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Showing papers in "Metabolism-clinical and Experimental in 1990"


Journal ArticleDOI
TL;DR: It is concluded that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.
Abstract: Twenty-three healthy men (age 25 to 50 years), covering a wide range of fatness and body fat distribution, were studied. An oral glucose tolerance test was performed and adipose tissue areas were calculated from computed tomography (CT) scans made at the level of L4/L5. Visceral fat area was associated with elevated concentrations of insulin and C-peptide and with glucose intolerance before and after the oral glucose load. Concentrations of sex-hormone-binding globulin (SHBG), as well as total and free testosterone, were negatively correlated with waist/hip circumference ratio and visceral fat area and also negatively associated with increased glucose, insulin, and C-peptide concentrations. In multiple linear regression, adjusting for age, body mass index, and visceral fat area, serum concentrations of free testosterone were still negatively correlated with glucose, insulin, and C-peptide levels. Without claiming any causality in the observed associations, we conclude that, unlike in women, abdominal fat distribution, insulin, glucose, and C-peptide levels are negatively associated with serum testosterone levels in men.

584 citations


Journal ArticleDOI
TL;DR: Hypertension emerges as part of a syndrome characterized by major abnormalities of carbohydrate, insulin, and lipid metabolism, which independently or in concert may act as important risk factors for cardiovascular disease.
Abstract: The relationship between abnormalities in carbohydrate metabolism and hypertension was studied in 143 newly detected hypertensive patients (59% obese) of both sexes (90 males, 53 females) and compared with 51 normotensive controls. Insulin-mediated glucose disposal assessed with the euglycemic insulin clamp technique was significantly decreased in both non-obese (7.2 ± 2.1 mg/kg/min; P < .05) and obese hypertensives (5.1 ± 2.1 mg/kg/min; P < .01) compared with the controls (8.4 ± 1.8 mg/kg/min). The decrease in insulin sensitivity and increase in basal insulin as well as a decreased rate of glucose disposal after an intravenous glucose tolerance test (IVGTT) were verified also after statistical adjustment for sex, age, body mass index, and waist-hip ratio. The insulin index (ratio between peak and basal insulin) during IVGTT was significantly decreased in the hypertensive patients (P < .001). After the statistical adjustment for the factors mentioned the following lipid abnormalities were still significant: total cholesterol (6.25 ± 1.12 mmol/L non-obese; 6.06 ± 1.20 mmol/L obese; 5.41 ± 1.02 mmol/L controls), triglycerides (1.70 ± 0.74 mmol/L nonobese; 2.26 ± 1.13 mmol/L obese; 1.24 ± 0.53 mmol/L controls) and free fatty acids (0.57 ± 0.20 mmol/L nonobese; 0.59 ± 0.20 mmol/L obese; 0.48 ± 0.15 mmol/L controls). This study shows that after correction for a series of probable confounding variables, hypertension emerges as part of a syndrome characterized by major abnormalities of carbohydrate, and lipid metabolism, which independently or in concert may act as important risk factors for cardiovascular disease.

565 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examined insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls.
Abstract: Insulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance.

346 citations


Journal ArticleDOI
TL;DR: The data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity, which becomes enhanced when it isassociated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.
Abstract: Recent epidemiologic studies have shown that abdominal obesity, characterized by a high waist to hip circumference ratio (WHR), is associated with increased cardiovascular morbidity and mortality. The present study examines components of the fibrinolytic system in obese and lean middle-aged women with a high and low WHR. Ten women in each group were carefully matched with respect to age, body weight, lean body mass, and body fat. Fibrinogen and endothelial type of plasminogen activator inhibitor -1 (PAI-1) were significantly elevated in the obese women with a high WHR compared with the obese women with a low WHR or with both groups of lean women. In addition, obese women with a high WHR exhibited a greater metabolic risk profile (elevated glucose, insulin, and triglyceride levels). When all subjects were pooled for the analyses, both fibrinogen and PAI-1 levels correlated positively with glucose and insulin levels. PAI-1 was also negatively related to degree of insulin sensitivity measured with the euglycemic clamp technique. In the obese groups, WHR but not body mass index (BMI), correlated with PAI-1 levels. No such correlations were seen in the lean groups. In conclusion, the data show that a high WHR in obese, but not lean middle-aged women, is associated with an impaired fibrinolytic activity. This perturbation becomes enhanced when it is associated with hyperinsulinemia and insulin resistance, which is a typical feature of abdominal obesity.

342 citations


Journal ArticleDOI
TL;DR: Interestingly, a large variety of human tumors also contain SS receptors with similar characteristics as those found in normal tissue; in numerous tumors, the SS receptor density is even higher than in healthy tissue counterparts.
Abstract: Specific receptors for somatostatin (SS), mediating the various actions of this peptide, have been described in SS target tissues in animal and man Using homogenate binding assays, as well as receptor autoradiography, the presence of SS receptors has been demonstrated in various regions of the brain (cortex, limbic system, basal ganglia), the anterior pituitary, the endocrine and exocrine pancreas, the gastrointestinal tract, and the adrenals There are species-, as well as age-, related variations Furthermore, there is evidence for different SS receptor subtypes Interestingly, a large variety of human tumors also contain SS receptors with similar characteristics as those found in normal tissue; in numerous tumors, the SS receptor density is even higher than in healthy tissue counterparts Most GH- and TSH-producing pituitary adenomas, but also a subgroup of endocrine inactive pituitary adenomas, have SS receptors; most carcinoids and islet cell carcinomas, as well as their metastases, also contain SS receptors Several differentiated (usually EGF receptor negative) glia tumors possess SS receptors, whereas undifferentiated (EGF receptor positive) glia tumors lack such receptors Furthermore, a subgroup of breast tumors, usually steroid receptor positive and neuroendocrine-differentiated, contain SS receptors Finally, small cell lung carcinomas, but not non-small cell carcinomas, often possess SS receptors These receptors are likely to be functional since in 11 acromegalics and 18 gastroenteropancreatic tumor patients, a positive correlation was observed between their SS receptor status and their hormone secretion sensitivity to Sandostatin

