Decrease In C-peptide Research Articles

Diagnosis and treatment of allograft rejection in islet transplantation

Islet transplantation stabilizes glycemic control in patients with complicated diabetes mellitus. Rapid functional decline could be due to islet allograft rejection. However, there is no reliable method to assess rejection, and treatment protocols are absent. We aimed to characterize diagnostic features of islet allograft rejection and assess effectiveness of high-dose methylprednisolone treatment. Over a median follow-up of 61.8 months, 22% (9 of 41) of islet transplant recipients experienced 10 suspected rejection episodes (SREs). All first SREs occurred within 18 months after transplantation. Important features were unexplained hyperglycemia (all cases), unexplained C-peptide decrease (ΔC-peptide, 77.1% [−59.1% to −91.6%]; ΔC-peptide:glucose, −76.3% [−49.2% to −90.4%]), predisposing event (5 of 10 cases), and increased immunologic risk (5 of 10 cases). At 6 months post-SRE, patients who received protocolized methylprednisolone (n = 4) had significantly better islet function than untreated patients (n = 4), according to C-peptide (1.39 ± 0.59 vs 0.14 ± 0.19 nmol/L; P = .007), Igls score (good [4 of 4 cases] vs failure [3 of 4 cases] or marginal [1 of 4 cases]; P = .018) and β score (6.0 [6.0-6.0] vs 1.0 [0.0-3.5]; P = .013). SREs are prevalent among islet transplant recipients and are associated with loss of islet graft function. Timely treatment with high-dose methylprednisolone mitigates this loss. Unexplained hyperglycemia, unexpected C-peptide decrease, a predisposing event, and elevated immunologic risk are diagnostic indicators for SRE.

The Transition From a Compensatory Increase to a Decrease in C-peptide During the Progression to Type 1 Diabetes and Its Relation to Risk.

To define the relationship between glucose and C-peptide during the progression to type 1 diabetes (T1D). We longitudinally studied glucose and C-peptide response curves (GCRCs), area under curve (AUC) for glucose, and AUC C-peptide from oral glucose tolerance tests (OGTTs), and Index60 (which integrates OGTT glucose and C-peptide values) in Diabetes Prevention Trial-Type 1 (DPT-1) (n = 72) and TrialNet Pathway to Prevention Study (TNPTP) (n = 82) participants who had OGTTs at baseline and follow-up time points before diagnosis. Similar evolutions of GCRC configurations were evident between DPT-1 and TNPTP from baseline to 0.5 years prediagnosis. Whereas AUC glucose increased throughout from baseline to 0.5 years prediagnosis, AUC C-peptide increased from baseline until 1.5 years prediagnosis (DPT-1, P = 0.004; TNPTP, P = 0.012) and then decreased from 1.5 to 0.5 years prediagnosis (DPT-1, P = 0.017; TNPTP, P = 0.093). This change was mostly attributable to change in the late AUC C-peptide response (i.e., 60- to 120-min AUC C-peptide). Median Index60 values of DPT-1 (1.44) and TNPTP (1.05) progressors to T1D 1.5 years prediagnosis (time of transition from increasing to decreasing AUC C-peptide) were used as thresholds to identify individuals at high risk for T1D in the full cohort at baseline (5-year risk of 0.75-0.88 for those above thresholds). A transition from an increase to a decrease in AUC C-peptide ∼1.5 years prediagnosis was validated in two independent cohorts. The median Index60 value at that time point can be used as a pathophysiologic-based threshold for identifying individuals at high risk for T1D.

