Detectable C-peptide Levels Research Articles

Metabolic impact of residual C-peptide secretion in type 1 diabetes mellitus.

This study aimed to evaluate the association of detectable C-peptide levels with various continuous glucose monitoring (CGM) metrics and diabetes complications in patients with type 1 diabetes mellitus (T1DM). Retrospective, descriptive study of 112 patients with T1DM undergoing intensive insulin therapy, categorized according to fasting C-peptide level into undetectable (<0.05 ng/mL) and detectable (≥0.05 ng/mL) groups. The patients' median age at diagnosis was 22 (12-34) years and the median T1DM duration was 18.5 (12-29) years. Patients with detectable versus undetectable C-peptide levels were older (27.5 [16.5-38.5] versus 17.5 [9.8-28.8] years, respectively, p = 0.002) and had shorter disease duration (14 [9-24] versus 20 [14-32] years, respectively, p = 0.004). After adjustment for covariates (sex, disease duration, body mass index, and use of continuous subcutaneous insulin infusion), detectable C-peptide level was associated with lower time above range (TAR; aβ -11.03, p = 0.002), glucose management indicator (GMI, aβ -0.55, p = 0.024), and average glucose (aβ -14.48, p = 0.045) and HbA1c (aβ -0.41, p = 0.035) levels. Patients with detectable versus those with undetectable C-peptide level had significantly higher time in range (TIR) before (β = 7.13, p = 0.044) and after (aβ = 11.42, p = 0.001) adjustments. Detectable C-peptide level was not associated with lower time below range (TBR), coefficient of variation (CV), or prevalence of chronic microvascular and macrovascular complications. Persistent C-peptide secretion in patients with T1DM was associated with significantly better metabolic control reflected by different glucose metrics, namely, TIR, TAR, GMI, and HbA1c.

Abstract #1401677: Pembrolizumab Induced Autoimmune Diabetes Mellitus

Immune checkpoint inhibitors (ICIs) are integral in the treatment of a myriad of malignancies. While ICIs have significantly improved outcomes and cancer survivorship, they have also been implicated in immune related adverse events (irAEs), particularly autoimmune endocrinopathies. Common ICI associated endocrine disorders include hypothyroidism, hyperthyroidism, and primary adrenal insufficiency but rarely diabetes mellitus (DM). ICI induced DM is defined as severe and persistent insulin deficiency after treatment with an ICI. Here, we present a rare case of pembrolizumab induced DM presenting with hyperglycemic hyperosmolar state (HHS). A 77-year-old male with a past medical history of prediabetes on no medical therapy and melanoma of the right upper extremity was admitted with progressive polydipsia, polyuria and acute encephalopathy. Notably, the patient completed two cycles of pembrolizumab two weeks prior to admission. Initial workup demonstrated a glucose of 837 mg/dL (65-99), anion gap of 10 (3-11), small amounts of serum acetone and beta hydroxybutyrate, and a serum osmolality of 369 mOsm/kg (279-295). Venous blood gas revealed a pH of 7.33 (7.31-7.41), pCO2 45 mmHg (41-51), HCO3 24 mEq/L (23-29). Objective data supported the diagnosis of HHS. Hemoglobin A1c prior to initiation of pembrolizumab was 6.1% (< 5.7%) and on admission was 9.1%. He improved with intravenous insulin and fluids. After transition to basal/bolus insulin the patient’s fasting glucose was 126 mg/dL (65-99) with a c-peptide level of 0.41 ng/mL (0.80-3.85), consistent with insulin insufficiency. Glutamic acid decarboxylase 65 autoantibodies were positive, while islet cell and IA-2 autoantibodies were negative. Pembrolizumab was discontinued after the diagnosis of ICI induced DM was established. Our case highlights the unique course of a patient with prediabetes on pembrolizumab who developed ICI induced DM. Pembrolizumab (anti PD-1 monoclonal antibody) can cause an abnormal cytotoxic T cell (CD8+ T cell) mediated beta cell destruction and development of ICI induced DM. ICI induced DM shares characteristics of Type 1 DM with positive autoantibodies and insulin insufficiency. Insulin deficiency often precipitates diabetic ketoacidosis which was not seen in our patient. Given low but detectable c-peptide levels, our patient was likely insulin insufficient and not yet insulin deficient. This case highlights the importance of closely monitoring patients on ICIs, especially those with a predisposition to DM. In patients receiving immunotherapy, early identification of adverse events and risk stratification is essential in reducing morbidity and providing comprehensive care.

