In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study

T. J. Orchard, A. M. Secrest, R. G. Miller and T. Costacou

Aims/hypothesis: The FinnDiane Study has reported that mortality in type 1 diabetes is not increased over a 7 year follow-up in the absence of renal disease (RD). Using the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study population (n = 658) of childhood-onset type 1 diabetes (age <17 years), the present study sought to replicate and expand these findings to a 20 year follow-up (as of 1 January 2008) and examine cause of death by renal status.

Methods: At baseline (1986–1988), mean age and duration of diabetes were 28 and 19 years, respectively. RD was defined as an albumin excretion rate ≥20 μg/min from multiple samples and grouped as microalbuminuria (MA; 20–200 μg/min), overt nephropathy (ON; >200 μg/min), or end stage renal disease (ESRD; dialysis or renal transplantation).

Results: At baseline, 311 (47.3%) individuals had RD (MA 21.3%, ON 22.2% and ESRD 3.8%). During a median 20 year follow-up, there were 152 deaths (23.1%). Mortality was 6.2 (95% CI 5.2–7.2) times higher than expected, with standardised mortality ratios of 2.0 (1.2–2.8) for normoalbuminuria (NA); 6.4 (4.4–8.4) for MA; 12.5 (9.5–15.4) for ON; and 29.8 (16.8–42.9) for ESRD. Excluding those (n = 64) with NA who later progressed to RD, no significant excess mortality was observed in the remaining NA group (1.2, 0.5–1.9), whose deaths were largely unrelated to diabetes.

Conclusion: These data confirm the importance of RD, including persistent microalbuminuria, as a marker of mortality risk and suggest that type 1 diabetes patients without renal disease achieve long-term survival comparable to the general population.

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Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus

P. L. Yau, D. C. Javier, C. M. Ryan, W. H. Tsui, B. A. Ardekani, S. Ten and A. Convit

Aims/hypothesis: Central nervous system abnormalities, including cognitive and brain impairments, have been documented in adults with type 2 diabetes who also have multiple co-morbid disorders that could contribute to these observations. Assessing adolescents with type 2 diabetes will allow the evaluation of whether diabetes per se may adversely affect brain function and structure years before clinically significant vascular disease develops.

Methods: Eighteen obese adolescents with type 2 diabetes and 18 obese controls without evidence of marked insulin resistance, matched on age, sex, school grade, ethnicity, socioeconomic status, body mass index and waist circumference, completed MRI and neuropsychological evaluations.

Results: Adolescents with type 2 diabetes performed consistently worse in all cognitive domains assessed, with the difference reaching statistical significance for estimated intellectual functioning, verbal memory and psychomotor efficiency. There were statistical trends for executive function, reading and spelling. MRI-based automated brain structural analyses revealed both reduced white matter volume and enlarged cerebrospinal fluid space in the whole brain and the frontal lobe in particular, but there was no obvious grey matter volume reduction. In addition, assessments using diffusion tensor imaging revealed reduced white and grey matter microstructural integrity.

Conclusion: This is the first report documenting possible brain abnormalities among obese adolescents with type 2 diabetes relative to obese adolescent controls. These abnormalities are not likely to result from education or socioeconomic bias and may result from a combination of subtle vascular changes, glucose and lipid metabolism abnormalities and subtle differences in adiposity in the absence of clinically significant vascular disease. Future efforts are needed to elucidate the underlying pathophysiological mechanisms.

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Oral disease and subsequent cardiovascular disease in people with type 2 diabetes: a prospective cohort study based on the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial

Q. Li, J. Chalmers, S. Czernichow, B. Neal, B. A. Taylor, S. Zoungas, N. Poulter, M. Woodward, A. Patel and B. de Galan, et al.

Aims/hypothesis: While there are plausible biological mechanisms linking oral health with cardiovascular disease (CVD) and mortality rates, no study, to our knowledge, has examined this association in a representative population of people with type 2 diabetes.

Methods: We used the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) study, a large, detailed, randomised controlled trial among a general population of individuals with type 2 diabetes. For the purposes of the present analyses, data from the trial are used within a prospective cohort study design. A total of 10,958 men and women, aged 55 to 88 years and with type 2 diabetes, participated in a baseline medical examination, during which they counted their number of natural teeth and reported the number of days that their gums had bled over the preceding year. Study members were followed up for mortality and morbidity over 5 years.