217 citations


Journal ArticleDOI
TL;DR: It is concluded that CS-045 may act directly on muscle and liver cells to increase glucose utilization and be effective in reducing glucose production, and may account in part for the ability ofCS-045 to reduce blood sugar levels in vivo.
Abstract: The mechanism of action of CS-045, a new orally active antidiabetic agent, was studied in vitro using cultured hepatoma cells (Hep G2) and muscle cells (BC3H-1). Treatment of both types of cultured cells with varying doses of CS-045 did not significantly alter insulin receptor binding. Basal and insulin-stimulated glucose transport in BC3H-1 cells was also unaltered by the drug. In contrast, CS-045 increased glycogen synthase I activity in both cell types. This effect was maximal after 24 hours and in Hep G2 cells was associated with a threefold increase in the apparent affinity of the enzyme for glucose-6-phosphate. Gluconeogenesis from lactate in Hep G2 cells was greatly reduced by CS-045 treatment. We conclude that CS-045 may act directly on muscle and liver cells to increase glucose utilization. It is also effective in reducing glucose production. These multiple effects may account in part for the ability of CS-045 to reduce blood sugar levels in vivo.

178 citations


Journal ArticleDOI
TL;DR: Results might mean that obese men and abdominally obese women have a large potential to release free fatty acids (FFA) from intraabdominal depots and this might be followed by metabolic derangements seen in such groups of obese subjects.
Abstract: In groups of obese men and women with an abdominal type of fat distribution, we measured fat cell size, lipoprotein lipase (LPL) activity and lipolysis stimulated by norepinephrine (NE) or isoproterenol (ISO) or inhibited by insulin, in subcutaneous abdominal and retroperitoneal (nonportal), as well as in omental and mesenteric (portal) adipose tissues. Both men and women had large intraabdominal adipocytes. No differences were found between the two groups of obese subjects in fat cell size or LPL activity in the different adipose tissue regions. Women had as high NE- or ISO-stimulated lipolysis in the portal as in nonportal fat tissues, equally high as that found in men. In comparisons with a previous study in nonobese men and women, these results show an increased fat cell size in all tissues in obese women and an increased lipolysis in portal tissues in obese women and in nonportal tissues in obese men. Taken together, these results might mean that obese men and abdominally obese women have a large potential to release free fatty acids (FFA) from intraabdominal depots. This might be followed by metabolic derangements seen in such groups of obese subjects.

171 citations


Journal ArticleDOI
TL;DR: It is concluded that adiposity and aging are independently associated with decreased plasma IGF-I concentrations, and sex differences in the gonadal steroid milieu, combined with declining GH secretion in both sexes, may contribute to the age-associated development of obesity in males.
Abstract: Aging is associated with both a relative accumulation of body fat and a reduction in growth hormone (GH) secretion. This study was devised to investigate the relationship between plasma insulin-like growth factor-I (IGF-I), an index of GH secretion, and anthropometric indices of body fat in normal subjects of various ages. Somatic and biochemical indices of nutrition were assessed in 107 subjects between the ages of 17 and 83 years who attended an outpatient clinic for general health supervision. Plasma IGF-I correlated negatively with age in both males (r = -.44, P = .001) and females (r = -.40, P = .005). In addition, plasma IGF-I correlated negatively with body mass index (BMI) (r = .35, P = .006), percentage of standard triceps skinfold (TSF) (r = -.26, P = .05), and percentage of standard weight (r = -.35, P = .006) in males, but not in females. Multiple regression analysis indicated that in males, BMI and percentage of standard weight correlated with plasma IGF-I independent of the effect of age. We conclude that adiposity and aging are independently associated with decreased plasma IGF-I concentrations. The negative correlations between indices of adiposity and IGF-I were observed only in males, whereas the age-associated decline in IGF-I was present in both males and females. We speculate that sex differences in the gonadal steroid milieu, combined with declining GH secretion in both sexes, may contribute to the age-associated development of obesity in males.

164 citations


Journal ArticleDOI
TL;DR: Results show that Bio-GH-induced retention of sodium involves the activation of the renin-angiotensin system, which may explain in part the occurrence of plasma volume expansion and hypertension in acromegaly and suggests a risk of fluid retention and possibly hypertension in subjects receiving supraphysiological doses of bio-hGH for treatment of short stature.
Abstract: Previous studies using human pituitary extracts have not resolved whether the sodium retaining effects of human growth hormone (hGH) are mediated in part by increased aldosterone secretion. We have studied the effects of an authentic biosynthetic GH (bio-hGH) preparation on sodium metabolism and on the activity of the renin-angiotensin system. Six young men were administered this preparation at 0.2 U/kg/d subcutaneously for five consecutive days. Twenty-four-hour urine collections were obtained for measurement of sodium excretion and osmolality and blood collected for quantitating changes in sodium, osmolality, plasma renin activity (PRA), aldosterone, and arginine vasopressin (AVP) concentrations. Bio-hGH administration resulted in a fall in 24-hour urinary sodium excretion (197 +/- 38 to 42 +/- 20 mmol, mean +/- SD, P less than .005), a reduction in urine volume (1,652 +/- 182 to 848 +/- 348 mL, P less than .05) but not osmolality. PRA increased significantly from 1,118 +/- 73 to 3,608 +/- 1,841 fmol angiotensin 1 L/s (P less than .005), which was associated with a sevenfold increase in plasma aldosterone concentration (52 +/- 12 to 402 +/- 99 pg/mL, P less than .001). Plasma osmolality and AVP concentrations did not change significantly. The results show that Bio-GH-induced retention of sodium involves the activation of the renin-angiotensin system. This mechanism may explain in part the occurrence of plasma volume expansion and hypertension in acromegaly and suggests a risk of fluid retention and possibly hypertension in subjects receiving supraphysiological doses of bio-hGH for treatment of short stature.

