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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. [ABSTRACT FROM AUTHOR]

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. What is already known on this topic Diabetic peripheral neuropathy (DPN), a common complication of diabetes, significantly impairs the quality of life. Although increased level of serum glucagon in T2DM patients has been well documented, the impact of glucagon on T2DM patients with DPN remains unclear. What this study adds 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. How this study might affect research, practice, or policy In clinical practice, patients with T2DM with a long duration of disease should pay attention to the occurrence and progression of DPN when using antidiabetic drugs target glucagon. [ABSTRACT FROM AUTHOR]

Background: Viral respiratory infections may precipitate type 1 diabetes (T1D). A possible association between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, and the incidence of T1D is being determined. This study was carried out using Portuguese registries, aiming at examining temporal trends between COVID-19 and T1D. Methods: Hospital data, comparing the incidence before and during the COVID-19 pandemic, from children and young adults diagnosed with new-onset T1D, was acquired beginning in 2017 and until the end of 2022. Data was obtained from nine different Portuguese hospital units. The impact of the COVID-19 pandemic, beginning in March 2020, was assessed comparing the annual numbers of new-onset T1D cases. The annual median levels of glucose, glycated hemoglobin (HbA1c) and fasting C-peptide at T1D diagnosis were compared. The annual number of diabetic ketoacidosis (DKA) episodes among new T1D cases was also assessed at two centers. Results: In total, data from 574 newly diagnosed T1D patients was analyzed, including 530 (92.3%) children. The mean ages for child and adult patients were 9.1 (SD 4.4) and 32.8 (SD 13.6) years, respectively. 57.8% (331/573) were male, one patient had unknown sex. The overall median (25–75 percentiles) levels of glucose, HbA1c and fasting C-peptide at diagnosis were 454 mg/dL (356–568), 11.8% (10.1–13.4) and 0.50 µg/L (0.30–0.79), respectively. DKA at T1D diagnosis was present in 48.4% (76/157). For eight centers with complete 2018 to 2021 data (all calendar months), no overall significant increase in T1D cases was observed during the COVID-19 pandemic, i.e. 90 cases in 2018, 90 cases in 2019, 112 in 2020 and 100 in 2021 (P for trend = 0.36). Two of the centers, Faro (CHUA) and Dona Estefânia (CHULC) hospitals, did however see an increase in T1D from 2019 to 2020. No significant changes in glucose (P = 0.32), HbA1c (P = 0.68), fasting C-peptide (P = 0.20) or DKA frequency (P = 0.68) at the time of T1D diagnosis were observed over the entire study period. Conclusion: The T1D incidence did not increase significantly, when comparing the years before and during the COVID-19 pandemic, nor did key metabolic parameters or number of DKA episodes change. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated the effect of long-term intensive metabolic control with hybrid closed-loop (CL) on residual C-peptide secretion and glucose control compared with standard insulin therapy in youth with type 1 diabetes over 48 months. RESEARCH DESIGN AND METHODS: Following the 24-month primary phase of a multicenter, randomized, parallel trial of 96 newly diagnosed youth aged 10 to 16.9 years, participants were invited to an extension phase using treatment allocated at randomization. They continued with hybrid CL using the Cambridge algorithm or standard insulin therapy (control) until 48 months after diagnosis. Analysis was by intention-to-treat. RESULTS: At 24 months after diagnosis, 81 participants (mean ± SD age 14 ± 2 years) continued in the extension phase (47 CL, 34 control). There was no difference in fasting C-peptide corrected for fasting glucose at 48 months between groups (CL: 5 ± 9 vs. control: 6 ± 14 pmol/L per mmol/L; mean adjusted difference −2 [95% CI −7, 4; P = 0.54]). Central laboratory HbA1c remained lower in the CL group by 0.9% (10 mmol/mol [95% CI 0.2, 1.5; 3, 17 mmol/mol); P = 0.009). Time in target range of 3.9 to 10.0 mmol/L was 12 percentage points (95% CI 3, 20; P = 0.008) higher in the CL group compared with control. There were 11 severe hypoglycemic events (6 CL, 5 control) and 7 diabetic ketoacidosis events (3 CL, 4 control) during the extension phase. CONCLUSIONS: Improved glycemic control was sustained over 48 months after diagnosis with CL insulin delivery compared with standard therapy in youth with type 1 diabetes. This did not appear to confer a protective effect on residual C-peptide secretion. [ABSTRACT FROM AUTHOR]

