Prediabetes (intermediate hyperglycaemia) is a high-risk state for diabetes that is defined by glycaemic variables that are higher than normal, but lower than diabetes thresholds. 5–10% of people per ...year with prediabetes will progress to diabetes, with the same proportion converting back to normoglycaemia. Prevalence of prediabetes is increasing worldwide and experts have projected that more than 470 million people will have prediabetes by 2030. Prediabetes is associated with the simultaneous presence of insulin resistance and β-cell dysfunction—abnormalities that start before glucose changes are detectable. Observational evidence shows associations between prediabetes and early forms of nephropathy, chronic kidney disease, small fibre neuropathy, diabetic retinopathy, and increased risk of macrovascular disease. Multifactorial risk scores using non-invasive measures and blood-based metabolic traits, in addition to glycaemic values, could optimise estimation of diabetes risk. For prediabetic individuals, lifestyle modification is the cornerstone of diabetes prevention, with evidence of a 40–70% relative-risk reduction. Accumulating data also show potential benefits from pharmacotherapy.
Summary 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 β-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 β-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).
Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass ...index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.
We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991-2009 for a median of 14.1 years (interquartile range IQR: 8.7-16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the "stable overweight" group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of "progressive weight gainers" (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The "persistently obese" (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.
Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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 log(e) C-reactive protein (β=-0.07; 95% confidence interval, -0.12 to -0.02) and log(e) interleukin-6 (β=-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 log(e) C-reactive protein (β coefficient=-0.05; 95% confidence interval, -0.10 to -0.001) and log(e) interleukin-6 (β coefficient=-0.06; 95% confidence interval, -0.09 to -0.03) at follow-up.
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.
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.
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.
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).
The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control.
US National Institutes of Health, UK Medical Research Council.
Aims/hypothesis
South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age ...suggest that impaired insulin secretion is a particular feature of diabetes development among South Asians. We therefore aimed to examine ethnic differences in early changes in glucose metabolism prior to incident type 2 diabetes.
Methods
In a prospective British occupational cohort, subject to 5 yearly clinical examinations, we examined ethnic differences in trajectories of fasting plasma glucose (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI
0,120
) among 120 South Asian and 867 white participants who developed diabetes during follow-up (1991–2013). We fitted cubic mixed-effects models to longitudinal data with adjustment for a wide range of covariates.
Results
Compared with white individuals, South Asians had a faster increase in FPG before diagnosis (slope difference 0.22 mmol/l per decade; 95% CI 0.02, 0.42;
p
= 0.03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48;
p
= 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log
e
-transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46;
p
< 0.001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI
0,120
declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2hPG trajectories.
Conclusions/interpretation
We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced a more rapid decrease in insulin sensitivity and faster increases in FPG compared with white individuals. These findings suggest more marked disturbance in beta cell compensation prior to diabetes diagnosis in South Asian individuals.
Objective: Diabetes is an increasingly important public health concern, but little is known about the contribution of psychological factors on diabetes risk. We examined whether personality is ...associated with risk of incident diabetes and diabetes-related mortality. Method: An individual-participant meta-analysis of 34,913 adults free of diabetes at baseline (average age 53.7 years, 57% women) from 5 prospective cohort studies from the United States and United Kingdom. Personality dimensions included extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience based on the Five Factor Model. Results: During an average follow-up of 5.7 years, 1845 participants became diabetic. Of the 5 personality dimensions, only low conscientiousness was associated with an elevated diabetes risk (OR = 0.87, 95% CI = 0.82-0.91 per 1 standard deviation increment in conscientiousness). This association attenuated by 60% after adjustment for obesity and by 25% after adjustment for physical inactivity. Low conscientiousness was also associated with elevated risk of diabetes mortality (HR = 0.72, CI = 0.53-0.98 per 1 standard deviation increment in conscientiousness). Other personality traits were not consistently associated with diabetes incidence or mortality. Conclusions: Low conscientiousness-a cognitive-behavioral disposition reflecting careless behavior and a lack of self-control and planning-is associated with elevated risk of diabetes and diabetes-related mortality. The underlying mechanisms are likely to involve health behaviors, such as poor weight management, physical inactivity, and adherence to medical management recommendations.
Elevated Levels of the Anti-Inflammatory Interleukin-1 Receptor Antagonist Precede the Onset of Type 2 Diabetes
The Whitehall II Study
Christian Herder , PHD 1 ,
Eric J. Brunner , PHD 2 ,
Wolfgang ...Rathmann , MD, MSPH 3 ,
Klaus Strassburger , PHD 3 ,
Adam G. Tabák , MD 2 4 ,
Nanette C. Schloot , MD 1 5 and
Daniel R. Witte , PHD 2 6
1 Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Institute for Diabetes Research,
Düsseldorf, Germany
2 Department of Epidemiology and Public Health, University College London, London, U.K.
3 Institute of Biometrics and Epidemiology, German Diabetes Center at Heinrich Heine University, Leibniz Institute for Diabetes
Research, Düsseldorf, Germany
4 Semmelweis University, Budapest, Hungary
5 Center for Internal Medicine, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
6 Steno Diabetes Center, Gentofte, Denmark
Corresponding author: Christian Herder, christian.herder{at}ddz.uni-duesseldorf.de
Abstract
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.
Footnotes
Published ahead of print at http://care.diabetesjournals.org on 10 December 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted November 24, 2008.
Received June 26, 2008.
DIABETES CARE
OBJECTIVE To compare screen-detected diabetes prevalence and the degree of diagnostic agreement by ethnicity with the current oral glucose tolerance test (OGTT)-based and newly proposed A1C-based ...diagnostic criteria. RESEARCH DESIGN AND METHODS Six studies (1999-2009) from Denmark, the U.K., Australia, Greenland, Kenya, and India were tested for the probability of an A1C > or =6.5% among diabetic case subjects based on an OGTT. The difference in probability between centers was analyzed by logistic regression adjusting for relevant confounders. RESULTS Diabetes prevalence was lower with the A1C-based diagnostic criteria in four of six studies. The probability of an A1C > or =6.5% among OGTT-diagnosed case subjects ranged widely (17.0-78.0%) by study center. Differences in diagnostic agreement between ethnic subgroups in the U.K. study were of the same magnitude as between-country comparisons. CONCLUSIONS A shift to an A1C-based diagnosis for diabetes will have substantially different consequences for diabetes prevalence across ethnic groups and populations.
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