Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because abnormalities of the autonomic nervous system have been described in several animal models of obesity, and because galanin has been proposed to be a sympathetic neurotransmitter in the endocrine pancreas, we hypothesized that the hyperinsulinemia observed in genetically obese (ob/ob) mice may result either from defective ability of galanin to inhibit insulin release or from a reduced degree of pancreatic galaninergic innervation. To address these possibilities, we examined the effect of exogenous galanin on immunoreactive insulin (IRI) levels in ob/ob mice and compared the pancreatic content of galaninlike immunoreactivity (GLIR) in ob/ob mice with that in lean littermates. Intravenous administration of synthetic porcine galanin significantly reduced basal IRI levels in ob/ob mice, suggesting that a defect in galanin action is unlikely to account for the hyperinsulinemia in this model. In contrast, reduced pancreatic galaninergic innervation was supported by findings that pancreatic content of GLIR in ob/ob mice was less than 10% of that in age- and sex-matched lean littermates. The reduction of pancreatic GLIR in ob/ob mice appeared organ specific; no such reduction was observed in adrenal GLIR content when comparing obese and lean mice. In addition, the relationship between pancreatic GLIR content and plasma IRI levels was examined in groups of obese and lean mice. It was found in young females, young males, and older mice of mixed sex that there was a significant negative correlation between pancreatic GLIR and plasma IRI in lean mice, whereas no such correlation was observed in obese mice.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Reduced pancreatic content of the inhibitory neurotransmitter galanin in genetically obese, hyperinsulinemic mice. 137 40

Insulin is the principal regulator of hepatic insulin-like growth factor binding protein-1 (IGFBP-1) production, mediating the rapid decrease in plasma IGFBP-1 in response to nutritional intake. In this study, we defined IGFBP-1 regulation by insulin in upper and lower body obesity, conditions associated with insulin resistance and chronic hyperinsulinemia. Overnight postabsorptive IGFBP-1 levels in obese and nonobese women showed an inverse, nonlinear relationship with plasma insulin concentrations. Maximum suppression of IGFBP-1 was seen at 70-90 pmol/L plasma insulin. Both groups of obese women had mean fasting plasma insulin concentrations above this threshold level and, consequently, markedly suppressed IGFBP-1 levels. To assess the dynamics of insulin regulated IGFBP-1, 10 obese and 8 nonobese women were studied during sequential saline infusion (0-90 min), hyperinsulinemia (insulin infusion; 90-210 min) and hypoinsulinemia (somatostatin + GH infusion; 210-330 min). Insulin infusion rapidly decreased plasma IGFBP-1 levels in nonobese subjects (60% decrease in 2 h), but had little or no further suppressive effect in obese subjects. Complete insulin withdrawal resulted in a significant rise in plasma IGFBP-1 concentrations in all subjects, but the response was blunted in obese compared to nonobese groups. In contrast to plasma IGFBP-1, IGF-I concentrations did not vary during hyper- and hypoinsulinemic infusion periods and were not significantly different between groups. Basal GH levels were significantly higher in nonobese when compared to obese women, but did not change with infusions. In conclusion, low IGFBP-1 levels in obesity are related to elevated insulin levels which are, in turn, related to body fat distribution and insulin resistance. The chronically depressed levels of IGFBP-1 may promote IGF bioactivity as well as its feedback regulation of GH secretion, thus contributing to the metabolic and mitogenic consequences of obesity. In addition, our findings imply that hepatic insulin sensitivity in terms of IGFBP-1 production is preserved despite peripheral insulin resistance in obesity.
 ...
PMID:Insulin regulation of insulin-like growth factor binding protein-1 in obese and nonobese humans. 137

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.
 ...
PMID:Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. 138 62

A well-established epidemiologic association exists between hyperinsulinemia and macrovascular disease. However, the mechanism or mechanisms by which hyperinsulinemia promotes atherogenesis is unknown. Recent evidence indicates that the adrenal steroid dehydroepiandrosterone (DHEA) exerts multiple antiatherogenic effects and also suggests that hyperinsulinemia may reduce serum DHEA and DHEA-sulfate levels by decreasing production and enhancing metabolic clearance. We advance the hypothesis that hyperinsulinemia promotes macrovascular disease in part by reducing serum DHEA and DHEA-sulfate levels and illustrate how this may be the case in two clinical conditions characterized by hyperinsulinemic insulin resistance: aging and obesity.
 ...
PMID:Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis? 138 59