155 citations


Journal ArticleDOI
TL;DR: Investigation of postprandial vitamin A metabolism by measuring retinyl ester, triglyceride, and apolipoprotein (apo)B-48 in the plasma lipoproteins of human subjects before and after fat-feeding showed that changes in the postPRandial plasma concentration of retinyl Ester occurred 1 to 2 hours after changes inThe plasma triglyceride concentration.
Abstract: We investigated postprandial vitamin A metabolism by measuring retinyl ester, triglyceride, and apolipoprotein (apo)B-48 in the plasma lipoproteins of human subjects before and after fat-feeding. Following a 14-hour fast, eight healthy subjects (two men, six women, 28 to 79 years) were given a fat-rich meal (1 g fat/kg body weight) containing vitamin A (40 retinol equivalents per kilogram body weight). Blood was collected every 3 hours for 12 hours and lipoproteins were isolated by sequential ultracentrifugation. Mean plasma retinyl ester concentration peaked 6 hours after the fat-rich meal, whereas mean plasma triglyceride peaked at 3 hours. Data obtained from hourly samples in 3 subjects showed that changes in the postprandial plasma concentration of retinyl ester occurred 1 to 2 hours after changes in the plasma triglyceride concentration. In triglyceride-rich lipoproteins (TRL) of d less than 1.006 g/mL, retinyl ester similarly peaked at 6 hours, whereas triglyceride as well as apoB-48 peaked at 3 hours. Although retinyl esters were found mainly in TRL in the initial postprandial period (84%, 3 hours; 83%, 6 hours), in fasting and postprandial plasma, particularly 9 or more hours after fat-feeding, a large percentage of plasma retinyl esters were in low-density lipoproteins (LDL) (44%, fasting; 9%, 3 hours; 9%, 6 hours; 19%, 9 hours; 32%, 12 hours). A small percentage of retinyl esters were also found in postprandial high-density lipoproteins (HDL) (2% to 7%). ApoB-48 was not detected in LDL of fasting or postprandial plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

153 citations


Journal ArticleDOI
TL;DR: There were no changes in total cholesterol, triglycerides, or insulin in any group but, in the MeT group, apo AI levels decreased and low-density lipoprotein cholesterol (LDL-C) increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: We examined the influence of aromatization of testosterone on serum high-density lipoprotein cholesterol (HDL-C) and postheparin plasma hepatic triglyceride lipase activity (HTLA) in men. Eighteen healthy lean nonsmokers (ages, 20 to 33) were administered androgens in a weekly total dose of 280 mg for 12 weeks in one of three groups: testosterone enanthate (TE) (280 mg/wk intramuscularly [IM]); TE (280 mg/wk IM) + testolactone (TL) (250 mg orally [PO] four times daily); or methyltestosterone (MeT) (20 mg PO twice daily). Serum testosterone achieved steady state levels by 4 weeks with >40 nmol/L (TE and TE + TL) and 250 pmol/L (TE) or remained below 70 pmol/L (TE + TL and MeT). LH fell to less than 5 U/L (TE and TE + TL) but remained unchanged with MeT. By 4 weeks, HDL-C had decreased significantly from 1.20 ± 0.13 to 0.77 ± 0.13 mmol/L (MeT), from 1.18 ± 0.15 to 0.89 ± 0.13 mmol/L (TE + TL), and demonstrated no decrease in the TE group across the time course of the study. These changes were preceded by mean increases in HTLA of 102% (MeT) and 55% (TE + TL) over baseline, and no significant change with TE. The changes in HDL-C and HTLA returned to baseline within 2 weeks of steroid cessation. There were no changes in total cholesterol, triglycerides, or insulin in any group but, in the MeT group, apo AI levels decreased and low-density lipoprotein cholesterol (LDL-C) increased. After 12 weeks of treatment, sex hormone binding globulin (SHBG) levels were decreased to 37% (MeT), 54% (TE + TL), and 73% (TE) of baseline levels; these changes were evident by the second week of treatment and returned to baseline by the second week following treatment cessation. These results suggest that TE has little effect on HTLA but when a corresponding increase in E2 levels is prevented, HTLA increases. MeT, which is not metabolized to E2, produced the most dramatic HTLA increases, even at a dose that did not reduce serum LH; thus, hepatic specific properties of 17-alkylated androgens may further increase the atherogenic potential of this class of androgens.

Journal ArticleDOI
TL;DR: Dietary fish oil appears to limit triglyceride accumulation in adipose tissue and thereby limit fat cell trophic growth in rats.
Abstract: Total body mass, fat pad mass, and fat cell size were examined after feeding rats diets containing 20% triglycerides from fish oil or lard. Although food consumption, weight gain, and fat balance on the two diets were similar, lard-fed rats had 77% more fat in perirenal fat pads and 51% more fat in epididymal fat pads compared with fish oil-fed rats. There was no difference between the two groups in fat cell number in each region; however, adipocytes were significantly smaller in fish oil-fed rats. Thus dietary fish oil appears to limit triglyceride accumulation in adipose tissue and thereby limit fat cell trophic growth.

