Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study
Open accessAbstract
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).
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Control participants did not experience a change in insulin parameters during the study period.
“Conversely, control participants did not experience a change in insulin parameters during the study period.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
The Results section on HOMA β-cell function reports that calculated insulin secretion was flat in controls between 13 and 4 years before the end of follow-up. But the Results section on HOMA insulin sensitivity reports that controls’ insulin sensitivity decreased during part of the study period. The claim is therefore too broad in saying that control participants had no change in insulin parameters. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEvidence from epidemiological studies with repeated measures of glucose and insulin parameters over many years suggests that the development of T2DM is a gradual process.
“Evidence from epidemiological studies with repeated measures of glucose and insulin parameters over many years suggests that the development of T2DM is a gradual process 54, 55.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
Individuals who developed T2DM had lowered insulin sensitivity at baseline and showed a marked decrease in insulin sensitivity in the 5 years before onset of the disease.
“Individuals who developed T2DM had lowered insulin sensitivity at baseline and showed a marked decrease in insulin sensitivity in the 5 years before onset of the disease.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
In control participants who did not develop T2DM, glucose parameters increased slightly over time (average fasting value of 5.26 mmol/l at baseline, increasing to 5.31 mmol/l at the end of follow-up) but no abrupt rises in concentrations were detected.
“In the control participants who did not develop T2DM, glucose parameters increased slightly over time (average fasting value of 5.26 mmol/l at baseline, increasing to 5.31 mmol/l at the end of follow-up) but no abrupt rises in concentrations were detected.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
In incident T2DM cases, glucose values increased in a linear manner (average fasting value of 5.47 mmol/l at baseline) until 2-6 years before T2DM diagnosis, when abrupt elevations in glucose concentrations occurred (average fasting value ranging from 5.79 mmol/l 3 years before diagnosis to 7.40 mmol/l at the end of follow-up).
“The glucose values of the incident T2DM cases increased in a linear manner (average fasting value of 5.47 mmol/l at baseline), until 2-6 years before T2DM diagnosis when abrupt elevations in glucose concentrations (average fasting value ranging from 5.79 mmol/l 3 years before diagnosis to 7.40 mmol/l at the end of follow-up) were observed.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
Individuals who developed T2DM had elevated insulin secretion until 3-4 years before diagnosis, when the levels of insulin declined steeply.
“These participants also had elevated insulin secretion until 3-4 years before diagnosis when the levels of insulin declined steeply.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
Data from over 6,500 initially healthy individuals suggest that fasting levels of glucose and post-load glucose concentrations are higher among individuals who develop T2DM than in those who do not develop it up to 13 years before disease onset.
“For example, data from over 6,500 initially healthy individuals suggest that fasting levels of glucose and post-load glucose concentrations are higher among individuals who develop T2DM than in those who do not develop it up to 13 years before disease onset 55.”
From Type 2 diabetes mellitus and psychological stress — a modifiable risk factor (2017) · cites this paper as [55]
In progression to type 2 diabetes, beta cell function is initially increased, maintaining glucose levels at higher but still normal levels; around 3 years before onset, decreasing insulin secretion and an accelerated rise in blood glucose levels are observed.
“Initially, beta cell function is increased, maintaining glucose levels at higher but still normal levels and below the diagnostic threshold for diabetes. However, the ability of the beta cell to maintain this response is finite in some individuals. As the beta cells undergo a process of failure that has been linked with a number of molecular processes, including oxidative and endoplasmic reticulum”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [75]
Natural history studies of cohorts progressing to type 2 diabetes have demonstrated early impairments in insulin sensitivity evident more than 10 years in advance of diabetes development.
“Natural history studies of cohorts progressing to type 2 diabetes have demonstrated early impairments in insulin sensitivity, which are evident more than 10 years in advance of diabetes development.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [75]
The development of diabetes from normal glucose tolerance is a continuous process.
“As evidenced by studies with repeat measures of glucose levels, insulin sensitivity and insulin secretion, the development of diabetes from NGT is a continuous process.35,36,40,41”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
In the Whitehall II study, people who developed diabetes had increased glucose values 13 years before diagnosis, with glucose tightly regulated within the normal range until 2-6 years before diagnosis, when an abrupt increase occurred.