Estimation of a Machine Learning-Based Decision Rule to Reduce Hypoglycemia Among Older Adults With Type 1 Diabetes: A Post Hoc Analysis of Continuous Glucose Monitoring in the WISDM Study.

The Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) study demonstrated continuous glucose monitoring (CGM) reduced hypoglycemia over 6 months among older adults with type 1 diabetes (T1D) compared with blood glucose monitoring (BGM). We explored heterogeneous treatment effects of CGM on hypoglycemia by formulating a data-driven decision rule that selects an intervention (ie, CGM vs BGM) to minimize percentage of time <70 mg/dL for each individual WISDM participant. The precision medicine analyses used data from participants with complete data (n = 194 older adults, including those who received CGM [n = 100] and BGM [n = 94] in the trial). Policy tree and decision list algorithms were fit with 14 baseline demographic, clinical, and laboratory measures. The primary outcome was CGM-measured percentage of time spent in hypoglycemic range (<70 mg/dL), and the decision rule assigned participants to a subgroup reflecting the treatment estimated to minimize this outcome across all follow-up visits. The optimal decision rule was found to be a decision list with 3 steps. The first step moved WISDM participants with baseline time-below range >1.35% and no detectable C-peptide levels to the CGM subgroup (n = 139), and the second step moved WISDM participants with a baseline time-below range of >6.45% to the CGM subgroup (n = 18). The remaining participants (n = 37) were left in the BGM subgroup. Compared with the BGM subgroup (n = 37; 19%), the group for whom CGM minimized hypoglycemia (n = 157; 81%) had more baseline hypoglycemia, a lower proportion of detectable C-peptide, higher glycemic variability, longer disease duration, and higher proportion of insulin pump use. The decision rule underscores the benefits of CGM for older adults to reduce hypoglycemia. Diagnostic CGM and laboratory markers may inform decision-making surrounding therapeutic CGM and identify older adults for whom CGM may be a critical intervention to reduce hypoglycemia.

Simultaneous Pancreas-kidney Transplantation Candidates With Type 2 Diabetes Mellitus: Elevated C-peptide Levels Warrant Scrutiny, May Portend Worse Outcomes.

Simultaneous Pancreas-kidney Transplantation Candidates With Type 2 Diabetes Mellitus: Elevated C-peptide Levels Warrant Scrutiny, May Portend Worse Outcomes.

Preserved C‐peptide in survivors of COVID‐19: Post hoc analysis

Preserved <scp>C</scp>‐peptide in survivors of <scp>COVID</scp>‐19: Post hoc analysis

Insulin micro-secretion in Type 1 diabetes and related microRNA profiles

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10–20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)–upper quartile (UQ)] 5.0 (2.6–28.7) versus 650.9 (401.2–732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ–UQ) 4.2 (2.6–12.2) pmol/L vs. 8.0 (2.3–80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05). Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.

Inheritance of Mildly Activating ABCC8 Mutation From a Mother With MODY Causes Permanent Neonatal Diabetes Mellitus (NDM) in Two Siblings Who Also Carry a Second Inactivating Mutation: Genetic Testing Allows for Improved Treatment With Sulfonylureas (SU)

