High residual C-peptide likely contributes to glycemic control in type 1 diabetes

Abstract

BACKGROUNDResidual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known.METHODSWe studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017-0.200; n = 16), intermediate (>0.200-0.400; n = 15), or high (>0.400; n = 17). We compared the groups' glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp.RESULTSLow and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group.CONCLUSIONThese results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control.FUNDINGFunding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.

Keywords: Beta cells; Diabetes; Endocrinology; Islet cells.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. Study design.

Eligibility was determined at a screening visit where measurement of nonfasting C-peptide was used to balance recruitment of participants to C-peptide groups. C-peptide group was ultimately determined from the mixed-meal tolerance test (MMTT) peak C-peptide measured at visit 1. Participants in the detectable (low, intermediate, and high) C-peptide groups underwent a glucose-potentiated arginine test at visit 2, and participants in the undetectable (negative) and detectable C-peptide groups underwent a hyperinsulinemic-euglycemic followed by hypoglycemic clamp at visit 3, as well as continuous glucose monitoring (CGM).

Figure 2. Mixed-meal tolerance test (MMTT).

(A and B) Serum C-peptide response to ingestion of a standardized liquid meal was different by group based on peak C-peptide level (negative, <0.007 pmol/mL [<0.02 ng/mL]; low, 0.017–0.200 pmol/mL [0.05–0.60 ng/mL]; intermediate, >0.200–0.400 pmol/mL [>0.60–1.20 ng/mL]; high, >0.400 pmol/mL [>1.20 ng/mL]), and by continuous relationship to peak C-peptide. (C and D) Plasma glucagon response was not different while plasma glucose-dependent insulinotropic polypeptide (GIP) response was different in response to meal ingestion by peak C-peptide level group. Data are means with error bars denoting 95% confidence intervals (CIs).

Figure 3. Glucose-potentiated arginine (GPA) test.

(A and B) Serum C-peptide and proinsulin responses to an approximately 230-mg/dL hyperglycemic clamp and to the injection of arginine after 45 minutes of glucose infusion were different by group based on MMTT peak C-peptide level. (C) Plasma glucagon responses to GPA were not different by group. (D and E) Relationship between the acute C-peptide and proinsulin responses to GPA and MMTT peak C-peptide. Data are means with error bars denoting 95% CIs.

Figure 4. Hyperinsulinemic-euglycemic (EU) followed by hypoglycemic (HYPO) clamp.

(A) Serum insulin levels were not statistically different across groups based on MMTT peak C-peptide levels during the EU or HYPO phase of testing. (B) Serum glucose levels were well matched across groups during the EU (~90 mg/dL) and HYPO (~50 mg/dL) phases of testing. Data are means with error bars denoting 95% CIs.

Figure 5. β Cell and α cell responses from the euglycemic (EU) to hypoglycemic (HYPO) clamp condition.

(A and B) Suppression of C-peptide and increase in glucagon were greater by group based on MMTT peak C-peptide level. (C and D) Relationships of the change in C-peptide and glucagon levels between the EU and HYPO conditions to MMTT peak C-peptide. Data are means with error bars denoting 95% CIs.

Figure 6. Glucose counterregulatory responses from the euglycemic (EU) to hypoglycemic (HYPO) clamp condition.

No differences were seen across groups based on MMTT peak C-peptide level for responses of counterregulatory endogenous glucose production (A), serum free fatty acids (B), plasma epinephrine (C), or autonomic symptom generation (D). Data are means with error bars denoting 95% CIs.

Figure 7. Glucose time in range by MMTT peak C-peptide.

Relationship between proportion of glucose time in range of 70–180 mg/dL by CGM and MMTT peak C-peptide. All individuals in the high C-peptide group (MMTT peak C-peptide >0.400 pmol/mL) maintained greater than 50% time in the target glucose range.