Key Clinical Message: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: We aimed to analyze the relationship between non-alcoholic fatty liver and progressive fibrosis and serum 25-hydroxy vitamin D (25(OH)D) in patients with type 2 diabetes mellitus. Methods: A total of 184 patients with T2DM who were hospitalized in the Department of Endocrinology of the ShiDong Clinical Hospital between January 2023 and June 2023 were selected. We compared review of anthropometric, biochemical, and inflammatory parameters and non-invasive scores between groups defined by ultrasound NAFLD severity grades.We determine the correlation between 25(OH)D and FLI and FIB-4 scores, respectively. Results: Statistically significant differences were seen between BMI, WC, C-peptide levels, FPG, ALT, serum 25(OH)D, TC, HDL, lumbar spine bone density, FLI, and FIB-4 in different degrees of NAFLD. Multivariate logistic regression analysis showed that 25(OH)D (OR = 1.26, p = 0.001), age (OR = 0.93, P < 0.001) and BMI (OR = 1.04, p = 0.007) were independent predictors of NAFLD in patients with T2DM. Conclusions: This study revealed the correlation between serum 25(OH)D levels and NAFLD in patients with T2DM. We also demonstrated that serum 25(OH)D levels were negatively correlated with FLI/FIB-4 levels in patients with T2DM with NAFLD, suggesting that vitamin D deficiency may promote hepatic fibrosis progression in T2DM with NAFLD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the correlation between C‐peptide index (CPI) at 2 h post‐meal and endogenous insulin secretory capacity and to develop clinical models to predict the possibility of withdrawal from insulin therapy in patients with type 2 diabetes. Method: This was a single‐centre retrospective study of patients with type 2 diabetes admitted to our hospital. Patients were divided into a withdrawal group (n = 72) and a non‐withdrawal group (n = 75) based on whether they were able to withdraw from insulin therapy at discharge, and the correlation between CPI at 2 h after meal and diabetes‐related parameters was evaluated. In addition, we created two clinical models to predict the possibility of withdrawal from insulin therapy using machine learning. Results: The glycated haemoglobin values of the study participants were 87.8 ± 22.6 mmol/mo. The CPI at 2 h post‐meal was 1.93 ± 1.28 in the non‐withdrawal group and 2.97 ± 2.07 in the withdrawal group (p < 0.001). CPI at 2 h post‐meal was an independent predictor of withdrawal from insulin therapy. In addition, CPI at 2 h post‐meal was a better predictor than fasting CPI. Six factors associated with insulin therapy withdrawal (age, duration of diabetes, creatinine, alanine aminotransferase, insulin therapy until hospitalization, and CPI at 2 h post‐meal) were used to generate two clinical models by machine learning. The accuracy of the generated clinical models ranged from 78.3% to 82.6%. Conclusion: The CPI at 2 h post‐meal is a clinically useful measure of endogenous insulin secretory capacity under non‐fasting conditions. [ABSTRACT FROM AUTHOR]

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 I2 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. [ABSTRACT FROM AUTHOR]

Background: 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. [ABSTRACT FROM AUTHOR]

