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Diabetes, Obesity & Metabolism Oct 2022Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice,... (Review)
Review
Impaired beta-cell function is a recognized cornerstone of diabetes pathophysiology. Estimates of insulin secretory capacity are useful to inform clinical practice, helping to classify types of diabetes, complication risk stratification and to guide treatment decisions. Because C-peptide secretion mirrors beta-cell function, it has emerged as a valuable clinical biomarker, mainly in autoimmune diabetes and especially in adult-onset diabetes. Nonetheless, the lack of robust evidence about the clinical utility of C-peptide measurement in type 2 diabetes, where insulin resistance is a major confounder, limits its use in such cases. Furthermore, problems remain in the standardization of the assay for C-peptide, raising concerns about comparability of measurements between different laboratories. To approach the heterogeneity and complexity of diabetes, reliable, simple and inexpensive clinical markers are required that can inform clinicians about probable pathophysiology and disease progression, and so enable personalization of management and therapy. This review summarizes the current evidence base about the potential value of C-peptide in the management of the two most prevalent forms of diabetes (type 2 diabetes and autoimmune diabetes) to address how its measurement may assist daily clinical practice and to highlight current limitations and areas of uncertainties to be covered by future research.
Topics: Adult; Biomarkers; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Secretion
PubMed: 35676794
DOI: 10.1111/dom.14785 -
Diabetic Medicine : a Journal of the... Jul 2013C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion... (Review)
Review
C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes. This article reviews the use of C-peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C-peptide test and its use to assist diabetes classification and choice of treatment. We provide recommendations for where C-peptide should be used, choice of test and interpretation of results. With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important. Advances in assays have made C-peptide measurement both more reliable and inexpensive. In addition, recent work has demonstrated that C-peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice. The key current clinical role of C-peptide is to assist classification and management of insulin-treated patients. Utility is greatest after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes. Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology.
Topics: C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Insulin; Insulin Resistance; Insulin Secretion; Prognosis
PubMed: 23413806
DOI: 10.1111/dme.12159 -
JAMA Mar 2023In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death....
IMPORTANCE
In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta cell apoptosis and is involved in glucotoxicity-induced beta cell death. Calcium channel blockers reduce these effects and may be beneficial to beta cell preservation in type 1 diabetes.
OBJECTIVE
To determine the effect of verapamil on pancreatic beta cell function in children and adolescents with newly diagnosed type 1 diabetes.
DESIGN, SETTING, AND PARTICIPANTS
This double-blind, randomized clinical trial including children and adolescents aged 7 to 17 years with newly diagnosed type 1 diabetes who weighed 30 kg or greater was conducted at 6 centers in the US (randomized participants between July 20, 2020, and October 13, 2021) and follow-up was completed on September 15, 2022.
INTERVENTIONS
Participants were randomly assigned 1:1 to once-daily oral verapamil (n = 47) or placebo (n = 41) as part of a factorial design in which participants also were assigned to receive either intensive diabetes management or standard diabetes care.
MAIN OUTCOMES AND MEASURES
The primary outcome was area under the curve values for C-peptide level (a measure of pancreatic beta cell function) stimulated by a mixed-meal tolerance test at 52 weeks from diagnosis of type 1 diabetes.
RESULTS
Among 88 participants (mean age, 12.7 [SD, 2.4] years; 36 were female [41%]; and the mean time from diagnosis to randomization was 24 [SD, 4] days), 83 (94%) completed the trial. In the verapamil group, the mean C-peptide area under the curve was 0.66 pmol/mL at baseline and 0.65 pmol/mL at 52 weeks compared with 0.60 pmol/mL at baseline and 0.44 pmol/mL at 52 weeks in the placebo group (adjusted between-group difference, 0.14 pmol/mL [95% CI, 0.01 to 0.27 pmol/mL]; P = .04). This equates to a 30% higher C-peptide level at 52 weeks with verapamil. The percentage of participants with a 52-week peak C-peptide level of 0.2 pmol/mL or greater was 95% (41 of 43 participants) in the verapamil group vs 71% (27 of 38 participants) in the placebo group. At 52 weeks, hemoglobin A1c was 6.6% in the verapamil group vs 6.9% in the placebo group (adjusted between-group difference, -0.3% [95% CI, -1.0% to 0.4%]). Eight participants (17%) in the verapamil group and 8 participants (20%) in the placebo group had a nonserious adverse event considered to be related to treatment.
CONCLUSIONS AND RELEVANCE
In children and adolescents with newly diagnosed type 1 diabetes, verapamil partially preserved stimulated C-peptide secretion at 52 weeks from diagnosis compared with placebo. Further studies are needed to determine the longitudinal durability of C-peptide improvement and the optimal length of therapy.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04233034.