Results: After controlling for a range of potential confounding factors, the group with no teeth had a markedly increased risk of death due to all causes (HR 1.48, 95% CI 1.24–1.78), CVD (1.35, 1.05–1.74) and non-CVD (1.64, 1.26–2.13), relative to the group with the most teeth (≥22 teeth). Frequency of bleeding gums was not associated with any of the outcomes of interest. There was no suggestion that treatment group or sex modified these relationships.

Conclusion: In people with type 2 diabetes, oral disease, as indexed by fewer teeth, was related to an increased risk of death from all causes and of death due to CVD and non-CVD.

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HbA1c as predictor of all-cause mortality in individuals at high risk of diabetes with normal glucose tolerance, identified by screening: a follow-up study of the Anglo–Danish–Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION), Denmark

M. V. Skriver, K. Borch-Johnsen, T. Lauritzen and A. Sandbaek

Aims/hypothesis: Stepwise screening for type 2 diabetes will not only identify people with the disease or some other form of dysglycaemia (impaired fasting glucose or impaired glucose tolerance), but also many individuals who are phenotypically at high risk of developing diabetes, but currently have normal glucose tolerance (NGT). We therefore sought to assess whether HbA1c adds prognostic information in relation to all-cause mortality in people who have NGT and a high risk of type 2 diabetes mellitus.

Methods: In a Danish population-based stepwise screening programme for type 2 diabetes mellitus in general practice, we identified 15,634 persons at high risk of type 2 diabetes, who had NGT and a recorded HbA1c measurement. As comparison groups, we included 1,401 people identified as having type 2 diabetes mellitus and 8,149 individuals characterised as being at low risk of diabetes. All individuals were followed from time of screening (April 2001 to December 2006) until death or 31 October 2009. Excess mortality was estimated using Cox proportional hazard models with all-cause mortality as the outcome measure.

Results: Compared with individuals with NGT and HbA1c below 6.0%, adjusted hazard ratios were: 1.21 (95% CI 0.95–1.56) for individuals with NGT and HbA1c between 6.0% and 6.5%; 2.48 (95% CI 1.23–4.99) for individuals with NGT and HbA1c 6.5% or above (in this group there were eight deaths among 68 individuals); 1.73 (95% CI 1.40–2.13) for individuals with type 2 diabetes mellitus.

Conclusion: HbA1c level in people with NGT and at high risk of diabetes was clearly associated with increased all-cause mortality.

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Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study

T. M. E. Davis, R. Ting, J. D. Best, M. W. Donoghoe, P. L. Drury, D. R. Sullivan, A. J. Jenkins, R. L. O’Connell, M. J. Whiting and P. P. Glasziou, et al.

Aims/hypothesis:Fenofibrate caused an acute, sustained plasma creatinine increase in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies. We assessed fenofibrate’s renal effects overall and in a FIELD washout sub-study.

Methods:Type 2 diabetic patients (n = 9,795) aged 50 to 75 years were randomly assigned to fenofibrate (n = 4,895) or placebo (n  = 4,900) for 5 years, after 6 weeks fenofibrate run-in. Albuminuria (urinary albumin/creatinine ratio measured at baseline, year 2 and close-out) and estimated GFR, measured four to six monthly according to the Modification of Diet in Renal Disease Study, were pre-specified endpoints. Plasma creatinine was re-measured 8 weeks after treatment cessation at close-out (washout sub-study, n = 661). Analysis was by intention-to-treat.

