Future clinical prospects of C-peptide testing in the early diagnosis of gestational diabetes

Gestational diabetes is typically diagnosed in the late second or third trimester of pregnancy.It is one of the most common metabolic disorders among expectant mothers,with potential serious short-and long-term complications for both maternal and offspring health.C-peptide is secreted from pancreatic beta-cells into circulation in equimolar amounts with insulin.It is a useful biomarker to estimate the beta-cell function because it undergoes negligible hepatic clearance and consequently it has a longer half-life compared to insulin.Pregnancy induces increased insulin resistance due to physiological changes in hormonal and metabolic homeostasis.Inadequate compensation by islet beta-cells results in hyperglycemia.The standard oral glucose tolerance test at 24-28 wk of gestation sets the diagnosis.Accumulated evidence from prospective studies indicates a link between early pregnancy C-peptide levels and the risk of subsequent gestational diabetes.Elevated C-peptide levels and surrogate glycemic indices at the beginning of pregnancy could prompt appropriate strategies for secondary prevention.

C-peptide as a key risk factor for non-alcoholic fatty liver disease in the United States population

AIM To determine whether fasting C-peptide is an independent predictor for non-alcoholic fatty liver disease(NAFLD) in United States population.METHODS Using the National Health and Nutrition Examination Survey(NHANES) 1988-1994, NAFLD participants aged 20 or greater without any other liver diseases were included in this study. Excessive alcohol intake is defined as > 2 drinks per day for males and > 1 drink per day for females. C-peptide and 27 other factors known to be associated with NAFLD(e.g., age, gender, body mass index, waist circumference, race/ethnicity, liver chemistries, and other diabetes tests) were tested in both univariate and multivariate level using logistic regression with a P-value 0.05.RESULTS Of 18825 participants aged ≥ 20, 3235 participants(n = 3235) met inclusion criteria. There were 23 factors associated with NAFLD by univariate analysis. 9 factors, ranked by the highest change in pseudo R2, were found to be significant predictors of NAFLD in multivariate model: waist circumference, fasting C-peptide, natural log of alanine aminotransferase(ALT), total protein, beingMexican American, natural log of glycated hemoglobin, triglyceride level, being non-Hispanic white, and ferritin level. CONCLUSION Together with waist circumference and ALT, fasting C-peptide is among three most important predictors of NAFLD in United States population in the NHANES data set. Further study is needed to validate the clinical utility of fasting C-peptide in diagnosis or monitoring insulin resistance in NAFLD patients.

C-peptide and Diabetic Encephalopathy

With the changes of life style, diabetes and its complications have become a major cause of morbidity and mortality. It is reasonable to anticipate a continued rise in the incidence of diabetes and its complications along with the aging of the population, increase in adult obesity rate, and other risk factors. Diabetic en- cephalopathy is one of the severe microvascular complications of diabetes, characterized by impaired cogni- tive functions, and electrophysiological, neurochemical, and structural abnormalities. It may involve direct neuronal damage caused by intracellular glucose. However, the pathogenesis of this disease is complex and its diagnosis is not very clear. Previous researches have suggested that chronic metabolic alterations, vascular changes, and neuronal apoptosis may play important roles in neuronai loss and damaged cognitive functions. Multiple factors are responsible for neuronal apoptosis, such as disturbed insulin growth factor （IGF） system, hyperglycemia, and the aging process. Recent data suggest that insulin/C-peptide deficiency may exert a primary and key effect in diabetic encephalopathy. Administration of C-peptide partially improves the condition of the IGF system in the brain and prevents neuronal apoptosis in the hippocampus of diabetic patients. Those findings provide a basis for application of C-peptide as a potentially effective therapy for diabetes and diabetic encephalopathy.

Pathological consequences of C-peptide deficiency in insulin-dependent diabetes mellitus

Diabetes is associated with several complications such as retinopathy, nephropathy, neuropathy and cardiovascular diseases. Currently, insulin is the main used medication for management of insulin-dependentdiabetes mellitus(type-1 diabetes). In this metabolic syndrome, in addition to decrease of endogenous insulin, the plasma level of connecting peptide(C-peptide) is also reduced due to beta cell destruction. Studies in the past decade have shown that C-peptide is much more than a byproduct of insulin biosynthesis and possess different biological activities. Therefore, it may be possible that C-peptide deficiency be involved, at least in part, in the development of different complications of diabetes. It has been shown that a small level of remaining C-peptide is associated with significant metabolic benefit. The purpose of this review is to describe beneficial effects of C-peptide replacement on pathological features associated with insulin-dependent diabetes. Also, experimental and clinical findings on the effects of C-peptide on wholebody glucose utilization, adipose tissue metabolism and tissues blood flow are summarized and discussed. The hypoglycemic, antilipolytic and vasodilator effects of C-peptide suggest that it may contribute to fine-tuning of the tissues metabolism under different physiologic or pathologic conditions. Therefore, C-peptide replacement together with the classic insulin therapy may prevent, retard, or ameliorate diabetic complications in patients with type-1 diabetes.