Journal ArticleDOI
TL;DR: To assess genetic variation of murine lipoprotein profiles, plasma lipoproteins of 11 inbred strains, including C3H/HeJ and SWR/J strains, were analyzed by gel-permeation chromatography (fast peptide liquid chromatography) and nondenaturing gradient gel electrophoresis.
Abstract: To assess genetic variation of murine lipoprotein profiles, plasma lipoproteins of 11 inbred strains, AKR/J, BALB/cByJ, C3H/HeJ, C57BL/6J, C57BL/6ByJ, C57L/J, DBA/1LacJ, 129/J, NZB/B1NJ, PL/J, and SWR/J, were analyzed by gel-permeation chromatography (fast peptide liquid chromatography) and nondenaturing gradient gel electrophoresis. Vena caval blood was drawn after 18 to 20 hours of fasting. Plasma triglyceride and cholesterol concentrations ranged from 12.9 mg/dL (C57BL/6ByJ) to 66.9 mg/dL (C3H/HeJ) and from 54.8 mg/dL (AKR/J) to 128.5 mg/dL (NZB/B1NJ), respectively. Mouse strain-related heterogeneities of very low-, low-, and high-density lipoprotein (VLDL, LDL, and HDL, respectively) concentrations were documented; VLDL-triglyceride concentrations ranged from 7.5 mg/dL to 38.8 mg/dL, LDL cholesterol from 12.0 mg/dL to 39.6 mg/dL, and HDL cholesterol from 41.3 mg/dL to 92.4 mg/dL. Hyper-VLDL-triglyceridemia was present in C3H/HeJ and SWR/J strains and hyper-LDL-cholesterolemia in NZB/B1NJ, C3H/HeJ, and DBA/1LacJ. VLDL cholesterol/VLDL triglyceride ratios also ranged widely among strains (0.13 to 0.43), with C57BL/6J, C57BL/6ByJ, and C57L/J, the strains particularly susceptible to diet-induced atherosclerosis, having the highest VLDL-lipid ratio. LDL and HDL size heterogeneities were also observed. LDL and HDL diameters ranged between 24.1 nm and 29.4 nm, and between 9.24 nm and 10.32 nm, respectively. Although LDL sizes showed no segregation, HDL sizes fell into two groups. C57L/J and C57BL/6J possessed low HDL-cholesterol concentrations and small-sized HDL. HDL sizes were positively correlated with HDL-cholesterol concentrations (r = .90, P less than .001) and LDL-cholesterol concentrations (r = .85, P less than .001), but LDL sizes did not correlate with lipoprotein concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal ArticleDOI
TL;DR: It is concluded that, in the skeletal tissues of vertebrates, the IGFs are conserved and may be important regulators of osteogenesis.
Abstract: Previous studies have shown that insulin-like growth factor I and insulin-like growth factor II (IGF I and IGF II) constitute an important family of skeletal growth-regulating peptides. We undertook this study to determine if, as in the case of sera in various animals, IGF I and IGF II are conserved in the skeletal tissues of various vertebrates. Skeletal tissues of ten animals representing five of the six vertebrate classes were studied: monkey, dog, sheep, adult mice, neonatal mice, chicken, lizard, frog, trout, and shark. The skeletal tissues were pulverized and demineralized with 10% ethylenediaminetetraacetic acid (pH 7.0) to extract the soluble matrix proteins. The tissue extracts were concentrated, dialized, and subjected to specific human IGF assays. IGF I and IGF II were measured with a radioimmunoassay and a radioreceptor assay, respectively. We found that 1) there are detectable human IGF I- and II-like substances in all extracts, 2) IGF values obtained in the skeletal extracts were not caused by binding protein artifacts, 3) in general there is more IGF II than IGF I, and 4) the skeletal tissue levels of the IGFs are comparable with their respective serum levels. We conclude that, in the skeletal tissues of vertebrates, the IGFs are conserved and may be important regulators of osteogenesis.

Journal ArticleDOI
TL;DR: In this article, indirect calorimetry was performed in 18 human immunodeficiency virus (HIV)-infected men free of clinically active opportunistic infections for at least two months.
Abstract: Even in the absence of anorexia and malabsorption, weight loss is frequently observed in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). To investigate whether increased resting energy expenditure (REE) might be responsible for this weight loss, indirect calorimetry was performed in 18 human immunodeficiency virus (HIV)-infected men free of clinically active opportunistic infections for at least 2 months. Patients with AIDS (n = 11) or ARC (n = 7) had 9% higher rates of REE when compared with 11 healthy volunteers (P less than .05) with similar food intake and of the same body composition. The results obtained from patients with AIDS or ARC were identical. As no differences were found between patients and controls in plasma concentrations of catecholamines, thyroid hormones, cortisol, or tumor necrosis factor, except for lower concentrations of norepinephrine in the patients (mean +/- SD, 233 +/- 111 v 367 +/- 125 ng/L, patients v controls, P less than .01), this hypermetabolism is not explained by higher levels of these catabolic hormones. The results indicate that even in the absence of acute concomitant infections, increased REE may contribute to the weight loss in patients with AIDS or ARC.