Results: During fenofibrate run-in, plasma creatinine increased by 10.0 μmol/l (p < 0.001), but quickly reversed on placebo assignment. It remained higher on fenofibrate than on placebo, but the chronic rise was slower (1.62 vs 1.89 μmol/l annually, p = 0.01), with less estimated GFR loss (1.19 vs 2.03 ml min−1 1.73 m−2 annually, p < 0.001). After washout, estimated GFR had fallen less from baseline on fenofibrate (1.9 ml min−1 1.73 m−2, p = 0.065) than on placebo (6.9 ml min−1 1.73 m−2, p < 0.001), sparing 5.0 ml min−1 1.73 m−2 (95% CI 2.3–7.7, p < 0.001). Greater preservation of estimated GFR with fenofibrate was observed with baseline hypertriacylglycerolaemia (n = 169 vs 491 without) alone, or combined with low HDL-cholesterol (n = 140 vs 520 without) and reductions of ≥0.48 mmol/l in triacylglycerol over the active run-in period (pre-randomisation) (n = 356 vs 303 without). Fenofibrate reduced urine albumin concentrations and hence albumin/creatinine ratio by 24% vs 11% (p < 0.001; mean difference 14% [95% CI 9–18]; p < 0.001), with 14% less progression and 18% more albuminuria regression (p < 0.001) than in participants on placebo. End-stage renal event frequency was similar (n = 21 vs 26, p = 0.48).

Conclusion: HbA1c level in people with NGT and at high risk of diabetes was clearly associated with increased all-cause mortality.

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Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups: an analysis of 15,780 patients from the INTERHEART study

H. C. Gerstein, S. Islam, S. Anand, W. Almahmeed, A. Damasceno, A. Dans, C. C. Lang, M. A. Luna, M. McQueen, S. Rangarajan, A. Rosengren, X. Wang, S. Yusuf

Aims/hypothesis: Although diabetes is an established risk factor for myocardial infarction (MI), disease control may vary. HbA1c is a reliable index of ambient glucose levels and may provide more information on MI risk than diabetes status.

Methods: The relationship between HbA1c levels in MI patients and controls who participated in the 52 country INTERHEART study was analysed.

Results: In 15,780 participants with a HbA1c value (1,993 of whom had diabetes), the mean (SD) levels for HbA1c were 6.15% (1.10) in the 6,761 MI patients and 5.85% (0.80) in the control participants. After adjustment for age, sex and nine major MI risk factors (including diabetes), higher HbA1c fifths above the lowest fifth (HbA1c <5.4%) were associated with progressively higher OR of MI, with OR for the highest HbA1c fifth (≥6.12%) being 1.55 (95% CI 1.37–1.75). When analysed as a continuous variable after adjustment for the same factors, every 1% higher HbA1c value was associated with 19% (95% CI 14–23) higher odds of MI, while every 0.5% higher HbA1c was associated with 9% higher odds of MI (95% CI 7–11). Concordant relationships were noted across subgroups, with a higher OR noted in younger people, patients without diabetes or hypertension, and those from some regions and ethnicities.

Conclusions/interpretation: The HbA1c value provides more information on MI odds than self-reported diabetes status or many other established risk factors. Every 1% increment independently predicts a 19% higher odds of MI after accounting for other MI risk factors including diabetes.

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Healthcare costs in patients with diabetes mellitus and comorbid mental disorders—a systematic review

N. Hutter, A. Schnurr and H. Baumeister

Aims/hypothesis: We systematically reviewed the impact of comorbid mental disorders on healthcare costs in persons with diabetes.

Method: We conducted a comprehensive search for studies investigating adult persons (≥18 years old) with diabetes mellitus. All studies that allowed comparison of healthcare costs between diabetic patients with mental disorders and those without were included.

Results: We identified 4,273 potentially relevant articles from a comprehensive database search. Of these, 31 primary studies (39 publications) fulfilled inclusion criteria, of which 27 examined comorbid depression. Hospitalisation rates and hospitalisation costs, frequency and costs of outpatient visits, emergency department visits, medication costs and total healthcare costs were mainly increased with small to moderate effect sizes in patients with diabetes and comorbid mental disorders compared with diabetic patients without such problems. Frequency (standardised mean difference [SMD] = 0.35–1.26) and costs (SMD = 0.33–0.85) of mental health specialist visits were increased in the group with mental health comorbidity. Results regarding diabetes-related preventive services were inconsistent but point to a reduced utilisation rate in diabetic patients with comorbid mental disorders. Statistical heterogeneity between studies was high (I 2 range 64–98%). Pooled overall effects are therefore not reported. Studies included differ substantially regarding sample selection, assessment of diabetes and comorbid mental disorders, as well as in assessment of cost variables.

Conclusions/interpretation: In light of the increased healthcare costs and inadequate use of preventive services, comorbid mental disorders in patients with diabetes must become a major focus of diabetes healthcare and research.