“In people who developed diabetes, increased glucose values were observed already at the beginning of the follow-up, 13 years before diagnosis, although glucose values seemed to be tightly regulated within the normal range until 2–6 years before diagnosis when an abrupt increase was found.”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
Most recent attempts to improve diabetes prediction using measurements from genetics and transcriptomics have not shown significant improvements in predictive performance.
“Most recent attempts to improve diabetes prediction using measurements from genetics and transcriptomics have not shown significant improvements in predictive performance but it is unknown whether serial measurements may decrease variations in non-genetic biomarkers allowing for a more precise estimation of their levels.34–36”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
Much of the first and second stages of diabetes development occur before the prediabetic phase is achieved.
“Much of the first and second stages therefore occur before the prediabetic phase is achieved.”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
In Whitehall II, insulin sensitivity was reduced 13 years before diabetes onset, with a steeper decline 5 years before diagnosis.
“Figure 2 shows that insulin sensitivity was reduced already 13 years before the onset of diabetes, with a steeper decline observed 5 years before diagnosis.”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
In Whitehall II, insulin secretion was elevated throughout the 13-year observation period, increased markedly 4-3 years before diagnosis, and then steeply decreased until diagnosis.
“Insulin secretion was elevated throughout the 13-year observation period and showed a marked increase 4-3 years before diagnosis, followed by a steep decrease until diagnosis.36”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
The second stage likely starts when fasting and postload glucose levels are within the normal range and is usually accompanied by a decrease in acute insulin secretion at FPG levels around 5.6 mmol/L.
“This period is likely to start when fasting and postload glucose levels are within the normal range36,39,43 and is usually accompanied by a decrease in acute insulin secretion that is present at FPG levels around 5.6 mmol/L.39”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
The third stage of diabetes development probably extends from prediabetes to manifest diabetes.
“This period probably extends from prediabetes to manifest diabetes.”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
The third stage is the unstable early decompensation period, when β-cells become unable to compensate for insulin resistance and glucose levels start to increase rapidly.
“During the unstable early decompensation period, the third stage of diabetes development, the β-cells become unable to compensate for a given insulin resistance and consequently glucose levels start to increase rapidly39,43 as it was seen in Whitehall II and other longitudinal studies.36,41”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [36]
By the time type 2 diabetes is diagnosed through hyperglycemia from relative insulin deficiency, significant pancreatic alpha-cell insufficiency has already occurred.
“by the time relative insulin deficiency manifests itself as hyperglycemia and the diagnosis of type 2 diabetes is made, significant pancreatic α-cell insufficiency has already occurred1.”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [1]
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- Authors
- Tabák, A. G., Jokela, M., Akbaraly, T. N., Brunner, E. J., Kivimäki, M., & Witte, D. R.
- Affiliations
- University of Helsinki (FI)
- Inserm (FR)
- University College London (GB)
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2009-06
- Volume
- 373
- Issue
- 9682
- Pages
- 2215-2221
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC2726723
- OpenAlex
- W2100271953
- Cited by
- 898
- References
- 45
- Citations by year
- 2026: 52 · 2025: 44 · 2024: 57 · 2023: 63 · 2022: 60 · 2021: 66 · 2020: 53 · 2019: 49 · 2018: 52 · 2017: 53 · 2016: 62 · 2015: 52 · 2014: 52 · 2013: 56 · 2012: 50
- FWCI
- 30.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- John D. and Catherine T. MacArthur Foundation (HS06516)
- National Institute for Health and Care Research
- British Heart Foundation (HS06516, RG/07/008/23674)
- Health and Safety Executive
- Agency for Healthcare Research and Quality (HS06516)
- Medical Research Council (HS06516)
- Economic and Social Research Council
- National Institute on Aging (AG 13196, R37AG013196, R01AG013196)
- National Heart, Lung, and Blood Institute (HL36310, R01HL036310)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 2 diabetes, prediabetes, insulin sensitivity, insulin secretion, beta-cell function, fasting blood glucose, post-load glucose, HOMA, diabetes risk prediction, Whitehall II study, public sector employees, occupational cohort, oral glucose tolerance test, HOMA-IR
- MeSH terms
- Adult, Blood Glucose, Diabetes Mellitus, Type 2, Fasting, Female, Glucose Tolerance Test, Homeostasis, Humans, Insulin, Insulin Resistance, London, Male, Mass Screening, Middle Aged, Prediabetic State, Prospective Studies, Risk Factors, Time Factors, Biomarkers, Linear Models, Risk Assessment, Insulin-Secreting Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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