Journal ArticleDOI
TL;DR: The close correlation between in vivo insulin action, muscle glycogen synthesis, and muscle insulin receptor tyrosine kinase activity is consistent with an important role of the enzyme in the insulin resistance of diabetes and its improvement following metformin treatment.
Abstract: The mechanism (both at the whole body and cellular level) by which metformin improves insulin sensitivity has yet to be defined. In the present study, we examined in vivo insulin-mediated whole-body glucose disposal, glycogen synthesis, hepatic glucose production, and insulin secretion, as well as in vitro muscle insulin receptor tyrosine kinase activity in eight control, eight neonatal streptozotocin diabetic rats, and eight diabetic rats before and after treatment with metformin. Ten weeks after birth diabetic rats had higher fasting (132 + 5 v 101 + 2 mg/dL) and postmeal (231 + 10 v 133 + 3) plasma glucose levels compared with controls (P less than .001). Metformin treatment was followed by a significant decrease in the growth rate and normalized glucose tolerance without enhancing the deficient insulin response. Insulin-mediated glucose uptake in diabetic versus control rats was reduced (P less than .01) during the high-dose (15.4 + 0.6 v 18.3 + 1.0 mg/kg.min) insulin clamp study and was increased to values greater (P less than .05) than controls following metformin treatment. Muscle glycogen synthetic rate in vivo, measured by incorporation of 3H-3-glucose radioactivity, was diminished by 25% (P less than .01) in diabetic rats, restored to normal values with metformin, and correlated closely (r = .82, P less than .002) with total-body glucose uptake during the insulin clamp in all three groups. Insulin receptor tyrosine kinase activity, measured in partially purified insulin receptors, was reduced in diabetic rats and increased to supernormal levels after metformin. The decrease in muscle tyrosine kinase activity in diabetic versus control animals was entirely accounted for by a reduction in maximal velocity (Vmax) (32 v 45 pmol/mg.min, P less than .01) and increased to supernormal levels following metformin (91 pmol/mg.min, P less than .001) without any change in affinity (Km). Muscle tyrosine kinase activity was closely correlated with both the muscle glycogen synthetic rate (r = .82, P less than .002) and total-body insulin-mediated glucose disposal (r = .64, P less than .01) in vivo. The close correlation between in vivo insulin action, muscle glycogen synthesis, and muscle insulin receptor tyrosine kinase activity is consistent with an important role of the enzyme in the insulin resistance of diabetes and its improvement following metformin treatment.

Journal ArticleDOI
TL;DR: Evidence is provided for diminished insulin sensitivity and increased insulin response in young, nonobese, normoglycemic Mexican Americans.
Abstract: The contributions of diminished insulin sensitivity and decreased insulin response to the development of non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Nondiabetics in high-risk populations for NIDDM, including Pima Indians and Mexican Americans, are characterized by obesity and hyperinsulinemia relative to nondiabetics in the lower-risk white population. However, it is not clear to what extent diminished insulin sensitivity in the high-risk groups reflects obesity per se or is an inherent characteristic of these groups. Insulin sensitivity and secretion were determined in 10 nonobese, normoglycemic Mexican Americans (mean body mass index [BMI], 23.8 kg/m2) and 11 normoglycemic non-Hispanic whites (mean BMI, 22.5 kg/m2) using the intravenous glucose tolerance test (IVGTT) and the minimal model approach of Bergman et al. Age, BMI, sum of skinfolds, and the ratio of waist-to-hip circumference (WHR) were similar in both ethnic groups. Mexican Americans had decreased insulin sensitivity compared with non-Hispanic whites (4.06 +/- 0.72 in Mexican Americans v 7.56 +/- 1.13 in non-Hispanic whites, P = .017). The areas under the C-peptide and insulin curves were significantly greater in Mexican Americans than in non-Hispanic whites (P less than .01), suggesting greater insulin secretion in the former. This study provides evidence for diminished insulin sensitivity and increased insulin response in young, nonobese, normoglycemic Mexican Americans.

Journal ArticleDOI
TL;DR: It is concluded that the energy cost of the increased TG/FA cycling rate may account for as much as half of the delayed component of EPOC.
Abstract: After exercise, there is a prolonged increase in O2 consumption termed the excess postexercise O2 consumption (EPOC). In this study, we have assessed the relative contribution of the triglyceride/fatty acid ( TG FA ) substrate cycle to EPOC. Six healthy, young men exercised for 2 hours at 51% of maximal O2 uptake. The total energy expenditure and the rate of FA oxidation were estimated from measurements of O2 uptake, respiratory exchange ratio, and urinary nitrogen excretion while the subjects rested in bed for 3.5 hours postexercise. During the last part of the recovery period, the rate of FA mobilization was determined by infusion of glycerol. The rate of TG FA cycling was calculated from the difference between the rate of FA mobilization and oxidation. An identical control study without exercise was also performed. The total EPOC during the recovery period was 7.82 ± 1.51 L O2 (a 15% ± 3% increase above the control O2 consumption). The rate of FA oxidation increased from 252 ± 36 μmol/min (control) to 360 ± 27 μmol/min (3 hours postexercise). The rate of FA mobilization increased from 666 ± 108 μmol/min (control) to 1833 ± 456 μmol/min (3 hours postexercise). TG FA cycling was found to increase from 414 ± 90 μmol FA/min (control) to 1473 ± 435 μmol FA/min (3 hours postexercise). The energy cost of these rates of TG FA cycling was found to be 0.09 ± 0.02 kJ/min (control) and 0.31 ± 0.09 kJ/min (3 hours postexercise). It is concluded that the energy cost of the increased TG FA cycling rate may account for as much as half of the delayed component of EPOC.

Journal ArticleDOI
TL;DR: In this paper, the authors compared denervated and unweighted soleus muscle with chloroquine and methylamine and found that denervation increased the lysosomal proteolysis.
Abstract: Mechanisms of accelerated proteolysis were compared in denervated and unweighted (by tail-cast suspension) soleus muscles. In vitro and in vivo proteolysis were more rapid and lysosomal latency was lower in denervated than in unweighted muscle. In vitro, lysosomotropic agents (eg, chloroquine, methylamine) did not lessen the increase in proteolysis caused by unweighting, but abolished the difference in proteolysis between denervated and unweighted muscle. Leucine methylester, an indicator of lysosome fragility, lowered latency more in denervated than in unweighted muscle. 3-Methyladenine, which inhibits phagosome formation, increased latency similarly in all muscles tested. Mersalyl, a thiol protease inhibitor, and 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), which antagonizes sarcoplasmic reticulum release of Ca2+, reduced accelerated proteolysis caused by unweighting without diminishing the faster proteolysis due to denervation. Calcium ionophore (A23187) increased proteolysis more so in unweighted than control muscles whether or not Ca2+ was present. Different mechanisms of accelerated proteolysis were studied further by treating muscles in vivo for 24 hours with chloroquine or mersalyl. Chloroquine diminished atrophy of the denervated but not the unweighted muscle, whereas mersalyl prevented atrophy of the unweighted but not of the denervated muscle, both by inhibiting in vivo proteolysis. These results suggest that (1) atrophy of denervated, but not of unweighted, soleus muscle involves increased lysosomal proteolysis, possibly caused by greater permeability of the lysosome, and (2) cytosolic proteolysis is important in unweighting atrophy, involving some role of Ca2(+)-dependent proteolysis and/or thiol proteases.