Carbohydrate metabolism in patients after pancreatoduodenal resection

Introduction. Pancreatic resection is a common surgical treatment option for chronic pancreatic diseases. Diabetes mellitus, which develops as a result of surgical interventions on the pancreas, belongs to a specific type – pancreatogenic. To assess the state of carbohydrate metabolism in patients after surgery in the volume of pancreatoduodenal resection (PDR), a retrospective single-stage single-center study was performed.Aim. Assessment of the state of carbohydrate metabolism in patients after surgery in the volume of PDR.Materials and methods. In Botkin City Clinical Hospital 70 case histories of patients who underwent PDR were selected. The reason for the PDR was pancreatic head cancer (55 people), chronic pancreatitis (7 people), chronic calculous pancreatitis (8 people). Data on age, gender, date of surgery, glycemia levels before and after surgery, as well as C-peptide, insulin, and HbA1c were analyzed.Results. Out of 70 people in the initial group, diabetes mellitus was diagnosed before surgery in 8 people or in 11.5% of the entire sample. Indicators of carbohydrate metabolism did not differ significantly from each other. However, the level of C-peptide decreased in all patients, while in the group of patients with malignant tumors of the pancreas, despite the decrease in C-peptide, the level of fasting glycemia also decreased.Conclusion. If before the operation diabetes mellitus was diagnosed in 11.5% of patients, then after the operation the diagnosis of diabetes mellitus was established in 23.6%. Late detection of diabetes mellitus worsens not only the quality of life of patients, but also the overall prognosis, morbidity, and tolerability of chemotherapy. Obviously, the postoperative monitoring algorithm should include regular monitoring of glycemia, glycated hemoglobin at least once a year with normoglycemia in order to early diagnose carbohydrate metabolism disorders and prescribe therapy.

Assessment of circulating fibrotic proteins (periostin and tenascin -C) In Type 2 diabetes mellitus patients with and without retinopathy.

Diabetic retinopathy is a leading cause of vision impairment. Surging diabetic population and poor visual care raises the need for better diagnostic tools. Hence, it is worthwhile to look for biomarkers associated with the disease pathogenesis. Periostin and tenascin-C are matricellular proteins mediating fibrillogenesis in retinopathy. Their serum levels and association with the presence and severity of retinopathy in diabetics is of importance to be explored. The study involved two groups of type 2 diabetes patients, 38 controls without retinopathy and 38 cases with retinopathy. We obtained serum sample and performed biochemical autoanalysis for routine parameters. Special parameters periostin, tenascin-C, and C-peptide were estimated by ELISA. Periostin and tenascin-C were significantly elevated in the retinopathy group. Periostin progressively increased among subgroups. C-peptide decreased significantly in retinopathy group and had a negative correlation with duration of DM, duration of retinopathy, HbA1c and tenascin-C. We observed a positive correlation for periostin and tenascin-C with duration of diabetes. The AUC for C-peptide was the highest (0.750) amongst our parameters. HOMA 2 (%B) index was significantly lower in retinopathy group. Serum Levels of PO and TnC increased in retinopathy. As the disease advances, periostin level increases, indicating continuing fibrosis and fibrovascular membrane formation. Periostin and tenascin-C increase with duration of retinopathy whereas levels of C-peptide decrease. C-peptide has a better differentiating potential for DR from DM. Reduced insulin production as indicated by declined HOMA 2-%BETA in retinopathy favors hyperglycemia and chronic inflammatory state for the disease progression.

A decrease in plasma glucose levels is required for increased endogenous glucose production with a single administration of a sodium-glucose co-transporter-2 inhibitor tofogliflozin.

To investigate whether changes in endogenous glucose production (EGP) and insulin and glucagon levels are elicited by the decrease in plasma glucose (PG) levels induced by the sodium-glucose co-transporter-2 (SGLT2) inhibitor tofogliflozin. We evaluated EGP in 12 Japanese patients with type 2 diabetes under the conditions of no drugs administered (CON), single administration of the SGLT2 inhibitor tofogliflozin (TOF), and single administration of TOF with adjustment of PG levels with exogenous glucose infusion to mimic changes in PG levels observed with CON (TOF + G). We evaluated changes in EGP and levels of C-peptide and glucagon from baseline to 180 minutes after drug administration. Endogenous glucose production decreased in the CON (-0.22 ± 0.11 mg/kg·min) and TOF + G experiments (-0.31 ± 0.24 mg/kg·min), but not in the TOF experiment (+0.08 ± 0.19 mg/kg·min). The decrease in C-peptide was significantly greater in the TOF experiment (-0.11 ± 0.06 nmol/L) than in the CON (-0.03 ± 0.06 nmol/L) and the TOF + G experiments (-0.01 ± 0.11 nmol/L), while the increase in glucagon was significantly greater in the TOF experiment (+11.1 ± 6.3 pmol/L), but not in the TOF + G experiment (+8.6 ± 7.6 pmol/L) compared to the CON experiment (+5.1 ± 4.3 pmol/L). These results indicate that the decrease in PG levels induced by SGLT2 inhibitor administration is required for the increase in EGP and decrease in insulin secretion.

