Circulating Levels Of C-peptide Research Articles

Pancreas Transplantation in Minorities including Patients with a Type 2 Diabetes Phenotype

Background: Prior to year 2000, the majority of pancreas transplants (PTx) were performed as simultaneous pancreas-kidney transplants (SPKTs) in Caucasian adults with end stage renal failure secondary to type 1 diabetes mellitus (T1DM) who were middle-aged. In the new millennium, improving outcomes have led to expanded recipient selection that includes patients with a type 2 diabetes mellitus (T2DM) phenotype, which excessively affects minority populations. Methods: Using PubMed® to identify appropriate citations, we performed a literature review of PTx in minorities and in patients with a T2DM phenotype. Results: Mid-term outcomes with SPKT in patients with uremia and circulating C-peptide levels (T2DMphenotype) are comparable to those patients with T1DM although there may exist a selection bias in the former group. Excellent outcomes with SPKT suggests that the pathophysiology of T2DM is heterogeneous with elements consisting of both insulin deficiency and resistance related to beta-cell failure. As a result, increasing endogenous insulin (Cp) production following PTx may lead to freedom checking blood sugars or taking insulin, better metabolic counter-regulation, and improvements in quality of life and life expectancy compared to other available treatment options. Experience with solitary PTx for T2DM or in minorities is limited but largely mirrors the trends reported in SPKT. Conclusions: PTx is a viable treatment option in patients with pancreas endocrine failure who are selected appropriately regardless of diabetes type or recipient race. This review will summarize data that unconventional patient populations with insulin-requiring diabetes may gain value from PTx with an emphasis on contemporary experiences and appropriate selection in minorities in the new millennium.

Circulating C-peptide levels in living children and young people and pancreatic beta cell loss in pancreas donors across type 1 diabetes disease duration

Circulating C-peptide levels in living children and young people and pancreatic beta cell loss in pancreas donors across type 1 diabetes disease duration

Circulating C-Peptide Levels in Living Children and Young People and Pancreatic β-Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration.

C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in the UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N = 235), stratified by recently reported age at diagnosis endotypes (<7, 7–12, ≥13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (<1-year duration: age <7 years: 18 of 20 [90%], 7–12 years: 107 of 110 [97%], ≥13 years: 58 of 61 [95%] vs. 1–5 years postdiagnosis: <7 years: 172 of 522 [33%], 7–12 years: 604 of 995 [61%], ≥13 years: 225 of 289 [78%]). A similar profile was observed in β-cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) β-cells <1 year postdiagnosis: age <7 years: 23 of 26 (88%), 7–12 years: 32 of 33 (97%), ≥13 years: 22 of 25 (88%) vs. 1–5 years postdiagnosis: <7 years: 1 of 12 (8.3%), 7–12 years: 7 of 13 (54%), ≥13 years: 7 of 8 (88%). These data should be considered in the planning and interpretation of intervention trials designed to promote β-cell retention and function.

Insulin-Like Growth Factor I Receptor (IGF-IR) Ligands and BMI in Squamous Intra-Epithelial Lesion (SIL) of Cervix.

