Higher C-peptide Research Articles

1290 Years of Undiagnosed Recurrent Hypoglycemia in a Child

INTRODUCTION: Below we present a case of a child with an insulinoma, a rare and difficult to diagnose cause of hypogylcemia. CASE DESCRIPTION/METHODS: A previously healthy 12-year-old child presented to the emergency department with an unresponsive episode. Her father found her in bed, “unable to open her eyes” and extremely lethargic. Her blood sugar was noted to be less than 20 and she had ketones in her urine. Her glucose improved with oral intake and was discharged with a presumptive diagnosis of a well known cause of hypoglycemia in this age group, ketotic hypoglycemia. She remained well for around a year but then returned to the ED with lethargy. She was deemed have symptoms consistent with her originally diagnosed condition and was discharged. After an illness free period of 18 months, she presented to the ED with a low glucose of 33, high insulin of 14, and high c-peptide of 3.3. She had a negative CT scan was again discharged home. For the next few months, she having daily symptoms of fatigue and “cranky” behaviors, with only partial response to glucose intake. At age 16, after being seen by an endocrinologist, an insulinoma was considered as a possible diagnosis. MRI was ordered, but didn't detect a mass in the pancreas. Thus, GI was consulted for endoscopic ultrasound (EUS) and a 2 cm mass in the uncinate process was detected. FN-B of the pancreatic mass was consistent with neuroendocrine tumor. The patient had a surgical resection and, eventually, complete resolution of symptoms. DISCUSSION: Insulinomas are a very rare cause of hypoglycemia, with around 1 to 4 new cases occurring per million persons per year, and particularly uncommon in children with only limited number of published case reports. Classically, the “Whipple's triad” is expected with insulinoma: a low plasma glucose, symptoms consistent with hypoglycemia, relief of symptoms when the glucose is raised to normal. This patient did have certain aspects of the triad of symptoms, but she didn't always respond to glucose thus complicating diagnosis. This case is a reminder that, while rare, insulinoma is a important cause of hyperinsulinemic hypoglycemia in the pediatric population. Also important to know I is that while CT is generally considered first line for diagnosis of insulinoma and has good sensitivity and specificity and MRI has even better accuracy, neither test is perfect, thus EUS is sometimes required to identify lesions.

Metabolic hormones and breast cancer risk among Mexican American Women in the Mano a Mano Cohort Study

C-peptide, insulin, leptin, and other metabolic hormones are assumed to play roles in breast cancer development; though, results are inconsistent. In this prospective case-control study nested within the Mano a Mano Cohort Study, we assessed the risk of breast cancer with regard to plasma levels of c-peptide, gastric inhibitory polypeptide, insulin, leptin, monocyte chemoattractant protein-1, pancreatic polypeptide, and peptide YY. Among women followed for a median of 8.5 years, 109 breast cancer cases were identified and frequency-matched to 327 controls at a ratio of 1:3. Overall, only c-peptide was observed significantly associated with breast cancer risk. High c-peptide levels (≥ the median level of controls) were significantly associated with increased breast cancer risk (odds ratio [OR] = 1.39, 95% confidence interval [CI]: 1.01, 2.44). In an analysis of participants stratified by age, the significant association between c-peptide levels and breast cancer risk was evident in only women age ≥51 years (OR = 1.53, 95% CI: 1.02, 3.27). Among women age <51 years, high leptin levels were significantly associated with decreased breast cancer risk (OR = 0.49, 95% CI: 0.24, 0.82). Our findings suggest that selected metabolic hormones are associated with breast cancer development in Mexican American women.

