Biomedical subjects

L H Storlien

Publications and source records attributed to L H Storlien.

At least 73 records · Page 4Linked to original sources

PubMed1993

Dietary lipid profile is a determinant of tissue phospholipid fatty acid composition and rate of weight gain in rats.

Modifications in membrane fatty acid composition and insulin action are possible through dietary intervention. We examined the metabolic fate of (n-3) fatty acids in male Wistar rats, using three isocaloric, high fat diets. The ET-L, OL-L and SAF-L diets contained edible tallow, olive oil and safflower oil, respectively, with identical amounts of (n-3) fatty acids as linseed oil. Despite isocaloric feeding, weight gain was lower (P < 0.001) in rats fed the more highly saturated ET-L diet (69 +/- 8 g) than in those fed either the high (n-9) fatty acid OL-L diet (93 +/- 2 g) or the high (n-6) fatty acid SAF-L diet (108 +/- 4 g). Analysis of red quadricep fatty acid composition revealed phospholipid (n-3) fatty acid levels in the ET-L-fed group (21.6 +/- 0.8 g/100 g fatty acids) to be significantly higher than in either the OL-L-fed (17.7 +/- 0.6 g/100 g fatty acids, P < 0.05) or SAF-L-fed (15.3 +/- 0.7 g/100 g fatty acids, P < 0.05) group. A similar pattern was observed in other muscles and white adipose tissue. A follow-up study using 14C-labeled (n-3) fatty acids in the diet showed greater (n-3) fatty acid incorporation in the ET-L-fed group relative to the other two groups and conversely lower 14CO2 production than in the SAF-L-fed group. These results demonstrate that metabolic fate of dietary fatty acids is strongly influenced by the overall fatty acid profile of the diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1993

Muscle glucose uptake during and after exercise is normal in insulin-resistant rats.

It is not generally known whether impaired stimulation of muscle glucose metabolism in insulin-resistant states is specific to insulin stimulation. Our aim was to examine whether glucose uptake responded normally to exercise and postexercise recovery in insulin-resistant high-fat-fed (HFF) rats. Three-week HFF or Chow-fed [control (Con)] adult rats were studied 5 days after cannulation. Before, during, or immediately after (recovery) 50 min of treadmill exercise, bolus 2-deoxy-[3H]glucose and [14C]glucose were administered to estimate muscle glucose uptake (R'g) and glycogen incorporation rates. Mean exercise and recovery plasma glucose levels were similar in HFF and Con rats. In hindlimb muscles sampled, exercise and recovery R'g were similar in HFF and Con (e.g., red quadriceps exercise 104 +/- 13 vs. 113 +/- 8, recovery 45.3 +/- 3.9 vs. 47.7 +/- 4.5 mumol.100 g-1.min-1, respectively). Moreover, muscle glucose transporter (GLUT-4) content was not reduced in HFF rats. Glycogen resynthesis accounted almost entirely for R'g during recovery and was equivalent between groups. We conclude that impaired muscle glucose uptake and glycogen synthesis in HFF rats are characteristic of insulin but not of exercise or postexercise stimulation.

Analysis of Variance↗

PubMed1993

In vivo insulin sensitivity of the pyruvate dehydrogenase complex in tissues of the rat.