Background: CD8+ T regulatory (Treg) cells that recognize the nonclassical class 1b molecule Qa-1/human leukocyte antigen E (Q/E CD8+ Treg cells) are important in maintaining self-tolerance. We sought to investigate the role that these T cells play in type 1 diabetes (T1D) pathogenesis and whether an intervention targeting this mechanism may delay T1D progression. Methods: We conducted a phase 1/2, randomized, double-blind, placebo-controlled trial of the autologous dendritic cell therapy AVT001 that included participants at least 16 years of age, within 1 year of T1D diagnosis, and with ex vivo evidence of a defect in Q/E CD8+ Treg function. Patients were randomly assigned in a 2:1 ratio to AVT001 or placebo, which was administered in three monthly intravenous infusions. The primary end point was safety; efficacy end points included changes from baseline in C-peptide area under the curve (AUC) during a 4-hour mixed meal, hemoglobin A1c (HbA1c), and insulin dose. Results: Sixteen patients received AVT001, and nine received placebo. Similar rates and severity of adverse events were observed in both groups. None of the patients in the AVT001 group had serious adverse events through visit day 360. Compared with placebo, treatment with ATV001 was associated with less decline from baseline log-transformed C-peptide AUC (nmol/l), with the treatment effect between AVT001 and placebo at day 150 of 0.09 (95% confidence interval [CI], 0.03 to 0.15) and at day 360 of 0.10 (95% CI, 0.04 to 0.15). No clear differences in change in HbA1c and insulin dose from baseline were observed between groups. Estimated treatment effects of AVT001 versus placebo at day 360 were -0.17% (95% CI, -0.60 to 0.26%) for HbA1c and -0.06 U/kg/day (95% CI, -0.14 to 0.02) for daily insulin dose. Conclusions: In this phase 1/2 trial, AVT001 did not result in dose-limiting adverse events. Potential signals of efficacy observed here warrant further evaluation in a fully powered trial. (Funded by Avotres Inc. and the Division of Diabetes, Endocrinology, and Metabolic Diseases; ClinicalTrials.gov number, NCT03895996.) [ABSTRACT FROM AUTHOR]

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Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes characterized by hyperglycemia that remits during infancy with a tendency to recur in later life. This case report presents the history of a male infant with transient neonatal diabetes mellitus. The patient was treated with a continuous subcutaneous insulin infusion (CSII) and a continuous glucose monitoring (CGM) system until the age of 2 months, when the normoglycemia connected with a withdrawal of treatment was noted. The genetic test results excluded the majority of known mutations related to TNDM. This case report focuses on various genetic mutations and the clinical features connected with them that cause TNDM and highlights the difficulties in the diagnostic and therapeutic processes of this disease. CSII and CGM systems seem to be a safe and effective treatment option in TNDM and may be used in the therapy. [ABSTRACT FROM AUTHOR]

Abstract 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

Background 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

Background 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 C-peptide 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.

Tong Zhang,1– 3,&ast; Han Wu,1,2,&ast; Chenling Qiu,1,2 Mingxin Wang,1,2 Haiting Wang,1,2 Shunhua Zhu,1,4 Yinhai Xu,2 Qingli Huang,1,4 Shibao Li1,2 1Medical Technology School of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 2Department of Laboratory Medicine, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China; 3Chuzhou Center for Disease Control and Prevention, Chuzhou City, Anhui, 239000, People’s Republic of China; 4Public Experimental Research Center of Xuzhou Medical University, Xuzhou City, Jiangsu, 221004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qingli Huang; Shibao Li, Email qlhuang@xzhmu.edu.cn; sdjnshlb@xzhmu.edu.cnIntroduction: 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.Keywords: surface-enhanced Raman scattering, SERS, nanocomposites, insulin, C-peptide

Abstract 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.

Abstract 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.

Lina Chang,&ast; Xiaohui Ma,&ast; Menghua Yuan,&ast; Li Ding, Yian Gu, Lili Liu, Yan Li, Hua Shu, Ming Liu, Qing He Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing He; Ming Liu, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China, Email heqing202301@tmu.edu.cn; mingliu@tmu.edu.cnPurpose: 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. Keywords: C-peptide, glucose control, glucagon, type 2 diabetes mellitus

