Type 2 diabetes as an inflammatory cardiovascular disorder

Type 2 diabetes carries a 2-6-fold increased risk of cardiovascular disease (CVD) and death. Indeed, the risk of major cardiovascular events in Type 2 diabetic patients without history of coronary heart disease (CHD) is equivalent to that observed in non-diabetic subjects with CHD. However, atherosclerosis may also precede the development of diabetes, suggesting that both disorders share common genetic and environmental antecedent factors ("common soil" hypothesis). One such a possible ancestor is insulin resistance which constitutes both a major feature of Type 2 diabetes and an independent risk factor for CHD. It is well documented that inflammatory processes play an important role in the causation of atherosclerotic CVD. Inflammatory mediators play a paramount role in the initiation, progression, and rupture of atherosclerotic plaques. Thus, markers of inflammation and endothelial dysfunction may provide additional information about a patient's risk of developing CVD and may become new targets for treatment. On the other hand, evidence has emerged suggesting that inflammation is also involved in the development of Type 2 diabetes. Prospective studies have demonstrated that increased levels of pro-inflammatory markers such as CRP or reduced levels of anti-inflammatory markers such as adiponectin predict the development of Type 2 diabetes. Thus, there is accumulating evidence suggesting that inflammation is the bridging link between atherosclerosis and the metabolic syndrome. Interventions by lifestyle modification or agents with anti-inflammatory properties may reduce the risk of both conditions. Drugs exerting anti-inflammatory and vascular effects have future potential to be used within an array of interventions aimed at reducing the enormous cardiovascular burden associated with Type 2 diabetes.     

Type 2 diabetes as an inflammatory disease

Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.     

Type 2 diabetes mellitus as risk factor for colorectal cancer

Colorectal cancer occurs more frequently in patients with type 2 diabetes mellitus. The hyperinsulinemia-hypothesis suggests that elevated levels of insulin and free IGF-1 promote proliferation of colon cells and lead to a survival benefit of transformed cells, ultimately resulting in colorectal cancer. In patients with type 2 diabetes mellitus, epidemiological studies show an increased risk for colorectal cancer and an even higher risk if patients are treated with sulphonylureas or insulin. Moreover, tumour progression at hyperinsulinemia is more rapid and tumour-associated mortality is increased. Colorectal cancer can be avoided by screening. Recommendations for colorectal cancer screening should employ the recent epidemiologic evidence. All patients with type 2 diabetes mellitus should be recommended to undergo colonoscopy before starting insulin therapy, and screening intervals should not exceed 5 years. For this concept, a review of the evidence is presented, and a screening algorithm for colorectal cancer in patients with type 2 diabetes mellitus is proposed.     

Type 1 diabetes as a mask of a neuroendocrine tumour of pancreas

Neuroendocrine tumours of pancreas originating from pancreatic islet cells are uncommon neoplasms with clinical manifestation depending on a type of hormone secreted. Diabetes as a clinical sign of such a tumour has been reported many times and is not an uncommon finding but it is generally mild and makes only a part ofa whole pattern of symptoms. We report on a case of a malignant neuroendocrine pancreatic tumour in 19 years old patient, where diabetes, with a clinical course typical for type 1 diabetes, was the first and the main symptom of the disease.     

Activation of carboxylation as a factor in correcting the metabolic disorder in diabetes mellitus

The paper deals with studies of the effect of the 10-day complex therapy with carbostimulin application on the content of the tricarboxylic cycle and glycolysis metabolites, total lipids, cholesterol, triglycerides in blood and potassium and sodium in blood serum of patients with diabetes mellitus. It is established that under the effect of carbostimulin the content of oxaloacetate, lactate and alpha-glycerophosphate becomes normal, the lactate/pyruvate ratio elevated in diabetes decreases, which evidences for intensification of reduction processes in the cytoplasm.     

Type 2 diabetes: an atherothrombotic syndrome

Insulin resistance is found in around 80-90% of subjects with older onset (type 2) diabetes and in approximately 25% of the general population. Insulin resistance prior to the development of frank type 2 diabetes and type 2 diabetes itself is associated with a significant increase in the risk of atherothrombotic disease, which is due in part to a disruption in the balance of factors regulating coagulation and fibrinolysis. Both insulin resistance and type 2 diabetes are associated with the development of endothelial dysfunction, and enhanced platelet aggregation and activation. Whilst the plasma levels of many clotting factors including fibrinogen, FVII, FVIII, FXII, FXIII b-subunit are elevated, the fibrinolytic system is relatively inhibited as a consequence of an increase in plasminogen activator inhibitor type-1 (PAI-1) levels. These changes favour the development of a hypercoagulable pro-thrombotic state, which may in turn enhance cardiovascular risk by increasing the likelihood of developing an occlusive thrombus within a coronary/cerebral artery, and/or contributing to the development of atherosclerotic lesions. This article reviews the current published evidence of the pro-thrombotic changes that occur in association with type 2 diabetes and insulin resistance, and the putative underlying mechanisms which lead to these changes.     