Activity of the insulin-activated pyruvate dehydrogenase complex (PDHC) is necessary for the complete oxidation of glucose to carbon dioxide or the conversion of glucose to fatty acids in lipogenic tissues. To determine the in vivo insulin sensitivity of PDHC activity in rat tissues, we measured the amount of PDHC in the active form in heart, diaphragm, red quadriceps, white adipose tissue (WAT), and brown adipose tissue (BAT) of rats exposed to five different circulating insulin concentrations under euglycemic clamp conditions. PDHC was measured in mitochondrial extracts of tissues rapidly dissected from rats in the starved state or after euglycemic clamp (4 mM) at insulin infusion rates of 0, 0.125, 0.25, and 2.0 U.kg-1.h-1. Increasing the insulin concentration increased the PDHC activity in all tissues, but the magnitude of this activation was different in different tissues (heart: 3.5-fold; diaphragm: 2.5-fold; red quadriceps: 1.8-fold; WAT: 3.4-fold; and BAT: 10.5-fold). Calculation of the half-maximal effective dose (ED50) for the activation of PDHC produced values that were similar in all tissues (heart: 112 pM; diaphragm: 108 pM; red quadriceps: 146 pM; WAT: 120 pM; and BAT: 118 pM). The insulin sensitivity of PDHC in these tissues correlated particularly well with the ED50 for the insulin effect of decreasing circulating nonesterified fatty acids (NEFA; 122 pM). The differences in the magnitude of the effect of increasing insulin on PDHC activity implies a tissue difference in the requirement for an increased capacity for glucose oxidation after insulin stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1993

Effects of blockade of fatty acid oxidation on whole body and tissue-specific glucose metabolism in rats.

We examined the effect of the long-chain fatty acid oxidation blocker methyl palmoxirate (methyl 2-tetradecyloxiranecarboxylate, McN-3716) on glucose metabolism in conscious rats. Fasted animals [5 h with or without hyperinsulinemia (100 mU/l) and 24 h] received methyl palmoxirate (30 or 100 mg/kg body wt po) or vehicle 30 min before a euglycemic glucose clamp. Whole body and tissue-specific glucose metabolism were calculated from 2-deoxy-[3H]-glucose kinetics and accumulation. Oxidative metabolism was assessed by respiratory gas exchange in 24-h fasted animals. Pyruvate dehydrogenase complex activation was determined in selected tissues. Methyl palmoxirate suppressed whole body lipid oxidation by 40-50% in 24-h fasted animals, whereas carbohydrate oxidation was stimulated 8- to 10-fold. Whole body glucose utilization was not significantly affected by methyl palmoxirate under any conditions; hepatic glucose output was suppressed only in the predominantly gluconeogenic 24-h fasted animals. Methyl palmoxirate stimulated glucose uptake in heart in 24-h fasted animals [15 +/- 5 vs. 220 +/- 28 (SE) mumol x 100 g-1 x min-1], with smaller effects in 5-h fasted animals with or without hyperinsulinemia. Methyl palmoxirate induced significant activation of pyruvate dehydrogenase in heart in the basal state, but not during hyperinsulinemia. In skeletal muscles, methyl palmoxirate suppressed glucose utilization in the basal state but had no effect during hyperinsulinemia; pyruvate dehydrogenase activation in skeletal muscle was not affected by methyl palmoxirate under any conditions. The responses in skeletal muscle are consistent with the operation of a mechanism similar to the Pasteur effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Syndromes of insulin resistance in the rat. Inducement by diet and amelioration with benfluorex.

Insulin resistance, mainly in skeletal muscle, is linked to a cluster of prevalent diseases including NIDDM, dyslipidemias, hypertension, and cardiovascular disease. To determine if an oversupply of lipid is associated with the development of skeletal muscle insulin resistance, we examined the effect of the hypolipidemic agent benfluorex in dietary models of insulin resistance. Adult, male Wistar rats were divided into six groups and maintained for 4 wk on diets high in complex carbohydrate, fructose or fat, with or without 50 mg.kg-1.day-1 of benfluorex, given orally. Insulin action was assessed using a hyperinsulinemic (approximately 100 mU/L) euglycemic clamp, with 2-deoxyglucose tracer for individual tissue evaluation, in chronically cannulated conscious animals. Compared with starch feeding, fructose and fat feeding significantly impaired insulin action at the whole-body level (-46% and -41%, respectively, both P < 0.001), as well as in individual skeletal muscles. Fructose feeding increased circulating TGs (by 80%, P < 0.01) but not skeletal muscle TGs; whereas, fat feeding increased skeletal muscle TGs (by 59%, P < 0.01) but not circulating TGs. With benfluorex, however, diet had no effect on circulating and storage TGs; and development of skeletal muscle insulin resistance in the two diet groups was prevented. Feeding fructose but not fat significantly increased mean arterial BP (by 13%, P < 0.05), an effect prevented by benfluorex. These effects support the hypothesis that the development of muscle insulin resistance in these models is linked to local or systemic oversupply of lipid. These diet models--and the parallel effect of benfluorex on insulin resistance, lipids, and hypertension--may prove useful in the search for the mechanisms that underlie the human disorders associated with insulin resistance.