Abstract 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

Purpose: The purpose of the present study was to identify predictors of severe white matter hyperintensity (WMH) with obesity (SWO), and to build a prediction model for screening obese people with severe WMH without Nuclear Magnetic Resonance Imaging (MRI) examination. Patients subjects and methods: From September 2020 to October 2021, 650 patients with WMH were recruited consecutively. The subjects were divided into two groups, SWO group and non-SWO group. Univariate and Logistic regression analysis were was applied to explore the potential predictors of SWO. The Youden index method was adopted to determine the best cut-off value in the establishment of the prediction model of SWO. Each parameter had two options, low and high. The score table of the prediction model and nomogram based on the logistic regression were constructed. Of the 650 subjects, 487 subjects (75%) were randomly assigned to the training group and 163 subjects (25%) to the validation group. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. By resampling the area under the curve (AUC) of the subject's operating characteristics and calibration curves 1,000 times, nomogram performance was verified. A decision curve analysis (DCA) was used to evaluate the nomogram's clinical usefulness. Results: Logistic regression demonstrated that hypertension, uric acid (UA), complement 3 (C3) and Interleukin 8 (IL-8) were independent risk factors for SWO. Hypertension, UA, C3, IL-8, folic acid (FA), fasting C-peptide (FCP) and eosinophil could be used to predict the occurrence of SWO in the prediction models, with a good diagnostic performance, Areas Under Curves (AUC) of Total score was 0.823 (95% CI: 0.760--0.885, p < 0.001), sensitivity of 60.0%, specificity of 91.4%. In the development group, the nomogram's AUC (C statistic) was 0.829 (95% CI: 0.760--0.899), while in the validation group, it was 0.835 (95% CI: 0.696, 0.975). In both the development and validation groups, the calibration curves following 1,000 bootstraps showed a satisfactory fit between the observed and predicted probabilities. DCA showed that the nomogram had great clinical utility. Conclusion: Hypertension, UA, C3, IL-8, FA, FCP and eosinophil models had the potential to predict the incidence of SWO. When the total score of the model exceeded 9 points, the risk of SWO would increase significantly, and the nomogram enabled visualization of the patient's WMH risk. The application prospect of our models mainly lied in the convenient screening of SWO without MRI examination in order to detect SWO and control the WMH hazards early. [ABSTRACT FROM AUTHOR]

We describe 2 families with 5 members from 2 generations whose clinical and laboratory characteristics over up to 15 years were consistent with dysglycemia/impaired glucose tolerance. In both families (2 probands and 3 family members), long-term follow-up excluded diabetes type 1 and type 2. Diabetes type 1 antibodies were persistently negative and C-peptide levels were normal. In Family 1, the proband, during a follow-up of 7 years (10.3-17.5 years of age), exhibited persistently high HbA1c (>5.7%) with fasting blood glucose levels mostly higher than 100 mg/dl and postprandial glucose levels up to 180 mg/dl. She eventually required oral anti-diabetics with an improvement in glycemic balance. The father and sister also had persistent mild hyperglycemia with borderline high HbA1c (mostly > 5.7%) levels over 15 and 6.2 years respectively. In Family 2, the proband exhibited borderline high fasting hyperglycemia (>100 mg/dl) at age 16.2 years with increasing HbA1c levels (from 5.6%–5.9%) and impaired glucose tolerance at age 18.3 years (2 h blood glucose 156 mg/dl after 75 g glucose). His sister also exhibited borderline hyperglycemia with borderline high HbA1c over 2 years (13.6-15.4 years). These subjects shared a unique phenotype. They are tall and slim with decreased BMI. Three subjects from Generation II failed to thrive during infancy. In view of the data from 2 generations suggesting maturity-onset diabetes of the young (MODY) with autosomal dominant inheritance, we sought to analyze the MODY genes. In Family 1, the molecular analysis by the MODY panel including 11 genes and whole exome sequencing did not detect any mutation in the proband. In Family 2, the MODY panel was also negative in the proband's sister. These families may represent a hitherto unidentified syndrome. Unique features described in this report may help to reveal additional families with similar characteristics and to decipher the molecular basis of this syndrome. In selected cases, oral antidiabetics in adolescents may improve the glycemic balance. [ABSTRACT FROM AUTHOR]

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. Plain Language Summary: Effect on biomarkers in patients with fatty liver after weight loss surgery A sleeve gastrectomy is an operation when patient have obesity and need to lose weight. This operation help people with obesity who also have fatty liver disease that's not related to alcohol use. Researchers are looking for simple blood tests to track the disease. In this study, they checked how well 4 of these tests worked before and after the surgery in 70 people. They found that the patients lost a lot of weight and their liver health improved. One test, in particular, called CK-18, was really good at showing these changes. Another test, MACK-3, also showed promise, but more research is needed to be sure. The other 2 tests didn't seem to be linked to signs of fatty liver disease. This suggests that CK-18 could be a useful tool for doctors to see how patients are doing after this surgery [ABSTRACT FROM AUTHOR]