The obese Zucker rat (fa/fa) is an animal model for genetic obesity characterized by hyperphagia, hyperinsulinemia, and severe insulin resistance in peripheral tissues. Adrenal steroids seem to play an important role in the onset of fatty syndrome in these animals. There is strong evidence of abnormal regulation of the hypothalamic-pituitary-adrenal axis in obese Zucker rats. Considering the physiological function of arginine vasopressin (AVP) as an adrenocorticotropic hormone secretagogue, the present study was carried out to investigate the role of glucocorticoids in the control of hypothalamic AVP systems in lean and obese Zucker rats. In the first experiment, mifepristone (RU 38486), a glucocorticoid receptor antagonist, was administered for 4 days (10 mg/kg orally twice daily), and the expression of AVP mRNA in hypothalamic paraventricular and supraoptic nuclei was measured using in situ hybridization, and the concentrations of AVP in the pituitary gland and in the median eminence were quantified. Plasma corticosterone levels were also analyzed. Mifepristone treatment resulted in a threefold increase in plasma corticosterone levels in lean Zucker rats, but it did not change corticosterone secretion in obese animals. Mifepristone treatment decreased AVP mRNA levels in lean animals in the supraoptic nuclei, while in obese animals the AVP mRNA content was increased in the paraventricular nuclei. Mifepristone treatment significantly increased the concentration of AVP in the median eminence in lean rats and decreased it in obese animals. Mifepristone treatment did not change concentrations of AVP in the pituitary gland. In the second experiment, mifepristone was given for 4 days (10 mg/kg orally twice daily), and its effects on 24-hour food intake and plasma AVP concentrations were measured.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Differential hypothalamic arginine vasopressin response to glucocorticoid receptor antagonism in lean and obese Zucker rats. 140 82

Hyperinsulinemia is associated with an adverse pattern of cardiovascular risk factors, including obesity, elevated triglyceride levels, low levels of high-density lipoprotein (HDL) cholesterol, and elevated blood pressure. Whether hyperinsulinemia precedes (and perhaps causes) this deterioration in the risk factors or merely accompanies the deterioration is controversial. We therefore examined the 8-year changes in lipids, lipoproteins, and blood pressure as a function of baseline levels of fasting insulin in 1,383 nondiabetic Mexican-American and non-Hispanic white subjects enrolled between October 1979 and November 1982 in the San Antonio Heart Study, a population-based longitudinal study of cardiovascular risk factors and diabetes in San Antonio, Texas. After age and concomitant changes in body mass index were adjusted for, fasting insulin at baseline was found to be correlated positively with 8-year changes in triglyceride levels and negatively with 8-year changes in HDL cholesterol levels (p less than 0.05). Among the non-Hispanic whites, insulin was more strongly correlated with a decline in HDL cholesterol levels in women than in men (p less than 0.001). Fasting insulin was also positively correlated with changes in both systolic and diastolic blood pressure in non-Hispanic whites, but not in Mexican Americans, although these correlations were slightly diminished and no longer achieved statistical significance after subjects receiving antihypertensive medications were excluded. These results support the hypothesis that in nondiabetic subjects, insulin has a direct regulatory effect on triglyceride and HDL cholesterol levels. These data provide evidence for a possible role for insulin in blood pressure regulation, at least in non-Hispanic whites, although further analysis of this issue is warranted.
 ...
PMID:The relation between serum insulin levels and 8-year changes in lipid, lipoprotein, and blood pressure levels. 141 28

Glucoregulation and body composition were examined in 3-mo-old C57BL/6 ob/ob mice 6 wk after streptozotocin (STZ) or STZ plus adrenalectomy. STZ depressed somatic growth in ob/ob mice but did not cause hyperglycemia until immunoreactive insulin (IRI) was 40% (100 microU/ml) that of intact ob/ob mice. When IRI approached that of lean mice (40 microU/ml), ob/ob mice displayed severe hyperglycemia (800+ mg/dl) and other sequelae of type I diabetes but still maintained the same 50% body fat as untreated obese mice. In contrast, STZ diabetes in lean mice caused disproportionate reductions in body fat. Adrenalectomy before STZ led to the same insulinopenia, depressed growth, and hyperglycemia as STZ alone, but, after combined treatment, percent body fat declined in proportion to IRI. Thus a subgroup of severely diabetic adrenalectomized STZ obese mice with very low IRI (20 microU/ml) had body fat contents and fat-free masses equal to those of weight-matched lean mice. The data suggest that hypercorticoidism rather than hyperinsulinemia is largely responsible for obesity in ob/ob mice. However, in the absence of adrenal glucocorticoids, or perhaps with just their normalization, hyperinsulinemia appears necessary for maintaining excessive body energy stores.
 ...
PMID:Interactions between insulin and glucocorticoids in the maintenance of genetic obesity. 141 35

