[Metabolic and humoral variations during the development of essential hypertension].
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Some metabolic and humoral deviations found in normotensive offspring from hypertensive families can be modified in the course of years either as a result of ageing or of the clinical manifestation of essential hypertension (EH). The authors compared therefore some metabolic indicators (blood sugar level, IRI, C-peptide and plasma lipids) and humoral factors (plasma catecholamines, renin activity, atrial natriuretic factor and endothelin) in four groups of subjects: 27 young normotensive sons from normotensive families (SNF) and 30 from hypertensive families (SHF) with the findings of normotonics (NT) (n = 21) and patients with EH (n = 21) by 15 years older. Despite a tendency towards higher blood sugar levels in SHF and EH, the basal as well as oGTT stimulated blood sugar values were within the normal range. They were, however, associated with higher IRI and C-peptide concentrations in SHF with a further increase in NT and a much higher increase in EH. This indicates that normal blood sugar homeostasis in these groups is achieved only by an increased insulin secretion. The reduction of the blood sugar/IRI ratio in older NT accentuated in EH, suggests an increasing insulin resistance. In the lipid spectrum the authors found an increase of total cholesterol with advancing age, this being most marked in EH where also a decline of HDL cholesterol was recorded. As to humoral factors, higher catecholamine concentrations were found in SHF. Their increase with advancing age was more marked in EH. The plasma renin activity declined with age in NT as well as in EH.(ABSTRACT TRUNCATED AT 250 WORDS)Keywords:
Essential hypertension
Plasma renin activity
Blood sugar
Homeostasis
Atrial natriuretic peptide
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Effect of age and moderate food restriction on insulin sensitivity in Wistar rats: role of adiposity
Insulin resistance develops with ageing in humans and rodents. Here, we have studied the evolution of insulin sensitivity with ageing trying to discriminate the role of adiposity from that of ageing in this process. We performed oral glucose tolerance tests and determined overall and tissue-specific glucose utilization under euglycemic-hyper-insulinemic conditions in 3-, 8-, and 24-month-old rats fed ad libitum, and in 8- and 24-month-old rats after 3 months of calorie restriction. Body composition and adipocyte-derived cytokines such as leptin, resistin, and adiponectin were analyzed. Overall insulin sensitivity decreases with ageing. Calorie restriction improves global insulin sensitivity in 8- but not in 24-month-old rats. Insulin-stimulated glucose utilization in adipose tissues decreases in 8 months, while in oxidative muscles it reaches significance only in older rats. Calorie restriction restores adipose tissue insulin sensitivity only in 8-month-old rats and no changes are observed in muscles of 24-month-old rats. Resistin and leptin increase with ageing. Food restriction lowers resistin and increases adiponectin in 8-month-old rats and decreases leptin in both ages. Visceral and total fat increase with ageing and decrease after calorie restriction. We conclude that accretion of visceral fat plays a key role in the development of insulin resistance after sexual maturity, which is reversible by calorie restriction. With aging, accumulation of retroperitoneal and total body fat leads to impaired muscle glucose uptake and to a state of insulin resistance that is difficult to reverse.
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Insulin therapy, administered by continuous subcutaneous infusion with osmotic pumps over a 28 day period at doses of 2.5 and 5.0 units/day, resulted in a statistically significant increase in body weight of diabetic rats. The concentration of blood glucose was reduced by 68% to 109 mg/dl blood sugar by the higher dose of insulin and only partial control of diabetes was achieved by the lower dose (185 mg/dl blood sugar, -39%). Blood pressure was normalized by both doses of insulin. Elevated serum angiotensin converting enzyme activity and plasma renin activity, expressed as generated angiotensin I, were unaffected by the lower dose of insulin, but were reduced by 26% and 40%, respectively at the higher dose. These data suggest that elevated serum ACE and plasma renin activity, commonly found in the streptozotocin-diabetic rat, may not be primarily responsible for hypertension in this model.
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Essential hypertension is associated with multiple metabolic abnormalities, among them, hyperinsulinemia. This hyperinsulinemia is attributed to the presence of decreased insulin sensitivity (insulin resistance) with consequent compensatory insulin secretion. We tested the hypothesis that decreased insulin clearance is present in hypertensive subjects and contributes to hyperinsulinemia independently of the degree of insulin resistance. Seventy-five subjects were studied (48 hypertensive and 27 normotensive). Both groups were comparable in terms of age, body fat content, waist-to-hip ratio, and sex distribution. A primed continuous insulin infusion at 40 mU/m 2 per minute was performed. Glucose was maintained at baseline levels with the euglycemic clamp technique. Hypertensive subjects were characterized by decreased insulin sensitivity (insulin-mediated glucose uptake: 5.14±0.28 versus 7.26±0.61 mg glucose/kg fat-free mass per minute, hypertensive versus normotensive, P =.002), increased insulin levels during the insulin infusions (804±36 versus 510±38 pmol/L, hypertensive versus normotensive, P <.001), and decreased insulin metabolic clearance rate (328±15 versus 521±30 mL/min per meter squared, hypertensive versus normotensive, P <.001). In an ANCOVA (including sex, degree of obesity, waist-to-hip ratio, and insulin sensitivity as covariates) the differences in insulin metabolic clearance rate between normotensive and hypertensive subjects remained highly significant ( P <.001). Insulin metabolic clearance rate was significantly associated with fasting insulin levels. We conclude that essential hypertension is independently associated with decreased insulin metabolic clearance rate in addition to insulin resistance. A low insulin metabolic clearance rate may be a contributory factor to the hyperinsulinemia observed in essential hypertension.