Cancer cervix is the most common cancer in women in developing countries like India. Several studies have linked insulin-like growth factors-I & II (IGF-I and IGF-II) and IGF binding proteins-3 (IGFBP-3) with pathogenesis of Squamous Intraepithelial Lesion of cervix (SIL). To the best of our knowledge, no study has shown any correlation between circulating C-Peptide levels and SIL. The present study has attempted to evaluate the correlation between SIL and IGF-IR ligands (IGF-I, IGF-II, C-Peptide), IGF binding protein (IGFBP-3) and Body Mass Index (BMI). The present case-control study consisted of 31 histologically proven SIL cases and 31 age matched controls without evidence of SIL. A 10 ml blood sample was collected in heparinized vial. Plasma was separated immediately using centrifugation and was stored at -80(0) C till further analysis. Plasma levels of IGF-I, IGF-II, C-peptide and IGFBP3 were measured using commercially available Enzyme Linked Immunosorbent Assay (ELISA) kit. Height and weight was noted for calculation of BMI. Bio-effective molar ratio (BEMR) was calculated as 3.72 x {(0.25 x IGF-I) + (0.032 x IGF-II) + (0.0025 x C-peptide)} / {(1435 + IGFBP-3) - (2.79 x IGF-I) - (2.87 x IGF-II)}. Statistical analysis was performed using SPSS and Microsoft Excel software employing student t-test, Mann-Whitney and Chi-square test for trend while binary logistic regression was used to estimate the odds ratios (OR) and corresponding 95% Confidence Intervals (CI). IGF-I, IGF-II levels and BEMR were significantly increased in SIL compared to controls (p= 0.001, p <0.001, and p <0.001, respectively). C-Peptide levels were higher in controls than SIL (p = 0.04). IGFBP-3 & BMI in SIL were not significantly related when compared with controls. Risk of SIL in 4(th) quartile for BEMR, IGF-I, and IGF-II was 12.18(95% CI= 3.13-47.39), 3.94(95% CI = 1.24-12.56), and 4.57(95% CI = 1.42-14.7), respectively. Elevated levels of IGF-I and IGF-II are associated with risk of SIL while BEMR emerges out to be a derived factor strongly associated with risk of SIL.

A Community-Based Exercise and Support Group Program Improves Quality of Life in African-American Breast Cancer Survivors: A Quantitative and Qualitative Analysis.

African-American (AA) breast cancer (BCa) survivors have higher mortality rates, more comorbidities and are less likely to meet national physical activity guidelines after diagnosis compared to Caucasian BCa survivors. We previously reported that a 20-week resistance exercise intervention coupled with a support group and home walking program, conducted using facilities and personnel at a community cancer support center, in Stage I-III AA BCa survivors improved strength, fitness and circulating C-peptide levels. Here, we report our findings on changes in quality of life (QoL) and other behavioral measures associated with this 20-week intervention and, discuss findings from a qualitative analysis of semi-structured patient interviews. We found a clinically relevant improvement in QoL using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B) (Baseline, B: 101.1 ± 21.5; End-of-Intervention, EOI: 108.5 ± 21.6; p = 0.05) and, a significant decrease in depression using the Beck Depression Inventory-II (B: 11.9 ± 8.1; EOI: 9.0 ± 5.5; p = 0.03). Our analysis of the patient interviews support improvements in these behavioral measures in that participants stated that they "feel better", were "more motivated" and "uplifted" after the program. The patient interviews also provided insights to the primary motivators (e.g., social support, improvements in strength and function, weight loss) and barriers (e.g., family and health issues) in adhering to the program and provided suggestions for improving the program (e.g., incorporating nutritional and treatment related side-effect discussions). Our results suggest that community-based lifestyle interventions may improve QoL and depression in AA BCa survivors and lend insights for improving future programs.

A Community-Based Exercise and Support Group Program in African-American Breast Cancer Survivors (ABCs)

African-American (AA) women have higher rates of breast cancer (BCa) mortality than Caucasian women, and a recent study using data from the Surveillance, Epidemiology and End Results (SEER) registry suggests that this disparity may be due, in part, to the poorer health status of AAs at diagnosis and not treatment related issues. Randomized controlled trials involving supervised aerobic and resistance exercise have shown improved body composition and improvement in cancer-related biomarkers in BCa patients and may lead to improved recurrence and survival rates; however, most trials have focused on Caucasians and many have been conducted in academic- and clinic-based settings. We evaluated the feasibility of conducting a 20-week, supervised, resistance training, group exercise intervention coupled with a support group and home walking program utilizing facilities and personnel at a community cancer support center (The Gathering Place, Beachwood, Ohio) in AA Stage I-III BCa survivors who were within 12 months of completing treatment (surgery, chemotherapy, and/or breast irradiation); and, evaluated the potential effects of this intervention on physical measures and cancer-related biomarkers. 27 patients provided informed consent and 19 participated in the program. On average, attendance rates were 70.0% ± 19.1% for the exercise sessions and 63.1% ± 13.8% for the support group. We observed a significant decrease in circulating C-peptide levels (B: 893.9 ± 399.1 pg/mL; EOI: 723.9 ± 319.0 pg/mL; p=0.01). Although we did not observe a significant decrease in weight in the entire sample, there was a significant decrease in waist circumference and percent total body fat among those who attended 70% or more of the exercise sessions. In summary, we demonstrated that conducting lifestyle interventions in AA BCa survivors in a community setting is feasible. Future interventions should invoke strategies to enhance adherence and include a structured dietary intervention to enable greater weight loss.