Journal ArticleDOI
TL;DR: It is indicated that a decrease rate of IMGU in muscle is primarily responsible for the whole body insulin resistance seen during hypermetabolic sepsis, and that the impairment of insulin action in skeletal muscle is not dependent on fiber type or to changes in blood flow.
Abstract: Gram-negative hypermetabolic sepsis has been previously reported to produce whole body insulin resistance. The present study was performed to determine in vivo which tissues are responsible for the sepsis-induced decrease in insulin-mediated glucose uptake (IMGU), and whether that decrease was related to a change in regional blood flow. Vascular catheters were placed in rats and sepsis was induced by subcutaneous injections of Escherichia coli. Insulin action was assessed 20 hours after the first injection of bacteria by the combined use of the euglycemic hyperinsulinemic clamp and the tracer 2-deoxyglucose (dGlc) technique. Insulin was infused at various rates in separate groups of septic and nonseptic rats for 3 hours to produce steady-state insulin levels between 70 and 20,000 microU/mL. Rats were injected with [U-14C]-dGlc 140 minutes after the start of the euglycemic hyperinsulinemic clamp for the determination of the glucose metabolic rate (Rg) in selected tissues. The maximal response to insulin was decreased 30% to 40% in the gastrocnemius, and in the red and white quadriceps. The former two muscles also showed a decrease in insulin sensitivity. However, the insulin resistance seen in hindlimb muscles was not evident in all muscles of the body, since IMGU by abdominal muscle, diaphragm, and heart was not impaired by sepsis. The basal Rg by skin, spleen, ileum, and lung was increased by sepsis, and was higher than the insulin-stimulated increases in Rg by these tissues in nonseptic animals. Cardiac output was similar in septic and nonseptic rats and did not change during the infusion of insulin. Under basal conditions, sepsis appeared to redistribute blood flow away from the red quadriceps and skin, and increased flow to the liver (arterial), lung, and small intestine. When plasma insulin levels were elevated, hepatic arterial blood flow was increased, and flow to the red quadriceps and skin was decreased in nonseptic animals. Hyperinsulinemia did not produce any consistent change in regional blood flow in septic animals. The results of this study indicate that a decrease rate of IMGU in muscle is primarily responsible for the whole body insulin resistance seen during hypermetabolic sepsis, and that the impairment of insulin action in skeletal muscle is not dependent on fiber type or to changes in blood flow.

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TL;DR: The findings suggest that subjects with NIDDM or IGT have had higher dietary intake of saturated fatty acids, and the possibility that the fatty acid composition of plasma and membrane lipids has a role in insulin resistance and blood glucose regulation deserves further investigation.
Abstract: The fatty acid composition of serum cholesterol esters was investigated in 325 subjects with normal glucose tolerance, 97 subjects with impaired glucose tolerance (IGT), and 98 subjects with non-insulin-dependent diabetes mellitus (NIDDM) identified by population-based screening. The proportions of palmitic acid (16:0) and palmitoleic acid (16:1) in serum cholesterol esters increased from the normal glucose tolerance group to the IGT and diabetic groups. On the other hand, the proportion of linoleic acid (18:2) was lower in diabetic subjects than in the subjects with IGT or normal glucose tolerance. The proportions of γ-linolenic (18:3), dihomo-γ-linolenic (20:3), and arachidonic (20:4) acids were highest in diabetic subjects and lowest in subjects with normal glucose tolerance. Our findings suggest that subjects with NIDDM or IGT have had higher dietary intake of saturated fatty acids. Both serum insulin and blood glucose concentrations probably have an effect on the elongation and desaturation of fatty acids, but the metabolism of linoleic acid to prostaglandin precursors seems to be different in different types of diabetes, NIDDM patients showing no abnormalities. The possibility that the fatty acid composition of plasma and membrane lipids has a role in insulin resistance and blood glucose regulation deserves further investigation.

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TL;DR: The results suggest that growth factors, as well as insulin, may be important determinants in SHBG production.
Abstract: Sex hormone-binding globulin (SHBG) is a glycoprotein whose production has been demonstrated to be regulated by both sex steroids, as well as by thyroid hormone and peptide hormones such as insulin. However, none of these regulatory factors would explain the marked decrease in serum SHBG seen throughout the prepubertal and pubertal time period in both boys and girls. Furthermore, current in vitro data show that both androgens and estrogens can stimulate SHBG production by the human hepatoblastoma cell line Hep G2; yet, in vivo androgens appear to suppress SHBG levels, while estrogens are associated with elevated levels. This study was undertaken to determine possible mechanisms to explain this phenomenon. Hep G2 cell cultures were incubated with insulin-like growth factor I (IGF-I), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), or dehydroepiandrosterone (DHEA). Significant decreases in the level of SHBG in the culture medium relative to control cultures occurred for each of the growth factors (P less than .01), whereas an increase in SHBG levels was observed in the medium of DHEA-treated cells. When cells were coincubated with IGF-I and thyroxine (T4), which alone stimulates SHBG production both in vivo and in vitro, the SHBG response to T4 was blunted. These results suggest that growth factors, as well as insulin, may be important determinants in SHBG production.

