Adam G. Tabak

Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study

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).

Antidepressant Medication Use, Weight Gain, and Risk of Type 2 Diabetes A population-based study

OBJECTIVE To examine antidepressant medication use as a risk factor for type 2 diabetes and weight gain. RESEARCH DESIGN AND METHODS A series of nested studies within a prospective cohort of 151,347 working-aged men and women including 9,197 participants with continuing antidepressant medication, 224 with severe depression, and 851 with incident type 2 diabetes during a mean follow-up of 4.8 years, as indicated by national health and prescription registers (the Public Sector study, Finland 1995–2005). RESULTS In the first analysis, the case subjects were individuals with incident type 2 diabetes compared with matched diabetes-free control subjects. Antidepressant use of ≥200 defined daily doses was associated with a doubling of diabetes risk in both participants with no indication of severe depression (odds ratio 1.93 [95% CI 1.48–2.51]) and participants with severe depression (2.65 [1.31–5.39]). In further analyses, the exposed group was antidepressant users and the reference group was nonusers matched for depression-related characteristics. The 5-year absolute risk of diabetes was 1.1% for nonusers, 1.7% for individuals treated with 200–399 defined daily doses a year, and 2.3% for those with ≥400 defined daily doses (Ptrend < 0.0001). An average self-reported weight gain, based on repeated surveys, was 1.4 kg (2.5%) among nonusers and 2.5 kg (4.3%) among users of ≥200 defined daily doses (Ptrend < 0.0001). Separate analyses for tricyclic antidepressants and selective serotonin reuptake inhibitors replicated these findings. CONCLUSIONS In these data, continuing use of antidepressant medication was associated with an increased relative risk of type 2 diabetes, although the elevation in absolute risk was modest.

Physical Activity and Inflammatory Markers Over 10 Years Follow-Up in Men and Women From the Whitehall II Cohort Study

Background— Inflammatory processes are putative mechanisms underlying the cardioprotective effects of physical activity. An inverse association between physical activity and inflammation has been demonstrated, but no long-term prospective data are available. We therefore examined the association between physical activity and inflammatory markers over a 10-year follow-up period. Methods and Results— Participants were 4289 men and women (mean age, 49.2 years) from the Whitehall II cohort study. Self-reported physical activity and inflammatory markers (serum high-sensitivity C-reactive protein and interleukin-6) were measured at baseline (1991) and follow-up (2002). Forty-nine percent of the participants adhered to standard physical activity recommendations for cardiovascular health (2.5 h/wk moderate to vigorous physical activity) across all assessments. Physically active participants at baseline had lower C-reactive protein and interleukin-6 levels, and this difference remained stable over time. Compared with participants who rarely adhered to physical activity guidelines over the 10-year follow-up, the high-adherence group displayed lower loge C-reactive protein (&bgr;=−0.07; 95% confidence interval, −0.12 to −0.02) and loge interleukin-6 (&bgr;=−0.07; 95% confidence interval, −0.10 to −0.03) at follow-up after adjustment for a range of covariates. Compared with participants who remained stable, those who reported an increase in physical activity of at least 2.5 h/wk displayed lower loge C-reactive protein (&bgr; coefficient=−0.05; 95% confidence interval, −0.10 to −0.001) and loge interleukin-6 (&bgr; coefficient=−0.06; 95% confidence interval, −0.09 to −0.03) at follow-up. Conclusions— Regular physical activity is associated with lower markers of inflammation over 10 years of follow-up and thus may be important in preventing the proinflammatory state seen with aging.

Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes: The Whitehall II Study

OBJECTIVE—Interleukin-1 receptor antagonist (IL-1Ra), a natural inhibitor of interleukin-1β, has been shown to improve β-cell function and glycemic control in patients with type 2 diabetes. The aim of this study was to investigate whether baseline systemic levels of IL-1Ra are associated with incident type 2 diabetes during more than 10 years of follow-up. RESEARCH DESIGN AND METHODS—We measured serum IL-1Ra concentrations in a nested case-control study (181 case and 376 age-, sex-, and BMI-matched normoglycemic control subjects) within the Whitehall II cohort (U.K.). RESULTS—IL-1Ra concentrations were higher in case subjects (P = 0.0006) and associated with incident type 2 diabetes (odds ratio for a 1-SD increase of IL-1Ra 1.48 [95% CI 1.21–1.80]). This association remained significant after adjustment for multiple potential confounders but was attenuated by adjusting for 2-h glucose. CONCLUSIONS—Our findings indicate that individuals who will develop type 2 diabetes are characterized by a complex immune activation that also includes upregulation of the anti-inflammatory cytokine IL-1Ra.

