Plasma alpha-defensin is associated with cardiovascular morbidity and mortality in type 1 diabetic patients

CONTEXT: alpha-Defensins are antimicrobial peptides of the innate immune system. In addition, experimental evidence suggests that alpha-defensins are proatherogenic. OBJECTIVE: The objective of the study was to examine the predictive value of plasma alpha-defensin as a clinical marker of cardiovascular disease (CVD) in patients with type 1 diabetes. METHODS: In an observational, prospective design, 389 patients with long-lasting type 1 diabetes were examined for CVD at study start (1993; baseline) and followed up through the Danish National Register for a median of 10.1 yr (range 0.2-10.4 yr). Plasma was collected in 1993 and stored at -80 C until analysis of plasma alpha-defensin using an in-house RIA. RESULTS: At baseline, plasma alpha-defensin was significantly higher in patients with than without nephropathy [median and interquartile ranges: 305 (205-321) vs. 223 (182-263) mug/liter; P < 0.0001]. During follow-up, 98 patients reached the primary end point (fatal and nonfatal events of CVD). Prospectively a baseline alpha-defensin within the upper vs. the lower tertile significantly increased the covariate-adjusted risk for CVD-related morbidity and mortality to a hazard ratio of 2.8 (1.3-5.9) (median and 95% confidence intervals, P = 0.006). CONCLUSION: This study suggests that plasma alpha-defensin may serve as a clinical risk marker for CVD-related morbidity and mortality in type 1 diabetes. However, future studies are needed to clarify whether plasma alpha-defensin is causally linked to the development of CVD or an innocent bystander.     

Autoantibodies and HLA class II DR-DQ genotypes in Ugandan children and adolescents with type 1 diabetes mellitus

International Journal of Diabetes in Developing Countries - The aims were to determine the prevalence of autoantibodies in type 1 diabetes mellitus (T1DM) and further to investigate the human...     

Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes

Abstract. Forsblom C, Thomas MC, Moran J, Saraheimo M, Thorn L, Wadén J, Gordin D, Frystyk J, Flyvbjerg A, Groop P‐H, on behalf of the FinnDiane Study Group (Folkhälsan Institute of Genetics, Helsinki; Department of Medicine Helsinki University Central Hospital, Helsinki, Finland; The Baker IDI Heart and Diabetes Institute, Melbourne, Vic.; The Queen Elizabeth Hospital, Woodville, SA, Australia; and Aarhus University Hospital, Aarhus C., Denmark). Serum adiponectin concentration is a positive predictor of all‐cause and cardiovascular mortality in type 1 diabetes. J Intern Med 2011; 270 : 346–355. Background. Adiponectin is widely regarded as an anti‐atherogenic, antioxidant and anti‐inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. Objective. To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. Design. Multicentre prospective cohort study. Setting. Primary and tertiary care. Subjects. Finnish adults with type 1 diabetes (n = 2034). Main outcome measures. All‐cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. Results. During a median of 11 years of follow‐up, there were 173 deaths (8.5%, 1.0 per hundred person‐years). Adiponectin was linearly associated with all‐cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01–1.03, P < 0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00–1.04, P = 0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre‐existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. Conclusions. Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all‐cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.     

Different contribution of class II HLA in fulminant and typical autoimmune type 1 diabetes mellitus

Aims/hypothesis Fulminant type 1 diabetes, which is characterised by a markedly acute onset of diabetes and an absence of islet-related autoantibodies, accounts for 20% of type 1 diabetes in Japan. We aimed to clarify the contribution of the HLA subtype to fulminant type 1 diabetes in Japanese. Methods We determined the serological subtypes of HLA-A, -DR and -DQ in 115 patients with fulminant type 1 diabetes, 98 patients with typical type 1A diabetes and 190 normal control subjects. Results The frequency of HLA-DR4, but not DR9, was significantly higher in fulminant type 1 diabetes, while those of HLA-DR1, DR2, DR5 and DR8 were significantly lower than those in controls. In contrast, DR9 but not DR4 was more frequent and DR2 was extremely rare in typical type 1A diabetes. Haplotype analysis revealed that DR4-DQ4 was significantly more frequent, and both DR2-DQ1 and DR8-DQ1 were less frequent in fulminant diabetes. In type 1A diabetes, DR2-DQ1 was extremely rare while DR9-DQ3 was significantly more frequent. In the combination analysis, the homozygotes of DR4-DQ4 in fulminant type 1 diabetes and DR9-DQ3 in typical type 1A diabetes indicated high odds ratios (13.3 and 13.3, respectively). Conclusions/interpretation Our results suggest that class II HLA contributes to the development of fulminant type 1 diabetes. Susceptibility and resistance of the HLA subtype to type 1 diabetes are distinct between fulminant and typical autoimmune type 1 diabetes. An erratum to this article is available at .     