Serum C-peptide immunoreactivity (CPR)/immunoreactive insulin (IRI) molar ratio was determined in 136 subjects without renal, hepatic and thyroid disorders, at fasting, and during the initial period of 75 g-oral glucose tolerance test. The subjects were divided into 4 groups based on their body weight and age; Group A, young (< 55 years) and normal body weight (body mass index [BMI, kg/m2] < or = 25) subjects; Group B, young and overweight (BMI > 25) subjects; Group C, aged (> or = 55 years) and normal body weight (BMI < or = 25) subjects; Group D, aged and overweight subjects. Fasting CPR/IRI ratio and absolute CPR level negatively correlated in Groups B and D but not in A and C. After oral glucose load with elevation of insulin, CPR/IRI ratio invariably declined in all groups and significant negative correlation between CPR/IRI and CPR was found in Groups A, B and D but not in C. Slope of the regression lines obtained for correlation between CPR/IRI ratio and CPR were significantly steeper at fasting compared to the post-stimulation phase. CPR/IRI ratio is affected by hyperinsulinemia and oral glucose load but not by obesity alone. Assuming that CPR/IRI ratio reflects hepatic extraction of insulin, the insulin clearance at fasting is progressively reduced with increasing insulin secretion in overweight subjects: failure to detect such phenomenon in normal body weight subjects may be due to a narrower CPR range in this population. Insulin metabolism at fasting and during glucose stimulation is likely to be regulated by distinct factors.
 ...
PMID:Differential effects of body weight, hyperinsulinemia and oral glucose load on serum C-peptide/insulin molar ratio. 142 14

The role of hyperinsulinemia in the development of hypertension is not well understood, particularly insofar as both conditions relate to obesity. The present analysis examines the hypothesis that hyperinsulinemia, independent of obesity, precedes hypertension and natural blood pressure increases in women. The subjects were 50-year-old women from a prospective population study in Gothenburg, Sweden. Fasting insulin levels were determined at baseline (1968-1969) and were evaluated in relation to subsequent hypertension. Blood pressures were measured at the initial physical examination and at the 6- and 12-year follow-up examinations. The first analysis presented here (n = 278) identified incident cases of hypertension during the 12-year follow-up period, whereas the second analysis (n = 219) examined continuous changes in blood pressure. In both analyses, degree, type, and changes in obesity were considered as possible confounding factors. High fasting insulin values were predictive of subsequent incidence of hypertension over the 12-year follow-up period. Subjects with insulin values above the 75th percentile experienced three times more hypertension than did those below the 25th percentile. There was also a significant association between insulin at baseline and increases in diastolic (but not systolic) blood pressure. The positive relations between fasting insulin, on one hand, and diastolic blood pressure changes and hypertension, on the other, could not be explained by confounding effects of body mass index, waist/hip ratio, or weight gain. These findings are consistent with the hypothesis that fasting insulin levels may be one predisposing factor in the etiology of hypertension.
 ...
PMID:Fasting insulin in relation to subsequent blood pressure changes and hypertension in women. 145 95

The authors summarize the principles of the therapeutic approach to the 5H syndrome [1. hyperinsulinism, 2. hyperglycaemia (NIDDM), 3. hyperlipoproteinaemia (obesity), 4. hypertension, 5. hirsutism], in particular its two components, i.e. NIDDM and arterial hypertension. The authors found that early treatment of hyperinsulinism, e.g. already in the stage of impaired glucose tolerance or NIDDM with oral antidiabetics, their disproportionate increase with regard to the blood sugar level and glycosylated haemoglobin without making "hygienic" provisions (radical weight reduction; increased physical activity to the maximum possible individual level; energy restricted diet in particular as regards carbohydrates and fat) does not prevent progression of the components of the 5H syndrome to the clinical stage. In treatment of arterial hypertension associated with 5H syndrome non-selective beta-blockers and thiazide diuretics are unsuitable because they worsen the HPLP and enhance insulin resistance. Suitable preparations are combinations of ACE-inhibitors, calcium antagonists, selective beta-blockers in particular with ISA and beta-blockers with a partial selective sympathomimetic activity (devalol and celiprolol). Hygienic provisions must be started in childhood, or when hyperinsulinism is detected.
 ...
PMID:[How should we implement the basic principles of treatment of type 2 diabetes mellitus from the aspect of the hormono-metabolic syndrome X (5H)?]. 145 53


<< Previous 1 2 3 4 5 6 7 8 9 10