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Query: UMLS:C0011860 (type 2 diabetes)
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The clinical linkage of hypertensive cardiovascular disease, left ventricular hypertrophy, and accelerated atherosclerosis with a spectrum of metabolic disturbances including peripheral insulin resistance, hyperinsulinemia, obesity, and frank non-insulin dependent diabetes mellitus, has been increasingly appreciated. However, the underlying biologic basis mediating this clinical association remains unclear. Nuclear magnetic resonance techniques have been used to measure various intracellular ion species in human erythrocytes and have found that common, shared intracellular abnormalities of cytosolic free calcium, free magnesium, and pH occur in each of these clinical syndromes. Specifically, essential hypertension is characterized by higher fasting free cytosolic calcium concentrations and reciprocally lower intracellular free magnesium and pH levels compared with those of normotensive control subjects. Furthermore, for all subjects, free calcium and free magnesium levels were closely related both to the left ventricular mass and to the degree of insulin resistance present. Moreover, these same intracellular ionic lesions were found in normotensive obese and/or non-insulin diabetic individuals. Last, evidence has recently been provided that the cardiovascular consequences of increased dietary sugar and salt intake may well be determined by their concurrent influence on cellular ion metabolism. These data led to a hypothesis for a central role for altered cellular ion homeostasis in mediating the clinical linkage of cardiovascular and metabolic disease. According to this ionic hypothesis, essential hypertension, non-insulin dependent diabetes, and their frequently associated features of obesity, left ventricular hypertrophy, and accelerated atherosclerosis all derive from and reflect different clinical manifestations of the same underlying cellular lesion, characterized at least in part by elevated cytosolic free calcium and suppressed free magnesium levels.
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PMID:Cellular ions in hypertension, insulin resistance, obesity, and diabetes: a unifying theme. 145 64

In this review, the relationship between hypertension and abnormal carbohydrate metabolism is explored. A review of the current literature reveals that people with hypertension are also likely to suffer from insulin resistance, glucose intolerance, and hyperinsulinemia. Likewise, hypertension is prevalent in obese and diabetic patients. Deficiency of insulin at the cellular level may be a common mechanism in the development of hypertension in patients with type I or type II diabetes mellitus. Essential hypertension appears to be an insulin-resistant state. Insulin resistance may engender hypertension by increasing peripheral vascular resistance as well as by increasing salt retention at the level of the kidney. Therefore effective antihypertensive therapy should include agents that do not adversely affect carbohydrate metabolic abnormalities. Commonly used antihypertensive agents, such as thiazide, thiazide-like diuretics, and beta-blockers, are associated with glucose intolerance and increased insulin resistance. In contrast, angiotensin-converting enzyme inhibitors, calcium antagonists, and peripheral alpha-blockers (such as prazosin and terazosin) do not adversely affect glucose tolerance or insulin sensitivity. In addition, alpha-blockers have a positive effect on the serum lipid profile. The entire multifactorial cardiac risk profile must be considered when choosing therapeutic agents for conditions that have an impact on cardiovascular disease.
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PMID:Is hypertension an insulin-resistant state? Metabolic changes associated with hypertension and antihypertensive therapy. 187 73

An epidemic of renal disease is occurring among the Zuni Indians in western New Mexico. In 1985, 1.6% of Zunis had clinically recognized renal disease and 1% had renal insufficiency. The incidence of end-stage renal disease (ESRD) in 1984 and 1985 was 14 times the rate for US whites, and three times the rates of other Indians in ESRD network 6. One third of the cases of renal disease and ESRD is due to type 2 diabetes, but the etiology of disease in most of the remainder is unknown. Affected subjects range from early childhood to old age. Early signs are hematuria, mild to moderate proteinuria, normal BP, and low total hemolytic complement, normal or low C3 and C4 levels, in about 40% of the cases. The clinical course varies from benign to rapidly progressive renal failure. Biopsies usually reflect an immune-complex mediated mesangiopathic glomerulonephritis, with IgA, IgG, IgM, and C3 variably present in the mesangium. In some cases, there is a very strong familial pattern suggesting autosomal dominant inheritance or a marked communal exposure effect. This may be a genetic disease educed by the consanguinity in the ethnically homogeneous Zuni population. Mesangiopathic renal disease is common in some Oriental populations, and this phenomenon may reflect the American Indians' Oriental ancestry. This disease may also be due to toxic exposures related to jewelry-making, potting, Zuni water, Zuni salt, or herbal or other products used for medicinal or religious purposes. This epidemic is much morbidity and generating huge costs for ESRD treatment. Further study is needed to better understand its etiology.
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PMID:Epidemic renal disease of unknown etiology in the Zuni Indians. 359 94