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Type 2 diabetes mellitus as a risk factor for the onset of depression: a systematic review and meta-analysis

A. Nouwen, K. Winkley, J. Twisk, C. E. Lloyd, M. Peyrot, K. Ismail, F. Pouwer and for the European Depression in Diabetes (EDID)

Aims/hypothesis: An earlier meta-analysis showed that diabetes is a risk factor for the development and/or recurrence of depression. Yet whether this risk is different for studies using questionnaires than for those relying on diagnostic criteria for depression has not been examined. This study examined the association of diabetes and the onset of depression by reviewing the literature and conducting a meta-analysis of longitudinal studies on this topic.

Methods: EMBASE, MEDLINE and PsycInfo were searched for articles published up to September 2009. All studies that examined the relationship between type 2 diabetes and the onset of depression were included. Pooled relative risks were calculated using fixed and random effects models.

Results: Eleven studies met our inclusion criteria for this meta-analysis. Based on the pooled data, including 48,808 cases of type 2 diabetes without depression at baseline, the pooled relative risk was 1.24 (95% CI 1.09–1.40) for the random effects model. This risk was significantly higher for studies relying on diagnostic criteria of depression than for studies using questionnaires. However, this difference was no longer significant when controlled for year of publication.

Conclusions/interpretation: Compared with non-diabetic controls, people with type 2 diabetes have a 24% increased risk of developing depression. The mechanisms underlying this relationship are still unclear and warrant further research.

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Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity

J. Hoffstedt, E. Arner, H. Wahrenberg, D. P. Andersson, V. Qvisth, P. Löfgren, M. Rydén, A. Thörne, M. Wirén, M. Palmér, A. Thorell, E. Toft, P. Arner

Aims/hypothesis: The aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity.

Methods: In 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism.

Results: Visceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulin-induced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from −0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined.

Conclusions/interpretation: In morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity.

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Maturity-onset diabetes of the young (MODY): how many cases are we missing?

B. M. Shields, S. Hicks, M. H. Shepherd, K. Colclough, A. T. Hattersley and S. Ellard

Aims/hypothesis: Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence.

Methods: UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures.

Results: MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from <20 per million in Wales and Northern Ireland to >50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million.

Conclusions/interpretation: Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.

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Leisure-time physical activity and type 2 diabetes during a 28 year follow-up in twins

K. Waller, J. Kaprio, M. Lehtovirta, K. Silventoinen, M. Koskenvuo and U. M. Kujala

Aims/hypothesis: The study aimed to investigate whether baseline physical activity protects against the occurrence of type 2 diabetes during a 28 year follow-up, after controlling for childhood environment and genetic predisposition.

Methods: At baseline in 1975 same-sex twin pairs born in Finland before 1958 were sent a questionnaire including questions on physical activity. The participants (20,487 individuals, including 8,182 complete twin pairs) were divided into quintiles by leisure-time physical activity metabolic equivalent (MET) index (MET h/day). Type 2 diabetes was determined from nationwide registers for the follow-up period (1 January 1976–31 December 2004). Individual and pairwise Cox proportional hazard models were used.

Results: During follow-up, 1,082 type 2 diabetes cases were observed. Among all individuals, participants in MET quintiles (Q) III–V had significantly decreased risk for type 2 diabetes compared with sedentary individuals (QI). The pairwise analysis on pairs discordant for physical activity showed that participants in MET QII to V had significantly lower hazard ratios (0.61, 0.59, 0.61, 0.61) compared with sedentary participants. These findings from the pairwise analysis persisted after adjusting for BMI. In the pairwise analysis, the BMI-adjusted hazard ratio for type 2 diabetes was lower for physically active members of twin pairs (combined QII–V) than for inactive co-twins (HR 0.54; 95% CI 0.37–0.78). Similar results were obtained for both dizygotic and monozygotic pairs, as well as for the subgroup of twin pairs defined as free of co-morbidities in 1981 (HR 0.36; 95% CI 0.17–0.76).

Conclusions/interpretation: Leisure-time physical activity protects from type 2 diabetes after taking familial and genetic effects into account.