Analysis of Variance↗

PubMed1992

D-fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates.

In order to test the hypothesis that the anorectic effects of D-fenfluramine involve mediation by increased serotonin (5-HT) activity we examined the effects of acute and chronic D-fenfluramine on the hypothalamic activities of 5-HT as well as the other major monoamine neurotransmitters noradrenaline (NA) and dopamine (DA). Precise and specific gas chromatograph/mass spectrometer analyses of NA, 5-HT and DA and their primary metabolites dihydroxphenylethyleneglycol (DHPG), 5-hydroxyindolacetic acid (5-HIAA) and dihydroxyphenylacetic acid (DOPAC), respectively, were made in combination with analysis of the hormonal correlates of the monoamines, glucose and adrenocorticotropin for NA, thyroid-stimulating hormone for 5-HT and prolactin for DA. Acute D-fenfluramine increased NA, while reducing 5-HT, functional activity. Chronic and acute after chronic, D-fenfluramine decreased both NA and 5-HT functional activity. The effect of acute D-fenfluramine on the DA system is consistent with a post-synaptic blockade which is compensated for by chronic treatment. Since chronic D-fenfluramine acted to depress noradrenergic tone, a further study was undertaken which showed that chronic D-fenfluramine does not impair the ability noradrenergic/sympathetic system to respond to stress. The results indicate that D-fenfluramine may not exert its anorectic and weight loss effects via serotonergic agonism and involvement of the NA and/or DA systems is likely.

Animals↗

PubMed1992

The effects of sympathetic nervous system activation and psychological stress on glucose metabolism and blood pressure in subjects with type 2 (non-insulin-dependent) diabetes mellitus.

The sympathetic nervous system may contribute to excessive hepatic glucose output in Type 2 (non-insulin dependent) diabetes mellitus and could be implicated in the interrelated problem of hypertension. The aim of these studies was to determine whether subjects with Type 2 diabetes had normal sensitivity (compared with age- and weight-matched non-diabetic subjects) to noradrenaline infusion (60 ng.kg-1.min-1 for 60 min) and to compare the responses with oral tyramine administration (800 mg), and psychological stress (using competitive computer games). Noradrenaline infusion caused significantly greater plasma glucose (mean increment 2.1 +/- 0.4 vs 0.6 +/- 0.1 mmol/l, p less than 0.005) and pressor responses (mean systolic increment 21 +/- 3 vs 11 +/- 1 mmHg, p less than 0.02) in the diabetic subjects. The excessive glycaemia was due to increased hepatic glucose output rather than reduced glucose disposal. Tyramine administration caused significantly increased hepatic glucose output and plasma glucose levels, but with similar responses in the diabetic and non-diabetic subjects; the pulse and pressor responses were also similar between the groups. The psychological stressor induced significant increases in pulse, blood pressure and non-esterified fatty acid levels in the combined group of subjects (p less than 0.01) but did not influence plasma glucose levels in either diabetic or non-diabetic subjects. We conclude that pharmacologically-induced sympathetic nervous stimulation can induce hyperglycaemia. Subjects with uncomplicated Type 2 diabetes have increased sensitivity to exogenous noradrenaline but may not hyperrespond to endogenous sympathetic activation.

Blood Glucose↗

PubMed1992

Insulin action and determinants of glycaemia in a rat model of type 2 (non-insulin-dependent) diabetes mellitus.