Efficacy and reproducibility of insulin administered intranasally as an insulin-deoxycholate 1% (w/v) aerosol to normal and diabetic subjects were assessed by measurements of blood glucose and serum insulin levels. Following administration of 0.5 U insulin/kg with the unconjugated bile salt to fasting volunteers (N = 29), peak serum insulin levels of 103 +/- 49 microU/ml above baseline were observed at 10 min. Blood glucose concentration began to fall by 10 min, reaching 54 +/- 14% of control levels by 30 min, and returning to baseline by 60-80 min. Blood glucose response and peak serum insulin levels were reproducible when the same aerosol dose was repeatedly administered to the same subjects; however, intersubject variations were noted. By comparing serum insulin levels after i.v. and nasal routes of administration, nasal insulin absorption was approximately 10% as efficient as intravenous insulin. Dose response studies revealed that peak serum insulin concentrations were a linear function of the administered dose. In subjects with type I and type II diabetes mellitus, serum insulin levels increased in a manner similar to controls, and resulted in a prompt reduction of blood glucose concentration. However, in contrast to normal subjects, the duration of the glucose response was more prolonged, lasting as long as 5 h. Nasal administration of insulin as an aerosol with bile salts or bile salt analogs should be further evaluated as a possible nonparenteral approach to insulin therapy.
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PMID:Insulin administered intranasally as an insulin-bile salt aerosol. Effectiveness and reproducibility in normal and diabetic subjects. 635 2

Obesity is the most common reason for insulin resistance with consequent hyperinsulinemia. Other reasons for hyperinsulinemia are type II diabetes mellitus and a genetic predisposition with a family history of hypertension. Hyperinsulinemia is considered to cause blood pressure elevation and is generally accepted as an independent risk factor for atherosclerosis. However, insulin per se does not elevate blood pressure, but rather reduces total peripheral vascular resistance in experimental studies. Blood pressure might be elevated by other mechanisms secondary to hyperinsulinemia, however, such as enhanced renal sodium retention, elevated intracellular free calcium, and increased activity of the sympathetic nervous system. Indeed, subjects whose blood pressure is salt-sensitive exhibit hyperinsulinemia after glucose loading, and normotensive subjects with glucose-induced hyperinsulinemia will develop hypertension within 5 years more often than normoinsulinemic subjects. In primary hypertension, the incidence of insulin resistance and hyperinsulinemia is much higher than in normotensive controls. However, not all reported studies show a relationship between hyperinsulinemia and blood pressure elevation, and in some experimental studies no blood pressure elevation could be induced by prolonged hyperinsulinemia. Therefore, it is still unclear whether hyperinsulinemia induces hypertension or is only casually associated with it. Nevertheless, treatment of hyperinsulinemia is recommended to avoid secondary complications. Treatment should begin with weight reduction and physical exercise, which will improve insulin resistance. Hypertension benefits more from weight reduction than from exercise. If drug therapy of hypertension is required, angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers are the drugs of first choice. In addition, beta-blockers and centrally acting drugs appear to be of certain benefit. However, diuretics must be used carefully, because they ameliorate insulin resistance, induce dyslipoproteinemia, and stimulate the sympathetic nervous system.
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PMID:Hyperinsulinemia, insulin resistance, and hypertension. 789 93

