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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
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PMID:Pathogenesis of NIDDM. A balanced overview. 153 77

To determine whether plasma endothelin, a potent vasoconstrictive peptide, is elevated in NIDDM patients, we compared a group of 15 NIDDM patients with macroangiopathy of mean age 60.60 +/- 2.33 years with 15 NIDDM randomly selected matched patients without macroangiopathy. Plasma endothelin levels were significantly increased in NIDDM patients with macroangiopathy (4.22 +/- 0.57 pmol/L) and in NIDDM patients without macroangiopathy (3.81 +/- 0.51 pmol/L). Although endothelin values did not differ between NIDDM groups, both represented significant difference from control values (2.46 +/- 0.24 pmol/L). No significant correlations were found between plasma endothelin and age (rs = 0.11), duration of diabetes mellitus (rs = 0.06), BMI (rs = 0.19), plasma glucose (rs = 0.15), plasma fructosamine (rs = 0.02). These findings confirm that in diabetes mellitus a primary disturbance in endothelin production from vascular endothelium exists as an early phenomenon rather than a result of advanced stage of the disease.
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PMID:Plasma endothelin levels in NIDDM patients with macroangiopathy. 764 86

Subtle abnormalities of carbohydrate metabolism and overt diabetes mellitus are both associated with a substantial increase in the prevalence of hypertension and the accelerated development of atherosclerosis. Hypertension is also a presumed independent risk factor for atherosclerosis, although some of the atherogenic properties of hypertension may be related to the recently recognized subtle metabolic abnormalities commonly found in persons with essential hypertension. The results of epidemiologic studies suggest that the elevated fasting and postprandial insulin levels that often occur in patients with essential hypertension, as well as in patients with type II diabetes mellitus, are an independent risk factor for atherosclerotic cardiovascular disease. Elevated glucose levels in patients with diabetes and hypertension appear to contribute to the acceleration of atherosclerosis, perhaps through toxic effects on the vascular endothelium. Other cardiovascular risk factors that are accentuated in persons with carbohydrate intolerance and hypertension include abnormalities in platelet function, clotting factors, the fibrinolytic system, and dyslipidemia. The goals of both nonpharmacologic and pharmacologic therapy for patients with abnormal carbohydrate metabolism and hypertension are to decrease cardiovascular risk as well as lower blood pressure.
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PMID:Hyperinsulinemia, insulin resistance, and hyperglycemia: contributing factors in the pathogenesis of hypertension and atherosclerosis. 839 10

Microvascular disease is an important cause of morbidity in diabetes. There is evidence that impaired autoregulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. The vascular endothelium plays a central role in the regulation of vascular tone. Endothelin (ET)-1 is a potent endothelium-derived vasoconstrictor substance that contributes to basal vascular tone. Impaired vasoconstriction in response to endogenous ET could result in hyperperfusion and subsequent microvascular damage. The purpose of our study was to determine whether vascular responses to locally administered ET-1 are impaired in NIDDM. Nine patients with NIDDM and 12 control subjects underwent cannulation of the nondominant brachial artery. Forearm blood flow (FBF) was measured at baseline and during the drug infusion using strain-gauge venous occlusion plethysmography. ET-1 (5 pmol/min) was infused for 60 min at a rate of 1 ml/min. FBF was measured during the first 5 min of the infusion and at 5-min intervals thereafter. Results were expressed as change in FBF from baseline (ml.100 ml-1.min-1) and were analyzed using repeated measures analysis of variance and Dunnett's test of multiple comparisons. Control subjects showed a gradual onset of vasoconstriction in response to ET-1, which reached maximum at 35 min (1.1 ml.100 ml-1.min-1; P < 0.01). There was no reduction in FBF in response to ET-1 in the diabetic group. The differences between the diabetic and control groups were significant (P < 0.03). In conclusion, ET-1 infused locally at 5 pmol/min does not cause vasoconstriction in patients with NIDDM.
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PMID:Impaired vasoconstriction to endothelin 1 in patients with NIDDM. 852 53