Background: Heterozygous activating mutations in KCNJ11 or ABCC8 are the most common cause of neonatal diabetes (NDM). ABCC8 (SUR1) mutations more often cause transient NDM. Inactivating ABCC8 mutations can cause congenital hyperinsulinism (HI), but very rarely will such mutations be inherited together. Mildly activating KATP mutations can also be a cause of MODY, but even if genetic testing is considered, many commercial testing panels do not include these genes, despite the significant difference in treatment that can result due to sulfonylurea (SU) responsiveness.Clinical Case: The proband was diagnosed with DM at 11 months old and fortuitously treated with SU for 3 years. He was switched to insulin and had poor DM control thereafter. Sister was diagnosed at 3.5 months old and had poor DM control on insulin. Mother was diagnosed with DM at 27 years old and treated with various medications including insulin. Genetic testing revealed that mother carried ABCC8 mutation R1380C previously described to cause transient NDM and/or later-onset DM consistent with her phenotype. Both children inherited this mutation from her and inherited a variant (L1148R) from their father without diabetes that has been reported in association with HI. The L1148R allele may reduce cell surface expression thereby increasing the relative expression and pathogenic effect of the R1380C allele that has not previously been described to cause permanent NDM.We assessed SU responsiveness by measuring maximal beta-cell function through combined mixed meal and arginine testing. Mother exhibited easily detectable C-peptide levels at baseline that improved by SU treatment. In contrast, the children displayed almost undetectable baseline beta-cell function with variable response to SU: the sister who had been chronically poorly controlled on insulin therapy displayed barely improved C-peptide production, while her brother who had previously been treated with SU as an infant had markedly improved beta-cell function on SU. Within two months of continued treatment with high doses of SU only, he was able to start lowering his SU dose with improved glycemia. His sister was started on high-dose SU in addition to insulin, but continued to have difficulty adhering to her treatment regimen. Her blood sugar improved after the addition of long-acting GLP-1 agonist (liraglutide) but she later became pregnant and returned to insulin only. Her glycemic control improved when re-started on SU after pregnancy. The mother exhibited excellent DM on a lower dose of exclusive SU therapy.Clinical Lesson: Genetic testing can dramatically alter management and must be pursued in both NDM and family members with diabetes later in life. Careful assessment of clinical characteristics along with genetic testing for segregation patterns in family members can greatly improve understanding of the causality of previous uncharacterized variants.

Residual β-cell function after 10 years of autoimmune type 1 diabetes: prevalence, possible determinants, and implications for metabolism.

BackgroundType 1 diabetes (T1D) has long been considered a progressive autoimmune disease resulting in the failure of pancreatic β-cell function and absolute endogenous insulin deficiency. However, several studies have demonstrated patients with T1D have detectable C-peptide levels long after diagnosis, which has remarkable clinical significance. Since this issue has not been systematically explored in non-Caucasian populations, we aimed to identify the prevalence of residual β-cell function and its related clinical features in Chinese long-term T1D patients.MethodsWe enrolled 109 patients with T1D for ≥10 years and administered a mixed-meal tolerance test (MMTT). Fasting and postprandial C-peptide (FCP/PCP) levels were measured to evaluate the insulin secretion function of β-cells. Patients whose FCP and PCP levels were both below the lower detection limit (16.7 pmol/L) were grouped as ‘β-cell function depleted’, while others were thought to have ‘residual β-cell function’. Demographic data, metabolic status, and diabetic complications were compared between patients with or without residual β-cell function.Results38.5% of subjects retained residual β-cell function, and among those, 33.3% responded to MMTT by a two-fold or greater rise of their FCP levels. Clinical features associated with residual β-cell function were older age of diagnosis [27.5 (interquartile range:11.5–37.0) vs. 17.0 (interquartile range: 8.0–30.0) years, P=0.037], lower HbA1c (64.6±20.3 vs. 72.4±18.5 mmol/mol, P=0.026), and reduced rate of hypoglycemia (23.8% vs. 52.2%, P=0.003). Age of diagnosis was positively correlated with detectable FCP level (r=0.393, P=0.020). Individuals diagnosed after 30 years of age tended to retain residual β-cell function (OR =3.016, P=0.044). We found no association between residual β-cell function and chronic diabetic complications.ConclusionsResidual β-cell function can be found in nearly 40% of long-term patients with T1D in China and is associated with older age at diagnosis and better glucose control. The relationship between residual β-cell function and chronic diabetic complications remains to be explored.

Preserved C-peptide secretion in patients with type 1 diabetes and incipient chronic complications is associated with lower serum resistin and higher uric acid levels.