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TL;DR: This reduced TEF observed in the older subjects was associated with only a slight, nonsignificant, blunting of the SNS response to the meal, and was unrelated to either glucose or insulin concentrations in either group.
Abstract: We have previously published direct evidence that approximately one third of the thermic effect of feeding (TEF) in young healthy men can be accounted for by the meal-induced increment in sympathetic nervous system (SNS) activity. The elderly are known to have abnormal beta-adrenergic mechanisms and blunted responsiveness to sympathetic stimulation. Therefore, we postulated that the elderly might also have a blunted thermic response to a meal. In the present study, we evaluated the TEF in 25 young (age, 29.4 +/- 4.6 years) and 12 older (66.6 +/- 7.0 years), healthy weight-stable, untrained, nonsmoking men on no medications. Energy expenditure (ventilated hood system) and SNS activity (arterialized plasma catecholamine concentrations and norepinephrine [NE] kinetics) were measured before and following ingestion of an 800-kcal high-carbohydrate meal. At baseline, arterialized plasma NE concentration (P = .001) and appearance rate (P = .05) were 40% and 28% higher, respectively, in the elderly. Resting energy expenditure was related to fat-free mass (r = .54, P less than .01), and was 21% lower in the older men (P less than .01). Energy expenditure increased in both groups following the meal, but this TEF was 48% lower in the older men (P less than .001). This reduced TEF observed in the older subjects was associated with only a slight, nonsignificant, blunting of the SNS response to the meal. The TEF was related to the arterialized plasma NE appearance rate in the young, but not the older group. The TEF was unrelated to either glucose or insulin concentrations in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

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TL;DR: To determine whether somatostatin receptor subtypes arise from molecular heterogeneity of the receptor protein, the putative receptor is cross-linked in normal rat tissues and in AtT-20 and GH3 cells, both chemically with SS-14, SS-28 and Tyr3 SMS ligands, as well as by photoaffinity labeling with an azido derivative of Tyr2 SMS (EE 581).
Abstract: To determine whether somatostatin receptor subtypes arise from molecular heterogeneity of the receptor protein, we have cross-linked the putative receptor in normal rat tissues and in AtT-20 and GH3 cells, both chemically with SS-14, SS-28 and Tyr3 SMS ligands, as well as by photoaffinity labeling with an azido derivative of Tyr3 SMS (EE 581). Three prominent somatostatin receptor proteins of 58-kDa, 32-kDa, and 27-kDa size have been identified. These proteins exhibit a tissue-specific distribution, ligand selectivity, and relative preference for SS-14 and SS-28 binding, and thus qualify as somatostatin receptor subtypes. Using EE 581 as a photoaffinity probe, the 58-kDa and 32-kDa proteins have been purified to homogeneity from brain and AtT-20 cells by successive SDS-PAGE. The 58-kDa form has been trypsinized and amino acid sequence data obtained from four tryptic fragments. With the help of synthetic oligonucleotides derived from these sequences, work is currently in progress to clone the 58-kDa protein to elucidate its complete sequence, its expression, and its functional relationship to the somatostatin receptor and its pharmacological subtypes.

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TL;DR: The AIDS patients showed a starvation-type response to protein and glucose metabolism, and depressed protein synthesis and energy substrate cycling are not likely to be the primary cause of immunodeficiency, but may represent an important facilitating factors contributing to the decreased ability of the patient to respond effectively to opportunistic infections.
Abstract: The objective of this study was to investigate protein and glucose metabolism in ambulatory, asymptomatic acquired immunodeficiency syndrome (AIDS) patients. Nine asymptomatic AIDS patients were compared against 13 controls. We measured whole-body protein synthesis (PSRM), breakdown (PBRM), and the fractional fibrinogen synthesis rate with 15N glycine, glucose cycling from the difference between the glucose appearance rates as measured with 2-d (Ra2-d)- and 6,6-d2 (Ra6,6-d)-labeled glucose. All of these parameters are increased with hypermetabolism and decreased with undernutrition. In addition, we also determined the plasma aminogram. The principal findings were (1) whole-body protein synthesis and breakdown and the fibrinogen fractional synthesis rate were significantly lower in the AIDS patients; (2) glucose cycling was markedly lower in the AIDS patients, and most of this effect was due to a decrease in Ra2-d; there was no difference in the endogenous glucose production rate, Ra6,6d; and (3) the plasma aminogram showed decreased total amino acids and a reduced ratio of essential to nonessential amino acids in the AIDS group. We concluded that the AIDS patients showed a starvation-type response. While the depressed protein synthesis and energy substrate cycling are not likely to be the primary cause of immunodeficiency, they may represent an important facilitating factors contributing to the decreased ability of the patient to respond effectively to opportunistic infections.

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TL;DR: Baseline concentrations of low-density lipoprotein (LDL) cholesterol in untreated FH patients were not influenced by the apo E phenotype; the hypolipidemic response to lovastatin was also independent of the api-E phenotype of the patients.
Abstract: Apolipoprotein E (apo E) phenotypes have been previously shown to influence plasma lipoprotein concentrations in normal populations and to affect the response to some lipid lowering drugs. The purpose of the present study was to determine if variations in the apo E phenotype also affect basal lipoprotein concentrations in patients with heterozygous familial hypercholesterolemia (FH) and if the apo E phenotype influenced their subsequent response to lovastatin. Apo E phenotypes were determined on plasma from 134 FH patients. The relative frequencies of the epsilon 2, epsilon 3, and epsilon 4 alleles were .090, .772, and .138, respectively. Plasma triglycerides were found to be 34% higher in E3/2 heterozygotes relative to E3/3 patients. Baseline concentrations of low-density lipoprotein (LDL) cholesterol in untreated FH patients were not influenced by the apo E phenotype; the hypolipidemic response to lovastatin (20 or 40 mg twice daily) was also independent of the apo-E phenotype of the patients.