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Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study

C. Andersson, J. B. Olesen, P. R. Hansen, P. Weeke, M. L. Norgaard, C. H. Jørgensen, T. Lange, S. Z. Abildstrøm, T. K. Schramm, A. Vaag, L. Køber, C. Torp-Pedersen, G. H. Gislason

Aims/hypothesis: The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark.

Methods: All patients aged ≥30 years hospitalised for the first time for heart failure in 1997–2006 were identified and followed until the end of 2006. Patients who received treatment with metformin, a sulfonylurea and/or insulin were included and assigned to mono-, bi- or triple therapy groups. Multivariable Cox proportional hazard regression models were used to assess the risk of all-cause mortality.

Results: A total of 10,920 patients were included. The median observational time was 844 days (interquartile range 365–1,395 days). In total, 6,187 (57%) patients died. With sulfonylurea monotherapy used as the reference, adjusted hazard ratios for all-cause mortality associated with the different treatment groups were as follows: metformin 0.85 (95% CI 0.75–0.98, p = 0.02), metformin + sulfonylurea 0.89 (95% CI 0.82–0.96, p = 0.003), metformin + insulin 0.96 (95% CI 0.82–1.13, p = 0.6), metformin + insulin + sulfonylurea 0.94 (95% CI 0.77–1.15, p = 0.5), sulfonylurea + insulin 0.97 (95% CI 0.86–1.08, p = 0.5) and insulin 1.14 (95% CI 1.06–1.20, p = 0.0001).

Conclusions/interpretation: Treatment with metformin is associated with a low risk of mortality in diabetic patients with heart failure compared with treatment with a sulfonylurea or insulin.

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Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age

J. Agudo, M. Martin, C. Roca, M. Molas, A. S. Bura, A. Zimmer, F. Bosch and R. Maldonado

Aims/hypothesis: The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism.

Methods: Mice deficient in CB2R (Cb2 −/− [also known as Cnr2]) were studied at different ages (2–12 months). Two-month-old Cb2 −/− and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet.

Results: The lack of CB2R in Cb2 −/− mice led to greater increases in food intake and body weight with age than in Cb2 +/+ mice. However, 12-month-old obese Cb2 −/− mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2 −/− mice were fed a high-fat diet, reduced body weight gain and normal insulin sensitivity were observed.

Conclusions/interpretation: These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance.

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Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study

P. L. Drury, R. Ting, D. Zannino, C. Ehnholm, J. Flack, M. Whiting, R. Fassett, J.-C. Ansquer, P. Dixon and T. M. E. Davis, et al.

Aims/hypothesis: We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

Methods: Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5 years.

Results: Lower estimated GFR (eGFR) vs eGFR ≥90 ml min−1 1.73 m−2 was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01–1.29] for eGFR 60–89 ml min−1 1.73 m−2; 1.59 [1.28–1.98] for eGFR 30–59 ml min−1 1.73 m−2; p < 0.001; adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01–1.54] and 1.19 [0.76–1.85], respectively; p = 0.001 for trend) when eGFR ≥90 ml min−1 1.73 m−2. CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure.

Conclusions/interpretation: Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models.

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HbA1c and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study

R. Borg, J. C. Kuenen, B. Carstensen, H. Zheng, D. M. Nathan, R. J. Heine, J. Nerup, K. Borch-Johnsen, D. R. Witte and on behalf of the ADAG Study Group

Aims: Increased glucose excursions and postprandial hyperglycaemia have been suggested as unique risk factors for cardiovascular disease (CVD) and mortality in patients with diabetes mellitus. Much of the evidence is based on a single 2 h glucose value after oral glucose tolerance testing in epidemiological studies. We examined the association between various indices of glycaemia measured during everyday activities and metabolic CVD risk factors in the A1C-Derived Average Glucose (ADAG) study.

Methods: Participants (268 with type 1 diabetes, 159 with type 2 diabetes) completed 16 weeks of intensive continuous glucose monitoring (CGM) and self-monitoring of blood glucose (SMBG). From these data, common indices of postprandial glycaemia, overall hyperglycaemia, glucose variability and HbA1c were derived. The associations between glycaemic indices and known CVD risk factors (lipids, high-sensitivity C-reactive protein and blood pressure) were explored in linear regression models.