Previous studies suggested that long-term perseverance of beta-cell function in patients with type 1 diabetes (T1DM) is associated with lower incidence of microvascular complications. The objective of this study was to evaluate preserved C-peptide secretion in patients with T1DM without overt chronic complications and to explore associations with resistin and uric acid as biomarkers of microvascular complication pathogenesis. We assessed residual beta-cell function in 164 T1DM patients (male/female = 91/73; age/diabetes duration range = 18-70/1-30years) using an ultrasensitive C-peptide ELISA assay with detection limit of 2.5pmol/L and total coefficient of variation (CV) 5,8% (Mercodia, Sweden). Serum level of uric acid was measured by enzymatic method (AU680, Beckman Coulter, USA) while resistin concentration was determined by the ELISA assay (Biovendor, Czech Republic). C-peptide secretors had shorter diabetes duration (5.1 vs. 16years; p< 0,001), lower resistin (4.53 vs. 4.93mg/mL p= 0.045), and higher uric acid (259 vs 238μmol/L, p= 0.048) level than T1DM patients with no detectable C-peptide levels, while no differences in routine anthropometric and laboratory variables, including HbA1c, were observed. Although the proportion of C-peptide secretors significantly decreased across categories of diabetes duration (70%, 38%, 17% and 15% for <5, 5-10, 10-20 and 20-30years of duration, respectively; p< 0,001), detectable C-peptide was found in 5/23 T1DM patients who were diagnosed with T1DM more than 20years ago. The results of our study revealed that patients with detectable C-peptide had lower resistin and higher uric acid level compared to patients with undetectable C-peptide.

Exenatide extended release in patients with type 1 diabetes with and without residual insulin production.

To test whether a long-acting GLP-1 receptor agonist would improve glucose control in patients with type 1 diabetes (T1D) and to determine whether the presence of residual beta cell function would affect the response. In addition, we sought to determine whether the drug would affect beta cell function. We performed a randomized placebo-controlled trial of exenatide extended release (ER) in participants with T1D with and without detectable levels of C-peptide. Seventy-nine participants were randomized to exenatide ER 2 mcg weekly, or placebo, stratified by the presence or absence of detectable C-peptide levels. The primary outcome was the difference in glycated haemoglobin (HbA1c) levels at 24 weeks. Participants were followed for another 6 months off study drug. At week 24, the time of the primary outcome, the least squares (LS) mean HbA1c level was 7.76% (95% confidence interval [CI] 7.42, 8.10) in the exenatide ER group versus 8.0% (95% CI 7.64, 8.35) in the placebo group (P = 0.08). At week 12 the LS mean HbA1c levels were 7.71% (95% CI 7.37, 8.05) in the exenatide ER group versus 8.05% (95% CI 7.7, 8.4) in the placebo group (P = 0.01). The improvement at week 12 was driven mainly by those with detectable levels of C-peptide. Those treated with exenatide ER lost weight at 12 and 24 weeks compared to those treated with placebo (P <0.001 and P = 0.007). The total insulin dose was lower, but not when corrected for body weight, and was not affected by residual insulin production. Adverse events were more frequent with exenatide ER, but hypoglycaemia was not increased. Treatment with exenatide ER may have short-term benefits in some individuals with T1D who are overweight or who have detectable levels of C-peptide, but short-term improvements were not sustained.

1917-P: Alpha-Cell Function in Patients with Type 1 Diabetes Is Compromised with Different Levels of Residual C-Peptide

Objective: It is poorly understood α-cell function changes to respond to the different detectable C-peptide levels in patients with type 1 diabetes (T1D). This study aims to investigate the relationship between glucagon secretion and declining β-cell function in patients with T1D. Methods: Eighty-seven subjects [68, autoimmune type 1 diabetes (T1AD); 4, fulminant type 1 diabetes (FT1D); 15 healthy controls] were enrolled. All participants underwent a 100g steamed bread meal tests (SBMT). T1AD patients were divided into C-peptide negative (CPN), C-peptide middle (CPM) and C-peptide high (CPH) group based on peak C-peptide levels. Both fasting and postprandial of glucose, C-peptide and glucagon were measured. Glucagon among groups were compared by a linear mixed-effects model. The relationship between C-peptide, glucose and glucagon responses was evaluated by regression analysis. Results: At baseline, fasting glucagon concentrations were comparable between CPN, CPM and CPH group (F=0.099, P=0.906). After SBMT, 180min-glucagon in CPN group were higher than in CPM (P=0.004) and in CPH group (P&amp;lt;0.001). The iAUC30-180 of glucagon was lower in CPH than in CPN (P=0.001) and in CPM group (P=0.034), whereas the iAUC0-30 glucagon did not differ among CPN, CPM and CPH group (F=1.246, P=0.295). The same results were observed in iAUC of glucagon/glucose. After adjustment for age, BMI and diabetes duration, the iAUC30-180 glucagon in T1AD was inversely related to peak C-peptide and positively related to peak glucose levels (Radj2=0.315, P&amp;lt;0.001); however, the iAUC0-30 glucagon in T1AD was only positively related to 30min-glucose (Radj2=0.466, P&amp;lt;0.001). Conclusions: This study demonstrates α-cell function in patients with T1D are compromised with different levels of residual C-peptide. Glucose is also a contributor factor for postprandial hyperglucagonemia. Disclosure L. Zhang: None. Y. Shi: None. Y. Huang: None. Q. Hu: None. Y. Qin: None. M. Zhang: None. Funding National Natural Science Foundation of China (81670756, 81974103), Provincial Key Research and Development Foundation of Jiangsu (BE2018748)