The prevalence of hypertension in diabetes is significantly higher than in non-diabetics, perhaps twice as common. The excess is related to diabetic nephropathy, mainly in type 1 diabetes, to obesity, mainly in type 2 diabetes, but also to increased sympathetic activity. Furthermore, the increased prevalence of hypertension may relate to insulin resistance and its sequelae. Insulin resistance leads to hyperinsulinemia, relates to increased LDL and reduced HDL levels, causes the development of impaired glucose tolerance and type 2 diabetes and might also be causally related to the onset of hypertension. Syndrome X has relevant therapeutic implications in the management of hypertension. Hypertension is a major risk factor for large vessel disease in diabetics and also a risk factor for microangiopathy, particularly nephropathy. The incidence of atherosclerotic disease is dramatically increased in both type 1 and type 2 diabetics and is the major cause of morbidity and premature death mainly in patients with raised urinary albumin excretion. Thus, diabetics show a two-fold increased risk of coronary heart disease, 2-6 fold increased risk of stroke and a several-fold increased risk of peripheral vessel disease. Some evidence suggests that hypertension may be a risk factor for retinopathy, particularly its progression, but surely hypertension is a significant risk factor for nephropathy, accelerating its progression and perhaps even causing the onset of the glomerulopathy. The mechanisms by which hypertension might contribute to the evolution of both large vessel as well as small vessel disease is still unknown, although increased capillary leakage and vascular endothelium alterations might be important factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hypertension and diabetes]. 856 58

I have presented data to support an interaction of insulin with the vascular endothelium to cause the release of NO and vasodilation. In effect, insulin-mediated vasodilation can be viewed as a novel test of endothelial function. The physiologic significance of insulin-mediated, endothelium-dependent vasodilation is not fully understood, but some insight has been gained. Insulin-mediated vasodilation in skeletal muscle appears to be an important mechanism to amplify insulin's overall action to stimulate skeletal muscle glucose uptake in insulin-sensitive man. Insulin-resistant states of obesity, hypertension, and NIDDM exhibit blunted insulin-mediated vasodilation and impaired endothelium-dependent vasodilation. Together, the data suggest that endothelial dysfunction is an integral aspect of the syndrome of insulin resistance, independent of hyperglycemia, and as such may contribute to worsen insulin resistance, increase vascular reactivity, 32 and predispose to macrovascular disease. Thus, the insulin/EDNO interaction provides a potential mechanism (but certainly not the only one) linking insulin resistance, hypertension, thrombosis, and atherosclerosis-key features of the insulin resistance syndrome (Figure 7). Future research into the signal transduction steps leading to insulin-mediated, endothelium-derived NO production and its dysregulation in insulin-resistant states will be extremely useful to elucidate the mechanisms underlying the increased macrovascular risk in insulin-resistant man.
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PMID:Insulin and the vasculature--old actors, new roles. 895 21

Insulin resistance has been proposed as the metabolic basis of atherogenesis. This hypothesis is based on the concept of the "insulin resistance syndrome," according to which insulin resistance is viewed as the primary abnormality that gives rise to dyslipidemia, essential hypertension, impaired glucose tolerance, and NIDDM. However, this hypothesis takes no account of the well-established and central role of vascular endothelium in the atherogenic process. Although endothelial injury is an early and prominent feature of atherogenesis, relatively little attention has been given to its metabolic consequences. In subjects with NIDDM, we have shown that endothelial dysfunction is associated with insulin resistance, raising the question of whether this relationship could be causal. In this article, we review the factors that are considered to be responsible for the development of endothelial dysfunction during atherogenesis, together with the metabolic consequences of endothelial dysfunction. While dysfunction of the endothelium in large and medium-sized arteries plays a central role in atherogenesis, we argue that dysfunction of peripheral vascular endothelium, at arteriolar and capillary level, plays the primary role in the pathogenesis of both insulin resistance and the associated features of the insulin resistance syndrome. We propose that the insulin resistance syndrome, together with many aspects of atherogenesis, can be viewed as the diverse consequences of endothelial dysfunction in different vascular beds. This new and testable hypothesis accounts for both the endothelial and metabolic abnormalities associated with atherogenesis.
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PMID:Endothelial dysfunction: cause of the insulin resistance syndrome. 928 92