Results: For both diabetes types, the overall strongest associations with CVD risk factors were seen for the measures of average glycaemia (mean blood glucose and HbA1c). Associations between self-monitored postprandial and fasting glucose and CVD risk factors were weaker, but significant. Measurements of blood glucose variability showed non-significant associations. Overall, calculations based on CGM were not more informative than those based on frequent SMBG.

Conclusions/interpretation: Mean glycaemia and HbA1c show consistent and stronger associations with CVD risk factors than fasting glucose or postprandial glucose levels or measures of glucose variability in patients with diabetes.

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Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test

A. P. Gjesing, L. L. Kjems, M. A. Vestmar, N. Grarup, A. Linneberg, C. F. Deacon, J. J. Holst, O. Pedersen and T. Hansen

Aims/hypothesis: The transcription factor 7-like 2 (TCF7L2) rs7903146 T allele associates with type 2 diabetes in several populations, possibly mediated via decreased incretin secretion and/or action and altered beta and alpha cell function. We aimed to study circulating levels of glucose, proinsulin, insulin, C-peptide, glucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) and gastric inhibitory polypeptide (GIP) among individuals carrying the high-risk rs7903146 TT genotype and low-risk CC genotype following a meal test.

Methods: A meal challenge was performed in 31 glucose-tolerant men (age 54 ± 7 years and BMI 26 ± 3 kg/m2) with rs7903146 TT genotype and 31 glucose-tolerant age- and BMI-matched men with CC genotype (age 53 ± 6 years and BMI 26 ± 3 kg/m2). Serum proinsulin, insulin, C-peptide and plasma glucose, glucagon, GLP-1, GLP-2 and GIP were obtained 0, 15, 30, 45, 60, 75, 90, 105, 120, 135, 150, 180, 210, and 240 min after ingestion of a standardised breakfast meal.

Results: An elevated incremental AUC for plasma glucose was observed among TT genotype carriers (CC carriers 21.8 ± 101.9 mmol/l × min vs TT carriers 97.9 ± 89.2 mmol/l × min, p = 0.001). TT carriers also had increased AUCs for proinsulin (CC carriers 6,030 ± 3,001 pmol/l × min vs TT carriers 6,917 ± 4,820 pmol/l × min, p = 0.03), C-peptide (CC carriers 397.6 ± 131.9 nmol/l × min vs TT carriers 417.1 ± 109.3 nmol/l × min, p = 0.04) and GIP (CC carriers 12,310 ± 3,840 pmol/l × min vs TT carriers 14,590 ± 5,910 pmol/l × min, p = 0.004).

Conclusions/interpretation: Middle-aged normoglycaemic individuals carrying the rs7903146 TCF7L2 risk TT genotype show early signs of dysregulated glucose metabolism, decreased processing of proinsulin and elevated GIP secretion following a meal challenge.

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Associations between physical fitness and HbA1c in type 2 diabetes mellitus

J. Larose, R. J. Sigal, F. Khandwala, D. Prud’homme, N. G. Boulé, G. P. Kenny and on behalf of the Diabetes Aerobic and Resistance Exercise (DARE) trial investigators

Aims/hypothesis: In people with type 2 diabetes, exercise improves glucose control (as reflected in HbA1c) and physical fitness, but it is not clear to what extent these exercise-induced improvements are correlated with one another. We hypothesised that reductions in HbA1c would be related: (1) to increases in aerobic fitness and strength respectively in patients performing aerobic training or resistance training; and (2) to changes in strength and aerobic fitness in patients performing aerobic and resistance training.

Methods: We randomly allocated 251 type 2 diabetes patients to aerobic, resistance, or aerobic plus resistance training, or to a sedentary control group. Peak oxygen consumption (VO2peak), workload, treadmill time and ventilatory threshold measurements from maximal treadmill exercise testing were measured at baseline and 6 months. Muscular strength was measured as the maximum weight that could be lifted eight times on the leg press, bench press and seated row exercises.

Results: With aerobic training, significant associations were found between changes in both VO2peak (p = 0.040) and workload (p = 0.022), and changes in HbA1c. With combined training, improvements in VO2peak (p = 0.008), workload (p = 0.034) and ventilatory threshold (p = 0.003) were significantly associated with changes in HbA1c. Increases in strength on the seated row (p = 0.006) and in mid-thigh muscle cross-sectional area (p = 0.030) were significantly associated with changes in HbA1c after resistance exercise, whereas the association between increases in muscle cross-sectional area and HbA1c in participants doing aerobic plus resistance exercise (p = 0.059) was of borderline significance.