Level of Fasting C-Peptide as a Predictor of <i>β</i>-Cell Function in Sudanese Patients with Type 2 Diabetes Mellitus

Objective: In this study, we assessed the level of fasting C-peptide as a predictor of β-cell function and insulin resistance in patients with Type 2 diabetes mellitus (T2DM), Gezira State-Sudan. Methods: In this cross-sectional study, 100 T2DM patients attending the Diabetic patients care Centre were recruited, thirty five patients were males and sixty five were females, the mean age of the patients was 50.29 ± 0.456 years, and body mass index (BMI) was 26.54 ± 0.437. We estimated β-cell function using fasting C-peptide levels;homeostatic model assessment for β-cell function (HOMA-B) and insulin resistance (HOMA-IR) were calculated from C-peptide and fasting blood glucose (FBG). Results: C-peptide was significantly and positively correlated with HOMA-B and HOMA-IR. FBG also showed significant negative correlation with HOMA-B, but was positively and significantly correlated with HOMA-IR. HbA1c was negatively and significantly correlated with HOMA-B. Patients with low C-peptide levels had increased FBG and HbA1c level, while patients with high C-peptide levels were having high HOMA-IR and HOMA-B. Conclusions: Fasting C-peptide is a useful marker of pancreatic β-cell function, and its circulating levels could be used to evaluate insulin secretion and insulin resistance. Moreover, HOMA-IR is an effective index to achieve glycemic control by appropriate pharmacologic treatment of T2DM.

Inverse relationship between glomerular hyperfiltration and C-peptide level in Type 1 diabetes

Background: Increased glomerular filtration rate (GFR) commonly develops in early diabetes and is closely correlated with the development of diabetic nephropathy. Objective: The aim was to study the relationship between GFR, C-peptide level and other parameters at diagnosis of Type 1 diabetes. Methods: We determined GFR, Cpeptide level, glycated hemoglobin (HbA1c), body mass index (BMI) SDS and loss of weight at diagnosis of Type 1 diabetes in 495 children (231 females). Linear and multiple regression analysis was used to test for the associations between GFR and other parameters. Results: In the 495 patients, GFR median (interquartile range) was increased vs normal values (p = 0.0001). GFR was significantly negatively correlated with age (p < 0.001) and C-peptide level (p = 0.001), and positively correlated with weight loss (p = 0.02). The multiple regression analysis showed that age (p = 0.001) and C-peptide level (p = 0.05) were independently and negatively related to GFR. Conclusions: This study shows that, at onset of Type 1 diabetes, higher the GFR, younger the age and lower the C-peptide level are. The role of this hyperfiltration in the development of later nephropathy and the putative preventive effect of C-peptide administration need to be evaluated.

Research Progress of C-Peptide and Its Physiological Function

As a product in the process of insulin synthesis, C-peptide’s physiological function is still not very clear. Recent studies have shown that C-peptide has many potential cell targets and has biological effects on a variety of tissue systems in humans and other animals. In this paper, the effects of C-peptide on diabetic complications, reproductive endocrine system, blood system, tissue repair, and neoplastic diseases were reviewed to provide references for further clarification of c-peptide related problems.

Role of C-Peptide in Relation to Levels of Anti-GAD and Islet Cell Antibodies in Characterizing Types of Diabetes in the Young, in Eastern India