We aimed to assess prandial responses, basal glucose turnover and insulin action (euglycaemic clamp) in a very low-dose neonatal streptozotocin model of Type 2 (non-insulin-dependent) diabetes mellitus. Male Wistar rats were injected at 2 days of age with 45 mg/kg streptozotocin or vehicle (control). At 8 weeks, the groups were subdivided and fed either a high-fat or high-starch diet for 3 weeks. Both the fat diet and streptozotocin treatments had independent hyperglycaemic effects (streptozotocin/fat 9.3 +/- 0.3 mmol/l; streptozotocin/starch 7.5 +/- 0.3 mmol/l; control/fat 7.4 +/- 0.1 mmol/l; all p less than 0.01 vs control/starch 6.4 +/- 0.1 mmol/l). The fat diet effect was associated with both a reduction in basal glucose clearance (p less than 0.001) and in basal hepatic glucose output (p less than 0.05). Streptozotocin increased basal hepatic glucose output. Significantly higher prandial glycaemia in the streptozotocin/starch group occurred despite similar insulin levels and appeared to be related to an impaired early insulin response. Whole-body and tissue-specific insulin sensitivity were significantly depressed in fat-fed animals compared to starch-fed animals, however there were no significant effects of streptozotocin treatment. We conclude that fasting hyperglycaemia associated with abnormalities in both glucose production and clearance can exist in the presence of a basal hepatic glucose output which is reduced compared to control animals. Furthermore, dietary-fat-induced insulin resistance is not exacerbated by the relative insulin deficiency and/or mild hyperglycaemia observed when dietary fat and neonatal streptozotocin-treatments are combined.

Adipose Tissue↗

PubMed1991

Enhanced responses to stress induced by fat-feeding in rats: relationship between hypothalamic noradrenaline and blood glucose.

High-fat-feeding in rats has been reported to enhance stress reactions, as assessed by elevation of blood glucose and corticosterone levels. This study was designed to investigate the relationship between changes in blood glucose and hypothalamic neuronal noradrenaline activity (HNNA), as indexed by the ratio of dihydroxyphenylethyleneglycol (DHPG) to noradrenaline (NA), following physiological stress in high-fat-fed rats. Two groups of adult male Wistar rats were fed isocaloric diets high in fat (59% of calories) or starch (70% of calories). After 3 weeks each of these groups was further subdivided into (a) control, (b) 2 min ambient temperature (20 degrees C) swim or (c) 2 min swim in ice-cold water. Animals were decapitated 20 min after commencing the swim; trunk blood and a sample of medial basal hypothalamus were obtained. Computerized gas chromatography/mass spectrometry was used to measure hypothalamic DHPG and NA concentrations. There were no differences between fat- and starch-fed rats in basal levels of serum glucose, insulin or corticosterone and no differences in DHPG, NA or DHPG/NA ratio. Compared to starch-fed rats, ambient swim stress in the fat-fed group produced significantly larger serum glucose (P less than 0.01), serum corticosterone (P less than 0.05), DHPG (P less than 0.05) and DHPG/NA (P less than 0.01) responses. Following cold swim stress similar differences between fat- and starch-fed animals were observed. In addition, serum insulin was found to be significantly suppressed in the fat-fed group (P less than 0.05) following cold swim.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1991

Heterogeneity of response to exercise of rat muscle pyruvate dehydrogenase complex.

Muscle glucose uptake is greatly stimulated by moderate exercise, but full oxidation of the glucose to CO2 depends on the activity of the pyruvate dehydrogenase (PDH) complex. Our aim was to determine how PDH complex in different muscle groups responds to varying periods of moderate exercise. Rats were run on a motor-driven treadmill for 5-30 min and muscle PDH complex activity was determined in heart, diaphragm and red quadriceps muscles after isolation of mitochondria in the presence of inhibitors of PDH complex interconversion. In heart and diaphragm muscle, exercise caused an increase in PDH complex activity after 5 min, but this was followed by a significant decrease in activity as exercise progressed. In red quadriceps muscle, PDH complex activity was reduced after 5 min of exercise and was decreased further as exercise continued. We conclude that increased duration of exercise can lead to reduced PDH complex activity in rat muscles. We propose that this is a consequence of elevated fatty acid oxidation, the products of which stimulate PDH kinase. This implies that increased glycolysis to lactate and increased fatty acid oxidation can simultaneously provide energy for contracting muscle.