Conclusions/interpretation: There appears to be a link between changes in fitness and HbA1c. The improvements in cardiorespiratory fitness with aerobic training may be a better predictor of changes in HbA1c than improvements in strength.

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Development, validation and use of an insulin sensitivity score in youths with diabetes: the SEARCH for Diabetes in Youth study

D. Dabelea, R. B. D’Agostino, C. C. Mason, N. West, R. F. Hamman, E. J. Mayer-Davis, D. Maahs, G. Klingensmith, W. C. Knowler and K. Nadeau

Aims/hypothesis: The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic–hyperinsulinaemic clamp in a subset (n = 85) of 12- to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA.

Methods: Youths with a diagnosis of type 1 (n = 60) or type 2 diabetes (n = 25) underwent a 3 h clamp to measure glucose disposal rate (GDR, mg kg−1 min−1). Demographic (age, sex, race), clinical (BMI, waist, Tanner stage) and metabolic characteristics (HbA1c, lipids, blood pressure, urine albumin:creatinine) were used to estimate logeIS score via stepwise linear regression on a model-development set (n = 53). Estimated IS score was evaluated for reproducibility on two validation sets: youths with diabetes (n = 33) and healthy control youths (n = 22).

Results: The best model included waist, triacylglycerol (TG) and HbA1c levels (R 2 = 0.74). Diabetes type did not enter the model and there were no significant interactions between diabetes type and other predictors. Estimated IS score correlated well (r = 0.65, p < 0.0001; r = 0.62, p = 0.002) with GDR on the two validation sets. Based on this analysis, we propose the following formula to estimate insulin sensitivity in youths with diabetes.

Conclusions/interpretation: Insulin sensitivity can be estimated in adolescents with diabetes using routinely collected measures. This score can be applied to epidemiological studies of youths with diabetes to characterise relationships between dimensions of diabetes type.

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Cardiovascular risk factors in children exposed to maternal diabetes in utero

N. A. West, T. L. Crume, M. A. Maligie and D. Dabelea

Aims/hypothesis: Recent studies have provided evidence that intrauterine exposure to maternal diabetes has lifelong effects on adult offspring, including increased risks of obesity, type 2 diabetes and cardiovascular disease. The aim of this study was to assess the relationship between exposure to maternal diabetes in utero and cardiovascular risk factors in healthy children and to investigate whether these associations are independent of maternal prepregnancy BMI and offspring attained BMI.

Methods: Data were from a retrospective cohort of children aged 6–13 years born during 1994–2002. Multiple linear regression was used to examine the associations between exposure and cardiovascular risk factors with adjustment for demographic factors and pubertal stage and additionally for maternal prepregnancy BMI and offspring attained BMI.

Results: Ninety-nine offspring of diabetic pregnancies had significantly increased E-selectin, vascular adhesion molecule 1 (VCAM1), leptin, waist circumference, BMI and systolic blood pressure and decreased adiponectin levels compared with 422 offspring of non-diabetic pregnancies after adjustment for age, sex and race/ethnicity (p < 0.05 for each risk factor). Additional adjustment for maternal prepregnancy BMI substantially attenuated group differences in the risk factors except for E-selectin, VCAM1 and waist circumference, which remained significantly higher in exposed children.

Conclusions/interpretation: Compared with unexposed children, healthy offspring exposed to maternal diabetes in utero have a worse cardiovascular risk profile. In particular, offspring have substantially increased levels of circulating cellular adhesion molecules, which are biomarkers of adverse endothelium perturbation and may be related to the earliest preclinical stages of atherosclerosis and diabetes.

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Cancer in patients admitted to hospital with diabetes mellitus aged 30 years and over: record linkage studies

C. J. Wotton, D. G. R. Yeates and M. J. Goldacre

Aims/hypothesis: The aim of this study was to determine the risk of cancer in people admitted to hospital for diabetes mellitus when aged 30 or older.