Lithium is the best available marker of proximal tubular reabsorption of fluid. The first part of the present thesis reviews the background for the use of the lithium clearance (CLi) method. Micropuncture studies on proximal reabsorption of lithium, showed that CLi is a reasonably correct measure of end-proximal fluid delivery rate, even during osmotic diuresis. During severe salt restriction, distal reabsorption of lithium renders the CLi method inappropriate in animals, but this problem does probably not occur in humans. The major current issue is whether a quantitatively significant reabsorption of lithium occurs in the loop of Henle. Available evidence is in accord with the interpretation that it does not occur. The interpretation of results form CLi studies depends to a surprising degree on the investigators beliefs about renal physiology. In the evaluation of proximal tubular function, the relevant parameter is the absolute proximal reabsorption rate of fluid and sodium. In the evaluation of integrated distal tubular reabsorption of sodium, the relevant parameter is the fractional distal reabsorption rate of sodium. The fractional CLi does not give meaningful information, and calculated absolute distal reabsorption rate of sodium is inherently not suited to detect modest changes in distal reabsorption leading to large changes in sodium excretion. Results from the use of the CLi method in relation to diabetes are reviewed in the second section. Even in IDDM patients with early diabetic nephropathy, the proximal reabsorption rate is elevated, resulting in a normal CLi despite glomerular hyperfiltration. Overnight euglycemia did not change GFR in IDDM patients, but during maintained euglycemia, GFR was normalized. A few hours of hyperglycemia prevented the decline in GFR, whereas CLi was unchanged. Thus hyperglycemia produced changes in renal function similar to those observed previously, but the time-course of the effect of euglycemia on kidney function is delayed. Plasma levels of atrial natriuretic peptide, renin and glucagon were not importantly affected by plasma glucose. In NIDDM patients CLi was normal, despite slight hyperfiltration, although this observation must be confirmed in a study with larger sample size. Prompted by the clinical observation of a marked decline in the GFR induced by carbonic anhydrase inhibitors, we studied the renal effects of acetazolamide in a controlled study.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Lithium clearance in the evaluation of segmental renal tubular reabsorption of sodium and water in diabetes mellitus. 818 64

Parathyroid hypertensive factor (PHF) in rats: PHF is an endogenous hypertensive substance which was originally associated with hypertension in spontaneously hypertensive rats (SHR). In this model, PHF was shown to act by increasing intracellular calcium levels in vascular smooth muscle and was linked with a characteristic pattern of abnormalities in overall calcium regulation. The action of PHF was blocked by calcium antagonists, suggesting that the effect of PHF was to increase extracellular calcium uptake. In SHR the parathyroid glands were shown to be the site of PHF secretion. This secretion was inhibited by an increase in dietary calcium. PHF was further shown to be unique to low-renin forms of hypertension, that is, those forms of hypertension characterized by abnormalities in calcium metabolism. PHF in humans: PHF was subsequently found in human low-renin salt-sensitive hypertension. As in SHR, calcium supplementation can lower PHF levels in humans. Similarly, there is circumstantial evidence for the parathyroid origin of PHF in humans. In human hypertensive patients, the presence of PHF has been shown to predict a favorable therapeutic response to calcium channel blockade. Recently, many of the abnormalities in calcium metabolism present in low-renin hypertension have also been described in other disease states. Notable among these diseases is non-insulin dependent diabetes mellitus. A survey of human non-insulin dependent diabetes mellitus has revealed that PHF was present in a disproportionate number of these patients independently of the blood pressure level. The significance of this latter finding needs to be explored, but PHF may prove to have relevance in diseases other than hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical aspects of parathyroid hypertensive factor. 820 59

GENETIC PREDISPOSITION: Insulin resistance and reactive hyperinsulinemia occur not only with obesity, impaired glucose tolerance or non-insulin-dependent (type 2) diabetes mellitus, but also in many non-obese, non-diabetic patients with essential hypertension and their currently normotensive, lean, young offspring, as well as in some other conditions known to promote hypertension. Insulin resistance impairs glucose tolerance, while insulin resistance and/or hyperinsulinemia promote dyslipidemia, body fat deposition and probably atherogenesis. Therefore, the common coexistence of a genetic predisposition for hypertension with insulin resistance helps to explain the frequent, although temporally often dissociated, occurrence of hypertension together with dyslipidemia, obesity and type 2 diabetes in a given patient. INSULIN RESISTANCE AND HYPERINSULINEMIA AS SLOW PRESSOR MECHANISMS: In the pathogenesis of hypertension, inappropriate vasoconstriction (due to an imbalance of vasoactive substances and/or raised cytosolic calcium) and/or structural vasculopathy is particularly important. Among the mosaic of assumed pressor mechanisms, distinct Na+ retention is almost invariably involved in diabetes mellitus, while sympathetic activation tends to occur in essential hypertension, particularly in association with obesity. Insulin resistance may develop as a consequence of an intracellular excess of Ca2+ or a decrease in Mg2+, an impaired insulin-mediated rise in skeletal muscle blood flow, increased sympathetic activity or excess body weight. Acute hyperinsulinemia causes arterial vasodilation on one hand and increases sympathetic activity and renal Na+ reabsorption on the other. Chronically, hyperinsulinemia may promote cardiovascular muscle cell proliferation and atherogenesis, while insulin resistance may be associated with certain transmembraneous cation transporters, leading to an increase in cytosolic Ca2+. Hyperinsulinemia and/or insulin resistance may also be associated with an increased blood pressure sensitivity to high salt intake. In the mosaic of many different blood pressure-raising mechanisms, insulin resistance and/or hyperinsulinemia is likely to represent an amplifying slow or very slow pressor factor.
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PMID:Insulin resistance and hyperinsulinemia in hypertension. 857 90