Animals↗

PubMed1991

Meal-time intranasal insulin delivery in type 2 diabetes.

Correction of the deficiency of early meal-time insulin secretion, using intravenous insulin in patients with Type 2 diabetes causes substantial improvement in post-prandial hyperglycaemia. The present study was designed to determine whether similar benefit would result from physiological supplementation using intranasal insulin delivery. Six patients with Type 2 diabetes were studied twice during a standard mixed meal. At the start of the meal they received a single intranasal spray containing either 15 units of insulin in 1% sodium glycocholate (adjuvant agent) or glycocholate alone (placebo) in a single-blind fashion. Intranasal insulin delivery resulted in rapid absorption of insulin with peak levels (92 +/- 8 (+/- SE) mU l-1) within 5-10 min. Peak insulin levels were at least equal to those in non-diabetic subjects, though occurring at an earlier time-point. However, no significant improvement in post-prandial hyperglycaemia was seen (peak blood glucose increment 4.9 +/- 0.6 vs 5.4 +/- 0.5 mmol l-1; total 3-h response 611 +/- 53 vs 668 +/- 41 mmol l-1 min). We conclude that an elevation of insulin levels, earlier and more transient than the normal physiological response, achieved by intranasal insulin delivery at the start of a meal, fails to significantly improve the blood glucose excursion in Type 2 diabetes.

Administration, Intranasal↗

PubMed1991

In vivo location of the rate-limiting step of hexose uptake in muscle and brain tissue of rats.

The uptake of glucose proceeds via facilitated transport from the plasma followed by phosphorylation of intracellular glucose. We have quantified the relative contribution of transport and phosphorylation to the overall rate of hexose utilization into the quadriceps muscle (red and white) and cerebellum of rats anesthetized with pentobarbital sodium. The method employed simultaneous infusions of radiolabeled 3-O-methyl-D-glucose and 2-deoxy-D-glucose. Results were expressed in terms of a parameter ft*, which has theoretical limits of 0 and 1 corresponding to phosphorylation and transport limitation, respectively. In cerebellum, basal rates of transport and phosphorylation were comparable (ft* = 0.32 +/- 0.02). Under conditions of hyperglycemia plus maximum insulin stimulation, phosphorylation limited glucose utilization to a greater extent (ft* = 0.12 +/- 0.02). No effect of hyperinsulinemia alone was observed. In red muscle, transport determined overall glucose utilization in the basal (ft* = 0.96 +/- 0.05) and euglycemic insulin-stimulated states (ft* = 0.90 +/- 0.02). A shift of the rate-limiting step from transport toward phosphorylation was observed in insulin-stimulated red muscle when blood glucose (ft* = 0.64 +/- 0.05) or epinephrine levels (ft* = 0.66 +/- 0.07) were elevated. Neither effect was seen in white muscle. We conclude that the transport step dominates but is not the only determinant of muscle hexose utilization under all conditions.

3-O-Methylglucose↗

PubMed1991

Comparison of the effects on insulin sensitivity of high carbohydrate and high fat diets in normal subjects.