Metabolic syndrome as a cardiovascular risk factor in patients with type 2 diabetes

INTRODUCTION AND OBJECTIVES: To assess the cardiovascular risk associated with the presence of metabolic syndrome in patients with type 2 diabetes.Patients and method. Prospective cohort study of patients with type 2 diabetes. The baseline presence of components of metabolic syndrome as defined by the World Health Organization was determined. The main dependent variable was a combination of coronary events (onset angina, fatal or nonfatal myocardial infarction) and cerebrovascular events (transient ischemic attack, fatal or nonfatal stroke and lower limb amputation). Secondary end points were coronary events and stroke. We calculated the predictive power of the presence of metabolic syndrome and of different numbers of its component features. RESULTS: 318 patients were included. Mean duration of follow-up was 4.6 years (SD 1.5 years). The prevalence of metabolic syndrome was 77.0%. The rates of cardiovascular events, coronary events and stroke, expressed per 1000 patient-years, were 14.0, 5.6, and 8.4 respectively in patients without metabolic syndrome, and 33.3, 20.7, and 11.7 respectively in patients with metabolic syndrome (P=.058 cardiovascular events; P=.05 coronary events). In the multivariate analysis, the simultaneous presence of all four metabolic syndrome components significantly increased the global cardiovascular disease risk (RR=5.0; 95% CI, 1.6-15.9; P=.006) and the risk of coronary heart disease (RR=7.4; 95% CI, 1.3-41.1; P=.02), but not the risk of stroke. CONCLUSIONS: The simultaneous presence of all four metabolic syndrome components is associated with an increase in the risk of cardiovascular events in patients with type 2 diabetes.     

Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men

Aims/hypothesis  

Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting.     

Oral treatments for type II diabetes in patients with cardiovascular disease

The incidence of type II diabetes mellitus is rising rapidly, both in the United States and worldwide. Often, the disease is first diagnosed by cardiologists during an evaluation for coronary or peripheral vascular disease. It is therefore important to understand the basic pathophysiology of insulin resistance, its role in the development of type II diabetes, and its association with accelerated atherosclerosis. An appreciation of when to begin testing for diabetes, how to make the diagnosis, and what treatment strategy to choose is imperative. While there are as yet little randomized data to guide hypoglycemic therapy as it pertains to reducing cardiovascular risk, evidence is accumulating that treatment of diabetes will have an impact on cardiovascular outcomes.     

Proteinuria modifies the effects of physical activity on total and cardiovascular disease mortality rates in patients with type 2 diabetes

Aims/hypothesis  

Physical activity reduces cardiovascular disease (CVD) and total mortality rates in patients with type 2 diabetes. However, it is not known whether or not the effects of physical activity on mortality rates depend on the presence of proteinuria in type 2 diabetic patients.     

Orosomucoid in urine predicts cardiovascular and over-all mortality in patients with Type II diabetes

Aims/hypothesis: Urinary orosomucoid excretion rate is increased in a substantial proportion of patients with Type II (non-insulin-dependent) diabetes mellitus and normal urinary albumin excretion rate. The aim of this study was to determine whether increased urinary orosomucoid excretion rate is predictive of increased mortality in patients with Type II diabetes. Methods: In a cohort study including 430 patients with Type II diabetes, baseline urinary samples were analysed for orosomucoid and albumin. Mean follow-up was 2.4 years. Results: We found that 188 (44 %) patients had normal and 242 (56 %) patients had increased urinary orosomucoid excretion rates. During the study period 41 patients died; out of these 23 patients died of cardiovascular diseases. Odds ratio for all-cause mortality was 2.50 (95 % CI 1.00–6.22) and odds ratio for cardiovascular mortality was 9.81 (1.31–73.6) having increased urinary orosomucoid excretion rate at baseline (odds ratios adjusted for age, sex, duration of diabetes, cardiovascular diseases, weight, medication, HbA_{1 c}, plasma creatinine and urinary albumin excretion rate). Urinary albumin excretion rate was an independent predictor of all-cause mortality when urinary orosomucoid excretion rate was not included in the analysis. Subgroup analysis revealed that 39 % of the patients with normal urinary albumin excretion rate (n = 251) had increased urinary orosomucoid excretion rates and that these patients had a higher cardiovascular mortality (p = 0.007) than patients with normal urinary albumin excretion rate and normal urinary orosomucoid excretion rates. Conclusion/interpretation: We found that urinary orosomucoid excretion rate predicted all-cause and cardiovascular mortality in patients with Type II diabetes independently from other risk factors. [Diabetologia (2002) 45: 115–120] Received: 24 July 2001 and in revised form: 17 September 2001     