Persistent C-Peptide Levels and Proliferative Retinopathy in Childhood-Onset Type 1 Diabetes (T1D)

Persistent C-peptide levels may protect against complications in T1D. To test this hypothesis, 185 subjects from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, a 30-year prospective study of childhood onset (&amp;lt;17 years) T1D, had serum C-peptide levels measured by Mercodia ultra-sensitive ELISA at their 25 year exam. Eighteen (9.7%) subjects had detectable C-peptide levels. Those with and without detectable C-peptide did not differ in age (51.8 vs. 51.1 years, p=0.70), age of onset (9.7 vs. 8.1 years, p=0.12), diabetes duration (42.1 vs. 43.0 years, p=0.61), or HbA1c at either baseline (8.1 vs. 8.5%, p=0.22) or 25 years (7.8 vs. 7.8%, p=0.91). In those with detectable C-peptide, non-HDL cholesterol levels were lower at baseline (104.4 vs. 124.1 mg/dl, p=0.01), but not 25 years (112.6 vs. 119.5 mg/dl, p=0.44) and pump use was marginally lower at 25 years (31.2% vs. 55.3%, p=0.07). Proliferative retinopathy was lower in those with detectable C-peptide levels (33.5% vs. 55.1%, p=0.08) and this difference remained marginally significant (p=0.08) after controlling for duration of T1D, HbA1c and non-HDL cholesterol. No significant differences in overt nephropathy (5.6% vs. 22.7%, p=0.13), peripheral neuropathy (61.1% vs. 77.2%, p=0.15), or renal failure (0 vs. 4.2%, p=1.00) were found between the two groups when analyzed separately. When those with either retinopathy or nephropathy were combined, those with detectable C-peptide levels had lower rates of these complications (33.3% vs. 58.1%, p=0.045). This association remained significant in logistic regression after controlling for duration of diabetes and HbA1c with a statistically significant odds ratio 0.39 (95% CI: 0.08-0.94). When those with neuropathy were added to the overall microvascular complication group, no significant differences were found (p=0.13). These findings are consistent with the hypothesis that proliferative retinopathy and possibly nephropathy in T1D may be influenced by persistent C-peptide secretion. Disclosure K. Williams: None. T. Costacou: None. D.J. Becker: None. T.J. Orchard: None.

PDX1 -MODY and dorsal pancreatic agenesis: New phenotype of a rare disease.

Maturity-Onset Diabetes of the Young (MODY) type 4 or PDX1 -MODY is a rare form of monogenic diabetes caused by heterozygous variants in PDX1 . Pancreatic developmental anomalies related to PDX1 are reported only in neonatal diabetes cases. Here, we describe dorsal pancreatic agenesis in 2 patients with PDX1 -MODY. The proband presented with diabetes since 14 years of age and maintained regular glycemic control with low doses of basal insulin and detectable C-peptide levels after 38 years with diabetes. A diagnosis of MODY was suspected. Targeted next-generation sequencing identified a heterozygous variant in PDX1 : c.188delC/p.Pro63Argfs*60. Computed tomography revealed caudal pancreatic agenesis. Low fecal elastase indicated exocrine insufficiency. His son had impaired glucose tolerance, presented similar pancreatic agenesis, and harbored the same allelic variant. The unusual presentation in this Brazilian family enabled expansion upon a rare disease phenotype, demonstrating the possibility of detecting pancreatic malformation even in cases of PDX1 -related diabetes diagnosed after the first year of life. This finding can improve the management of MODY4 patients, leading to precocious investigation of pancreatic dysgenesis and exocrine dysfunction.

Long-lasting response to oral therapy in a young male with monogenic diabetes as part of HNF1B-related disease.