To examine whether achievable dietary changes influence insulin sensitivity, we performed euglycemic hyperinsulinemic glucose clamps in eight normal subjects who were prescribed high carbohydrate and high fat diets. The high carbohydrate diet was more than 50% (of energy intake) carbohydrate and less than 30% fat; the high fat diet was more than 45% fat (predominantly saturated) and less than 40% carbohydrate. The diets were consumed over consecutive 3-week periods in random sequence. The mean whole body glucose uptake during the glucose clamps was similar after the high carbohydrate (48.3 mumol/kg.min) and high fat diets (47.0 mumol/kg.min; P = 0.5; 95% confidence interval for the difference, -3.4 to 5.9 mumol/kg.min). Fasting blood glucose and serum insulin concentrations were also unchanged. In contrast, there were substantial effects on lipoprotein metabolism. During the high carbohydrate diet, fasting serum cholesterol decreased by 17% (P = 0.06), low density lipoprotein cholesterol decreased by 20% (P = 0.05), high density lipoprotein cholesterol decreased by 24% (P less than 0.005), and triglyceride increased by 33% (P = 0.06) compared with levels during the high fat diet. These results suggest that practically achievable high carbohydrate diets do not enhance insulin sensitivity in nondiabetic subjects and have net effects on lipoprotein metabolism that may be unfavorable.

Blood Glucose↗

PubMed1991

Development of muscle insulin resistance after liver insulin resistance in high-fat-fed rats.

Muscle and hepatic insulin resistance are two major defects of non-insulin-dependent diabetes mellitus. Dietary factors may be important in the etiology of insulin resistance. We studied progressive changes in the development of high-fat-diet-induced insulin resistance in tissues of the adult male Wistar rat. In vivo insulin action was compared 3 days and 3 wk after isocaloric synthetic high-fat or high-starch feeding (59 and 10% cal as fat, respectively). Basal and insulin-stimulated glucose metabolism were assessed in the conscious 5- to 7-h fasted state with the euglycemic clamp (600 pM insulin) with a [3-3H]-glucose infusion. Fat feeding significantly reduced suppressibility of hepatic glucose output by insulin after both 3 days and 3 wk of diet (P less than 0.01). However, a significant impairment of insulin-mediated peripheral glucose disposal was only present after 3 wk of diet. Further in vivo [3H]-2-deoxyglucose uptake studies supported this finding and demonstrated adipose but not muscle insulin resistance after 3 days of high-fat feeding. Muscle triglyceride accumulation due to fat feeding was not significant at 3 days but had doubled by 3 wk in red muscle (P less than 0.001) compared with starch-fed controls. By 3 wk, high-fat-fed animals had developed significant glucose intolerance. We conclude that fat feeding induces insulin resistance in liver and adipose tissue before skeletal muscle with early metabolic changes favoring an oversupply of energy substrate to skeletal muscle relative to metabolic needs. This may generate later muscle insulin resistance.

Animals↗

PubMed1991

Effects of exercise training and dietary manipulation on insulin-regulatable glucose-transporter mRNA in rat muscle.

Both exercise training and dietary manipulation (increasing omega-3/omega-6 fat ratio) can ameliorate insulin resistance caused by a high-fat diet in rats. We determined whether alterations in the expression of the insulin-regulatable (IR) and/or HepG2 glucose-transporter (GT) mRNAs were similarly affected. There was a significantly higher level of IRGT mRNA in skeletal muscle from exercise-trained versus sedentary high-fat-fed rats (27% increase, P less than 0.01). This difference is consistent with previously reported increases in muscle insulin-mediated glucose uptake. Skeletal muscle HepG2GT mRNA was too low to detect any training effect, but there was a tendency toward higher levels with training in cardiac muscle. In contrast, dietary manipulation, previously shown to lead to a much greater increase (100-300%) in muscle insulin-mediated glucose uptake, did not change IRGT or HepG2GT mRNA in skeletal muscle or heart. Thus, both dietary manipulation and exercise training increase insulin-stimulated glucose uptake in skeletal muscle, but only exercise training increases IRGT mRNA. Therefore, exercise training apparently increases GT production, whereas dietary manipulation improves glucose transport in skeletal muscle by other mechanisms.

Animals↗

PubMed1991

Influence of dietary fat composition on development of insulin resistance in rats. Relationship to muscle triglyceride and omega-3 fatty acids in muscle phospholipid.