Contribution of modifiable risk factors to social inequalities in type 2 diabetes: prospective Whitehall II cohort study

Objective To assess the contribution of modifiable risk factors to social inequalities in the incidence of type 2 diabetes when these factors are measured at study baseline or repeatedly over follow-up and when long term exposure is accounted for. Design Prospective cohort study with risk factors (health behaviours (smoking, alcohol consumption, diet, and physical activity), body mass index, and biological risk markers (systolic blood pressure, triglycerides and high density lipoprotein cholesterol)) measured four times and diabetes status assessed seven times between 1991-93 and 2007-09. Setting Civil service departments in London (Whitehall II study). Participants 7237 adults without diabetes (mean age 49.4 years; 2196 women). Main outcome measures Incidence of type 2 diabetes and contribution of risk factors to its association with socioeconomic status. Results Over a mean follow-up of 14.2 years, 818 incident cases of diabetes were identified. Participants in the lowest occupational category had a 1.86-fold (hazard ratio 1.86, 95% confidence interval 1.48 to 2.32) greater risk of developing diabetes relative to those in the highest occupational category. Health behaviours and body mass index explained 33% (−1% to 78%) of this socioeconomic differential when risk factors were assessed at study baseline (attenuation of hazard ratio from 1.86 to 1.51), 36% (22% to 66%) when they were assessed repeatedly over the follow-up (attenuated hazard ratio 1.48), and 45% (28% to 75%) when long term exposure over the follow-up was accounted for (attenuated hazard ratio 1.41). With additional adjustment for biological risk markers, a total of 53% (29% to 88%) of the socioeconomic differential was explained (attenuated hazard ratio 1.35, 1.05 to 1.72). Conclusions Modifiable risk factors such as health behaviours and obesity, when measured repeatedly over time, explain almost half of the social inequalities in incidence of type 2 diabetes. This is more than was seen in previous studies based on single measurement of risk factors.

Accelerated Increase in Serum Interleukin-1 Receptor Antagonist Starts 6 Years Before Diagnosis of Type 2 Diabetes Whitehall II Prospective Cohort Study

OBJECTIVE Although interleukin-1 receptor antagonist (IL-1Ra) treatment is associated with improved β-cell function and glycemic control in patients with type 2 diabetes, its role in the development of type 2 diabetes remains unclear. We used repeated measurements to characterize IL-1Ra trajectories in individuals who developed type 2 diabetes. RESEARCH DESIGN AND METHODS This case-cohort study, nested within the Whitehall II cohort, was based on 335 incident type 2 diabetes cases and 2,475 noncases. We measured serum IL-1Ra levels at up to three time points per individual and estimated retrospective trajectories of IL-1Ra before diabetes diagnosis (case subjects) or end of follow-up (control subjects) using multilevel analysis. Models were adjusted for age, sex, and ethnicity. RESULTS IL-1Ra levels were already higher in the case than control subjects 13 years before diabetes diagnosis/end of follow-up (mean [95% CI] 302 [290–314] vs. 244 [238–249] pg/ml). In control subjects, IL-1Ra levels showed a modest linear increase throughout the study period. In case subjects, IL-1Ra trajectories were parallel to those in control subjects until 6 years (95% CI 7.5–4.5) before diagnosis and then rose steeply to 399 (379–420) pg/ml at the time of diagnosis (P < 0.0001 for slope difference). Adjustment for BMI and waist circumference as time-varying covariates had little impact on these trajectories. CONCLUSIONS We show elevated IL-1Ra levels for 13 years and an accelerated increase during the last 6 years before type 2 diabetes diagnosis, indicating the presence of an anti-inflammatory response that may act to counterbalance the metabolic and immunologic disturbances that precede type 2 diabetes.