Background: Measuring fasting C-peptide (FCP) and antibodies against Glutamic acid decarboxylase (GADA) and Islet cell antibodies (ICA) are not so commonly explored in children and young adults. Objectives: To assess the levels of FCP, GADA and ICA in subjects below the age of 25 years with DM and compare their levels to differentiate between Autoimmune and Non-Autoimmune Type 1 DM. Methodology: Blood samples of 93 subjects diagnosed with DM, reporting to the tertiary care hospital, were analysed for ICA, GADA and FCP. Receiver operating characteristics (ROC) curves were analysed to check the ability of autoimmune markers, BMI and C-peptide to differentiate between Autoimmune (Ai) and Non-Autoimmune (NonAi) diabetes. Results: 30/93 (32.2%) were positive for anti-GAD ab and/or ICA and categorised as Autoimmune (Ai), the most common antibody being, anti-GAD ab (80%) in them. The level of FCP among Ai compared to NonAi, was significantly low (p 20.75 nmol/l) as a very dependable test for diagnosing Ai, Type 1 DM, in children and young adults. Its sensitivity and specificity are in the range of 86.2% and 96.8% respectively. Low level of C-peptide (Conclusion: This study revealed predominant positivity for anti-GAD ab (80%) among Ai+ patients. ROC analysis shows GADA above 20.75 nmol/l and Fasting C-peptide < 0.36 nmol/l as a good indicator for diagnosing Ai in children and young adults.

25-Hydroxyvitamin D Is Associated with Islet Homeostasis in Type-2 Diabetic Patients with Abdominal Obesity

Objective Isletαcells input is essential for insulin secretion fromβcells.The present study aims to investigate the association between 25-hydroxyvitamin D[25(OH)D]and islet function homeostasis in type-2 diabetes(T2D)patients.Methods A total of 4670 T2D patients from seven communities in Shanghai,China were enrolled.The anthropometric indices,biochemical parameters,serum 25(OH)D,and islet function[including C-peptide(C-p)and glucagon]were measured.Results The fasting plasma glucose(FPG),glycated hemoglobin(HbA1c),glucagon,and C-p levels exhibited a significantly decreasing trend in T2D patients as the 25(OH)D levels increased.Next,the population was divided into two groups:abdominal obesity and non-abdominal obesity groups.After adjustment,the 25(OH)D level was found to be associated with HbA1c,glucagon,and homeostasis model assessment ofβ(HOMA-β)in the non-abdominal obesity group.There was a significant relationship between 25(OH)D and HbA1c,glucagon,HOMA-IR,baseline insulin or C-p in the abdominal obesity group.In the abdominal obesity group,the ordinary least squares(OLS)regression and quantile regression revealed that 25(OH)D was obviously associated with glucagon and fasting C-p levels.In the abdominal obesity group,the moderate analysis revealed a significant interaction effect of 25(OH)D and glucagon on C-p(P=0.0124).Furthermore,the conditional indirect effect of 25(OH)D on the glucagon/C-p ratio was significantly lower at 1 standard deviation(SD)below the mean(P=0.0002),and lower at the mean of the course of diabetes(P=0.0007).Conclusion 25(OH)D was found to be negatively correlated to glucagon and C-p in T2D patients with abdominal obesity.The 25(OH)D influenced C-p in part by influencing glucagon.The effect of 25(OH)D on the glucagon/C-p ratio in T2D patients with abdominal obesity,in terms of islet homeostasis,is influenced by the course of diabetes.

Roux-en-Y gastric bypass for Chinese type 2 diabetes mellitus patients with a BMI,28kg/m^2:a multi-institutional study

Roux-en-Y gastric bypass surgery（RYGB） has been demonstrated to be successful for treating type-II diabetes2mellitus（T2DM） patients with a body mass index（BMI）,30 kg/m,but reports of RYGB for T2 DM patients with22 a BMI,28 kg/mare lacking.T2 DM patients with a BMI,28 kg/mwere prospectively recruited to participate in this study in four hospitals.The endpoint was T2 DM remission（defined by fasting blood glucose（FBG） level,110 mg/d L and hemoglobin（Hb）A1c level,6.0% at 12 months postoperatively）.Predictors of remission were investigated by univariate and multivariate analyses.Eighty-six patients were assessed.Eighty-five patients underwent RYGB,with one conversion to open surgery.We compared the values of various variables before and after2 surgery.The mean BMI decreased from 24.68±2.12 to 21.72±2.43 kg/m（P,0.001）.Fifty-eight（67.4%） patients were not treated by drugs or insulin after surgery,and 20 patients（23.3%） had complete remission of T2 DM at12 months after surgery with an acceptable number of complications.The mean Hb A1 c level in the remission group was significantly lower than that in the non-remission group.Patients with a higher weight,lower Hb A1 c level,higher C-peptide level,and higher FBG level were more likely to have T2 DM remission in multivariate2 analyses.In conclusion,RYGB was effective and safe for treating T2 DM patients with a BMI,28 kg/m.Complete remission can be predicted by cases having a higher weight,lower Hb A1 c level,higher C-peptide level,and higher FBG level.

