Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study.
Level 3 - non-randomized controlled study
Prospective cohort study with repeated measures over follow-up
PubMed 19515410 · doi:10.1016/S0140-6736(09)60619-X
What was done
Data were analyzed from the prospective Whitehall II occupational cohort of 6,538 British civil servants (71% male, 91% white) without diabetes at baseline, followed for a median of 9.7 years. A total of 505 incident diabetes cases were identified (49.1% diagnosed via oral glucose tolerance test). Retrospective trajectories of fasting glucose, 2-hour postload glucose, homeostasis model assessment (HOMA) insulin sensitivity, and HOMA beta-cell function were modeled up to 13 years before diagnosis (in diabetic participants) or the end of follow-up (in non-diabetic participants) using multilevel models adjusted for age, sex, and ethnic origin.
What was found
Non-diabetic participants (10,989 measurements) showed linear trends across metabolic measures, with insulin secretion remaining unchanged. In participants who developed diabetes (801 measurements): - Fasting glucose followed a linear rise followed by a steep increase from 5.79 mmol/L to 7.40 mmol/L starting 3 years before diagnosis. - 2-hour postload glucose increased rapidly starting 3 years before diagnosis, from 7.60 mmol/L to 11.90 mmol/L. - HOMA insulin sensitivity decreased steeply during the 5 years before diagnosis to 86.7%. - HOMA beta-cell function increased between years 4 and 3 before diagnosis (from 85.0% to 92.6%) and then decreased to 62.4% at diagnosis.
Why it matters
This study maps the timeline of pre-diabetic metabolic decline, identifying a critical window 3 to 6 years before diagnosis when insulin sensitivity drops, compensatory beta-cell secretion fails, and glycaemia rapidly accelerates.
Limits
The study sample is an occupational cohort that was overwhelmingly male (71%) and white (91%), limiting generalizability. Insulin sensitivity and beta-cell function were estimated using mathematical surrogate models (HOMA) rather than gold-standard clamp methods or direct dynamic testing.
Cited by
- supports It takes a time lag of 10 to 20 years for a person to progress from normal insulin function to overt diabetic abnormality.