Topics: Adolescent; Humans; Child; Female; Male; Diabetes Mellitus, Type 1; Hypoglycemic Agents; C-Peptide; Double-Blind Method; Verapamil; Insulin-Secreting Cells
PubMed: 36826844
DOI: 10.1001/jama.2023.2064 -
Diabetes Care Oct 2023In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1...
OBJECTIVE
In November 2022, teplizumab-mzwv became the first drug approved to delay the onset of stage 3 type 1 diabetes in adults and children age ≥8 years with stage 2 type 1 diabetes on the basis of data from the pivotal study TN-10.
RESEARCH DESIGN AND METHODS
To provide confirmatory evidence of the effects of teplizumab on preserving endogenous insulin production, an integrated analysis of C-peptide data from 609 patients (n = 375 patients receiving teplizumab and n = 234 control patients) from five clinical trials in stage 3 type 1 diabetes was conducted.
RESULTS
The primary outcome of the integrated analysis, change from baseline in stimulated C-peptide, was significantly improved at years 1 (average increase 0.08 nmol/L; P < 0.0001) and 2 (average increase 0.12 nmol/L; P < 0.0001) after one or two courses of teplizumab. An analysis of exogenous insulin use was also conducted, showing overall reductions of 0.08 (P = 0.0001) and 0.10 units/kg/day (P < 0.0001) at years 1 and 2, respectively. An integrated safety analysis of five clinical trials that enrolled 1,018 patients with stage 2 or 3 type 1 diabetes (∼1,500 patient-years of follow-up for teplizumab-treated patients) was conducted.
CONCLUSIONS
These data confirm consistency in the preservation of β-cell function, as measured by C-peptide, across multiple clinical trials. This analysis showed that the most common adverse events included lymphopenia, rash, and headache, a majority of which occurred during and after the first few weeks of teplizumab administration and generally resolved without intervention, consistent with a safety profile characterized by self-limited adverse events after one or two courses of teplizumab treatment.
Topics: Adult; Child; Humans; Diabetes Mellitus, Type 1; C-Peptide; Insulin, Regular, Human; Antibodies, Monoclonal, Humanized; Insulin
PubMed: 37607392
DOI: 10.2337/dc23-0675 -
Clinical Chemistry Sep 2017Assessment of endogenous insulin secretion by measuring C-peptide concentrations is widely accepted. Recent studies have shown that preservation of even small amounts of... (Review)
Review
BACKGROUND
Assessment of endogenous insulin secretion by measuring C-peptide concentrations is widely accepted. Recent studies have shown that preservation of even small amounts of endogenous C-peptide production in patients with type 1 diabetes reduces risks for diabetic complications. Harmonization of C-peptide results will facilitate comparison of data from different research studies and later among clinical laboratory results at different sites using different assay methods.
CONTENT
This review provides an overview of the general process of harmonization and standardization and the challenges encountered with implementing a reference measurement system for C-peptide.
SUMMARY
Efforts to harmonize C-peptide results are described, including those by the National Institute of Diabetes and Digestive and Kidney Diseases-led C-peptide Standardization Committee in the US, activities in Japan, efforts by the National Institute for Biological Standards and Control in the UK, as well as activities led by the Bureau International des Poids et Mesures and the National Metrology Institute in China. A traceability scheme is proposed along with the next steps for implementation. Suggestions are made for better collaboration to optimize the harmonization process for other measurands.
Topics: C-Peptide; Clinical Laboratory Services; Diabetes Mellitus, Type 1; Humans; Observer Variation; Reference Standards
PubMed: 28646033
DOI: 10.1373/clinchem.2016.269274 -
JAMA Mar 2023Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing...
IMPORTANCE
Near normalization of glucose levels instituted immediately after diagnosis of type 1 diabetes has been postulated to preserve pancreatic beta cell function by reducing glucotoxicity. Previous studies have been hampered by an inability to achieve tight glycemic goals.
OBJECTIVE
To determine the effectiveness of intensive diabetes management to achieve near normalization of glucose levels on preservation of pancreatic beta cell function in youth with newly diagnosed type 1 diabetes.
DESIGN, SETTING, AND PARTICIPANTS
This randomized, double-blind, clinical trial was conducted at 6 centers in the US (randomizations from July 20, 2020, to October 13, 2021; follow-up completed September 15, 2022) and included youths with newly diagnosed type 1 diabetes aged 7 to 17 years.
INTERVENTIONS
Random assignment to intensive diabetes management, which included use of an automated insulin delivery system (n = 61), or standard care, which included use of a continuous glucose monitor (n = 52), as part of a factorial design in which participants weighing 30 kg or more also were assigned to receive either oral verapamil or placebo.
MAIN OUTCOMES AND MEASURES
The primary outcome was mixed-meal tolerance test-stimulated C-peptide area under the curve (a measure of pancreatic beta cell function) 52 weeks from diagnosis.