1721-P: Effect of the TCF7L2 Variant rs7903146 T Allele on the Incretin Effect in Individuals with Normal Glucose Tolerance or Type 2 Diabetes

Background and Aim: The T allele of TCF7L2 rs7903146 is a common genetic variant associated with type 2 diabetes. The mechanisms underlying this association are not fully understood, but diminished incretin-induced insulin secretion has been suggested. We undertook this study to evaluate the effect of the TCF7L2 rs7903146 T allele on the incretin effect in normal glucose tolerant individuals and patients with type 2 diabetes. Methods: The incretin effect was assessed by relating the difference in integrated beta cell secretory responses to oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) to the response during OGTT in 36 normal glucose tolerant individuals (of whom 12 had the risk-conferring variant rs7903146 (TC/TT)) and 20 patients with type 2 diabetes (10 with TC/TT). Homeostatic model assessment (HOMA) was used to estimate insulin resistance. Results: No differences in incretin effect estimates between risk allele carriers and non-carriers in the two groups were observed. Normal glucose tolerant individuals with rs7903146 displayed higher C-peptide levels in the fasting state (P=0.029) as well as during OGTT (P=0.029) and IIGI (P=0.015) compared to normal glucose tolerant non-carriers. Normal glucose tolerant risk allele carriers were more insulin resistant compared to normal glucose tolerant non-carriers (P=0.042). No detectable differences in glucose metabolism were found between risk allele carriers and non-carriers in the type 2 diabetes group. Conclusions: The TCF7L2 rs7903146 T allele was not associated with reduced incretin effect in these relatively small cohorts of normal glucose tolerant individuals and patients with type 2 diabetes. Insulin resistance rather than beta cell secretory defects distinguished the normal glucose tolerant risk allele carriers examined here, from the normal glucose tolerant non-carriers. Disclosure D.S. Mathiesen: None. A.B. Lund: None. K.B. Hansen: None. A. Junker: None. T. Idorn: Employee; Self; Novo Nordisk A/S. M. Hornum: None. A. Jonsson: None. T. Hansen: None. T. Vilsbøll: None. J.I. Bagger: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp &amp; Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation (NNF17OC0029370)

1684-P: Using Index60 to Detect Heterogeneity and Identify Subpopulations with Characteristic Type 1 Diabetes (T1D) Profiles among Individuals with Normal Two-Hour Glucose Levels

We assessed whether Index60 could identify subpopulations with heterogeneous T1D features among autoantibody positive (Ab+) individuals with a normal 2-hour glucose. Index60 is a composite measure of fasting C-peptide, 60-minute C-peptide, and 60-minute glucose that has potential utility as a prediabetes endpoint when values are ≥1.00. Baseline 2-hour OGTTs of Ab+ TrialNet Pathway to Prevention participants in the normal 2-hour glucose (&amp;lt;140 mg/dl) range and low Index60 range (&amp;lt;1.00) were studied. The top 2-hour glucose &amp;lt;140 mg/dl quartile was compared with the top Index60 &amp;lt;1.00 quartile for characteristic T1D features (groups mutually exclusive). Those in the top Index60 quartile (Group B) or in both top quartiles (Group C) had profiles more typical of T1D than those in the top 2-hour glucose quartile (Group A), who had higher C-peptide levels, lower Ab+ frequencies, and were older (Table). Also, as indicated by within group odds ratios, Group A had less association of DR3-DQ2/DR4-DQ8 with the top quartile (Group A: 1.19, ns; Group B: 1.49, p&amp;lt;0.01; Group C: 1.63, p&amp;lt;0.01). In summary, Index60 can detect heterogeneity among those with normal 2-hour glucose levels, and identify subpopulations with appreciably more characteristic T1D features. The atypia of Group A demonstrates the importance of this Index60 utility. Disclosure B.M. Nathan: None. S. Geyer: None. L.E. Bocchino: None. J.P. Palmer: None. L.M. Jacobsen: None. M.J. Redondo: None. E.K. Sims: None. J.S. Skyler: Advisory Panel; Self; ADOCIA, Applied Therapeutics, Dance Biopharm Holdings Inc., Orgenesis Ltd., Tolerion, Inc., Viacyte, Inc. Board Member; Self; Dexcom, Inc., Intarcia Therapeutics, Inc., Moerae Matrix, Inc. Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dalcor, Dialogics, Elcelyx Therapeutics, Inc., Esperion, GeNeuro Innovation, Ideal Life, Immunomolecular Therapeutics, Intrexon, Kamada, Nestlé, Sanofi, Valeritas, Inc., Zafgen, Inc. Stock/Shareholder; Self; Dexcom, Inc., Ideal Life, Intarcia Therapeutics, Inc., Intrexon, Moerae Matrix, Inc. J.M. Sosenko: None. Funding National Institutes of Health; JDRF

