Trajectories of Glycaemia, Insulin Sensitivity, and Insulin Secretion Before Diagnosis of Type 2 Diabetes: An Analysis From the Whitehall II Study

Lancet. 2009 Jun 27;373(9682):2215-21. doi: 10.1016/S0140-6736(09)60619-X. Epub 2009 Jun 8.

Abstract

Background: Little is known about the timing of changes in glucose metabolism before occurrence of type 2 diabetes. We aimed to characterise trajectories of fasting and postload glucose, insulin sensitivity, and insulin secretion in individuals who develop type 2 diabetes.

Methods: We analysed data from our prospective occupational cohort study (Whitehall II study) of 6538 (71% male and 91% white) British civil servants without diabetes mellitus at baseline. During a median follow-up period of 9.7 years, 505 diabetes cases were diagnosed (49.1% on the basis of oral glucose tolerance test). We assessed retrospective trajectories of fasting and 2-h postload glucose, homoeostasis model assessment (HOMA) insulin sensitivity, and HOMA beta-cell function from up to 13 years before diabetes diagnosis (diabetic group) or at the end of follow-up (non-diabetics).

Findings: Multilevel models adjusted for age, sex, and ethnic origin confirmed that all metabolic measures followed linear trends in the group of non-diabetics (10,989 measurements), except for insulin secretion that did not change during follow-up. In the diabetic group (801 measurements), a linear increase in fasting glucose was followed by a steep quadratic increase (from 5.79 mmol/L to 7.40 mmol/L) starting 3 years before diagnosis of diabetes. 2-h postload glucose showed a rapid increase starting 3 years before diagnosis (from 7.60 mmol/L to 11.90 mmol/L), and 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 until diagnosis (to 62.4%).

Interpretation: In this study, we show changes in glucose concentrations, insulin sensitivity, and insulin secretion as much as 3-6 years before diagnosis of diabetes. The description of biomarker trajectories leading to diabetes diagnosis could contribute to more-accurate risk prediction models that use repeated measures available for patients through regular check-ups.

Funding: Medical Research Council (UK); Economic and Social Research Council (UK); British Heart Foundation (UK); Health and Safety Executive (UK); Department of Health (UK); National Institute of Health (USA); Agency for Health Care Policy Research (USA); the John D and Catherine T MacArthur Foundation (USA); and Academy of Finland (Finland).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Biomarkers / metabolism
  • Blood Glucose / metabolism*
  • Diabetes Mellitus, Type 2* / diagnosis
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / etiology
  • Diabetes Mellitus, Type 2* / metabolism
  • Fasting
  • Female
  • Glucose Tolerance Test
  • Homeostasis
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / metabolism
  • Linear Models
  • London / epidemiology
  • Male
  • Mass Screening
  • Middle Aged
  • Prediabetic State* / complications
  • Prediabetic State* / epidemiology
  • Prediabetic State* / metabolism
  • Prospective Studies
  • Risk Assessment / methods*
  • Risk Factors
  • Time Factors

Substances

  • Biomarkers
  • Blood Glucose
  • Insulin