Predicting impending beta cell loss and dysglycemia in asymptomatic type 1 diabetes - Validation of minimally invasive markers against the hyperglycemic clamp test.

We aim to monitor functional beta cell mass and insulin action using
the gold standard hyperglycemic clamp test (HCT) in asymptomatic
type 1 diabetes (T1D) in relation to known determinants of disease
progression. This may help to unravel the heterogeneous nature of
pre-T1D. The majority of beta cell loss is hypothesized to occur within
2 years prior to diagnosis. Simultaneously, promising minimally
invasive techniques (continuous glucose monitoring [CGM]-derived
indices of glycemic variability, proinsulin, proinsulin:C-peptide ratio),
will be validated against HCT in order to derive objective criteria for
identifying individuals at high risk of impending major beta cell loss
and clinical onset, and to develop an affordable simple screening for
large scale application. Using the capacity of a nationwide clinical
network to identify multiple autoantibody-positive (mAAb+) firstdegree relatives (FDRs) of T1D patients, normo- or dysglycemic
mAAb+ FDRs (5-39 years) are enrolled and followed twice a year by
oral glucose tolerance tests, CGM and HCT for at least 2 years or to
onset. Time-to-event analysis and machine learning techniques will
be used to identify best predictors of progression to dysglycemia or
clinical onset. The results may facilitate early diagnosis, avoidance of
ketoacidosis, development of new prevention trials in pre-T1D, and
might serve as a first step in the implementation of a cost-effective
population-wide screening and prevention strategy long-term.