Physical Activity, Nutrition and Hormone Levels of Postmenopausal Women With and Without Endometrial Cancer [40R

INTRODUCTION: This prospective study evaluated anthropometric data, reported physical activity, nutrition, and hormone levels between postmenopausal women undergoing hysterectomy for endometrial cancer and benign disease. METHODS: After IRB approval, participants completed questionnaires on physical activity, nutrition, menstrual history and hormone use, and provided preoperative blood samples. RESULTS: Of the 77 participants, mean age was 64.5 years, mean BMI was 35.0 kg/m2, and 80.5% had endometrial cancer. Few women (20.8%) achieved recommended weekly exercise and 47.2% did not exercise. Only 44.9% of women ate recommended servings of fruits and vegetables and 55.6% ate fast food weekly. Comparing women with and without cancer, a trend towards higher BMI (36.0 vs 31.1 kg/m2, P=.071) was noted but no significant differences with regard to gravidity, exercise, nutrition, glucose or hormone levels except that estradiol level was significantly lower in women with cancer (45.2 vs 53.8 pg/mL, P=.041). Obese women were significantly less likely to rate their health as excellent/very good (28.6% vs 56.5%, P=.022) and had statistically significant lower FSH (P=.021) and SHBG (P<0.001) but higher C-peptide (P=.019) compared to lean patients. Women were divided into 4 groups (obese or lean with and without cancer) with significant differences found in age (lean women with cancer were older, P=.006), FSH (obese women with cancer had lower levels, P=.012), SHBG (highest in lean women without cancer, P=.02) but not estradiol, androstenedione, C-peptide or diet/exercise. CONCLUSION: Estradiol levels in postmenopausal women with cancer were lower than benign patients and did not correlate with obesity or other diet/exercise habits.

Analysis of Predictors of Type 2 Diabetes Mellitus Remission After Roux-en-Y Gastric Bypass in 101 Chinese Patients.

To investigate prognostic factors for complete remission in type 2 diabetes mellitus (T2DM) patients who underwent gastric bypass (GBP) and to establish a prognostic model for risk stratification. We evaluated the baseline clinical features of patients with T2DM who received at Beijing Tian Tan Hospital from April 2012 to December 2015. Complete remission of T2DM was defined as meeting the following criteria: HbA1c < 6.5%, fasting plasma glucose (FPG) < 100mg/dL, and absence of hypoglycemic drugs for 1year following GBP. A total of 101 patients were enrolled in our study, and the complete remission rate of T2DM was 70.3% (71/101). Compared with patients with incomplete remission, patients with complete remission of T2DM had higher C-peptide levels, lower HbA1c, shorter disease duration, better β cell function, and an absence of insulin therapy. HbA1c level, fasting C-peptide, duration of T2DM, and history of medical therapy were important prognostic factors for complete remission of T2DM (P= 0.001, 0.002, 0.01, 0.028, respectively). Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5years, fasting C-peptide higher than 1.2ng/mL, and absence of insulin therapy before GBP achieved a higher complete remission rate of T2DM after GBP (AUC of the model was 0.825, 95% CI, 0.741-0.910; P= 0.001). The duration of T2DM, history of medical therapy, and levels of HbA1c and fasting C-peptide are independent predictors for the prognosis of T2DM patients undergoing GBP. Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5years, a fasting C-peptide higher than 1.2ng/mL, and an absence of insulin therapy may have a higher complete remission rate of T2DM after GBP.