Mutations in hepatocyte nuclear factor 1β gene (HNF1B) are responsible for a multisystemic syndrome where monogenic diabetes (classically known as MODY 5) and renal anomalies, mostly cysts, are the most characteristic findings. Urogenital malformations, altered liver function tests, hypomagnesemia or hyperuricemia and gout are also part of the syndrome. Diabetes in these patients usually requires early insulinization. We present the case of a young non-obese male patient with a personal history of renal multicystic dysplasia and a debut of diabetes during adolescence with simple hyperglycemia, negative pancreatic autoimmunity and detectable C-peptide levels. He also presented epididymal and seminal vesicle cysts, hypertransaminasemia, hyperuricemia and low magnesium levels. In the light of these facts we considered the possibility of a HNF1B mutation. The sequencing study of this gene confirmed a heterozygous mutation leading to a truncated and less functional protein. Genetic studies of his relatives were negative; consequently, it was classified as a de novo mutation. In particular, our patient maintained good control of his diabetes on oral antidiabetic agents for a long period of time. He eventually needed insulinization although oral therapy was continued alongside, allowing reduction of prandial insulin requirements. The real prevalence of mutations in HNF1B is probably underestimated owing to a wide phenotypical variability. As endocrinologists, we should consider this possibility in young non-obese diabetic patients with a history of chronic non-diabetic nephropathy, especially in the presence of some of the other characteristic manifestations.Learning points:HNF1B mutations are a rare cause of monogenic diabetes, often being a part of a multisystemic syndrome.The combination of young-onset diabetes and genitourinary anomalies with slowly progressive nephropathy of non-diabetic origin in non-obese subjects should rise the suspicion of such occurrence. A family history may not be present.Once diagnosis is made, treatment of diabetes with oral agents is worth trying, since the response can be sustained for a longer period than the one usually described. Oral treatment can help postpone insulinization and, once this is necessary, can help reduce the required doses.

A Single Center 11 Year Experience with 202Pancreas Transplants: Evolving Trends

A single center experience with pancreas transplantation (PTx) over an 11+ year period is reviewed. Methods: We retrospectively studied outcomes in 202 consecutive PTxs in 192 patients at our center. All patients received either rATG or alemtuzumab (Alem) induction with tacrolimus/MMF and tapered steroids or early withdrawal. 179 PTxs (89%) were performed with portal-enteric and 23 with systemic-enteric drainage. Results: From 11/01 to 3/13, we performed 162 simultaneous kidney-PTxs (SKPT), 35 sequential PTxs after kidney (PAK), and 5 PTx alone (PTA; 40 solitary PTxs [SPT]). 186 PTxs (92%) were primary and 16 pancreas retransplants. With a mean follow-up of 5.5 years, overall patient (87% SKPT versus 87.5% SPT), kidney (74% SKPT versus 82.5% SPT) and pancreas graft survival (both 65%) rates were comparable. Causes of PTx loss were also similar between SKPT and SPT; the rates of early thrombosis were 8.6% and 5%, respectively. Acute rejection rates were similar between groups (SKPT 29% versus SPT 26%, p=NS). A randomized trial of Alem versus rATG induction in SKPT demonstrated lower rates of acute rejection and infection in the Alemgroup; consequently, Alem induction has been used exclusively in all PTxs since 2009. Early steroid elimination has been feasible in most patients. Surveillance PTx biopsy-directed immunosuppression has contributed to equivalent long-term outcomes in SKPT and SPT. Good results have been achieved in African-American patients and in patients with a type 2 diabetes phenotype. Conclusions: Excellent 5 year outcomes following PTx can be achieved as >86% of patients are alive, >87% of surviving patients are dialysisfree, 80% of surviving patients remain insulin-free, and 88% of surviving patients have detectable C-peptide levels.

What We Do and Donʼt Understand About Pancreas Graft Failure.

