA or a research platform with the goal of stopping type 1 diabetes in its early stages like EDENT1FI will be instrumental to study these new strategies., (© 2024 S. Karger AG, Basel.)

Background: The prevalence of obesity has increased in patients with type 1 diabetes (T1D) and latent autoimmune diabetes of the adult (LADA), limiting the use of clinical features such as the body mass index for its differentiation with type 2 diabetes (T2D). Additionally, some patients with maturity-onset diabetes of the young (MODY) or LADA are misdiagnosed as having T2D. The evaluation of autoantibodies and genetic testing are not fully available. We aimed to evaluate the utility of a widely available and less expensive diagnostic tool such as C-peptide to differentiate between T1D, T2D, MODY, and LADA., Methods: Our study included 38 patients with T1D, 49 with T2D, 13 with MODY, and 61 with LADA. We recorded anthropometric measurements, biochemical profiles, and antidiabetic treatment and determined C-peptide, anti-GAD65, and anti-IA2 antibodies., Results: C-peptide concentration differed significantly among populations (T1D: 0.2 ng/mL; T2D: 2.4 ng/mL; MODY: 1.14 ng/mL; LADA: 1.87 ng/mL). Through a ROC curve, we observed that the C-peptide cut-off point of 0.95 ng/mL allows differentiation between T1D and T2D (sensitivity 82%, specificity 77%); 0.82 ng/mL between T1D and LADA (sensitivity 82%, specificity 77%); and 1.65 ng/mL between T2D and MODY (sensitivity 72%, specificity 72%)., Conclusions: C-peptide is useful for the diagnostic differentiation of patients with type 1, type 2 diabetes, MODY, and LADA.

Objective: To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM)., Research Design and Methods: Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison., Results: All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis., Conclusion: Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: Understanding factors that influence blood glucose levels in patients with type 2 diabetes mellitus (T2DM) is crucial for managing hyperglycemia. Currently, there is no standardized interpretation method for glucagon levels in oral glucose tolerance test (OGTT). This study aims to assess the relationship between the lowest glucagon/highest C-peptide ratio (Lglc/Hcp) in OGTT and glucose control levels in T2DM., Patients and Methods: Clinical data from 120 patients with T2DM were examined to compare the correlations of Lglc/Hcp and other pancreatic islet function-associated indices with fasting blood glucose (G0), glucose at 120 minutes in OGTT (G120), hemoglobin A1c (HbA1c), and the area under the glucose curve in OGTT (AUCglu). Additionally, the study investigated difference in Lglc/Hcp between patient groups based on the highest blood glucose levels (Hglu) in OGTT (Hglu ≥ 16.7 mmol/L vs Hglu < 16.7 mmol/L)., Results: The generalized linear model suggested that Lglc/Hcp significantly correlated with G0 (B = 0.85, P < 0.001), G120(B = 1.46, P < 0.001), HbA1c (B = 0.67, P < 0.001), and AUCglu (B = 3.46, P < 0.001). This correlation surpassed C-peptide and glucagon-related parameters, even after adjusting for confounding factors. Furthermore, Lglc/Hcp was notably higher in patients with Hglu ≥ 16.7 mmol/L compared to those with Hglu < 16.7 mmol/L (Z = -3.71, p < 0.001)., Conclusion: Lglc/Hcp in OGTT closely relates to blood glucose control in patients with T2DM, potentially reflecting the overall pancreatic islet function in regulating glucose levels. Moreover, inhibiting glucagon secretion may be a crucial consideration for patients requiring insulin treatment., Competing Interests: Dr Lina Chang, Dr Qing He, Dr Ming Liu and Dr Li Ding report a pending patent “A Calculation Method and Its Application of an Index Related to Pancreatic Regulation of Blood Glucose” (patent no: 202311654605.8). The authors report no other conflicts of interest in this work., (© 2024 Chang et al.)