A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations

PurposeTo investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY.MethodsWe examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation.ResultsConcentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients.ConclusionsPlasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.

Probing the Meaning of Persistent Propeptide Release in Type 1 Diabetes.

Type 1 diabetes is well recognized to be immune mediated, resulting in destruction of β-cells. That this eradication is not always complete was evident in an early report from the Diabetes Control and Complications Trial (DCCT) showing that 11% of adult participants with type 1 diabetes for more than 5 years had measurable C-peptide in the fasting state and following mixed-meal stimulation, while no adolescents had evidence of such (1). Further, in participants with measurable C-peptide responses, C-peptide declined in all after a year of randomized therapy, with this decline being less in those who received intensive insulin therapy. Subsequently, it was shown in adolescents that 2 weeks of intensive insulin therapy, compared with conventional therapy, resulted in improved β-cell function a year later along with superior glucose control (2). In addition to C-peptide, proinsulin has also been shown to be circulating in individuals with type 1 diabetes at the time of diagnosis and to be still measurable 30 months later (3,4). Thus, there is long-standing evidence that at the time of diagnosis and subsequently, individuals with type 1 diabetes have β-cells still capable of synthesizing proinsulin, and many can process it to C-peptide and insulin. In the current issue of Diabetes Care , Sims et al. (5) report longitudinal findings on proinsulin secretion in type 1 diabetes using a large number of samples from the T1D Exchange. They divided their subjects into three groups based on stimulated C-peptide responses to a mixed meal. We have categorized these groups as having absent, intermediate, and high C-peptide responses, although the latter are a great deal lower than what is observed in healthy people. Individuals in the absent group had C-peptide responses that were below the reliable lower detection limit of the assay, and they were not studied further. These …

Level of Fasting C-Peptide as a Predictor of &amp;lt;i&amp;gt;β&amp;lt;/i&amp;gt;-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.

Autoimmune hypoglycaemia caused by alpha-lipoic acid: a rare condition in Caucasian patients.

SummaryInsulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions.Learning points:IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients.It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery.It should be suspected in the presence of very high serum insulin levels (100–10 000 μU/mL) associated with high C-peptide levels.There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

Spontaneously remitting insulin autoimmune syndrome in a patient taking alpha-lipoic acid.

SummaryInsulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS.Learning points:Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid.Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available.The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

High fasting C-peptide levels and insulin resistance in non-lean & non-obese (BMI >19 to < 25 kg/m2) Asian Indians with type 2 diabetes are independently associated with high intra-abdominal fat and liver span

Background and objectivesWe aimed to compare C-peptide levels & measures of insulin resistance in non-lean & non-obese Asian Indian patients with type 2 diabetes (T2DM) vs. non-lean, non-diabetic controls and to correlate with anthropometric measures, volumes of abdominal adipose tissue depots, pancreas, & liver span. MethodsNon-lean, non-obese (BMI >19 and < 25 kg/m2) Asian Indian patients with T2DM, (cases n, 87), diagnosed within one year, on metformin mono therapy, were compared to BMI-matched non-diabetic subjects (controls, n, 37). Measures of glycaemia, insulin and C-peptide levels (fasting and post-prandial), lipid profile, and hepatic transaminases were analysed. Abdominal adipose tissue volumes [subcutaneous & intra-abdominal], pancreatic volume and liver span were assessed using 1.5 Tesla MRI scan. ResultsIn cases, the mean values of HbA1c, fasting and post prandial insulin and C-peptide levels, and 3 measures of insulin resistance were significantly higher than controls, but not for HOMA-B. Higher fasting C-peptide levels correlated significantly with HOMA-IR (r = 0.42, p < 0.001), Fasting Insulin Resistance Index (r = 0.42, p < 0.001), Bennett's Index (r = 0.38, p < 0.05), and volumes of SCAT and IAAT only in cases. The independent predictors of higher fasting C-peptide level were IAAT volume (β = 0.057; p = 0.002), liver span (β = 0.057, p = 0.005) and fasting insulin levels (β = 0.35, p = 0.02). ConclusionHigher fasting and post-prandial C-peptide levels and surrogate measures of insulin resistance in non-obese Asian Indian patients with T2DM are independently associated with IAAT volume and liver span.