The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key initial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucose medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte adhesion to HAECs under hyperglycemic conditions is via the 12-lipoxygenase (12-LO) pathway. In this study, we demonstrated in HAECs that the major LO metabolite of arachidonic acid was the 12-LO product, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultured under high-glucose conditions. Furthermore, treatment of HAECs with 12(S)-HETE induced monocyte, but not neutrophil, adhesion an average of 3-fold (range of 1.5- to 5-fold) compared with untreated cells (75+/-5 versus 26+/-1 monocytes per field, respectively, P<0.001). Expression of the adhesion molecules vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1 was not significantly increased. However, both glucose and 12(S)-HETE induced a 60% increase in HAEC surface expression of connecting segment-1 (ie, CS-1) fibronectin, a ligand for very late-acting antigen-4 (VLA-4). The antibodies used to block monocyte integrin VLA-4 and leukocyte function-related antigen-1, a monocytic counterreceptor for intercellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively demonstrate for the first time in HAECs that the 12-LO pathway can induce monocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results suggest that the 12-LO pathway may play a role in the increased susceptibility of diabetics to atherosclerosis.
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PMID:Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells. 1055 3

Insulin resistance is a uniform finding in type 2 diabetes, as are abnormalities in the microvascular and macrovascular circulations. These complications are associated with dysfunction of platelets and the neurovascular unit. Platelets are essential for hemostasis, and knowledge of their function is basic to understanding the pathophysiology of vascular disease in diabetes. Intact healthy vascular endothelium is central to the normal functioning of smooth muscle contractility as well as its normal interaction with platelets. What is not clear is the role of hyperglycemia in the functional and organic microvascular deficiencies and platelet hyperactivity in individuals with diabetes. The entire coagulation cascade is dysfunctional in diabetes. Increased levels of fibrinogen and plasminogen activator inhibitor 1 favor both thrombosis and defective dissolution of clots once formed. Platelets in type 2 diabetic individuals adhere to vascular endothelium and aggregate more readily than those in healthy people. Loss of sensitivity to the normal restraints exercised by prostacyclin (PGI(2)) and nitric oxide (NO) generated by the vascular endothelium presents as the major defect in platelet function. Insulin is a natural antagonist of platelet hyperactivity. It sensitizes the platelet to PGI(2) and enhances endothelial generation of PGI(2) and NO. Thus, the defects in insulin action in diabetes create a milieu of disordered platelet activity conducive to macrovascular and microvascular events.
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PMID:Platelet dysfunction in type 2 diabetes. 1147 89

Functional impairment of the vascular endothelium is an early event in the development of atherosclerosis, and soluble adhesion molecules in plasma are regarded as an indicator of the endothelial damage in diabetes mellitus. We compared the soluble vascular adhesion molecule levels in the patients with diabetic nephropathy in concerning with plasma 7-ketocholesterol levels, which is major cholesterol auto-oxidation products. Average value of plasma VCAM-1 in 31 patients with type 2 diabetes mellitus was 297.6+/-10.2 ng/ml (mean+/-SE), and the value was significantly higher than that in 8 age-matched healthy controls (231.9+/-15.0 ng/ml). Among the 31 diabetic patients, the group with macroalbuminuria (n = 8) had the higher levels of plasma VCAM-1 (349.5+/-26.0 ng/ml) than the levels in the group with normoalbuminuria (n=15; 280.6+/-12.3 ng/ml). The levels of plasma 7-ketocholesterol in diabetes (26.9+/-1.5 ng/ml) or the patients with macroalbuminuria (31.4+/-3.3 ng/ml) were significantly higher than the control (22.5+/-1.8 ng/ml). The level of soluble VCAM-1 showed significant correlation between the values of 7-ketocholesterol (r=0.42, p=0.024), TC (r=0.42, p=0.014) and LDL-C (r=0.38, p=0.044). However no correlation was demonstrated with HbA1c nor creatinine level. We conclude that soluble VCAM-1 in plasma may be an indicator of oxidative stress and vascular injury in diabetic nephropathy.
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PMID:Plasma levels of soluble vascular adhesion molecule-1 and cholesterol oxidation product in type 2 diabetic patients with nephropathy. 1168 11


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