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TL;DR: Observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin and the altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.
Abstract: Hyperlipidemia is a consistent feature of the nephrotic syndrome. In this study, low-density lipoprotein (LDL) metabolism has been investigated in nine patients with nephrotic syndrome and varying degrees of proteinuria. In subjects with moderate proteinuria (less than 10 g/d), total plasma cholesterol values were elevated to approximately 160% of normal due mainly to an increase in circulating LDL cholesterol. Metabolic studies showed that a defect in LDL clearance via the receptor pathway was responsible for its accumulation. The total amount of LDL apolipoprotein catabolized by this mechanism was only 55% of the value seen in controls; 60% more LDL was channelled into alternative, receptor-independent, catabolic pathways. Heavier proteinuria was associated with substantial increases in plasma triglyceride and very-low-density lipoprotein (VLDL) levels. The defect in LDL catabolism was aggravated by oversynthesis of the lipoprotein, which expanded the plasma LDL pool to 250% of normal. These observations indicate that the hyperlipidemia of the nephrotic syndrome is multifactorial in origin. The altered catabolism of LDL may be important in predisposing these subjects to premature atherosclerosis.

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TL;DR: Data suggest that in both IDD and NIDD patients, there may be a relation between modifications in the RBC lipid composition and rheological impairment of the R BC.
Abstract: Erythrocyte deformability was assessed in 40 diabetic patients, 24 insulin-dependent (IDD) and 16 non-insulin-dependent (NIDD), by measuring the initial filtration flow rate of whole blood, isolated red blood cells (RBC), and isolated RBC membranes with the Hanss hemorheometer, and its relationship to the plasma and ghost membrane lipid composition was investigated. RBC deformability was significantly reduced, whereas the deformability of the isolated RBC membranes did not differ significantly from the controls. In the plasma, the triglycerides were high, the high-density lipoprotein (HDL) cholesterol was reduced, and the ratio of total cholesterol over HDL cholesterol was high as compared with the controls. The RBC lipid composition expressed in μmol lipids/10 10 RBC showed significantly lower levels of free cholesterol, sphingomyelines, and phosphatidylcholine, which are the lipids principally located on the outer layer of the RBC membranes. These data suggest that in both IDD and NIDD patients, there may be a relation between these modifications in the RBC lipid composition and rheological impairment of the RBC.

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V. Grill1, J. Pigon1, S.G. Hartling1, C. Binder1, S. Efendic1 
TL;DR: The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR.
Abstract: We compared the effects of dexamethasone-induced insulin resistance on B-cell secretory performance in 12 low insulin responders (LIR) and in eight high insulin responders (HIR). A hyperglycemic clamp (120 minutes) was performed before and after the subjects had ingested dexamethasone 3 mg x 2 for 2 1/2 days. Fasting levels of blood glucose increased from 4.60 +/- 0.13 to 5.74 +/- 0.23 mmol/L after dexamethasone in LIR and from 4.37 +/- 0.18 to 5.26 +/- 0.13 mmol/L in HIR. Dexamethasone treatment increased fasting levels of total immunoreactive insulin (IRI), C-peptide, and proinsulin, as well as the proinsulin to IRI ratio to a similar degree in LIR and HIR. The amount of glucose infused to uphold hyperglycemia during the clamp decreased by 54% after dexamethasone in LIR and by 46% in HIR. Mean level of stimulated IRI during the clamp increased after dexamethasone by 43% in LIR and by 53% in HIR. Mean level of stimulated C-peptide increased by 11% (not significant) in LIR and by 24% in HIR. Mean level of stimulated proinsulin increased by 86% in LIR and by 93% in HIR. The effects of dexamethasone on insulin secretion varied among individuals, since steroid treatment failed to affect IRI responses to glucose in two LIR and two HIR. The magnitude of dexamethasone effects on secretion was not correlated to pre-dexamethasone insulin sensitivity as assessed by a somatostatin-insulin-glucose infusion test (SIGIT) or by M/I (glucose infused/insulin level) ratios of the control clamp.(ABSTRACT TRUNCATED AT 250 WORDS)

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TL;DR: The thermic effect of food was significantly greater for the lean than obese men for the first 3 hours of measurement, and over the entire 6 hours, the thermic effects of food were significantly greater than P less than .05.
Abstract: Controversy regarding defective postprandial thermogenesis in obesity may partly be due to methodological factors such as duration of measurement. To clarify further the role of blunted thermogenesis in obesity, the thermic effect of food was compared in seven lean (mean ± SEM, 15.7% ± 1.5% body fat, by densitometry) and seven obese men (37.3% ± 3% fat) over 3 and 6 hours. The groups were matched for age (35 ± 2 and 33 ± 2 years for the lean and obese groups; range, 25 to 39 years), fat-free mass (FFM), and aerobic fitness. Resting metabolic rate (RMR) was measured by indirect calorimetry for 6 hours on two mornings, in randomized order: (1) after a 720-kcal liquid mixed meal, which was 24% protein, 21% fat, and 55% carbohydrate; and (2) in the postabsorptive state. The thermic effect of food, calculated as postprandial minus postabsorptive RMR, was significantly greater for the lean than obese men for the first 3 hours of measurement (67 ± 6 v 49 ± 3 kcal3 hours; P < .01). During the second 3 hours, the thermic effect of food was marginally, but not significantly, greater for the lean than obese men (34 ± 8 v 20 ± 4 kcal3 hours; P = .10, NS). Over the entire 6 hours, the thermic effect of food was significantly greater for the lean than obese men (100 ± 12 v 69 ± 5 kcal6 hours; P < .05). Three hours after the meal the increment above fasting RMR was greater for the lean than obese men (28% ± 7% v 13% ± 3% above fasting; P < .05). However, 6 hours after the meal the elevation above fasting RMR was not significantly different between the lean (6% ± 3%) and obese men (0% ± 2%). These results indicate that the thermic effect of food is neither delayed nor more prolonged in obese compared with lean men and provide further evidence for defective thermogenesis in obesity.