C-peptide levels do not correlate with pancreas allograft failure: Multicenter retrospective analysis and discussion of the new OPT definition of pancreas allograft failure.

The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n=415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75ng/mL who had a posttransplant C-peptide value available (n=61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure.

Trajectories of body fatness from age 5 to 60 y and plasma biomarker concentrations of the insulin–insulin-like growth factor system

A major pathway through which obesity increases the risk of cardiometabolic diseases and cancer is by inducing hormonal and metabolic abnormalities, including hyperinsulinemia and altered insulin-like growth factor (IGF) signaling. However, little is known about the influence of lifetime adiposity on the relevant biomarkers. The aim of this study was to examine associations of trajectories of body fatness with plasma biomarker concentrations of the insulin-IGF system in 2 large prospective cohorts of US men and women. Associations between trajectories of body fatness and concentrations of plasma C-peptide, IGF-I, IGF-binding protein (IGFBP) 1, IGFBP-3, and the IGF-I-to-IGFBP-3 molar ratio was examined in 9386 women of the Nurses' Health Study and 3941 men of the Health Professionals Follow-Up Study. Group-based trajectory modeling was used to create trajectory groups on the basis of self-reported somatotype data at ages 5, 10, 20, 30, and 40 y and body mass index (BMI) at ages 45, 50, 55, and 60 y. We used multivariate linear regression models to examine the associations of trajectories with biomarker concentrations. Five trajectories of body fatness were identified: "lean-stable," "lean-moderate increase," "lean-marked increase," "medium-stable/increase," and "medium-marked increase." Compared with the lean-stable group, the lean-marked increase and medium-marked increase groups had significantly higher concentrations of C-peptide (percentage difference-women: 44% and 73%; men: 27% and 51%) and lower concentrations of IGFBP-1 (women: -61% and -78%; men: -47% and -65%). Adjustment for current BMI attenuated the association to null for the medium-marked increase group, but the lean-marked increase group still had modestly higher concentrations of C-peptide (women: 10%; men: 6%) and lower concentrations of IGFBP-1 (women: -18%; men: -21%) than the lean-stable group. Adiposity across the life span was associated with higher C-peptide and lower IGFBP-1 concentrations in adulthood. The associations were largely driven by attained adiposity and, to a lesser extent, weight gain in early-middle adulthood. This trial was registered at www.clinicaltrials.gov as NCT03419455.

C-peptide prevents SMAD3 binding to alpha promoters to inhibit collagen type IV synthesis

Activation of transforming growth factor β1 (TGFB1)/SMAD3 signaling may lead to additional synthesis of collagen type IV (COL4), which is a major contributor to extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). C-peptide can attenuate fibrosis to have unique beneficial effects in DN. However, whether and how C-peptide affects TGFB1/SMAD3-activated COL4 synthesis is unclear. In this study, pathological changes, expression of COL4 a1-a5 chains (Col4a1-a5), COL4 distribution and protein and TGFB1 and SMAD3 protein were first assessed in a rat model of diabetes. Then, rat mesangial cells were treated with high glucose (HG) and/or C-peptide to investigate the underlying mechanism. Col4a1-a5 expression, COL4 protein and secretion, TGFB1 protein, SMAD3 nuclear translocation and binding of SMAD3 to its cognate sites in the promoters of Col4a1a2, Col4a3a4 and Col4a5 were measured. It was found that C-peptide attenuated glomerular pathological changes and suppressed renal Col4a1-a5 mRNA expression, COL4 protein content and TGFB1 protein content. C-peptide had a dose-dependent effect to inhibit Col4a1-a5 mRNA expression, COL4 protein content and secretion, in HG-stimulated mesangial cells. In addition, the HG-induced increase in TGFB1 protein content was significantly reduced by C-peptide. Although not apparently affecting SMAD3 nuclear translocation, C-peptide prevented SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters in HG-stimulated mesangial cells. In conclusion, C-peptide could prevent SMAD3 from binding to its sites in the Col4a1a2, Col4a3a4 and Col4a5 promoters, to inhibit COL4 generation. These results may provide a mechanism for the alleviation of fibrosis in DN by C-peptide.