Objective: The relationships between carotid intima-media thickness (C-IMT) and β cell function and insulin resistance in patients with type 2 diabetes (T2D) have not been fully elucidated. This study is to investigate whether impaired glucose metabolism is etiologically associated with C-IMT in patients with T2D. Methods: The study group consisted of 490 (284 men, 206 women) participants. Venous blood specimens were obtained from all subjects for biochemical profiles after an >8-h overnight fast. C-IMT was measured as the distance between the luminal-intimal leading edge (I-line) and the medial-adventitial leading edge (M-line) on the far wall. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR). The acute insulin response to arginine was calculated as the mean of the three plasma insulin levels obtained within 2, 4, and 6 min after the arginine bolus minus the pre-stimulus plasma insulin levels. Results: There was a graded increase in C-IMT values according to tertiles of HOMA-IR in men; the values of C-IMT were significantly decreased across the tertiles of acute insulin and C-peptide responses in women. Multivariate analysis revealed that HOMA-IR and age were positively associated with C-IMT among men participants, and acute insulin response and current smoking were the independent determinants of C-IMT in women. Conclusion: Early insulin response stimulated by arginine is independently associated with C-IMT in women T2D individuals, whereas insulin resistance is positively correlated with C-IMT in men T2D subjects. [ABSTRACT FROM AUTHOR]

Objective: MODY (maturity onset diabetes of the young) is a rare, monogenic, autosomal dominant form of diabetes occurring in young (< 25 years) individuals. It has a wide phenotypic variability and can be misdiagnosed as type 1 diabetes mellitus (T1DM). Appropriate detection of MODY has therapeutic and genetic implications. This study aimed to detect MODY among long standing, clinically diagnosed T1DM patients with preserved C-peptide levels. Methods: This was a hospital-based cross-sectional study from central South India which included 100 clinically diagnosed T1DM patients (according to ADA criteria), with a duration of > 3 years. MODY probability score, urinary C-peptide to creatinine ratio (UCPCR), and relevant biochemical investigations were performed. Targeted next-generation sequencing (NGS) for MODY-related genes (13 genes) was done for individuals with UCPCR > 0.2. Results: A UCPCR value of > 0.2 (suggestive of preserved endogenous insulin secretion) was observed in eight individuals. The mean HbA1c values were lower, and the MODY probability score was higher in individuals with preserved endogenous insulin (8.07% vs 9.53% and 2.8% vs 1.5%; p-value: 0.005 and 0.004 respectively). One of the eight individuals (12.5%) had a non-pathogenic gene variant in KLF11. Conclusion: In a South Indian cohort of T1DM with preserved C-peptide, we could not find any case of MODY through targeted NGS. UCPCR can be used as a screening tool to identify cases needing genetic testing for MODY. Larger studies utilizing whole exome sequencing should be conducted to know the actual prevalence of MODY among T1DM. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic β-cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of β-cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of β-cell function have established a predictive relationship between stimulated C-peptide as a measure of β-cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of β-cell function but also as a specific, sensitive, feasible, and clinically meaningful outcome defining β-cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes. Article Highlights: Mixed-meal stimulated C-peptide level has been established as a biomarker of endogenous β-cell function and is used clinically to monitor disease progression in type 1 diabetes. Large prospective cohort studies and interventional trials of islet transplantation demonstrate the relationship between stimulated C-peptide levels and clinical benefits. A recent meta-analysis of interventional clinical trials aimed at preserving β-cell function in those recently diagnosed further supports stimulated C-peptide level as a validated surrogate end point for clinical trials of disease-modifying therapies in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Maturity onset diabetes of the young (MODY) is characterized by noninsulin-dependent diabetes diagnosed before the age of 25 years with an autosomal dominant inheritance. Rare mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene produce a syndrome that resembles MODY. About half of patients diagnosed with MODY type 5 due to HNF1B variants, carry a whole gene deletion, known as 17q12 deletion syndrome. 17q12 deletion syndrome is a rare chromosomal anomaly and is typified by deletion of more than 15 genes, including HNF1B resulting in kidney abnormalities and renal cysts, a diabetes syndrome and neurodevelopmental or neuropsychiatric disorders. A 12-year-old girl was referred after high blood sugar was detected in the hospital where she presented with polyuria and polydipsia, which had persisted for one month. Her serum magnesium (Mg) level was low at 1.5 mg/dL (normal value 1.6-2.6) and glycated hemoglobin was 14% (normal value 3.6-5.8) concurrent with a c-peptide of 1.54 ng/mL (normal value 0.8-4). MODY5 was suspected but the NGS gene panel (ABCC8, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEURODD1, PAX4, PDX1, RFX6, ZFP57, GLIS3, FOXP3, NEUROG3, G6PC2) did not identify any abnormality. During follow-up, her serum Mg remained low (1.2 mg/ dL) together with elevated urinary Mg excretion at 172.5 mg/day. An HNF1B variant was again suspected in a patient with chronic hypomagnesemia with normal basal C peptide level. Abdominal computed tomography and magnetic resonance imaging revealed a 43 mm diameter, cystic lesion in the head of the pancreas, with agenesis of the pancreatic neck, trunk and tail. Genetic testing using a microarray analysis was subsequently performed and a heterozygous deletion at 17q12, including HNF1B, was detected. In case of clinical suspicion of HNF1B variants, further genetic examination using other techniques such as MLPA and CGH array may be required to detect the variant. This is because deletions and duplications may not be detected using next generation screening panel techniques. [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]