A carbohydrate-restricted diet for patients with irritable bowel syndrome lowers serum C-peptide, insulin, and leptin without any correlation with symptom reduction

Alterations in gut endocrine cells and hormone levels have been measured in patients with irritable bowel syndrome (IBS). The hypothesis of the present study was that hormone levels would change after 4 weeks of a starch- and sucrose-reduced diet (SSRD) intervention corresponding to decreased carbohydrate intake and symptoms. Among 105 IBS patients from primary and tertiary healthcare, 80 were randomized to SSRD, while 25 followed their ordinary diet. Food diaries, Rome IV, and IBS-symptom severity score (IBS-SSS) questionnaires were completed, and blood samples were collected at baseline and after the intervention. Serum C-peptide, gastric inhibitory peptide, glucagon, glucagon-like peptide-1, insulin, leptin, luteinizing hormone, polypeptide YY, and glucose were measured, along with the prevalence of autoantibodies against gonadotropin-releasing hormone; its precursor, progonadoliberin-2, and receptor; and tenascin C. Carbohydrate intake was lower in the intervention group than in controls at week 4 (median: 88 [66-128] g vs 182 [89-224] g; P < .001). The change in carbohydrate intake, adjusted for weight, was associated with a decrease in C-peptide (β: 14.43; 95% confidence interval [CI]: 4.12-24.75) and insulin (β: 0.18; 95% CI: 0.04-0.32) levels. Glucose levels remained unchanged. The IBS-SSS scores were lower in the intervention group but not in controls (P < .001), without any association with changes in hormone concentrations. There was no difference in autoantibody prevalence between patients and healthy controls. In conclusion, the hypothesis that reduced carbohydrate intake corresponded to altered hormonal levels in IBS was accepted; however, there was no relationship between hormonal concentrations and symptoms.

Prospective association of physical activity and inflammatory biomarkers in older adults from the PREDIMED-Plus study with overweight or obesity and metabolic syndrome.

There is limited prospective evidence on the association between physical activity (PA) and inflammation in older adults. Our aim was to assess the associations between changes in PA and changes in the inflammatory profile in older individuals who are overweight or obese. This prospective study included 489 men and women, aged 55-75 years, from the PREDIMED-Plus trial. Levels of interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 18 (IL-18), monocyte chemo-attractant protein-1 (MCP-1), C-peptide, high-sensitivity C-reactive protein (hs-CRP), leptin, and regulated on activation, normal T-cell expressed and secreted chemokine (RANTES) were obtained from fasting blood samples and a composite inflammatory score based on these biomarkers was calculated. Physical activity was measured by a validated questionnaire. All measures were taken at baseline and one-year follow-up. Multiple linear regression models showed an association between an increase in total PA and a decrease in the inflammatory score (p=0.012), which was particularly driven by a decrease in C-peptide (p=0.037). Similarly, the inflammatory score decreased with increasing moderate PA (p=0.001), and moderate-to-vigorous PA (p=0.006). Increases in total PA, moderate and moderate-to-vigorous PA were associated with a decrease in the inflammatory profile of obese or overweight older individuals. This finding is relevant for PA recommendations and public health strategies. Clinical trial identifier: International Standard Randomized Controlled Trial 89898870.

Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats

In type 1 diabetes mellitus, the levels of insulin and C-peptide decrease at the periphery and in CNS. C-peptide potentiates the regulatory effects of insulin. We studied the effects of single and repeated (over 7 days) individual and combined nasal administration of C-peptide (10 μg/day) and insulin (20 μg/day) on activity of Akt kinase and kinase-3β-glycogen synthase (GSK3β), the components of 3-phosphoinositide pathway, in the hypothalamus of intact rats and rats with mild streptozotocin-induced type 1 diabetes mellitus. Phosphorylation of Akt kinase at Thr308 and Ser473 (stimulation) and GSK3β at Ser9 (inhibition) was evaluated. In diabetes, phosphorylation of Akt kinase and, to a lesser extent, GSK3β, is reduced. A single injection of insulin or C-peptide and insulin increased this process. Long-term combined treatment with C-peptide and insulin normalized activity of Akt kinase and GSK3β in diabetic rats, treatment with insulin alone produced less pronounced effect; monotherapy with C-peptide was ineffective. Intranasal co-administration of C-peptide and insulin effectively stimulates the insulin system in the hypothalamus that is weakened at diabetes mellitus type 1, which can be used in the treatment of this disease.

C-Peptide Suppression During Insulin Infusion in the Extremely Preterm Infant Is Associated With Insulin Sensitivity.

Little is known about the individual response of glucose-regulating factors to administration of exogenous insulin infusion in extremely preterm infants. To evaluate longitudinal serum concentrations of insulin, C-peptide, and plasma glucose levels in a high-frequency sampling regimen in extremely preterm infants treated with insulin because of hyperglycemia. Prospective longitudinal cohort study. Two university hospitals in Sweden between December 2015 and September 2016. Serum samples were obtained from nine extremely preterm infants, gestational age between 22 (+3) and 26 (+5) weeks (+ days), with hyperglycemia (plasma-glucose >10 mmol/L) at the start of insulin infusion, at 12, 24, and every 24 hours thereafter during ongoing infusion, and 12, 24, and 72 hours after the end of insulin infusion. Longitudinal serum concentrations of insulin and C-peptide and plasma glucose levels. During insulin infusion, the serum C-peptide concentrations decreased compared with at start of infusion (P = 0.036), and then increased after ending the infusion. Individual insulin sensitivity based on the nonfasting plasma glucose/insulin ratio at the start of insulin infusion correlated with the initial decrease in serum ΔC-peptide[after 12h] (P = 0.007) and the degree of lasting decrease in serum ΔC-peptide[after end of infusion] (P = 0.015). Exogenous insulin infusion suppressed the C-peptide concentration to individually different degrees. In addition, the effect of insulin infusion on β cells may be linked to individual insulin sensitivity, where a low insulin sensitivity resulted in a more pronounced decrease in C-peptide during insulin infusion.

Role of sex in post-transplant diabetes mellitus development: Are men and women equal?

IntroductionSex differences are defined as biology-linked differences between women and men that occur through the sex chromosomes and their effects on organ systems. Material and methodsThe objective of this prospective study was to determine risk factors for post-transplant diabetes mellitus (PTDM) in men and women. ResultsA total of 417 patients (271 men and 146 women) were included in the monitored group. Age at the time of kidney transplantation (KT) >60 years and hypovitaminosis D at the time of KT (<20 μg/l) were identified as independent risk factors for PTDM in both men and women. It was further confirmed as an independent risk factor for men a waist circumference at the time of KT >94 cm, C-peptide at the time of KT >5 ng/ml, HOMA-IR >2 and triacylglycerols at the time of KT >1.7 mmol/l. In case of women, the dominant factor was BMI at the time of KT >30 kg/m2 and menopause at the time of KT. A significant decrease in C-peptide was recorded in women with PTDM. ConclusionIt was confirmed that there are gender differences with regard to the development of PTDM after KT. Women show pancreas β cell dysfunction, whereas insulin resistance and metabolic syndrome are dominant in men.