RESULTS
Among 113 participants (mean [SD] age, 11.8 [2.8] years; 49 females [43%]; mean [SD] time from diagnosis to randomization, 24 [5] days), 108 (96%) completed the trial. The mean C-peptide area under the curve decreased from 0.57 pmol/mL at baseline to 0.45 pmol/mL at 52 weeks in the intensive management group, and from 0.60 to 0.50 pmol/mL in the standard care group (treatment group difference, -0.01 [95% CI, -0.11 to 0.10]; P = .89). The mean time in the target range of 70 to 180 mg/dL, measured with continuous glucose monitoring, at 52 weeks was 78% in the intensive management group vs 64% in the standard care group (adjusted difference, 16% [95% CI, 10% to 22%]). One severe hypoglycemia event and 1 diabetic ketoacidosis event occurred in each group.
CONCLUSIONS AND RELEVANCE
In youths with newly diagnosed type 1 diabetes, intensive diabetes management, which included automated insulin delivery, achieved excellent glucose control but did not affect the decline in pancreatic C-peptide secretion at 52 weeks.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04233034.
Topics: Female; Adolescent; Humans; Child; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Blood Glucose; Insulin-Secreting Cells; C-Peptide; Double-Blind Method; Glycemic Control; Blood Glucose Self-Monitoring; Glycated Hemoglobin; Insulin
PubMed: 36826834
DOI: 10.1001/jama.2023.2063 -
Annals of Laboratory Medicine Jul 2022Accurate measurements of serum insulin and C-peptide are needed for the therapy and classification of diabetes. This study investigated the status of serum insulin and...
BACKGROUND
Accurate measurements of serum insulin and C-peptide are needed for the therapy and classification of diabetes. This study investigated the status of serum insulin and C-peptide measurements in China by analyzing the results of five pooled serum samples measured in 94 laboratories.
METHODS
Patient serum samples were pooled into five groups according to insulin and C-peptide concentrations and measured in 94 laboratories using different measurement systems. The inter- and intra-laboratory %CV as well as inter- and intra-measurement system %CV were calculated to assess the status of insulin and C-peptide measurements. To verify whether the disagreement between laboratories was due to different calibrators, as reported in previous studies, one low-level and one high-level sample extracted from the five pooled serum samples were used to recalibrate clinical measurement systems.
RESULTS
The mean intra-laboratory, intra-measurement system, inter-laboratory, and inter-measurement system %CVs were 2.7%, 4.8%, 21.8%, and 22.4%, respectively, for insulin and 2.3%, 6.7%, 16.4%, and 24.5%, respectively, for C-peptide. The inter- and intra-laboratory %CVs for insulin decreased with increasing concentration. After recalibration with low- and high-level samples, the mean inter-measurement %CV decreased from 22.4% to 17.2% for insulin and from 24.5% to 5.7% for C-peptide.
CONCLUSIONS
The intra-laboratory and intra-measurement system imprecision values are satisfactory for serum insulin and C-peptide measurements. However, the results from laboratories using different measurement systems were not comparable, and there is still much work needed to achieve the standardization or harmonization of serum insulin and C-peptide measurements.
Topics: C-Peptide; Clinical Laboratory Services; Humans; Laboratories; Laboratories, Clinical; Reference Standards
PubMed: 35177563
DOI: 10.3343/alm.2022.42.4.428 -
Journal of Internal Medicine Jan 2017In this review, we present findings that support autocrine cell protection by C-peptide in the context of clinical studies of type 1 diabetes (T1D), which universally... (Review)
Review
In this review, we present findings that support autocrine cell protection by C-peptide in the context of clinical studies of type 1 diabetes (T1D), which universally measure C-peptide serum levels as a surrogate for β cell functional mass. Over the last decade, evidence has accumulated that supports models in which C-peptide, cosecreted with insulin by pancreatic β cells, acts on peripheral targets including the vascular endothelium to reduce oxidative stress and apoptosis subsequent to exposure to diabetic insults. In parallel, as assays have become more sensitive, C-peptide has been detected in the circulation of most subjects with T1D where higher C-peptide levels are associated with fewer and slower development of diabetic microvascular complications, consistent with antioxidant protection by C-peptide. Clinical trials investigating C-peptide-replacement therapy effects have demonstrated amelioration of T1D nephropathy and neuropathy. Recently, the antioxidant action of C-peptide was extended to the β cells secreting it, that is an autocrine mechanism. Autocrine protection has major implications for the treatment of diabetes because the more C-peptide secreted, the more protection provided to the same β cells resulting in a slower decay in β cell functional mass over the time course of disease. Why β cells evolved to cosecrete an antioxidant C-peptide hormone together with the glycaemia-lowering insulin hormone is explored in the context of proposed evolutionary advantages of physiologically transient oxidative stress and insulin resistance as an adaptation for survival through times of fuel scarcity. The importance of recognizing autocrine C-peptide protection of functional β cell mass in observational clinical studies, and its therapeutic implications in interventional C-peptide-replacement studies, will be discussed.