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It has been suggested that patients with essential hypertension have hyperprolactinemia, and that the disturbances in blood pressure and PRL may be secondary to abnormal central dopaminergic regulation. Interrelations between plasma PRL and age, posture, blood pressure, plasma and urinary electrolytes, PRA, and catecholamine excretion rates were studied in 27 normal subjects and 23 patients with essential hypertension. In normal subjects, upright plasma PRL correlated inversely with age; mean levels were significantly higher below the age of 40 yr than in older persons [8.1 ± 1.1 vs. 4.4 ± 0.6 (SEM) ng/ml; P < 0.005]. No significant age-PRL relationship was found in supine normal man or in essential hypertension. Assumption of upright posture slightly increased circulating PRL levels from 7.3 ± 1.0 to 10.1 ± 1.7 ng/ml (P < 0.01) in hypertensive but not in normal subjects (from 7.4 ± 0.7 to 6.9 ± 0.8 ng/ ml). Thus, the upright plasma PRL levels tended to be mildly elevated in essential hypertension (P < 0.05), but supine values were normal. Relationships between plasma PRL and blood pressure or pressor correlates such as plasma renin or norepinephrine excretion rate either were not significant or were significantly inverse in the two populations. It is concluded that circulating PRL, either directly or indirectly as an index of central dopaminergic activity, does not play an important pathogenic role in maintaining essential hypertension. Moreover, the data suggest that age and posture should be considered in the interpretation of plasma PRL measurements.
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Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
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Decompensation
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Objective:The objective of this study was to investigate the relationship between the activity of the renin-angiotensin system (RAS) and glucolipid metabolism and β-cell function in patients with essential hypertension. Method:A sample of 222 patients with essential hypertension was divided into three groups (normal glucose tolerance NGT, impaired glucose tolerance IGT, type 2 diabetes T2DM) according to the WHO (1999) diagnostic criteria of type 2 diabetes after a 75 g glucose tolerance test (OGTT). Insulin resistance and β-cell function were estimated through homeostasis model assessment (HOMA-IR) and HOMAβ respectively. Association between the activity of the renin, Ang Ⅱ, aldosterone, blood sugar, lipids, HOMA-IR, HOMAβ and area under the curve of insulin(AUCI) were compared by ONE-way ANOVA, correlation analysis and multiple linear regression analysis.Result:Plasma AngⅡ, HOMA-IR, TC and LDL-C were significantly elevated in patients with IGT and T2DM, and AngⅡ was positively correlated with Glu 0 min and Glu 120 min(r=0.320, r=0.459,respectively). Similar results were found using multiple linear regression analysis, which showed there was a significant positive correlation between Glu 0 min, Glu 120 min, HOMA-IR and AngⅡ (0.495≤r≤0.671).Conclusion:The activity of the plasma AngⅡwas remarkably increased in essential hypertension patients with glucose metabolic disturbance, which was independent of hypertension. There was a vacious cycle between AngⅡ, hyperglycaemia and insulin resistance. This study witnessed the facts that RAS blockers decreased incidence of type 2 diabetes in high risk group or reversed IGT to NGT.
Essential hypertension
Homeostasis
Plasma renin activity
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Plasma renin activity
Mineralocorticoid
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Insulin signaling in osteoblasts has been shown recently to contribute to whole-body glucose homeostasis in animals fed a normal diet; however, it is unknown whether bone contributes to the insulin resistance that develops in animals challenged by a high-fat diet (HFD). Here, we evaluated the consequences of osteoblast-specific overexpression of or loss of insulin receptor in HFD-fed mice. We determined that the severity of glucose intolerance and insulin resistance that mice develop when fed a HFD is in part a consequence of osteoblast-dependent insulin resistance. Insulin resistance in osteoblasts led to a decrease in circulating levels of the active form of osteocalcin, thereby decreasing insulin sensitivity in skeletal muscle. Insulin resistance developed in osteoblasts as the result of increased levels of free saturated fatty acids, which promote insulin receptor ubiquitination and subsequent degradation. Together, these results underscore the involvement of bone, among other tissues, in the disruption of whole-body glucose homeostasis resulting from a HFD and the involvement of insulin and osteocalcin cross-talk in glucose intolerance. Furthermore, our data indicate that insulin resistance develops in bone as the result of lipotoxicity-associated loss of insulin receptors.
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Lipotoxicity
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Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in -25 % of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the p-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration. Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant,
Hyperinsulinemia
Homeostasis
Decompensation
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