Role of Coconut Oil and Vitamin D in Alleviating Glucose, C-peptide and Histological Alterations in the Hepatic Tissues of Hyperglycemic albino rats

The purpose of the present study is to evaluate the effect of either vitamin D or coconut oil or both together on the histological changes of the hepatic tissues of diabetic adult male albino rats induced by using streptozotocin (STZ). The rats were divided into 7 equal groups (10 rats/each). The duration of the experiment was 4 weeks. Gp.I: normal control rats group without any treatments. Gp.II & Gp.III: non-diabetic rat groups received coconut oil in a dose of 7.5 ml /kg b.w/daily or vitamin D orally in a daily dose of 500 IU/kg b.w/daily, respectively. Gp. IV: diabetic rats group injected i.p. with a single dose of STZ dissolved in saline solution in a dose of 60 mg/kg b.w to induce diabetes. Gps.V, VI & VII: diabetic rats administered orally at the same previous doses with coconut oil or vitamin D or both together. The results recorded non-significant changes in the blood glucose and C-peptide levels of non-diabetic group. Significant increase in blood glucose level and a significant decrease in C-peptide of diabetic group as compared to the normal control ones. Diabetic group that received the coconut oil or vitamin D recorded a decrement in blood glucose levels and an increment in C-peptide; while the diabetic rats co-administered with vitamin D and coconut oil recorded a highly significant decrease in blood glucose levels and a highly significant increase in C-peptide as compared to diabetic group. Histologically, the rats of normal control group or that received either coconut oil or vitamin D showed normal structure of the liver tissue with H&E stain. The liver lobules are roughly hexagonal, and consist of plates of hepatocytes radiating from a central vein. The central vein joins to hepatic vein to carry blood out from liver. Between the hepatocyte plates are liver sinusoids, which are lined with two types of cells sinusoidal endothelial cells and phagocytic Kupffer cells. The diabetic rats demonstrated many histopathological changes in the liver tissue included loss of normal liver architecture, degeneration of hepatocytes, appearance of pyknotic nuclei, dilated and congested of central vein surrounded by fibrosis, dilation of hepatic sinusoids, proliferation of Kupffer cells, and infiltration of leucocytes. The diabetic rats administered with either coconut oil or vitamin D elucidated improvement of liver histology, few pyknotic nuclei were seen, slight dilatation in sinusoids and decrement of inflammatory cells. While diabetic rats given both coconut oil and vitamin D together detected obvious improvement in the liver structure with the appearance of normal hepatocytes.

Transient Hyperglycemia Alters Pancreatic Function and Peripheral Insulin Signaling in Preterm Baboons

Background: Premature infants develop transient hyperglycemia and insulin resistance. Hyperglycemia is not treated by intensivists to avoid caloric restriction and promote growth. Objective: To determine the effects of transient hyperglycemia on endocrine pancreas, skeletal muscle and liver at early stages of development in preterm baboons. Methods: Baboons were delivered prematurely (67% gestation; n=6) via c-section and ventilated for 14 days or sacrificed immediately after birth (n=6). Preterm ventilated animals were randomly assigned to tight glucose control (EUG; serum glucose 50-100mg/dL) or hyperglycemia (HYPER; serum glucose 150-250 mg/dL) from day of life (DOL) 0-5; tight glucose control thereafter. Hyperglycemic (HG) clamps were performed on DOL6 and DOL14. IHC was done for α-β-δ cells in pancreas tissue. Muscle and liver mRNA expression and protein content of key insulin signaling molecules were measured. Results: HYPER baboons had higher serum glucose compared to EUG (183±61 vs. 69±24 mg/dL, p&amp;lt;0.01) from DOL 0-5, and similar glucose from DOL 6-14. During the HG clamps, HYPER baboons had abnormally increased insulin secretion (2.7 fold, p&amp;lt;0.05) on DOL6, but normalized by DOL14. C-peptide was abnormally increased (3.3 fold, p&amp;lt;0.05) on DOL6; by DOL14 the same HYPER animals had a 38% decrease in c-peptide as compared to EUG (p=0.07). The α/β cell area was decreased in HYPER animals. Akt content was increased in the liver of HYPER baboons (2.8 fold, p&amp;lt;0.01) whereas IR/IRS and PEPCK-C didn’t change. Skeletal muscle GLUT1 was 70% decreased in HYPER animals (p&amp;lt;0.01); INSR, IRS-1, Akt and mitochondrial oxygen consumption were similar. Conclusion: Premature baboons exposed to transient hyperglycemia have an initial abnormal increase in insulin/c-peptide secretion followed by a decrease in c-peptide secretion a week later; alterations in α and β cell percent area are found at necropsy. Insulin signaling molecules are altered in liver/skeletal muscle of HYPER preterm baboons. Disclosure C. Blanco: None. A. Quinn: None. L.A. Winter: None. J. Valentine: None. N. Musi: None. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc..