Topics: Animals; C-Peptide; Diabetes Mellitus, Type 1; Disease Models, Animal; Endothelial Cells; Humans; Insulin Resistance; Insulin-Secreting Cells; Reactive Oxygen Species
PubMed: 27251308
DOI: 10.1111/joim.12522 -
Pediatric Endocrinology, Diabetes, and... 2021C-peptide, the molecule produced in an equimolar concentration to insulin, has become an established insulin secretion biomarker in diabetic patients. Measurement of... (Review)
Review
C-peptide, the molecule produced in an equimolar concentration to insulin, has become an established insulin secretion biomarker in diabetic patients. Measurement of C-peptide level can be helpful in clinical practice for assessing insulin-producing b-cells residual function, especially in the patients who have already started exogenous insulin therapy. Advances in assays have made measurement of C-peptide more reliable and inexpensive. Traditionally, C-peptide is widely used to differentiate between type 1, type 2 and monogenic types in diabetic patients of all ages, both when the diabetes occurs and even months and years after the initial diagnosis. Moreover, in the patients with type 1 diabetes, the C-peptide secretion can become a reliable predictor of the clinical partial remission in the first months after diagnosis, although noteworthy, its' any specified level is not included in the definition of this phase of the disease. Many other clinical factors such as age, use of innovative technologies, the intensity of physical activity or body mass influence the concentration of C-peptide as well as diabetes remission occurrence and duration. They may interfere the interpretation of C-peptide level in the diabetes course. There is a great need to assess the new, adjusted C-peptide levels in these situations. A multitude novel therapies including immunomodulative factors and stem cell transplants can also use C-peptide in the patient selection and post-therapeutic monitoring of the outcome in researches aimed in extension of remission period. Recent research proves C-peptide presence and preserved function and being the possible important player in better metabolic control in long-lasting diabetes type 1. These findings may open the area for trials to regenerate b-cells and save endogenous insulin secretion for many years after diagnosis. Last but not the least, C-peptide presents its own physiological effect on other tissues, among others on the endothelial function, thus participates in inhibiting micro- and macrovascular diabetes complications. The idea of C-peptide as a new, additional to insulin cure remains as much attractive as elusive.
Topics: Biomarkers; C-Peptide; Child; Diabetes Mellitus, Type 1; Humans; Insulin; Insulin Secretion
PubMed: 34514768
DOI: 10.5114/pedm.2021.107165 -
PloS One 2015C-peptide has intrinsic biological activity and may be renoprotective. We conducted a systematic review to determine whether C-peptide had a beneficial effect on renal... (Meta-Analysis)
Meta-Analysis Review
C-peptide has intrinsic biological activity and may be renoprotective. We conducted a systematic review to determine whether C-peptide had a beneficial effect on renal outcomes. MEDLINE, EMBASE, and the Cochrane Central Databases were searched for human and animal studies in which C-peptide was administered and renal endpoints were subsequently measured. We identified 4 human trials involving 74 patients as well as 18 animal studies involving 35 separate experiments with a total of 641 animals. In humans, the renal effects of exogenously delivered C-peptide were only studied in type 1 diabetics with either normal renal function or incipient nephropathy. Pooled analysis showed no difference in GFR (mean difference, -1.36 mL/min/1.73 m2, p = 0.72) in patients receiving C-peptide compared to a control group, but two studies reported a reduction in glomerular hyperfiltration (p<0.05). Reduction in albuminuria was also reported in the C-peptide group (p<0.05). In diabetic rodent models, C-peptide led to a reduction in GFR (mean difference, -0.62 mL/min, p<0.00001) reflecting a partial reduction in glomerular hyperfiltration. C-peptide also reduced proteinuria (mean difference, -186.25 mg/day, p = 0.05), glomerular volume (p<0.00001), and mesangial matrix area (p<0.00001) in diabetic animals without affecting blood pressure or plasma glucose. Most studies were relatively short-term in duration, ranging from 1 hour to 3 months. Human studies of sufficient sample size and duration are needed to determine if the beneficial effects of C-peptide seen in animal models translate into improved long-term clinical outcomes for patients with chronic kidney disease. (PROSPERO CRD42014007472).
Topics: Acute Kidney Injury; Animals; C-Peptide; Diabetes Mellitus, Experimental; Glomerular Filtration Rate; Humans; Kidney Diseases; Treatment Outcome
PubMed: 25993479
DOI: 10.1371/journal.pone.0127439