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. [ABSTRACT FROM AUTHOR]

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 ([99mTc]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. [ABSTRACT FROM AUTHOR]

C‐peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C‐peptide serves an anti‐inflammatory and anti‐atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C‐peptide protects endothelial cells by activating AMP‐activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia‐induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase‐3 activity and promoting expression of B‐cell lymphoma‐2. Additionally, C‐peptide suppresses platelet‐derived growth factor (PDGF)‐beta receptor and p44/p42 mitogen‐activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF‐kB) signaling, a major pro‐inflammatory cascade. Consequently, it is envisaged that supplementation of C‐peptide in T1DM might ameliorate or even prevent end‐organ damage. In marked contrast, C‐peptide increases monocyte recruitment and migration through phosphoinositide 3‐kinase (PI‐3 kinase)‐mediated pathways, induces lipid accumulation via peroxisome proliferator‐activated receptor γ upregulation, and stimulates VSMC proliferation and CD4+ lymphocyte migration through Src‐kinase and PI‐3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C‐peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C‐peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications. [ABSTRACT FROM AUTHOR]

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/m2 [95% CI −1.6; −0.3] vs. +0.4 kg/m2 [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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective Zinc transporter 8 autoantibodies (ZNt8A) are 1 of the 4 main autoantibodies used for the diagnosis of type 1 diabetes (T1D), with glutamic acid decarboxylase autoantibodies (GADA), islet antigen-2 autoantibodies (IA-2A), and insulin autoantibodies (IAA). The objective of this study is to evaluate the diagnostic efficiency of these autoantibodies for the diagnosis of T1D in pediatric patients. Methods A retrospective analysis of patients under 16 years of age with suspected T1D was made between June 2020 and January 2021. A total of 80 patients were included in the study, with 1 sample per patient. Subjects were classified according to diagnosis. Results Of the subjects included in the study, 50 developed T1D. The diagnostic efficacy was IA-2A (cutoff ≥ 28 U/L) sensitivity 0.26 (95% CI: 0.14-0.38) and specificity 0.97 (95% CI: 0.79-1.0); GADA (cutoff ≥ 17 U/mL) sensitivity 0.40 (95% CI: 0.26-0.54) and specificity 0.87 (95% CI: 0.75-0.99); ZnT8A (cut off ≥ 15 U/L) sensitivity 0.62 (95% CI: 0.49-0.75) and specificity 0.97 (95% CI: 0.90-1.0). ZnT8A obtained the most significantly global diagnostic accuracy (0.75), and GADA with ZnT8A showed the highest correlation. Conclusion The results obtained indicate a higher efficiency of anti-ZnT8 autoantibodies for the diagnosis of T1D in pediatric patients. Clinical efficiency of diabetic autoantibodies is method and assay dependent and influences combined diagnostic strategies. [ABSTRACT FROM AUTHOR]

