Impact of C-Peptide Preservation on Metabolic and Clinical Outcomes in the Diabetes Control and Complications Trial

Abstract

The Diabetes Control and Complications Trial established that a stimulated C-peptide concentration ≥0.2 nmol/L at study entry among subjects with up to a 5-year diabetes duration is associated with favorable metabolic and clinical outcomes over the subsequent 7 years of follow-up. Herein we further examine the association of both fasting and stimulated C-peptide numerical values with outcomes. In the intensive treatment group, for a 50% higher stimulated C-peptide on entry, such as from 0.10 to 0.15 nmol/L, HbA1c decreased by 0.07% (0.8 mmol/mol; P = 0.0003), insulin dose decreased by 0.0276 units/kg/day (P < 0.0001), hypoglycemia risk decreased by 8.2% (P < 0.0001), and the risk of sustained retinopathy was reduced by 25% (P = 0.0010), all in unadjusted analyses. Other than HbA1c, these effects remained significant after adjusting for the HbA1c on entry. While C-peptide was not significantly associated with the incidence of nephropathy, it was strongly associated with the albumin excretion rate. The fasting C-peptide had weaker associations with outcomes. As C-peptide decreased to nonmeasurable concentrations, the outcomes changed in a nearly linear manner, with no threshold or breakpoint. While preservation of stimulated C-peptide at ≥0.2 nmol/L has clinically beneficial outcomes, so also does an increase in the concentration of C-peptide across the range of values.

Demonstration of an Intrinsic Relationship Between Endogenous C-Peptide Concentration and Determinants of Glycemic Control in Type 1 Diabetes Following Islet Transplantation

“…It is of particular interest that this relationship is seen even in a program in which maintenance of sufficient insulin doses to achieve optimal glycemic control in all recipients at all time points is actively promoted using optimized multiple daily insulin injection or continuous subcutaneous insulin infusion regimens, as opposed to an approach targeted toward insulin withdrawal/cessation. This provides further evidence for an intrinsic and acute impact of current b-cell function on overall glycemic control, in keeping with the findings in C-peptidepositive participants in the DCCT (8,9).…”

“…Functional b-cell mass ,5% was not associated with measurable improvement in fasting glucose variability, and whether very low concentrations of C-peptide (,50 pmol/L) have meaningful effect will require further study. Reanalysis of DCCT data in shorter duration type 1 diabetes has also shown a near-linear relationship of C-peptide (without a discernible lower limit) with insulin dose, hypoglycemia risk, HbA 1c , and retinopathy (9).…”

“…Participants received a total of 20 islet transplants (single graft: n = 5; two grafts: n = 6; and three grafts: n = 1) with median (range) transplant mass per graft 5,830 (3,890-12,000) islet equivalents (IEQ)/kg body weight and overall transplant mass per recipient 11,232 (5,014-16,734) IEQ/kg. Median follow-up time was 18 (1-51) months posttransplant, and during this time, participants underwent 5 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) clinical assessments (Fig. 1).…”

“…This is justified by evidence from the Diabetes Control and Complications Trial (DCCT) that modest concentrations of C-peptide at study entry were associated with reduced microvascular complications over the next 6.5 years and reduced severe hypoglycemia (7,8). A recent reanalysis has demonstrated a continuous relationship between C-peptide concentration at trial commencement and subsequent insulin dose, HbA 1c , and retinopathy (9). The implication is that an increase in endogenous b-cell function facilitates improved glycemic control, leading to reduction in microvascular complications.…”

Prevalence of Detectable C-Peptide According to Age at Diagnosis and Duration of Type 1 Diabetes

“…A more recent DCCT report indicates that even lower levels of C-peptide are associated with fewer diabetes complications (6). Similarly, even individuals with type 1 diabetes who had only a partial response to islet cell transplantation (i.e., were not insulin independent or able to normalize glycemic control) were found to have a marked reduction in hypoglycemic events (7).…”