The purpose of this study was to analyze patterns of graft failure (GF) following pancreas transplantation (PT) in an attempt to develop a better understanding of GF. Methods: We retrospectively reviewed outcomes in 202 consecutive PTs in 192 patients at our center; all were insulin-requiring pretransplant and received either r-ATG or alemtuzumab induction with tacrolimus/mycophenolate ± steroids. GF was defined as a return to daily scheduled exogenous insulin therapy irrespective of dose. Results: From 11/01 to 3/13, we performed 162 simultaneous pancreas-kidney transplants (SPKT) and 40 solitary PTs. In the SPKT group, 51 patients had measurable pretransplant C-peptide levels. With a mean follow-up of 6 years, 76 (37.6%) pancreas GFs occurred including 20 deaths with functioning grafts (DWFG). The death-censored pancreas graft failure rate was 30.8%; of these 56 pancreas GFs, 20 occurred early (within 3 months of PT) and 36 occurred late. Rates of early thrombosis were 8% in SPKT and 5% in solitary PT patients. Death-censored causes of pancreas GF were acute/chronic rejection (34), thrombosis (18), infection (3) and one primary nonfunction. Allograft pancreatectomy (AP) was performed in 22 cases; rates of AP were 95% for early (<3 months) and 11.8% for late pancreas GF (p<0.001). After excluding DWFGs and pancreas GFs that resulted in AP, a total of 36 pancreas GFs remained, 10 of which did not have C-peptide data at the time of pancreas GF. Of the remaining 26 pancreas GFs, 13 occurred in patients who were C-peptide positive (mean pretransplant C-peptide level 5.7 ng/ml). In these 13 cases, the mean C-peptide level at the time of pancreas GF (insulin resumption) was 3.3 ng/ml (range 0.9-7.9). In all but one case, the C-peptide level at the time of pancreas GF was less than the pretransplant C-peptide level. Of 13 pancreas GFs in pretransplant C-peptide negative patients, the mean C-peptide level at the time of pancreas GF was 1.5 ng/ml (range 0-3.8); 5 had C-peptide levels ≥2.0, 4 had C-peptide levels 1-2, and 4 had C-peptide levels <1.0 ng/ml. Conclusions: DWFG and AP account for more than half of cases of pancreas GF. Of the remaining cases of GF (defined as loss of insulin independence), C-peptide levels appear to be of limited predictive value whether or not the patient had detectable C-peptide levels pretransplant.

Pancreas transplantation: The Wake Forest experience in the new millennium.

To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels. In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

The Evolution of Type 1 Diabetes

T YPE 1 DIABETES (T1D) OCCURS IN INDIVIDUALS WITH a genetic predisposition to the disease, predominantly from a human leukocyte antigen (HLA)related immunogenotype that accounts for approximately 60% of the genetic influence. In these individuals who are genetically at risk, an environmental trigger is thought to initiate an immune response targeting the insulin-secreting pancreatic islet cells. The initial immune response also may engender secondary and tertiary immune responses that contribute to the impairment of -cell function and destruction of cells. The rate of development of T1D varies, probably related to non-HLA genetic factors and additional environmental factors beyond the triggering exposure. The initial laboratory manifestation of -cell injury is seroconversion, the appearance of diabetes-related autoantibodies. These autoantibodies likely do not mediate -cell injury but rather are markers of such injury. With progressive impairment of -cell function, metabolic abnormalities become measurable, initially either as loss of early insulin response to intravenous glucose or as reduced -cell sensitivity to glucose resulting in decreased insulin secretion. Subsequently, glucose abnormalities manifest as dysglycemia, either impaired fasting glucose (plasma glucose concentration of 100125 mg/dL) impaired glucose tolerance (2-hour plasma glucose concentration of 140-199 mg/dL following an oral glucose test), or indeterminate glucose tolerance (plasma glucose concentration of 200 mg/dL at 30, 60, or 90 minutes following an oral glucose test). Eventually, overt diabetes presents with glucose concentrations meeting current criteria, fasting plasma glucose concentration of 126 mg/dL or 2-hour plasma glucose concentration of 200 mg/dL. At the point of development of overt diabetes there is still evidence of persistent -cell function shown through measurement of C-peptide. C-peptide is a component of the insulin precursor molecule proinsulin, which is secreted by cells on an equimolar basis as insulin but is not contained in commercial insulin preparations, thus allowing measurement of -cell function even in patients treated with insulin. After diagnosis of T1D, however, there is a progressive decline in C-peptide as -cell function becomes more impaired or absent. Nonetheless, even many years after diagnosis, some patients with T1D may have low detectable levels of C-peptide. Since the sequence of events leading to T1D involves immunogenotypes detectable at birth or in infancy, several groups have followed birth cohorts with the genetic risk. Working together, Ziegler and colleagues analyzing cohorts in Colorado, Finland, and Germany report in this issue of JAMA the risk of progression to T1D from the time of seroconversion by measuring detectable diabetes autoantibodies. Remarkably, the results are similar in all 3 cohorts. Among 585 children who developed 2 or more diabetes-related autoantibodies, nearly 70% (280 of 401 available for follow-up) had developed T1D within 10 years, and 84% (299 of 355 available for follow-up) had developed T1D within 15 years. This is the first reportof a longitudinal cohort followed frominfancy throughthedevelopmentofT1D.Because theparticipantswere recruited from both the general population (in Colorado and Finland) and offspring of parents with T1D (in Germany), the similar findings take on added significance, suggesting that the same sequence of events occurs in individuals with socalled sporadic T1D and in relatives of individuals with T1D. The findings in this report raise additional questions. The basis for the differential progression to T1D according to the type of single autoantibody and the pattern of multiple autoantibodies should be explored. Also, the nearly 2-fold higher prevalence of HLA DR3/DR4-DQ8 in participants with multiple autoantibodies (n=331) than in those with a single autoantibody, and the similar prevalence between participants with a single autoantibody and those with no autoantibodies need to be better understood. In addition, would the identification of those with higher titers provide even a greater likelihood of progression to T1D? Muchattention inrecentyearshas focusedonwhetherT1D can be prevented. To that end, studies have been conducted in individualswith thegenetic riskalone(primaryprevention) and in individuals who have autoantibodies (secondary prevention). Although no study has of yet convincingly demonstrateddelayorpreventionofT1D,someevidencesuggests this may be possible. Primary prevention studies have shown the potential todelay theappearanceof autoantibodiesbyvarying infant formula used at the time of weaning from breast milk, either by eliminating cow’s milk and instead using a formula with casein hydrolysate or by removing bovine insulin from the formula. It is unknown whether such actions will delay progression to T1D, but an international effort—the National InstituteofChildHealthandHumanDevelopment–sponsored Trial toReduceInsulin-DependentDiabetesMellitus intheGenetically At-Risk (TRIGR) study—is under way to test the casein hydrolysate formula, with results expected in 2017.