Methods: This study involved the analysis of two statistical datasets of linked hospital and mortality data, in an area in southern England, between 1963 and 1998 (the Oxford Record Linkage Study, ORLS1) and between 1999 and 2008 (ORLS2). Rates of cancer in the diabetes cohorts were compared with rates of cancer in reference cohorts and expressed as rate ratios.

Results: The rate ratio for all cancer in people admitted to hospital with diabetes was 1.01 (95% CI 0.95–1.06, based on 15,898 people with diabetes) for the years 1963–1998; and 1.09 (1.00–1.19, based on 7,771 people with diabetes) in the years 1999–2008. In both datasets, there were significantly high rate ratios for cancers of the liver (ORLS1 and ORLS2, respectively, 2.0 [95% CI 1.4–2.9]; 2.5 [95% CI 1.3–4.3]), pancreas (2.2 [95% CI 1.8–2.7]; 3.5 [95% CI 2.5–4.8]) and uterus (1.5 [95% CI 1.0–2.2]; 2.6 [95% CI 1.4–4.5]). There were significantly low rate ratios for cancer of the prostate (0.6 [95% CI 0.5–0.7]; 0.7 [95% CI 0.5–0.9]) and non-melanoma skin cancer (0.6 [95% CI 0.5–0.8]; 0.8 [95% CI 0.6–0.96]).

Conclusions/interpretation: Diabetes mellitus was associated with an elevated risk of some site-specific cancers and a reduction of risk of others. Considering the risk in diabetes of all cancers combined, the elevation of risk, if any, is likely to be small and numerically less important than other known complications of diabetes.

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Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

J. Ludvigsson, M. Hjorth, M. Chéramy, S. Axelsson, M. Pihl, G. Forsander, N.-Ö. Nilsson, B.-O. Samuelsson, T. Wood and J. Åman, et al.

Aims/hypothesis: The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up.

Methods: Seventy children and adolescents aged 10–18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent.

Results: One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 ± 0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 ± 0.039 and 0.184 ± 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years.

Conclusions/interpretation: Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide.

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Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes

S. Forbes, S. D. Taylor-Robinson, N. Patel, P. Allan, B. R. Walker and D. G. Johnston

Aims/hypothesis: Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes but it is unknown whether NAFLD is prevalent in European women at risk of type 2 diabetes. We studied the prevalence of, and risk factors for, NAFLD in European women with previous gestational diabetes (GDM) at high risk of type 2 diabetes.

Methods: A total of 110 women with previous GDM and 113 without previous GDM, with non-diabetic glucose tolerance were recruited retrospectively from antenatal databases. Participants underwent liver ultrasound scan examination, anthropometry and blood sampling for liver function tests and to determine levels of fasting lipids, NEFA and insulin and glucose concentrations in order to derive insulin sensitivity and insulin secretion indices (HOMA%S and HOMA%B, respectively).

Results: There was no significant difference in BMI in women with previous GDM compared with those without previous GDM (28.9 ± 0.6 vs. 27.9 ± 0.6 kg/m2, respectively; p = 0.12). Women with previous GDM had higher fasting and 2 h glucose concentrations following a 75 g OGTT ([mean ± SEM] fasting glucose 5.3 ± 0.1 vs. 5.1 ± 0.1 mmol/l, p = 0.02; 2 h glucose 6.8 ± 0.2 vs. 5.8 ± 0.3 mmol/l, p = 0.02), dyslipidaemia (LDL-cholesterol 3.3 ± 0.1 vs. 2.8 ± 0.1 mmol/l; HDL-cholesterol [median {interquartile range}] 1.3 [1.2–1.6] vs. 1.8 [1.5–1.9] mmol/l; triacylglycerol 1.3 [0.9–1.6] vs. 1.0 [0.7–1.7] mmol/l, all p ≤ 0.03), higher insulin secretion and lower insulin sensitivity. NAFLD prevalence was greater in women with previous GDM compared with those without previous GDM: 38% (95% CI 28–47%) vs. 17% (95% CI 10–24%), p = 0.001. In multiple logistic regression analysis, lower insulin sensitivity and raised serum alanine transaminase concentrations were associated with NAFLD.

Conclusions/interpretation: NAFLD is prevalent in European women with previous GDM. Impaired insulin sensitivity and increased liver transaminase activity are closely associated with NAFLD in these women.

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