EFFECTS OF GLUCAGON ON ISLET β CELL FUNCTION IN PATIENTS WITH DIABETES MELLITUS

Objective To evaluate islet β cell response to intravenous glucagon （ a non-glucose secretagogue） stimulation in diabetes mellitus. Methods Nineteen patients with type 1 diabetes （T1 D） and 131 patients with type 2 diabetes （T2D） were recruited in this study. T2D patients were divided into two groups according to therapy： 36 cases treated with insulin and 95 cases treated with diet or oral therapy. The serum C-peptide levels were determined at fasting and six minutes after intra- venous injection of 1 mg of ghicagon. Results Both fasting and 6-minute post-ghicagon-stimulated C-peptide levels in T1D patients were significantly lower than those of T2D patients （0. 76±0. 36 ng/mL vs. 1.81±0. 78 ng/mL, P 〈 0.05 ; 0.88±0.42 ng/mL vs. 3.68±0. 98 ng/mL, P 〈 0. 05 ）. In T1D patients, the C-peptide level after injection of ghicagon was similar to the fasting level. In T2D, patients treated with diet or oral drug had a significantly greater fasting and stimulated C-peptide level than those patients received insulin therapy （2.45±0. 93 ng/mL vs. 1.61±0. 68 ng/mL, P 〈 0.05 ; 5.26±1.24 ng/mL vs. 2.15±0.76 ng/mL, P 〈 0.05 ）. The serum C-peptide level after ghicagon stimulation was positively correlated with C-peptide levels at fasting in all three groups （ r = 0.76, P 〈 0.05 ）. Conclusions The 6-minute ghicagon test is valuable in assessing the function of islet β cell in patients with diabetes mellitus. It is helpful for diagnosis and treatment of diabetes mellitus.

Reduced endogenous insulin secretion in diabetic patients with low-titer positive antibodies against GAD

Aim: To investigate the clinical characteristics of diabetic patients with a low-titer positive for the anti-glutamic acid decarboxylase 65 antibody (GAD antibody). Methods: The subjects were 420 diabetic inpatients. The endogenous insulin secretion was estimated on the basis of the C-peptide immunoreactivity from a 24 h urine collection (uCPR). Clinical variables were compared between patients negative for the GAD antibody (GAD antibody titer < 1.5 U/mL), a low-titer positive GAD antibody (1.5 U/mL ≤ GAD antibody titer < 10 U/mL) and a high-titer positive GAD antibody (10 U/mL ≤ GAD antibody titer). Results: The low and high-titer positive GAD antibodies were found in 25 and 10 patients, respectively. The uCPR was significantly lower in both the patients with a low (37 ± 33 ug/24h) and high-titer (39 ± 27 ug/24h) positive GAD antibodies than in those negative for GAD antibodies (71 ± 52 ug/24h). The uCPR level was significantly lower in the low-titer positive GAD antibody group (29 ± 22 ug/24h) than in the negative group (67 ± 55 ug/24h) among the patients not taking insulin secretagogues. The difference disappeared in the subjects taking insulin secreagogues. In the stepwise multiple regression analysis, a low-titer positive GAD antibody was independently associated with the uCPR level. Conclusions: Endogenous insulin secretion is reduced in diabetic patients positive for GAD antibodies, even if the titer is low. Earlier initiation of insulin therapy might therefore protect the pancreatic β-cell function in diabetic patients with a low-titer positive GAD antibody.

Evaluation of Insulin Resistance Indices in Type 2 Diabetic Patients Treated with Different Anti-Diabetic Drugs

Clinically, determination of insulin resistance is important for diabetic patients. We evaluated the relationship among 20/(fasting C-peptide × fasting plasma glucose), HOMA-IR and QUICKI indices in type 2 diabetic patients. The study included 40 patients with type 2 diabetes. Patients divided into three groups based on their medication: metformin, metformin + glibenclamide and metformin + glitazone. Fasting blood sugar, and lipid profile were measured by enzymatic method, serum insulin, and C-peptide were measured by ELISA method. Insulin resistance was calculated by using of 20/(fasting C-peptide × fasting plasma glucose), HOMA-IR and QUICKI indices. There was no significant relationship between 20/(fasting C-peptide × fasting plasma glucose) index and other parameters in all studied groups except QUICKI in metformin group showed a significant correlation with 20/(fasting C-peptide × fasting plasma glucose) index (r = 0.56 and p = 0.03). There was a significant correlation between HOMA-IR and QUICKI indices in all studied groups. There was no significant relationship between 20/(fasting C-peptide × fasting plasma glucose) index with other clinical parameters. On the other hand, our data strongly suggested a significant correlation between HOMA-IR and QUICKI indices in studied subjects with type 2 diabetes.

