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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.

The state of intermediate hyperglycemia is indicative of elevated risk of developing type 2 diabetes 1 . However, the current definition of prediabetes neither reflects subphenotypes of pathophysiology of type 2 diabetes nor is predictive of future metabolic trajectories. We used partitioning on variables derived from oral glucose tolerance tests, MRI-measured body fat distribution, liver fat content and genetic risk in a cohort of extensively phenotyped individuals who are at increased risk for type 2 diabetes 2 , 3 to identify six distinct clusters of subphenotypes. Three of the identified subphenotypes have increased glycemia (clusters 3, 5 and 6), but only individuals in clusters 5 and 3 have imminent diabetes risks. By contrast, those in cluster 6 have moderate risk of type 2 diabetes, but an increased risk of kidney disease and all-cause mortality. Findings were replicated in an independent cohort using simple anthropomorphic and glycemic constructs 4 . This proof-of-concept study demonstrates that pathophysiological heterogeneity exists before diagnosis of type 2 diabetes and highlights a group of individuals who have an increased risk of complications without rapid progression to overt type 2 diabetes. Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.

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. 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). 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%). 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. 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).

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.

Here, we review insulin management options and strategies in nonpregnant adult patients with type 1 diabetes mellitus (T1DM). Most patients with T1DM should follow a regimen of multiple daily injections of basal/bolus insulin, but those not meeting individual glycemic targets or those with frequent or severe hypoglycemia or pronounced dawn phenomenon should consider continuous subcutaneous insulin infusion. The latter treatment modality could also be an alternative based on patient preferences and availability of reimbursement. Continuous glucose monitoring may improve glycemic control irrespective of treatment regimen. A glycemic target of glycated hemoglobin < 7% (53 mmol/mol) is appropriate for most nonpregnant adults. Basal insulin analogues with a reduced peak profile and an extended duration of action with lower intraindividual variability relative to neutral protamine Hagedorn insulin are preferred. The clinical advantages of basal analogues compared with older basal insulins include reduced injection burden, better efficacy, lower risk of hypoglycemic episodes (especially nocturnal), and reduced weight gain. For prandial glycemic control, any rapid-acting prandial analogue (aspart, glulisine, lispro) is preferred over regular human insulin. Faster-acting insulin aspart is a relatively new option with the advantage of better postprandial glucose coverage. Frequent blood glucose measurements along with patient education on insulin dosing based on carbohydrate counting, premeal blood glucose, and anticipated physical activity is paramount, as is education on the management of blood glucose under different circumstances. Plain Language Summary : Plain language summary is available for this article.

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.

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:--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.

Background Biomarkers of inflammation and adiponectin are associated with cardiovascular autonomic neuropathy (CAN) in cross-sectional studies, but prospective data are scarce. This study aimed to assess the associations of biomarkers of subclinical inflammation and adiponectin with subsequent changes in heart rate (HR) and heart rate variability (HRV) in non-diabetic and diabetic individuals. Methods Data are based on up to 25,050 person-examinations for 8469 study participants of the Whitehall II cohort study. Measures of CAN included HR and several HRV indices. Associations between baseline serum levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra) and adiponectin and 5-year changes in HR and six HRV indices were estimated using mixed-effects models adjusting for age, sex, ethnicity, body mass index (BMI), metabolic covariates and medication. A modifying effect of diabetes was tested. Results Higher levels of IL-1Ra were associated with higher increases in HR. Additional associations with measures of HRV were observed for hsCRP, IL-6 and IL-1Ra, but these associations were explained by BMI and other confounders. Associations between adiponectin, HR and HRV differed depending on diabetes status. Higher adiponectin levels were associated with more pronounced decreases in HR and increases in three measures of HRV reflecting both sympathetic and vagal activity, but these findings were limited to individuals with type 2 diabetes. Conclusions Higher IL-1Ra levels appeared as novel risk marker for increases in HR. Higher adiponectin levels were associated with a more favourable development of cardiovascular autonomic function in individuals with type 2 diabetes independently of multiple confounders.

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. 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. 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)). 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.