Simultaneous pancreas kidney transplants in diabetic patients with end‐stage renal disease: the 20‐yr experience

We are reporting the results over a 20yr period of simultaneous pancreas-kidney transplants in patients with end-stage renal disease and diabetes mellitus. The outcomes of the transplants, performed between 1989 and 2008, are stratified by pretransplant c-peptide value. One hundred and seventy-three patients with end-stage renal disease due to diabetes, and were stratified according to undetectable c-peptide (x<0.8ng/mL) and detectable c-peptide (x>0.8ng/mL) levels. Patients with detectable c-peptide (x>0.8ng/mL) were the oldest at diabetes diagnosis (24.2 vs. 15.4yr, p<0.0001), and oldest at transplant (42.8 vs. 38.5, p<0.0001) had fewer years of insulin use (19.19 vs. 22.57yr, p=0.012), and were heavier pre transplant (BMI: 26.09 vs. 23.1, p<0.0001), and heavier post transplant (29.8 vs. 24.7, p<0.0001). Those with detectable c-peptide levels (x>0.8ng/mL) had better graft survival than those with an undetectable c-peptide level (x<0.8ng/mL), p=0.064; while those with undetectable levels, had better patient survival than those with detectable c-peptide levels (p=0.019). Despite the differences between groups by BMI, age of onset of insulin use, and age at transplant, there was a difference in patient but not graft survival within the 20yr follow-up period.

Residual C-peptide in patients with Type 1 diabetes and multiethnic backgrounds

OBJECTIVE:To evaluate serum C-peptide in 88 patients from a multiethnic population with Type-1 diabetes and variable disease durations.METHOD:Eighty-eight patients with a mean disease duration of 8.1±7.6 years were included and underwent C-peptide measurement before and after glucagon stimulation. Chi-squared and Mann Whitney U-tests were used to compare the variables between groups (all two-tailed, α = 0.05). Spearmańs correlation coefficient was used to test the association between the continuous variables. Logistic regression was used for the multivariate analysis. Twenty-eight (31.8%) individuals had significantly detectable C-peptide levels after stimuli, particularly those with a shorter disease duration (p<0.001).RESULTS:Patients with detectable C-peptide levels required lower insulin doses (p<0.009) and had similar HbA1C results (p = 0.182) and fewer chronic complications (p = 0.029).CONCLUSION:C-peptide detection was common in Type-1 diabetics, particularly shortly after being diagnosed. This result may have clinical implications.