Sugar-sweetened and diet beverage consumption is associated with cardiovascular risk factor profile in youth with type 1 diabetes

The prevalence of cardiovascular disease (CVD) risk factors among youth with type 1 diabetes is high and associated with age, gender, and race/ethnicity. It has also been shown that youth with type 1 diabetes often do not follow dietary recommendations. The objective of this cross-sectional observational study was to explore the association of sugar-sweetened and diet beverage intake with A1c, plasma lipids, adiponectin, leptin, systolic, and diastolic blood pressure in youth with type 1 diabetes. We examined data from 1,806 youth age 10-22?years with type 1 diabetes, of which 22% were minority (10% Hispanic, 8% African Americans, 4% other races) and 48% were female. Sugar-sweetened beverage, diet beverage, and mineral water intake was assessed with a food frequency questionnaire. After adjustment for socio-demographic and clinical covariates, physical activity and total energy intake, high sugar-sweetened beverage intake (at least one serving per day vs. none), was associated with higher levels of total cholesterol, LDL cholesterol, and plasma triglycerides, but not with A1c. High diet beverage intake was associated with higher A1c, total cholesterol, LDL cholesterol, and triglycerides. These associations were partially confounded by body mass index, saturated fat and total fiber intake. High sugar-sweetened beverage intake may have an adverse effect on CVD risk in youth with type 1 diabetes. Diet beverage intake may be a marker of unhealthy lifestyle which, in turn, is associated with worse metabolic control and CVD risk profile in these youth. Youth with diabetes should be encouraged to minimize sugar-sweetened beverage intake.     

HLA class II influences humoral autoimmunity in patients with type 2 autoimmune hepatitis

BACKGROUND/AIMS: Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS: Frequencies of HLA class II alleles were compared between the 60 Caucasian children with type 2 AIH and 313 control subjects. The anti-LKM1 antibody reactivity directed against antigenic sites of CYP2D6 was analysed by ELISA. RESULTS: HLA-DQB1 *0201 allele was found to be the primary genetic determinant of susceptibility to type 2 AIH by conferring the highest odd-ratio (OR = 6.4). HLA-DRB1 *03 allele was significantly increased (P < 0.0001) among patients with both anti-LKM1 and anti-LC1 autoantibodies as well as in those with only anti-LC1(+) compared to those with anti-LKM1(+) alone. In contrast, HLA-DRB1 *07 allele was significantly associated (P < 0.0001) with anti-LKM1(+) alone compared to groups with both anti-LKM and anti-LC1 or with LC1+ alone. Children with the DRB1 *07 allele develop anti-LKM1 autoantibodies having a more restricted specificity (2 epitopes) than to those having HLA-DRB1 *03 allele (5 epitopes). CONCLUSIONS: The HLA-DR locus is involved in autoantibody expression, while the DQ locus appears to be a critical determinant for the development of type 2 AIH.     

Mild renal insufficiency as a cardiovascular risk factor in non-proteinuric type II diabetes

OBJECTIVES: To evaluate cardiovascular risk according to baseline renal function in a group of non-proteinuric type II diabetic patients. MATERIAL AND METHODS: Prospective study with a follow-up of 423 non-proteinuric type II diabetic patients with creatinine <150 micromol/l for an average of 4.7 years (S.D. 1.55). Creatinine clearance (CC) was estimated using the Cockcroft-Gault formula and expressed in millilitre per minute. The hazard ratio (HR) associated with each millilitre per minute decrease in baseline CC on fatal or non-fatal cardiovascular events and total mortality was evaluated using the Cox regression model. RESULTS: Baseline creatinine was 89 micromol/l (S.D. 15.9) and CC was 69.5 ml/min (S.D. 20). There were 63 cardiovascular events (15 unstable angina, 10 non-fatal myocardial infarctions, 25 non-fatal strokes, two amputations, nine fatal myocardial infarctions and two fatal strokes) and 39 total deaths (11 for cardiovascular causes). The cardiovascular event rate was 31.7/1000 patient-years and the total mortality rate was 19.6/1000 patient-years. The independent predictors of cardiovascular events were: CC (HR=1.035; confidence interval (CI) 95% 1.02-1.05; P<0.0001), total cholesterol/HDL cholesterol ratio (HR=1.25; CI 95% 1.1-1.4; P=0.0008), baseline coronary heart disease (HR=2.05; CI 95% 1.07-3.9; P=0.04) and baseline microalbuminuria (HR=2.3; CI 95% 1.3-3.8; P=0.003). The independent total mortality predictors were: CC (HR=1.04; CI 95% 1.02-1.08; P<0.0001), male (HR=2.1; CI 95% 1.1-4; P=0.027) and baseline microalbuminuria (HR=2.1; CI 95% 1.1-4;P=0.03). CONCLUSIONS: Mild renal insufficiency increases cardiovascular risk in non-proteinuric patients with type II diabetes.     

