Relationship between glycaemic variability and hyperglycaemic clamp-derived functional variables in (impending) type 1 diabetes

Abstract

Aims/hypothesis We examined whether measures of glycaemic variability (GV), assessed by continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG), can complement or replace measures of beta cell function and insulin action in detecting the progression of preclinical disease to type 1 diabetes. Methods Twenty-two autoantibody-positive (autoAb + ) firstdegree relatives (FDRs) of patients with type 1 diabetes who were themselves at high 5-year risk (50%) for type 1 diabetes underwent CGM, a hyperglycaemic clamp test and OGTT, and were followed for up to 31 months. Clamp variables were used to estimate beta cell function (first-phase [AUC 5-10 min ] and second-phase [AUC 120-150 min ] C-peptide release) combined with insulin resistance (glucose disposal rate; M 120-150 min ). Age-matched healthy volunteers (n =20) and individuals with recent-onset type 1 diabetes (n=9) served as control groups. Results In autoAb + FDRs, M 120-150 min below the 10th percentile (P10) of controls achieved 86% diagnostic efficiency in discriminating between normoglycaemic FDRs and individuals with (impending) dysglycaemia. M 120-150 min outperformed AUC 5-10 min and AUC 120-150 min C-peptide below P10 of controls, which were only 59-68% effective. Among GV variables, CGM above the reference range was better at detecting (impending) dysglycaemia than elevated SMBG (77-82% vs 73% efficiency). Combined CGM measures were equally efficient as M 120-150 min (86%). Daytime GV variables were inversely correlated with clamp variables, and more strongly with M 120-150 min than with AUC 5-10 min or AUC 120-150 min C-peptide. Conclusions/interpretation CGM-derived GV and the glucose disposal rate, reflecting both insulin secretion and action, outperformed SMBG and first-or second-phase AUC C-peptide in identifying FDRs with (impending) dysglycaemia or diabetes. Our results indicate the feasibility of developing minimally invasive CGM-based criteria for close metabolic monitoring and as outcome measures in trials.

Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio

“…They are in line with previous reports that insulin resistance makes only a borderline contribution to risk of progression to diabetes in individuals with an already compromised beta cell function [41–43]. Larger follow-up studies in risk groups comparing HOMA2-IR-corrected PI:C, clamp-derived measures [5], HbA1c [38], and glycemic variability [13] are needed to further document consistency of results over time, and to determine generally applicable cutoff values for HOMA2-IR-corrected PI:C in the perspective of further refining staging of presymptomatic type 1 diabetes [4], identifying rapid progressors and establishing minimally invasive criteria for inclusion in secondary prevention trials.…”

“…For large scale implementation more simple, minimally invasive alternatives to the hyperglycemic clamp are warranted [5, 13]. An increased proinsulin:C-peptide ratio (PI:C) has been proposed as functional screening marker to identify multiple autoantibody-positive individuals at high risk of impending diabetes [14–16].…”

ISPAD Clinical Practice Consensus Guidelines 2018: Stages of type 1 diabetes in children and adolescents

“…Interestingly, antibody positive individuals may experience episodes of hypoglycemia likely due to asynchronous release of insulin in response to meals . Consistent with this, continuous glucose monitoring detects increased blood glucose variability before the onset of insulin therapy and before progression to symptomatic dysglycemia …”

Dysregulation of glucose metabolism in preclinical type 1 diabetes

“…In a group of 14 children positive for islet autoantibodies a 4‐day CGM showed that these children have increased glycemic variability and spend more time above 140 mg/dL (7.8 mmol/L) when compared with autoantibody negative controls . Another study including 22 autoantibody positive FDRs of patients with T1D also found that glycemic variability during a 5‐day CGM was increased in these subjects as compared with 20 healthy autoantibody negative controls without a relative with T1D . These preliminary observations will be validated in multiple ongoing CGM studies.…”