Persistent C‐peptide is associated with reduced hypoglycaemia but not HbA_1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

Abstract

Aims Most people with Type 1 diabetes have low levels of persistent endogenous insulin production. The Diabetes Control and Complications Trial showed that close to diagnosis preserved endogenous insulin was associated with lower HbA1c, hypoglycaemia and complication rates, when intensively treated. We aimed to assess the clinical impact of persistent C‐peptide on rate of hypoglycaemia and HbA1c in those with long duration (> 5 years) Type 1 diabetes. Methods We conducted a cross‐sectional case–control study of 221 people (median age 24 years) with Type 1 diabetes. We confirmed ongoing endogenous insulin secretion by measuring C‐peptide after a mixed‐meal tolerance test. We compared self‐reported hypoglycaemia (n = 160), HbA1c, insulin dose and microvascular complications (n = 140) in those with preserved and low C‐peptide. Results Stimulated median (IQR) C‐peptide was 114 (43, 273) pmol/l and < 3 (< 3, < 3) pmol/l in those with preserved and low C‐peptide respectively. Participants with preserved C‐peptide had lower reported monthly rates of hypoglycaemia, with 21% fewer symptomatic episodes, 5.9 vs. 7.5 [incidence rate ratio (IRR) 0.79, P = 0.001], and 65% fewer asymptomatic episodes, 1.0 vs. 2.9 (IRR 0.35, P < 0.001). Those with preserved C‐peptide had a lower insulin dose (0.68 vs. 0.81 units/kg, P = 0.01) but similar HbA1c (preserved 69 vs. low 67 mmol/mol, P = 0.06). Conclusions Adults with Type 1 diabetes and preserved endogenous insulin production receiving usual care in the UK have lower daily insulin doses and fewer self‐reported hypoglycaemic episodes, but no difference in HbA1c. This is consistent with non‐intensive treatment in previous studies, and suggests a need to consider therapy intensification to gain full benefit of preserved endogenous insulin.

Preserved C-peptide secretion is associated with fewer low-glucose events and lower glucose variability on flash glucose monitoring in adults with type 1 diabetes

“…Size of dot corresponds to age at diagnosis. Horizontal lines represent 10 pmol/l and 50 pmol/l thresholds with findings from several previous investigations [9][10][11], although significant differences were limited to asymptomatic hypoglycaemia in our study. Marren et al [9] describe significant differences in self-reported symptomatic and asymptomatic hypoglycaemia in those with preserved C-peptide, although the median C-peptide concentration in this group (114 pmol/l) was substantially higher than in our study (32 pmol/l).…”

“…Horizontal lines represent 10 pmol/l and 50 pmol/l thresholds with findings from several previous investigations [9][10][11], although significant differences were limited to asymptomatic hypoglycaemia in our study. Marren et al [9] describe significant differences in self-reported symptomatic and asymptomatic hypoglycaemia in those with preserved C-peptide, although the median C-peptide concentration in this group (114 pmol/l) was substantially higher than in our study (32 pmol/l). While we report random plasma C-peptide and Marren et al [9] used values after a standard mixed-meal tolerance test, the correlation between random and post-mixed-meal C-peptide is known to be very strong (R = 0.91) and is unlikely to substantially limit the comparability of these studies [18].…”

“…These associations were not noted in the recent Joslin Medalist Study which assessed individuals with long-standing type 1 diabetes [5]. Preservation of C-peptide has been associated with lower self-reported rates of symptomatic, asymptomatic and severe hypoglycaemia, although not with measures of impaired awareness, in a number of observational studies [9][10][11]. Many C-peptide assays in current clinical use provide a limit of quantification at around 50 pmol/l; however, C-peptide levels >10 pmol/l have been independently associated with a lower risk of diabetes complications [10].…”

Fasting C‐peptide, a biomarker for hypoglycaemia risk in insulin‐naïve people with type 2 diabetes initiating basal insulin glargine 100 U/mL

“…However, the subgroup with the lowest FCP identified patients who were more vulnerable to hypoglycaemia despite requiring lower basal insulin doses, presumably related to impaired glucose counter‐regulation with deficient glucagon responses to hypoglycaemia consequent to pancreatic islet beta‐ and alpha‐cell dysregulation . Interestingly, even at persistently low FCP levels (0.02 nmol/L) in people with type 1 diabetes mellitus (T1DM), small differences of FCP above or below 0.02 nmol/L may contribute to changing the risk of hypoglycaemia . Therefore, groups/phenotypes with low or very low FCP levels in T2DM and particularly in T1DM, respectively, require a more cautious approach to initiating and titrating basal (and prandial) insulin to limit the risk of hypoglycaemia.…”

“…24 Interestingly, even at persistently low FCP levels (0.02 nmol/L) in people with type 1 diabetes mellitus (T1DM), small differences of FCP above or below 0.02 nmol/L may contribute to changing the risk of hypoglycaemia. 25 Therefore, groups/phenotypes with low or very low FCP levels in T2DM and particularly in T1DM, respectively, require a more cautious approach to initiating and titrating basal (and prandial) insulin to limit the risk of hypoglycaemia.…”