Use of class I and class II HLA loci for predicting age at onset of type 1 diabetes in multiple populations

Aims/hypothesis

The study aimed to assess, in multiple populations, the role of HLA alleles on early and late age at onset of type 1 diabetes.

Methods

Stepwise linear regression models were used to determine which HLA class I and class II risk alleles to include. High-resolution genotyping data for patients from the Type 1 Diabetes Genetics Consortium (T1DGC) collection (n?=?2,278) and four independent cohorts from Denmark, Sardinia and the USA (Human Biological Data Interchange [HBDI] and Joslin Diabetes Center) (n?=?1,324) (total n?=?3,602) were used to assess the role of HLA variation on age of onset and predict early onset (age ≤5?years) and late onset (age ≥15?years) of type 1 diabetes.

Results

In addition to carriage of HLA class I alleles A*24:02, B*39:06, B*44:03 and B*18:01, HLA class II DRB1-DQB1 loci significantly contributed to age at onset, explaining 3.4% of its variance in the combined data. HLA genotypes, together with sex, were able to predict late onset in all cohorts studied, with AUC values ranging from 0.58 to 0.63. Similar AUC values (0.59–0.70) were obtained for early onset for most cohorts, except in the Sardinian study, in which none of the models tested had significant predictive power.

Conclusions/interpretation

HLA associations with age of onset are consistent across most white populations and HLA information can predict some of the risk of early and late onset of type 1 diabetes. Considerable heterogeneity was observed between Sardinian and other populations, particularly with regard to early age of onset.     

Reduction of cardiovascular morbidity and mortality in type 2 diabetes. A rational approach to hypoglycemic therapy

Type 2 diabetes mellitus is the single most important risk factor for the development of coronary artery disease. Unfortunately, the traditional therapeutic strategies for the treatment of hyperglycemia have proven to be ineffective in preventing cardiovascular complications. In recent years the number of available hypoglycemic agents has increased and considerable progress has been made regarding the comprehension of the pathophysiology of diabetes and its vascular complications. In the present article we firstly present benefits and risks of intensive vs standard hypoglycemic intervention, and the pros and cons of therapy targeted to postprandial hyperglycemia. Secondly, we discuss the cardiovascular effects of sulfonylurea agents and insulin, focusing on the role of intensive insulin treatment in the context of acute coronary syndromes. Thirdly, we review the epidemiological, clinical and experimental evidence linking insulin resistance and cardiovascular disease. Finally, we present the rationale and the role of metformin and thiazolidinedionetherapy in the prevention of cardiovascular complications. We conclude that the optimal use of the full spectrum of hypoglycemic agents has the potential to play a key role in the prevention of diabetes-related macrovascular complications.     

Distinct trajectories in HbA1c are associated with different all-cause mortality and morbidity in newly diagnosed patients with type 2 diabetes

AimsTo identify trajectories of long-term HbA1c levels and examine associations with subsequent risk for morbidity and mortality.MethodsWe conducted a longitudinal follow-up among 27,724 patients, newly diagnosed with type 2 diabetes, in a large healthcare organization. We identified trajectories of long-term HbA1c levels during the first 5 years post diabetes onset to examine associations with subsequent risk for morbidity and all-cause mortality.ResultsWe identified two HbA1c trajectories; the “Steady-plateau HbA1c trajectory” in 93% of patients and a “Sharp-incline HbA1c trajectory” in 7% of patients. When compared to the steady-plateau group, patients in the sharp-incline group were younger, male, from a lower socio-economic background, and higher levels of HbA1c at baseline. Patients in the sharp-incline trajectory had a HR = 1.83 (95%CI: 1.58–2.12) for all-cause mortality, HR = 1.99 (95%CI: 1.74–2.27) for cardiovascular disease, and HR = 1.68 (95%CI: 1.51–1.86) for renal disease, compared to patients in the steady-plateau trajectory.ConclusionsPatients in the sharp-incline trajectory had a higher risk for all-cause mortality, cardiovascular disease, and renal disease, compared to patients in the steady-plateau trajectory. Estimation of HbA1c variability in the first years of diagnosis may be a useful indicator of those patients at high risk for diabetes related complications.