Investigation of biological systems often requires reconstruction of an unobservable continuous process from discrete time-series data sampled from a related process or processes. When the reconstructed process cannot be validated with experimental data, it is particularly important to quantify the uncertainty on the inferred process, and new methodologies are needed to support both the inference and uncertainty quantification. This work derives a novel statistical model that combines an established differential model of intra- and extravascular C-peptide dynamics with a Gaussian process model of insulin secretion rate (ISR) in order to provide clinical measures of betacell function with quantified uncertainty. These measures are computed from the ISR that is inferred from measured C-peptide data. The model is first validated using synthetic data, and then applied to oral glucose tolerance test (OGTT) data from youth participants with and without cystic fibrosis (CF). Because CF is characterized by scarring and fibrosis of the pancreas, impairment of beta-cell function, rather than reduced insulin sensitivity, is implicated in the early etiology of CF-related diabetes (CFRD). ISR-derived measures of beta-cell function show worsening beta-cell function from healthy control to CF to CFRD groups consistent with previous reports on dysglycemia in CF. However, the model additionally allows uncertainty in the data to be propagated to ISR and ISRderived measures of beta-cell function. These results provide insight into uncertainty in ISR-derived measures of beta cell function, characterize interindividual variability in CFRD etiology, and provide novel metrics to quantify the pathogenesis of CFRD. [ABSTRACT FROM AUTHOR]

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. 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). 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. • Nearly half of the patients undergoing Bariatric Surgery (BS) do not achieve T2D remission. • The study used a logarithmic transformation (ln) of the C-peptide/creatinine ratio to better reflect beta cell function. • Ln(C-peptide/creatinine) ratio has potential clinical application in assessing the likelihood of T2D remission after BS. [ABSTRACT FROM AUTHOR]

This article explores the topic of Latent Autoimmune Diabetes in Adults (LADA), a form of diabetes that combines characteristics of both type 1 and type 2 diabetes. The article emphasizes the need for standardized diagnostic criteria and recommends autoantibody testing for newly diagnosed type 2 diabetes patients. The management of LADA is still uncertain, and further research is necessary to determine the most effective interventions. The article also acknowledges the variability in the progression and long-term outcomes of LADA patients. The authors call for more scientific research and international collaborations to address the unanswered questions surrounding LADA and ultimately benefit those affected by the condition. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The classification of diabetes into type-1 (T1D) and type-2 (T2D) is a critical step in tailoring effective treatment strategies. This distinction relies on a nuanced evaluation of clinical and biochemical features. While age at diagnosis, autoimmune markers, and beta-cell function are among the crucial clinical parameters, biochemical indicators like C-peptide levels and antibody analyses play a pivotal role. This review comprehensively examines the utility of these features in accurately categorizing individuals into T1D and T2D subtypes, providing valuable insights for clinical practice. This scoping review systematically analyses 32 studies aimed at classifying T1D and T2D using various predictor variables. Clinical parameters including family history of diabetes, age at diagnosis, sex, history of insulin use, percent desirable weight or body mass index, waist, and blood pressure emerge as pivotal diagnostic tools. C-peptide measures, encompassing urinary C-peptide to creatinine ratio (UCPCR), and serum fasting and stimulated C-peptide levels further augment classification. Biochemical markers beyond C-peptide, such as serum level of adiponectin, triglycerides (TG), high-density lipoprotein–cholesterol (HDL-C), low-density lipoprotein (LDL-C), Total cholesterol, fasting and postprandial plasma glucose, and glycated hemoglobin (HbA1c), provide supplementary information for classification. Ketonuria and postglucagon or meal-stimulated C-peptide measurements contribute to nuanced classification, particularly in insulin-treated populations. Antibody analyses, particularly presence of GAD65, Zinc Transporter, and IA2 antibodies, highlight the autoimmune nature of T1D. In conclusion, this scoping review underscores the importance of a comprehensive approach that integrates clinical, biochemical, and immunological markers in accurately differentiating between T1D and T2D in clinical practice. [ABSTRACT FROM AUTHOR]