Arterial Stiffness, Physical Function, and Functional Limitation The Whitehall II Study

Arterial stiffness has been proposed as an indicator of vascular aging. We aimed to examine this concept by analyzing associations of arterial stiffness with age, subjective and objective measures of physical functioning, and self-reported functional limitation. We measured aortic pulse wave velocity by applanation tonometry among 5392 men and women aged 55 to 78 years. Arterial stiffness was strongly associated with age (mean difference [SE] per decade: men, 1.37 m/s [0.06 m/s]; women: 1.39 m/s [0.10 m/s]). This association was robust to individual and combined adjustment for pulse pressure, mean arterial pressure, antihypertensive treatment, and chronic disease. Participants took an 8.00-ft (2.44-m) walking speed test, a spirometry lung function test, and completed health functioning and (instrumental) activities of daily living questionnaires. Associations of stiffness and blood pressure with physical function scores scaled to SD of 10 were compared. One-SD higher stiffness was associated with lower walking speed (coefficient [95% CI]: −0.96 [−1.29 to −0.64] m/s) and physical component summary score (−0.91 [−1.21 to −0.60]) and poorer lung function (−1.23 [−1.53 to −0.92] L) adjusted for age, sex, and ethnic group. Pulse pressure and mean arterial pressure were linked inversely only with lung function. Associations of stiffness with functional limitation were robust to multiple adjustment, including pulse pressure and chronic disease. In conclusion, the concept of vascular aging is reinforced by the observation that arterial stiffness is a robust correlate of physical functioning and functional limitation in early old age. The nature of the link between arterial stiffness and quality of life in older people merits attention.

Noninvasive Evaluation of Neural Impairment in Subjects With Impaired Glucose Tolerance

OBJECTIVE—To evaluate neural dysfunction in subjects with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS—For this study, 46 subjects with IGT and 45 healthy volunteers underwent detailed neurological assessment. Cardiovascular autonomic function was assessed by standard cardiovascular reflex tests, and heart rate variability was characterized by the triangle index. Sensory nerve function was assessed using Neurometer (for current perception threshold) and Medoc devices. Peak plantar pressure was measured by dynamic pedobarography, and symptoms were graded using the neuropathy total symptom score. RESULTS—Subjects with IGT had significantly greater abnormalities detected by four of five cardiovascular reflex tests and greater heart rate variability characterized by the triangle index. They had a higher frequency of both hyperesthesia and hypoesthesia as detected by current perception threshold testing at 5 Hz, as well as increased heat detection thresholds. CONCLUSIONS—This study provides evidence that subclinical neural dysfunction is present in subjects with IGT and can be detected noninvasively. Cardiovascular autonomic neuropathy may contribute to increased cardiovascular risk in IGT subjects.

Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study.

Summary Background Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline. Methods 5653 participants from the Whitehall II cohort study (median age 54·4 years [IQR 50·3–60·3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997–99, 2002–04, and 2007–09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases. Findings Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline −0·13 SD, 95% CI −0·26 to −0·00; p=0·046), a 29% faster decline in reasoning (−0·10 SD, −0·19 to −0·01; p=0·026), and a 24% faster decline in the global cognitive score (−0·11 SD, −0·21 to −0·02; p=0·014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (−0·12 [–0·22 to −0·01]; p=0·034) and a decline in reasoning that approached significance (−0·07 [–0·15 to 0·00]; p=0·052). Interpretation The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control. Funding US National Institutes of Health, UK Medical Research Council.

Determinants of Aortic Stiffness: 16-Year Follow-Up of the Whitehall II Study

Background Aortic stiffness is a strong predictor of cardiovascular disease endpoints. Cross-sectional studies have shown associations of various cardiovascular risk factors with aortic pulse wave velocity, a measure of aortic stiffness, but the long-term impact of these factors on aortic stiffness is unknown. Methods In 3,769 men and women from the Whitehall II cohort, a wide range of traditional and novel cardiovascular risk factors were determined at baseline (1991–1993) and aortic pulse wave velocity was measured at follow-up (2007–2009). The prospective associations between each baseline risk factor and aortic pulse wave velocity at follow-up were assessed through sex stratified linear regression analysis adjusted for relevant confounders. Missing data on baseline determinants were imputed using the Multivariate Imputation by Chained Equations. Results Among men, the strongest predictors were waist circumference, waist-hip ratio, heart rate and interleukin 1 receptor antagonist, and among women, adiponectin, triglycerides, pulse pressure and waist-hip ratio. The impact of 10 centimeter increase in waist circumference on aortic pulse wave velocity was twice as large for men compared with women (men: 0.40 m/s (95%-CI: 0.24;0.56); women: 0.17 m/s (95%-CI: −0.01;0.35)), whereas the opposite was true for the impact of a two-fold increase in adiponectin (men: −0.30 m/s (95%-CI: −0.51;−0.10); women: 0.61 m/s (95%-CI: −0.86;−0.35)). Conclusion In this large prospective study, central obesity was a strong predictor of aortic stiffness. Additionally, heart rate in men and adiponectin in women predicted aortic pulse wave velocity suggesting that strategies to prevent aortic stiffening should be focused differently by sex.