Genotypic Associations with C-Peptide Persistence in People with Type 1 Diabetes

There is substantial variation in C-peptide levels in those with clinically diagnosed type 1 diabetes (T1DM). We examined the association of C-peptide levels with genotypic risk scores (GRS) for T1DM and T2DM in 5856 genotyped people diagnosed with T1DM and requiring insulin within 1 year of diagnosis (the SDRNT1BIO). Region-specific GRS and residual genome wide scores for T1DM and T2DM were computed based on publicly available summary GWAS data. Total genome wide scores were the sum of the residual and region specific scores. C-peptide was measured using a Roche ultrasensitive immunoassay on untimed serum. Overall 39% had detectable C-peptide (≥5 pmol/L) with prevalence being highest with older age of onset (p=6.9x10-05) and shorter duration (p=1.8x10-10). Heritability was 0.31 for age at onset and 0.26 for C-peptide adjusted for sex and age at onset. Lower T1DM genome-wide score and higher T2DM score were positively associated with C-peptide level, associations that were stronger with older age at onset (p=4.9x10- for T1DM score, p=0.009 for T2DM score interactions with age at onset). The T1DM and T2DM GRS were uncorrelated except at the HLA region. Most T1DM region specific scores were lower with increasing age at onset in particular at the HLA (p=3.2x10-34), INS (1.9x10-05) CTSH (9.1x10-06) and IKZF1 (p=0.0001) regions. Adjusted for age at onset, higher C-peptide level was also associated with lower T1DM GRS at the HLA (p=9.8x10-17) and INS (p=2.7x10-06) regions. Most T2DM region specific scores were higher with older age at onset and adjusted C-peptide except a T2DM associated HLA region score which was lower at higher age of onset (p=1.7x10-17) and higher C-peptide (p=1.1x10-09). These results show that in people diagnosed with T1DM, especially at older ages, the variation in persistence of C-peptide secretion in part reflects a continuous spectrum of genetic risk for T1DM and T2DM. The lack of correlation in T1DM and T2DM GRS is in keeping with this continuum rather than “misdiagnosis” of T1DM as T2DM. Disclosure P. McKeigue: Stock/Shareholder; Self; Bayer AG, Roche Pharma. A. Spiliopoulou: None. S. McGurnaghan: None. M. Colombo: None. T.J. McDonald: None. H. Colhoun: Research Support; Self; AstraZeneca, Boehringer Ingelheim GmbH. Stock/Shareholder; Self; Bayer AG. Research Support; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Eli Lilly and Company. Other Relationship; Self; Eli Lilly and Company. Advisory Panel; Self; Novartis Pharmaceuticals Corporation. Research Support; Self; Regeneron Pharmaceuticals, Inc.. Advisory Panel; Self; Regeneron Pharmaceuticals, Inc.. Speaker's Bureau; Self; Regeneron Pharmaceuticals, Inc.. Other Relationship; Self; Regeneron Pharmaceuticals, Inc.. Research Support; Self; Pfizer Inc., Roche Pharma. Stock/Shareholder; Self; Roche Pharma. Research Support; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi. Research Support; Self; Novo Nordisk Inc..