Metformin is the first-line treatment for type 2 diabetes (T2D) in youth but with limited sustained glycemic response. To identify common variants associated with metformin response, we used a genome-wide approach in 506 youth from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and examined the relationship between T2D partitioned polygenic scores (pPS), glycemic traits, and metformin response in these youth. Several variants met a suggestive threshold (P < 1 × 10-6), though none including published adult variants reached genome-wide significance. We pursued replication of top nine variants in three cohorts, and rs76195229 in ATRNL1 was associated with worse metformin response in the Metformin Genetics Consortium (n = 7,812), though statistically not being significant after Bonferroni correction (P = 0.06). A higher β-cell pPS was associated with a lower insulinogenic index (P = 0.02) and C-peptide (P = 0.047) at baseline and higher pPS related to two insulin resistance processes were associated with increased C-peptide at baseline (P = 0.04,0.02). Although pPS were not associated with changes in glycemic traits or metformin response, our results indicate a trend in the association of the β-cell pPS with reduced β-cell function over time. Our data show initial evidence for genetic variation associated with metformin response in youth with T2D.

Background: The efficacy of insulin and C-peptide suppression (ICPS) test using a rapid-acting insulin analog to induce hypoglycemia in the diagnosis of insulinoma has never been studied. Objective: To compare the efficacy of using plasma C-peptide (PCP) and plasma insulin (PI) responses to the ICPS test using insulin aspart and the supervised prolonged fast (SPF) test in the diagnosis of insulinoma. Methods: The ICPS test was performed in 15 patients with insulinoma (IN) and 6 patients with non-insulinoma causes of hypoglycemia (non-IN) by intravenous infusion of insulin aspart to induce hypoglycemia. Plasma glucose (PG), C-peptide (PCP), and insulin (PI) levels were measured before and at the end of the test (end-ICPS) when the patients had hypoglycemia, defined by the presence of either PG ≤50 mg/dL with hypoglycemic symptoms or PG ≤40 mg/dL regardless of hypoglycemic symptoms. PCP and PI were measured by an immunoassay system that does not cross-react to insulin aspart (Cobas Modular Analytics e801). The SPF test was also performed in IN. Results: IN had a higher median end-ICPS PI (34.77 versus 0.58 μIU/mL, p

Key Clinical Message 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.

A 15-year-old boy was admitted to the intensive care unit of our hospital with complaints of increased urination, extreme tiredness, and nausea for the past 15 days. He had also lost 6.5 kg of weight (almost 10% of total body weight) in 1 month. On admission, his plasma glucose was 780 mg/dL, glycated haemoglobin (HbA1c) 11.6%, serum ketones >10.0 mmol/L, osmolality 346 mosm/kg, arterial pH 7.28, and bicarbonate 9 mEq/L. The C-peptide report initially indicated poor pancreatic beta cell reserve (fasting: 0.41 pmol/mL and stimulated: 0.46 pmol/mL). He was diagnosed with diabetic ketoacidosis and responded well to treatment, after which time he was switched to subcutaneous insulin. Ten days later, in the outpatient clinic, his fasting blood glucose was 132 mg/dL, postprandial blood glucose was 183 mg/dL, and C-peptide had improved to fasting: 0.89 pmol/mL and stimulated: 1.42 pmol/mL. Considering the presence of acanthosis nigricans on the neck, a body mass index in the overweight range, a positive family history of diabetes, and negative tests for pancreatic autoantibodies, an early onset diagnosis of type 2 diabetes mellitus was considered. Insulin was gradually withdrawn, and he was switched to metformin. Sustained recovery of C-peptide in this case indicates that lack of insulin at admission was due to beta cell stunning, rather than a total and irreversible loss of beta cells as expected in type 1 diabetes mellitus. Beta cell stunning is often reversible, as shown in this case. [ABSTRACT FROM AUTHOR]