Classifying diabetes at diagnosis is crucial for disease management but increasingly difficult due to overlaps in characteristics between the commonly encountered diabetes types. We evaluated the prevalence and characteristics of youth with diabetes type that was unknown at diagnosis or was revised over time. We studied 2073 youth with new-onset diabetes (median age [IQR] = 11.4 [6.2] years; 50% male; 75% White, 21% Black, 4% other race; overall, 37% Hispanic) and compared youth with unknown versus known diabetes type, per pediatric endocrinologist diagnosis. In a longitudinal subcohort of patients with data for ≥ 3 years post-diabetes diagnosis (n = 1019), we compared youth with steady versus reclassified diabetes type. In the entire cohort, after adjustment for confounders, diabetes type was unknown in 62 youth (3%), associated with older age, negative IA-2 autoantibody, lower C-peptide, and no diabetic ketoacidosis (all, p < 0.05). In the longitudinal subcohort, diabetes type was reclassified in 35 youth (3.4%); this was not statistically associated with any single characteristic. In sum, among racially/ethnically diverse youth with diabetes, 6.4% had inaccurate diabetes classification at diagnosis. Further research is warranted to improve accurate diagnosis of pediatric diabetes type., (© 2024. The Author(s).)

Evidence suggests associations between COVID-19 patients or vaccines and glycometabolic dysfunction and an even higher risk of the occurrence of diabetes. Herein, we retrospectively analyzed pancreatic lesions in autopsy tissues from 67 SARS-CoV-2 infected non-human primates (NHPs) models and 121 vaccinated and infected NHPs from 2020 to 2023 and COVID-19 patients. Multi-label immunofluorescence revealed direct infection of both exocrine and endocrine pancreatic cells by the virus in NHPs and humans. Minor and limited phenotypic and histopathological changes were observed in adult models. Systemic proteomics and metabolomics results indicated metabolic disorders, mainly enriched in insulin resistance pathways, in infected adult NHPs, along with elevated fasting C-peptide and C-peptide/glucose ratio levels. Furthermore, in elder COVID-19 NHPs, SARS-CoV-2 infection causes loss of beta (β) cells and lower expressed-insulin in situ characterized by islet amyloidosis and necrosis, activation of α-SMA and aggravated fibrosis consisting of lower collagen in serum, an increase of pancreatic inflammation and stress markers, ICAM-1 and G3BP1, along with more severe glycometabolic dysfunction. In contrast, vaccination maintained glucose homeostasis by activating insulin receptor α and insulin receptor β. Overall, the cumulative risk of diabetes post-COVID-19 is closely tied to age, suggesting more attention should be paid to blood sugar management in elderly COVID-19 patients., (© 2024. The Author(s).)

Background: Sarcopenia, an age-related disorder characterized by loss of skeletal muscle mass and function, is recently recognized as a complication in elderly patients with type 2 diabetes mellitus (T2DM). Skeletal muscles play a crucial role in glycemic metabolism, utilizing around 80% of blood glucose. Accordingly, we aimed to explore the relationship between glucose metabolism and muscle mass in T2DM., Methods: We employed the AWGS 2019 criteria for diagnosing low muscle mass and 1999 World Health Organization (WHO) diabetes diagnostic standards. This study included data of 191 individuals aged 60 and above with T2DM of Shanghai Pudong Hospital from November 2021 to November 2022. Fasting C-peptide (FPCP), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (PPG) and postprandial 2-hour C-peptide (PPCP), glycated hemoglobin A1c (HbA1c), glycated albumin (GA), serum lipids spectrum, renal and hepatic function, hemoglobin, and hormone were measured. Based on the findings of univariate analysis, logistic regression and receiver operating characteristic (ROC) curves were established., Results: Participants with low muscle mass had significantly lower alanine and aspartate aminotransferase, and both FPCP and PPCP levels (P < 0.05). Compared with those without low muscle mass, low muscle mass group had significantly higher FPG, HbA1c, GA levels (P < 0.05). Body fat (BF, OR = 1.181) was an independent risk factor for low muscle mass. PPCP (OR = 0.497), BMI (OR = 0.548), and female (OR = 0.050) were identified as protective factors for low skeletal muscle. The AUC of BMI was the highest, followed by the PPCP, gender and BF (0.810, 0.675, 0.647, and 0.639, respectively), and the AUC of the combination of the above four parameters reached 0.895., Conclusions: In this cross-sectional study, BMI, Female, and PPCP associated with T2DM were protective factors for low muscle mass. BF was associated with T2DM and risk factor for low muscle mass., (© 2024. The Author(s).)