Microsampling Collection Methods for Measurement of C-peptide in Whole Blood.

Microsampling techniques are alternative methods to venous sampling for obtaining blood for measurement of circulating biomarkers, offering the convenience of reduced sample volume and elimination of the need for phlebotomists. Dried blood spot (DBS) microsampling methods have been used for many years while more recently a volumetric absorptive microsampling device (VAMS™) has been introduced. In diabetes mellitus, circulating C-peptide is commonly used as an indicator of endogenous insulin secretion and clinical measurement can aid in diagnosis as well as informing on therapy. This pilot study investigated the effectiveness of microsampling collection of capillary blood for measurement of C-peptide. Capillary blood was collected into capillary tubes and centrifuged for plasma samples. Simultaneous samples were also collected using both microsampling methods (DBS and VAMS). Blood from both microsamplers was extracted prior to assaying for C-peptide alongside the corresponding plasma samples, using specific immunoassays and results obtained from microsampling compared to the reference plasma concentrations. Stability was determined by collecting duplicate DBS and VAMS and assaying both in a single assay after storing one at -20°C immediately and one at room temperature for 48 hours post-collection. Good agreement was observed between C-peptide concentrations in plasma and equivalent DBS and VAMS samples ( R2 = .929 and .9231, DBS and VAMS, respectively), with mean differences of 75.7 and 8.4 pmol/L observed for DBS and VAMS. Small decreases in C-peptide of 11.6% and 0.1% were observed after 48 hours storage for DBS and VAMS, respectively. C-peptide collected using DBS and VAMS showed good agreement with reference plasma concentrations, suggesting both would be an effective microsampling method for collection and measurement of C-peptide.

Insulin tolerance test predicts non response vs. sustained efficacy of Liraglutide on glycemic control in type 2 diabetes patients: A prospective real-world setting study

AimsLess than half of type 2 diabetes patients treated with Glucagon-Like Peptide 1 (GLP-1) analogs displays good glycemic control, according to real life studies. Predictive markers of inefficacy/efficacy are therefore needed. The effectiveness of Liraglutide in terms of glycemic control and weight loss was then evaluated according to putative predictive parameters. Methods80 type 2 diabetes patients treated with Liraglutide were included in this prospective study. An Insulin Tolerance test (ITT) was performed at baseline to calculate velocity of C-Peptide decrease (C-peptide T½). Several clinical and biological parameters including HbA1c and weight were assessed at baseline and after 12, 24, 52 and 104 weeks of treatment. ResultsHbA1c decrease over the follow-up period was highly associated with C-peptide T½. A mean fall of 0.7% of HbA1c (7.7 mmol/mol) was predicted with 82% sensitivity and 80% specificity by C-peptide T½. In patients with rapid response during ITT (C-peptide T½ < 120 min), a HbA1c decrease of 1.5% (16.5 mmol/mol) was constantly found (p = .002) all over the follow-up. HbA1c remained unmodified for the rest of the patients (p = .34) compared to baseline. HbA1c evolution was not predicted by diabetes duration. Weight loss was predicted only by low baseline C-peptide plasma level. ConclusionsThis study suggests ITT as an efficient test to discriminate non–response from long-term efficacy before initiating Liraglutide. ITT could therefore help avoiding “try and see” prescription pattern by using a more precise and patient-centered strategy in order to reduce inertia in adapting treatment and so reduce subsequent complications.

The Association between Maternal 25-Hydroxyvitamin D Concentration during Gestation and Early Childhood Cardio-metabolic Outcomes: Is There Interaction with Pre-Pregnancy BMI?