Ethnicity and Common Genetic Variants Modulate Nonalcoholic Fatty Liver Disease (NAFLD) Metabolic Phenotype in Obese Youth

Background: Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) represents a major risk factor for insulin resistance and type 2 diabetes in adolescents. Methods: To characterize the clinical and genetic features associated with the development of pediatric NAFLD, 503 obese adolescents (191 Caucasians, 134 African Americans, and 178 Hispanics) underwent a MRI to quantify hepatic fat content, an oral glucose tolerance test to assess glucose tolerance and insulin sensitivity, and the genotyping of three SNPs associated with NAFLD (PNPLA3 rs738409, GCKR rs1260326, and TM6SF2 rs58542926). MRI and metabolic assessments were repeated in 133 patients after 2.27±1.44 years. Results: The prevalence of NAFLD was 42.9% in Caucasians, 15.7% in African Americans, and 59.6% in Hispanics (p&amp;lt;0.0001). Compared to Caucasians and Hispanics with NAFLD, African Americans adolescents with NAFLD had higher fasting glucose (p=0.03), insulin (p=0.0004), C-peptide (p=0.04), 2-h-glucose (p=0.04), HbA1c (p&amp;lt;0.0001), and lower insulin sensitivity (p=0.03), despite similar age (p=0.34) and gender distribution (p=0.37). This translated in a higher prevalence of prediabetes and type 2 diabetes in African Americans (66.6%) compared to Caucasians (24.4%) and Hispanics (31.1%) with NAFLD (p=0.0003). Analysis of the patients without NAFLD at baseline showed that ethnicity (p=0.02), high C-peptide levels (p=0.0006), changes in z-score BMI over time (p=0.0006) and common gene variants were strong predictors of NAFLD development at follow-up (AUROC curve 0.976). Conclusions: African American obese adolescents are relatively protected from NAFLD, but are more susceptible to the deleterious effects of NAFLD on glucose metabolism. The combination of ethnicity, markers of insulin resistance and genetic factors are strong predictors of pediatric NAFLD. Disclosure D. Trico: None. S. Caprio: None. G.R. Umano: None. A. Galderisi: None. M.M. Mata: None. J. Nouws: None. B. Pierpont: None. G. Kim: None. N. Santoro: None.

A Comparison of HbA1c and Index 60 Thresholds for Identifying Autoantibody Positive Individuals at High Risk for Type 1 Diabetes (T1D)

Current ADA standards include HbA1c values 5.7%-6.4% as an indicator of prediabetes. However, there is little information with regard to HbA1c as a specific predictor of T1D. We thus compared HbA1c with Index 60, a T1D marker, for identifying individuals at high risk for T1D. Index 60 was derived from a proportional hazards regression model for T1D that included log fasting C-peptide, 60-minute glucose, and 60-minute C-peptide. Diabetes Prevention Trial-type 1 participants with Index 60&amp;lt;2.00 at baseline were followed for the first (incident) OGTT exceeding an Index 60≥2.00 threshold (n=85). Similarly, those with HbA1c values &amp;lt;6.0% at baseline were followed for the first (incident) HbA1c ≥6.0% (n=77). Those with both incident Index 60≥2.00 and incident HbA1c ≥6.0 were excluded. At the incident OGTTs, those with HbA1c ≥6.0 were older (19.2±12.2 years vs. 12.7±7.2 years; p&amp;lt;0.001). The cumulative incidence for T1D was higher (log rank p&amp;lt;0.001) after Index 60≥2.00 than after HbA1c ≥6.0 (3- and 4-year risks for HbA1c ≥6.0: 0.41 and 0.45; 28/77 diagnosed vs. 3- and 4-year risks for Index 60≥2.00: 0.78 and 0.92; 60/85 diagnosed). The hazard ratio for Index 60≥2.00 vs. HbA1c ≥6.0 (with age adjustment) was significant [HR: 1.96 (1.20, 3.16); p=0.006]. Intervals from incident Index 60≥2.00 and HbA1c ≥6.0 to diagnosis were 1.2±0.9 (0.1-3.8) years and 1.0±1.0 (0-4.7) years, respectively (p=0.50). The 59 individuals who had OGTTs on the date of incident HbA1c ≥6.0 had higher 30-0 minute C-peptide (with age adjustment) than those with incident Index 60≥2.00 (2.8±1.9 ng/ml vs. 1.6±1.0 ng/ml; p&amp;lt;0.001). In conclusion, Index 60≥2.00 was superior to HbA1c ≥6.0 at identifying individuals at high risk for T1D. Moreover, those with incident HbA1c ≥6.0 were much older with higher C-peptide levels, suggesting heterogeneity. These findings add support for including C-peptide together with glucose in developing predictors and pre-diagnostic endpoints that are specific for T1D. Disclosure L.M. Jacobsen: None. H.M. Ismail: None. M.A. Clements: Speaker's Bureau; Self; Medtronic. Advisory Panel; Self; Glooko, Inc.. D. Schatz: None. J. Sosenko: None.