Short reaction of C-peptide, glucagon-like peptide-1, ghrelin and endomorphin-1 for different style diet in type 2 diabetic patients

Background Food composition and style is changing dramatically now, which causes inappropriate secretion of hormones from brain, gastrointestinal and endo-pancreas, may be related to unbalance of glucose in blood. The aim of this study was to explore the fast response of C-peptide, glucagon-like peptide-1 （GLP-1）, ghrelin and endomorphin-1 （EM-1） to the eastern and western style meals in patients with type 2 diabetes mellitus. Methods The study enrolled 57 patients with type 2 diabetes （20 men and 37 women, mean age （67.05±8.26） years）. Eastern style meal （meal A） and western style meal （meal B） were designed to produce the fullness effect. C-peptide, GLP-1, ghrelin and EM-1 were assessed before （0 hour） and after （2 hours） each diet. Results The delta （2h-0h） of C- peptide in meal A was significantly lower than that in meal B （P=0.0004）. C-peptide, GLP-1, ghrelin and EM-1 were obviously higher before meal B than those before meal A （P 〈0.0001, 〈0.0001, =0.001, =0.0004 respectively）. Blood glucose 2 hours and 3 hours after meal B were higher than those after meal A （P=0.0005, 0.0079 respectively）. Correlations between GLP-1 and ghrelin were strongly positive before both meals and 2 hours after both meals and also in relation to the delta of meal A and meal B （rA0h=0.7838, rB05=0.9368, rA25=0.7615, rB2h=0.9409, r A（2h-0h）=0.7531, rB（2h 05）=0.9980, respectively, P 〈0.0001）. Conclusion Western style meal （high fat and protein food） could make more response of C-peptide than eastern style meal, and could stimulate more gut hormones （GLP-1, ghrelin） and brain peptide （EM-1） at the first phase of digestion.

Assessment of long-term graft function following total pancreatectomy and autologous islet transplantation:the Leicester experience

Background:Total pancreatectomy and islet autotransplantation(TPIAT)is a recognised treatment for chronic pancreatitis(CP)with the potential to mitigate or prevent pancreatogenic diabetes.We present our 10-year follow-up of TPIAT patients.Methods:The University Hospitals of Leicester performed 60 TPIAT procedures from September 1994 to May 2011.Seventeen patients completed their 10-year assessment and were grouped using the modified Auto-Igls criteria;good response,n=5(insulin-independent for first 5 years post-TPIAT);partial response,n=6(insulin requirements<20 iU/day post-TPIAT)and poor response,n=6(insulin requirements≥20 iU/day post-TPIAT).C-peptide,haemoglobin A1c(HbA1c)and oral glucose tolerance test(OGTT)were undertaken preoperatively(baseline),then at 3,6 months and then yearly for 10 years.Data was analysed using analysis of variance(ANOVA).Results:Median C-peptide levels were significantly higher,120 minutes following OGTT,in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0001).All groups demonstrated preservation of C-peptide release.HbA1c levels were significantly lower in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0003 and P<0.0001).Median fasting glucose levels at 30 and 120 min following OGTT,were significantly lower in the“good response”compared to“partial”and“poor”groups(two-way ANOVA test,P<0.0001 and P<0.0001).Conclusions:TPIAT preserves long-term islet graft functions in 10-year follow up.Even in patients in the poor response group,there is evidence of C-peptide release(>0.5 ng/mL)after OGTT stimulation potentially preventing long-term diabetes-related complications.

Change of glutamic acid decarboxylase antibody and protein tyrosine phosphatase antibody in Chinese patients with acute-onset type 1 diabetes mellitus

Background Glutamic acid decarboxylase antibody （GADA） and protein tyrosine phosphatase antibody （IA-2A） are two major autoantibodies, which exert important roles in the process of type 1 diabetes mellitus （T1D）. Our study aimed to investigate the changes in positivity and titers of GADA and IA-2A during the course of Chinese acute-onset T1D patients and their relationships with clinical features.