Both maternal 25-hydroxyvitamin D(25OHD) status and pre-pregnancy BMI(pBMI) may influence offspring cardio-metabolic outcomes. Lower 25OHD concentrations have been observed in women with both low and high pBMIs, but the combined influence of pBMI and 25OHD on offspring cardio-metabolic outcomes is unknown. Therefore, this study investigated the role of pBMI in the association between maternal 25OHD concentration and cardio-metabolic outcomes in 5-6 year old children. Data were obtained from the ABCD cohort study and 1882 mother-child pairs were included. The offspring outcomes investigated were systolic and diastolic blood pressure, heart rate, BMI, body fat percentage(%BF), waist-to-height ratio, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose, C-peptide, and insulin resistance(HOMA2-IR). 62% of the C-peptide samples were below the detection limit and were thus imputed using survival analysis. Models were corrected for maternal and offspring covariates and tested for interaction with pBMI. Interaction with pBMI was observed in the associations with insulin resistance markers: in offspring of overweight mothers(≥25.0kg/m2), a 10 nmol/L increase in maternal 25OHD was associated with a 0.007(99%CI:-0.01,-0.001) nmol/L decrease in C-peptide and a 0.02(99%CI:-0.03,-0.004) decrease in HOMA2-IR. When only non-imputed data were analyzed, there was a trend for interaction in the relationship but the results lost significance. Interaction with pBMI was not observed for the other outcomes. A 10 nmol/L increase in maternal 25OHD was significantly associated with a 0.13%(99%CI:-0.3,-0.003) decrease in %BF after correction for maternal and child covariates. Thus, intrauterine exposure to both low 25OHD and maternal overweight may be associated with increased insulin resistance in offspring, while exposure to low 25OHD in utero may be associated with increased offspring %BF with no interactive effects from pBMI. Due to the limitations of this study, these results are not conclusive, however the observations of this study pose important research questions for future studies to investigate.

Recommendations for the definition of clinical responder in insulin preservation studies.

Clinical responder studies should contribute to the translation of effective treatments and interventions to the clinic. Since ultimately this translation will involve regulatory approval, we recommend that clinical trials prespecify a responder definition that can be assessed against the requirements and suggestions of regulatory agencies. In this article, we propose a clinical responder definition to specifically assist researchers and regulatory agencies in interpreting the clinical importance of statistically significant findings for studies of interventions intended to preserve β-cell function in newly diagnosed type 1 diabetes. We focus on studies of 6-month β-cell preservation in type 1 diabetes as measured by 2-h–stimulated C-peptide. We introduce criteria (bias, reliability, and external validity) for the assessment of responder definitions to ensure they meet U.S. Food and Drug Administration and European Medicines Agency guidelines. Using data from several published TrialNet studies, we evaluate our definition (no decrease in C-peptide) against published alternatives and determine that our definition has minimum bias with external validity. We observe that reliability could be improved by using changes in C-peptide later than 6 months beyond baseline. In sum, to support efficacy claims of β-cell preservation therapies in type 1 diabetes submitted to U.S. and European regulatory agencies, we recommend use of our definition.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

Abstract 3561: Effects of metformin on markers of insulin resistance and on breast cancer proliferation: The putative role of IGFBP-1 as a predictive biomarker