Novel insights into the puberty switch mechanisms of the sex bias in human asthma

Abstract The gender bias in human asthma prevalence changes with puberty, with males having a higher asthma incidence before puberty and females having higher rates after. The mechanisms involved in this switch are unknown. Our previous research showed that multiple hormonal systems are dysregulated in allergic disease. Because sex hormones interact with all endocrine system axes, we hypothesized that non-sex hormones and their downstream functions in allergic disease are driven by sex related changes in puberty. Measuring non-sex hormone protein levels from human serum samples by multiplex ELISAs, we found a striking sexual dimorphism in endocrine regulation. Pre-puberty asthmatic males had higher T3, T4, and GH levels compared to healthy controls, and pre-puberty asthmatic females had lower C-peptide and insulin levels. Interestingly, we saw the opposite pattern post-puberty. In a kinetic murine ovalbumin asthma model, adult male mice had higher C-peptide and insulin baseline levels, which were maintained during inflammation. Males also had higher GIP levels in the acute phase and higher PP, PYY, and resistin levels in the model’s late phase. Since hormones regulate tissue homeostasis, we examined the puberty switch in key epithelial remodeling markers in the inflamed mouse lung. Thbs2, Nes, Postn, Tnc, and Wnt5a expression was different relative to baseline in both sexes pre-puberty, but only females had altered expression of these markers post-puberty. Interestingly, though the Th2 immune response was higher in females post-puberty, there was no sexual dimorphism pre-puberty. These results implicate that sex hormones exert systemic level regulation determining the age and gender dependent progression of asthma pathogenesis.

METABOLIC ASPECTS OF ACUTE stage ISCHEMIC STROKE

Aim. To study the influence of hyperglycemia on the course of ischemic stroke in its acute period. Materials and methods. 116 patients with primary ischemic stroke, associated with arterial hypertension, and with no diabetes mellitus in anamnesis were examined. Fasting blood glucose, glycolyzed hemoglobin, immunoreactive insulin and C-peptide levels were determined. Results. Raised levels of glycemia to 5.31 ± 0.68 mmol/l, C-peptide to 0.90 ± 0.31 nmol/l and decreased level of insulin to 9.38 ± 4.34 mcIU/ml were detected. C-peptide to insulin ratio values were reliably higher in patients with severe course of stroke (by 35.6 %, p &lt; 0.05) and unfavorable outcome of disease (by 39.6 %, p &lt; 0.05). Conclusions. Development of ischemic stroke is accompanied by high blood C-peptide levels against the background of normo-and-hypoinsulinemia, hyperglycemia. Manifestation of disorders is connected with severity and clinical outcome of this disease.