Random non-fasting C-peptide testing can identify patients with insulin-treated type 2 diabetes at high risk of hypoglycaemia

Abstract

Aims/hypothesisThe aim of this study was to determine whether random non-fasting C-peptide (rCP) measurement can be used to assess hypoglycaemia risk in insulin-treated type 2 diabetes.MethodsWe compared continuous glucose monitoring-assessed SD of blood glucose and hypoglycaemia duration in 17 patients with insulin-treated type 2 diabetes and severe insulin deficiency (rCP < 200 pmol/l) and 17 matched insulin-treated control patients with type 2 diabetes but who had preserved endogenous insulin (rCP > 600 pmol/l). We then assessed the relationship between rCP and questionnaire-based measures of hypoglycaemia in 256 patients with insulin-treated type 2 diabetes and a comparison group of 209 individuals with type 1 diabetes.ResultsContinuous glucose monitoring (CGM)-assessed glucose variability and hypoglycaemia was greater in individuals with rCP < 200 pmol/l despite similar mean glucose. In those with low vs high C-peptide, SD of glucose was 4.2 (95% CI 3.7, 4.6) vs 3.0 (2.6, 3.4) mmol/l (p < 0.001). In the low-C-peptide vs high-C-peptide group, the proportion of individuals experiencing sustained hypoglycaemia ≤ 4 mmol/l was 94% vs 41% (p < 0.001), the mean rate of hypoglycaemia was 5.5 (4.4, 6.7) vs 2.1 (1.4, 2.9) episodes per person per week (p = 0.004) and the mean duration was 630 (619, 643) vs 223 (216, 230) min per person per week (p = 0.01). Hypoglycaemia ≤ 3 mmol/l was infrequent in individuals with preserved C-peptide (1.8 [1.2, 2.6] episodes per person per week vs 0.4 [0.1, 0.8] episodes per person per week for low vs high C-peptide, p = 0.04) and only occurred at night. In a population-based cohort with insulin-treated type 2 diabetes, self-reported hypoglycaemia was twice as frequent in those with rCP < 200 pmol/l (OR 2.0, p < 0.001) and the rate of episodes resulting in loss of consciousness or seizure was five times higher (OR 5.0, p = 0.001). The relationship between self-reported hypoglycaemia and C-peptide was similar in individuals with type 1 and type 2 diabetes.Conclusions/interpretationLow rCP is associated with increased glucose variability and hypoglycaemia in patients with insulin-treated type 2 diabetes and represents a practical, stable and inexpensive biomarker for assessment of hypoglycaemia risk.Electronic supplementary materialThe online version of this article (10.1007/s00125-017-4449-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Comment on: “Dulaglutide treatment results in effective glycaemic control in latent autoimmune diabetes in adults (LADA): A post‐hoc analysis of the AWARD‐2, −4 and −5 trials”

“…While AWARD-4 was a study in insulin-treated participants, those receiving multiple daily injections (≥ 3) were excluded, which will have reduced the prevalence of severe insulin deficiency, as these patients will commonly have progressed to basal-bolus therapy. 4 In addition, the threshold chosen for GAD positivity in the study by Pozzilli et al appears to have substantially lower specificity than that used in our cohort. As detectable GAD islet autoantibodies are a common finding in healthy individuals without diabetes, it is important that a threshold based on a centile cut-off derived from a control (without diabetes) population is used to robustly define a positive test.…”

Persistent C‐peptide is associated with reduced hypoglycaemia but not HbA1c in adults with longstanding Type 1 diabetes: evidence for lack of intensive treatment in UK clinical practice?

“…Hope et al [23] observed an approximate doubling in self-reported hypoglycaemia in those with Type 1 diabetes with C-peptide < 200 pmol/l compared with > 200 pmol/l. This study focused on people who were older when diagnosed, with group durations of 25 vs. 10 years respectively [23]. Kuhtreiber et al [8] also used the Clarke score to assess hypoglycaemia.…”

“…The limitation of achieving optimal glycaemic control with intensive treatment in Type 1 diabetes is usually hypoglycaemia, which prevents up-titration of insulin doses. The reduced glucose variability and better hypoglycaemia counter-regulation associated with preservation of endogenous insulin secretion [16,[23][24][25] means that with intensive treatment an adult with retained endogenous insulin secretion can obtain a lower HbA 1c at an acceptable level of hypoglycaemia than would be possible where endogenous insulin is absent. Our findings are consistent with previous research on the clinical impact of C-peptide.…”

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

“…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].…”

“…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]. C-peptide persistence has been associated with improved continuous glucose monitoring (CGM) 'time in range' in a largely paediatric cohort of people with recently diagnosed type 1 diabetes [12] and with lower glucose variability and low-glucose events in type 2 diabetes [11]. However, little is known of the effects in adults with type 1 diabetes and beyond the first few years after diagnosis.…”