Abstract Use of metformin has been associated with reduced breast cancer risk in observational studies in diabetic patients, but evidence for antitumor activity in randomized clinical studies is lacking. In a randomized trial in non-diabetic women with operable breast cancer who were allocated after tumor biopsy to either metformin, 850 mg bid (n=100) or placebo (n=100) for 4 weeks prior to surgery, we recently showed that the effect of the drug on breast cancer proliferation (Ki-67 labeling index) varies according to insulin resistance as assessed by HOMA index. Here we report effects of metformin on circulating markers of insulin resistance, including C-peptide, IGFBP-1, testosterone, SHBG and adiponectin. We observed a non-homogenous effect of metformin on some of these biomarkers, in a manner that is related to the dual effect of metformin on tumor Ki-67. Overall, metformin did not affect C-peptide (p=0.74) or IGFBP-1 levels (p=0.48), but there was a significant interaction with BMI (p=0.02), with a 19% decrease in C-peptide (p=0.105) in women with BMI &amp;gt;27 (75th percentile), and a 4% increase (p=0.367) in women with BMI β27. In women with baseline IGFBP-1 levels &amp;lt;2.0 ng/ml (20th percentile; n=43), metformin was associated with a 20% decrease in Ki-67 at surgery (95% CI: –36.1 to –0.01; P=0,05), while a 10% increase was observed in women with IGFBP-1 β2.0 ng/ml (95% CI: –1.7 to 22.2; p=0,099; n=153). Consistently, we observed a strong inverse correlation between baseline IGFBP-1 levels and HOMA index (spearman's rho = –0.455, p&amp;lt;0.0001), and BMI (spearman's rho = –0.279, p&amp;lt;0.0001). Interestingly, we found a significant correlation between baseline IGFBP-1 levels and Ki-67 (p=0.032; r= –0.120), independent of treatment. Metformin decreased testosterone levels by 20% in postmenopausal women only (p=0.002, n=99), regardless of BMI and HOMA index. Ki-67 at surgery was not significantly associated with testosterone levels at baseline (p=0.737), nor did we observe any interaction between testosterone and treatment on Ki-67. Metformin did not affect SHBG levels (p=0.787), nor did we observe any modification of SHBG by HOMA (p=0.9) or BMI (p=0.7). Finally, we observed a decrease by a mean of 0.94 ug/ml (95% CI: 0.90 to 0.99) in adiponectin levels under metformin (p=0.009) as compared with placebo, without any interaction with Ki-67. Conclusions: Serum IGFBP-1 concentration is inversely related to breast cancer proliferation as measured by Ki-67 labelling index, and defines a subpopulation of breast cancer patients in which metformin decreases tumor proliferation. These findings support the hypothesis that insulin resistance influences breast cancer biology, and have implications regarding both the mechanism of action of metformin at dose used and the optimum design of future clinical trials of biguanides in cancer prevention and treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3561. doi:1538-7445.AM2012-3561

Rescue of a Pancreatic Islet Graft After Steroid Therapy

Rescue of a Pancreatic Islet Graft After Steroid Therapy

Vitamin D Deficiency and Cardio-Metabolic Risk in a North Indian Community with Highly Prevalent Type 2 Diabetes

The purpose of this investigation was to examine serum vitamin D status in a population of Punjabi ancestry from Northern India with a high prevalence of type 2 diabetes (T2D) and evaluate the effects of 25(OH)D levels on cardio-metabolic traits. We assessed cardiovascular risk factors and 25(OH)D levels in 1,765 participants (887 T2D cases, 878 normoglycemic controls). 76% of individuals were deficient (<50 nmol/L) in vitamin D. A higher percentage of T2D participants(83%) were vitamin D deficient compared to normoglycemic controls (68%)(p<0.0001).The prevalence of vitamin D deficiency increased progressively with body mass index (BMI) categories (p<0.0001): BMI<23 kg/m2, 65%; BMI 23-27.5 kg/m2, 75%; and BMI>27.5 kg/m2, 81%. T2D participants had significantly decreased serum 25(OH)D levels (β=-0.41, p=2.8 × 10-20). Individuals with low serum 25(OH)D had elevated fasting glucose(β=-0.18, p=0.022), BMI (β=-0.71, p=1.4 × 10-7) and systolic blood pressure (β=-1.68, p=0.006). A positive association of increased 25(OH)D with HOMA-B (β=0.17, p=8.0×10-6), and C-peptide (β=0.09, 0.017) was observed. Non-medicated, normoglycemic, non-hypertensive individuals classified as vitamin D deficient (n=289) exhibited a significant increase in fasting glucose (p=0.02) and BMI (p<0.0001) as well as a significant decrease in C-peptide (p<0.0001) and amylin (p<0.0001) compared to vitamin D sufficient controls (n=150). Vitamin D deficiency appears to be a significant risk factor for T2D severity and associated cardio-metabolic risk. Early intervention may be considered to improve prevention of T2D related cardiovascular complications.