Recently it has been postulated that membrane fatty acid composition may be involved in the pathogenesis of insulin resistance and non-insulin dependent diabetes mellitus (NIDDM). The aim of this study was to determine whether alterations in tissue phospholipid (PL) fatty acids are present in hyperglycemic and hyperinsulinemic Psammomys obesus. On a native diet of salt bush, P. obesus (Israeli sand rat) remains lean and free of diabetes; however, when placed on a normal laboratory chow, a significant proportion of these animals develops a number of metabolic disorders associated with NIDDM, providing an ideal animal model of obesity and NIDDM. Four groups of mature P. obesus were studied: group A: normoglycemic and normoinsulinemic; group B: normoglycemic and hyperinsulinemic; group C: hyperglycemic and hyperinsulinemic; and group D: hyperglycemic and hypoinsulinemic. In liver and red gastrocnemius muscle, there were no significant differences between groups A, B, and C in fatty acid composition of PL. Minor differences in individual fatty acids were demonstrated in group D animals (increased liver 20:4n-6 and increased muscle 22:5n-3); however, the unsaturation indices in liver and muscle were not significantly different between any of the groups. In considering that the minor changes in group D animals were not demonstrated in hyperinsulinemic group B animals or hyperglycemic, hyperinsulinemic group C animals, it is likely that the differences in group D animals were secondary to the more severe disturbances in glucose homeostasis and hypoinsulinemia present in these animals. The results of this study suggest that in this rodent diabetic model significant disturbances in glucose homeostasis and hyperinsulinemia may develop independently of changes in tissue fatty acid composition.
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PMID:Non-insulin dependent diabetes mellitus in Psammomys obesus is independent of changes in tissue fatty acid composition. 907 69

European and American recommendations for coronary heart disease prevention put patients with clinically manifest coronary heart disease, or other major atherosclerotic disease, as the top priority for prevention. Coronary patients should have professional support to stop smoking, eat a healthier diet (reduce the dietary intake of fat to 30% or less of total energy; saturated fat to no more than one third of total fat intake, cholesterol to less than 300 mg per day; increase monounsaturated and polyunsaturated fat from both vegetables and marine sources; increase fresh fruit and vegetables) achieve optimal weight, and become physically fitter through regular aerobic exercise. The intensity of lifestyle intervention and the level of professional support required to achieve change should be determined by the absolute risk of a further major ischaemic event, based on an assessment of all risk factors, and this should also influence the threshold for drug therapy in relation to blood pressure, lipoproteins and glucose, rather than just the individual levels of these risk factors. In addition to lifestyle changes (reducing weight and restricting salt and alcohol as appropriate) blood pressure in coronary patients should be lowered if necessary with drug therapy. For these patients blood pressure should be consistently less than 140/90 mmHg. Lifestyle changes will reduce total cholesterol (and in particular LDL cholesterol) increase HDL cholesterol and lower triglycerides. Drug therapy may also be required and in coronary patients total cholesterol should be kept consistently below 4.8 mmol.l-1, and this threshold may be further reduced with the publication of new trial results. In insulin-dependent diabetes, rigorous metabolic control reduces the risk of microvascular complications and therefore for coronary patients with insulin-dependent or non-insulin dependent diabetes mellitus this is a desirable objective. As diabetics with coronary disease are at substantially higher risk of coronary morbidity and mortality compared with non-diabetics the threshold for treating blood pressure and lipids with drug therapy should be lower. In coronary patients, selected prophylactic drug therapy is indicated in the form of aspirin, beta-blockers, ACE inhibitors and systemic anticoagulants which, together with lipid lowering drug therapy, have all been shown to reduce coronary mortality and improve life expectancy. When a patient presents with coronary disease, and particularly when there is a family history of premature coronary heart disease, the opportunity of screening first degree relatives should be taken with a view to primary prevention.
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PMID:European and American recommendations for coronary heart disease prevention. 951 37


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