Atherogenic vascular and lipid phenotypes in young patients with Type 1 diabetes are associated with diabetes high-risk HLA genotype

Expression of human leukocyte antigen (HLA) class II molecules on islet endothelial cells is a central vascular event in the pathogenesis of Type 1 diabetes. Previous studies demonstrated the ability of other vascular endothelial cells to express HLA and thereby to process islet autoantigens on their surface. We investigated whether the HLA-DQ2/8 genotype, which confers the highest risk for Type 1 diabetes, is associated with early atherosclerosis in youths with this disease. Brachial artery endothelium-dependent, flow-mediated dilation (BA-FMD) and carotid artery intima-media thickness (CA-IMT), as well as markers of systemic inflammation [C-reactive protein (CRP), fibrinogen, and orosomucoid], HbA(1C), LDL, HDL, and total cholesterol, were assessed in 86 children and adolescents with Type 1 diabetes (mean age and diabetes duration, 15 and 7 yr, respectively) between 2004 and 2006. HLA genotypes were determined in dried blood spots by an oligoblot hybridization method. As a result, HLA-DQ2/8 was detected in 34 patients (DQ2/8). When this group was compared with the remaining patients (non-DQ2/8, n = 52), there were no differences in age, diabetes duration, HbA(1C), body mass index, inflammatory markers, and IMT (P > or = 0.4). In the DQ2/8 group, LDL-to-HDL ratio was elevated compared with that in the non-DQ2/8 group (1.8 vs. 1.3, respectively; P = 0.001), whereas FMD did not significantly differ between the groups (5.3% vs. 6.7%, respectively; P = 0.08). When patients were further categorized in relation to CRP (cut-off value, 1 mg/l), BA-FMD was significantly lower (3%, P < 0.01), whereas LDL-to-HDL ratio increased further (2.2, P < 0.001) in the subgroup of DQ2/8 and CRP > or = 1 patients compared with the remaining three subgroups. These associations remained significant after adjustment for age, diabetes duration, and HbA(1C) by analysis of covariance. The brachial artery responses to nitroglycerine were similar in all subgroups. In conclusion, the diabetes-predisposing HLA-DQ2/8 genotype in children and adolescents with Type 1 diabetes interferes with endothelial and lipid-related mechanisms of early atherosclerosis, possibly in part through inflammatory pathways.     

Addiction as a disorder of belief

Addiction is almost universally held to be characterized by a loss of control over drug-seeking and consuming behavior. But the actions of addicts, even of those who seem to want to abstain from drugs, seem to be guided by reasons. In this paper, I argue that we can explain this fact, consistent with continuing to maintain that addiction involves a loss of control, by understanding addiction as involving an oscillation between conflicting judgments. I argue that the dysfunction of the mesolimbic dopamine system that typifies addictions causes the generation of a mismatch between the top-down model of the world that reflects the judgment that the addict ought to refrain from drugs, and bottom-up input caused by cues predictive of drug availability. This constitutes a powerful pressure toward revising the judgment and thereby attenuating the prediction error. But the new model is not stable, and shifts under the pressure of bottom-up inputs in different contexts; hence the oscillation of all-things-considered judgment. Evidence from social psychology is adduced, to suggest that a similar process may be involved in ordinary cases of weakness of will.     

Reduced exercise arteriovenous O2 difference in Type 2 diabetes.

Maximal O(2) consumption (Vo(2 max)) is lower in individuals with Type 2 diabetes than in sedentary nondiabetic individuals. This study aimed to determine whether the lower Vo(2 max) in diabetic patients was due to a reduction in maximal cardiac output (Q(max)) and/or peripheral O(2) extraction. After 11 Type 2 diabetic patients and 12 nondiabetic subjects, matched for age and body composition, who had not exercised for 2 yr, performed a bicycle ergometer exercise test to determine Vo(2 max), submaximal cardiac output, Q(max), and arterial-mixed venous O(2) (a-v O(2)) difference were assessed. Maximal workload, Vo(2 max), and maximal a-v O(2) difference were lower in Type 2 diabetic patients (P < 0.05). Q(max) was low in both groups but not significantly different: 11.2 and 10.0 l/min for controls and diabetic patients, respectively (P > 0.05). Submaximal O(2) uptake and heart rate were lower at several workloads in diabetic patients; respiratory exchange ratio was similar between groups at all workloads. Vo(2 max) was linearly correlated with a-v O(2) difference, but not Q(max) in diabetic patients. These data suggest that a reduction in maximal a-v O(2) difference contributes to a decreased Vo(2 max) in Type 2 diabetic patients.     

Type 2 diabetes mellitus in children and adolescents: a review from a European perspective

Changes in food consumption and exercise are fueling a worldwide increase in obesity in children and adolescents. As a consequence of this dramatic development, an increasing rate of type 2 diabetes mellitus has been recorded in children and adolescents in the USA and, more recently, in many countries around the world. Both genetic and environmental factors contribute to the pathogenesis of type 2 diabetes. Lower susceptibility in white Caucasians and higher susceptibility in Asians, Hispanics and blacks have been noted. There is a high hidden prevalence and a lack of exact data on the epidemiology of the disease in Europe: in Germany only 70 patients below the age of 15 years were identified in the systematic, nationwide DPV (Diabetessoftware für prospektive Verlaufsdokumentation) diabetes survey, but our calculations suggest that more than 5000 young people in Germany at present would meet the diagnostic criteria of type 2 diabetes. In Australasia, the prevalence of type 2 diabetes is reportedly high in some ethnic groups and again is linked very closely to the obesity epidemic. No uniform and evidence-based treatment strategy is available: many groups use metformin, exercise programmes and nutritional education as a comprehensive approach to treat type 2 diabetes in childhood and adolescence. The lack of clear epidemiological data and a strong need for accepted treatment strategies point to the key role of preventive programmes. Prevention of obesity will help to counteract the emerging worldwide epidemic of type 2 diabetes in youth. Preventive programmes should focus on exercise training and reducing sedentary behaviour such as television viewing, encouraging healthy nutrition and supporting general education programmes since shorter school education is clearly associated with higher rates of obesity and hence the susceptibility of an individual to acquire type 2 diabetes.