New ways of insulin delivery

New ways of insulin delivery

Refining the high-dose streptozotocin-induced diabetic non-human primate model: an evaluation of risk factors and outcomes

In preparation for islet transplantation, diabetes was induced using streptozotocin (STZ) in non-human primates ranging from juveniles to adults with diverse body types: we studied the process with respect to the diabetic state and emergence of adverse events (AEs) and their severity, and identified risk factors for clinical and laboratory AEs. Pharmaceutical-grade STZ was given based on body surface area (BSA) (1050-1250 mg/m(2), equivalent to 80-108 mg/kg) or on body weight (BW) (100 mg/kg) to 54 cynomolgus and 24 rhesus macaques. AEs were related to risk factors, i.e. obesity parameters, BW and BSA, age and STZ dose in mg/m(2). Clinical AEs during the first days after infusion prompted euthanasia of three animals. Except for those three animals, diabetes was successfully induced as shown by circulating C-peptide levels, the intravenous glucose tolerance test and/or arginine stimulation test. C-peptide after infusion weakly correlated (P = 0.048) with STZ dose in mg/m(2). Grade ≥3 nephrotoxicity or hepatotoxicity (serum markers >3× baseline or >5 × baseline, respectively) occurred in about 10% of cases and were generally mild and reversible. Grade ≥2 clinical AEs occurred in seven of 78 animals, reversed in four cases and significantly correlated with obesity parameters. Taking girth-to-height ratio (GHtR) as an indicator of obesity, with threshold value 0.92-0.95, the positive predictive value of obesity for AEs was 92% and the specificity 94%. We conclude that diabetes is successfully induced in non-obese animals using a 100 mg/kg pharmaceutical grade STZ dose. Obesity is a significant risk factor, and animals with a higher than normal GHtR should preferably receive a lower dose. The incidence of relevant clinical or laboratory AEs is low. Careful monitoring and supportive medical intervention can result in recovery of AEs.

A dose range finding study of novel oral insulin (IN‐105) under fed conditions in type 2 diabetes mellitus subjects

The objective of the study was to establish the dose response of IN-105 tablets and explore a possible therapeutic window in type 2 diabetes subjects poorly controlled on metformin. The primary objective was to examine the effect of sequential single ascending doses of IN-105 on the plasma glucose concentration under fed conditions. All subjects received, sequentially, matching placebo, 10, 15, 20 and 30 mg IN-105 tablets in five consecutive periods. Tablets were administered 20 min prior to meal in all the periods. Plasma levels of immunoreactive insulin, C-peptide and glucose were measured up to 180 min from the time of dosing. The changes in postprandial glucose levels at 120 min in response to IN-105 administration were also compared against those of placebo. Changes in glucose from baseline (mean +/- s.d.) at 140 min (2 h postprandial) were 94.84 +/- 22.3, 79.45 +/- 43.00, 70.68 +/- 35.71, 63.47 +/- 42.75 and 53.06 +/- 47.27 mg/dL, respectively, and exhibited linear dose-response. The insulin C(max) values were found to be 50.8 +/- 26.0 mU/L for placebo, 100.3 +/- 66.7 with 10 mg IN-105, 177.69 +/- 150.3 with 15 mg IN-105, 246.2 +/- 245.2 with 20 mg IN-105 and 352.5 +/- 279.3 mU/L with 30 mg of IN-105. IN-105 absorption is proportional to the dose administered. The 2-h postprandial glucose excursion was reduced in a dose proportional manner. Circulating C-peptide levels were found to be suppressed in proportion to the IN-105 exposure. IN-105 reduces glucose excursion despite lower endogenous insulin secretion. IN-105 seems to have a wide therapeutic window as no clinical hypoglycaemia was observed at any of the doses studied.

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

BackgroundIslet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin–independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal FindingsTwenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters - including time until insulin independence, insulin independence at one year, and C-peptide levels over one year- remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/SignificanceIn this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial RegistrationClinicaltrials.gov NCT00623610

Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants.

The potential effects of islet transplantation on the renal function of 36 patients with type I diabetes mellitus and kidney transplants were studied with 4 yr of follow-up monitoring. Kidney-islet recipients were divided into two groups, i.e., patients with successful islet transplants (SI-K group) (n = 24, fasting C-peptide levels of >0.5 ng/ml for >1 yr) and patients with unsuccessful islet transplants (UI-K group) (n = 12, fasting C-peptide levels of <0.5 ng/ml). Kidney graft survival rates and function, urinary albumin excretion rates, and sodium handling were compared. Na(+)/K(+)-ATPase activity in protocol kidney biopsies and in red blood cells was cross-sectionally analyzed. The SI-K group demonstrated better kidney graft survival rates (100, 83, and 83% at 1, 4, and 7 yr, respectively) than did the UI-K group (83, 72, and 51% at 1, 4, and 7 yr, respectively; P = 0.02). The SI-K group demonstrated reductions in exogenous insulin requirements and higher C-peptide levels, compared with the UI-K group, whereas GFR values were similar. Microalbuminuria (urinary albumin index) increased significantly in the UI-K group only (UI-K, from 92.0 +/- 64.9 to 183.8 +/- 83.8, P = 0.05; SI-K, from 108.5 +/- 53.6 to 85.0 +/- 39.0, NS). In the SI-K group, but not in the UI-K group, natriuresis decreased at 2 and 4 yr (P < 0.01). The SI-K group demonstrated greater Na(+)/K(+)-ATPase immunoreactivity in renal tubular cells (P = 0.05) and higher activity in red blood cells (P = 0.03), compared with the UI-K group. The Na(+)/K(+)-ATPase activity in red blood cells was positively correlated with circulating C-peptide levels but not with glycated hemoglobin levels. Successful islet transplantation was associated with improvements in kidney graft survival rates and function among uremic patients with type I diabetes mellitus and kidney grafts.

Issues in clinical islet transplantation.

The Second International Islet Transplantation Symposium was held at UCLA in January, 1993. The symposium, sponsored by the Jerry's Foundation for Diabetes Research was focused on the issues in clinical islet transplantation. The leaders from each of the clinically active programs around the world were invited to discuss their clinical results and ways to achieve higher success rates. The Islet Transplantation Registry revealed there have been 178 islet transplants in human subjects worldwide: 11% of the patients have achieved insulin-independence; however, 20% of the patients have achieved insulin-independence during 1990-1992; 20% of the patients have functioning islet grafts as determined by circulating C-peptide levels; however 65% have functioning grafts during 1990-1992. These patients still require exogenous insulin; however, many demonstrate improved glucose control and decreased insulin requirements, and are considered to have a partially successful transplant. The major issues for clinical success are islet preparation, donor islet number, and prevention of rejection. We are hopeful that islet transplantation will realize its full potential this decade and await the advance in technology that will result in clinical success rates approaching that of solid organ transplantation.

C-peptide measurement: methods and clinical utility.

Proinsulin is the single chain precursor of insulin. It consists of insulin, plus a peptide which connects the A and B chains of insulin. This peptide is termed C-peptide. C-peptide an insulin are secreted in equimolar amounts from pancreatic beta-cells, Hence, circulating C-peptide levels provide a measure of beta-cell secretory activity. C-peptide measurements are preferable to insulin measurements because of lack of hepatic extraction, slower metabolic clearance rate, and lack of cross reactivity with antibodies to insulin. This article reviews the methods for determination of C-peptide levels in body fluids, and discusses the applications of C-peptide measurement. These include the investigation of hypoglycemia and the assessment of insulin secretory function in insulin-treated and non-insulin-dependent diabetics. The contribution of C-peptide measurement to the understanding of the interrelationships between insulin secretory function and age, sex, obesity, blood lipids, and blood glucose concentrations will also be evaluated.