High levels of some but not all dietary fats lead to insulin resistance in rats. The aim of this study was to investigate the important determinants underlying this observation. Insulin action was assessed with the euglycemic clamp. Diets high in saturated, monounsaturated (omega-9), or polyunsaturated (omega-6) fatty acids led to severe insulin resistance; glucose infusion rates [GIR] to maintain euglycemia at approximately 1000 pM insulin were 6.2 +/- 0.9, 8.9 +/- 0.9, and 9.7 +/- 0.4 mg.kg-1. min-1, respectively, versus 16.1 +/- 1.0 mg.kg-1.min-1 in chow-fed controls. Substituting 11% of fatty acids in the polyunsaturated fat diet with long-chain omega-3 fatty acids from fish oils normalized insulin action (GIR 15.0 +/- 1.3 mg.kg-1.min-1). Similar replacement with short-chain omega-3 (alpha-linolenic acid, 18:3 omega 3) was ineffective in the polyunsaturated diet (GIR 9.9 +/- 0.5 mg.kg-1.min-1) but completely prevented the insulin resistance induced by a saturated-fat diet (GIR 16.0 +/- 1.5 mg.kg-1.min-1) and did so in both the liver and peripheral tissues. Insulin sensitivity in skeletal muscle was inversely correlated with mean muscle triglyceride accumulation (r = 0.95 and 0.86 for soleus and red quadriceps, respectively; both P less than 0.01). Furthermore, percentage of long-chain omega-3 fatty acid in phospholipid measured in red quadriceps correlated highly with insulin action in that muscle (r = 0.97). We conclude that 1) the particular fatty acids and the lipid environment in which they are presented in high-fat diets determine insulin sensitivity in rats; 2) impaired insulin action in skeletal muscle relates to triglyceride accumulation, suggesting intracellular glucose-fatty acid cycle involvement; and 3) long-chain omega-3 fatty acids in phospholipid of skeletal muscle may be important for efficient insulin action.

Animals↗

PubMed1990

Medial basal hypothalamic monoamine activity associated with intracerebroventricular p-chlorophenylalanine-induced hyperphagia.

There is evidence for reciprocal interactions between the brain monoamine neurotransmitters serotonin and noradrenaline which may play a critical role in homeostasis. The aim of the present study was to establish the effect of drug-induced damage to the serotoninergic system on noradrenergic activity in the hypothalamus. Bilateral intracerebroventricular injections of p-chlorophenylalanine (PCPA; 3 mg/kg in 2 x 6 microliters) were made to induce destruction in the serotoninergic system. Relative to saline-injected controls, PCPA-injected rats began overeating by 3 days postinjection. On day 10, when the experimental rats were consuming approximately 120% that of controls, animals were 4-h food deprived, sacrificed and the medial basal hypothalamus was removed for later analysis (by gas chromatography/mass spectrometry) of noradrenaline (NA), serotonin (5-HT) and dopamine (DA) and their principal metabolites dihydroxyphenylethyleneglycol (DHPG), 5-hydroxyindoleacetic acid (5-HIAA) and 3,4-dihydroxyphenylacetic acid (DOPAC), respectively. The ratio of metabolite to monoamine provided an index of functional activity. Trunk blood was collected for analysis of serum insulin and glucose. PCPA-injected animals had higher levels of DHPG (P less than 0.05), an increase in the DHPG/NA ratio (P less than 0.02), lower serum insulin (P less than 0.05) and increased serum glucose (P less than 0.05). There were significant correlations between noradrenergic activity (DHPG/NA ratio) and: (1) food intake (day 9 and 10 average; r = 0.62, P less than 0.05); and (2) serum glucose (r = 0.59, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Effect of biosynthetic human growth hormone on insulin action in individual tissues of the rat in vivo.

Excessive endogenous production or exogenous administration of human growth hormone (hGH) causes insulin resistance at both the hepatic and extrahepatic levels. However, which extrahepatic tissues are involved have not been defined. We have examined the diabetogenic action of authentic biosynthetic hGH on whole body glucose disposal, hepatic glucose output, and glucose metabolism in individual peripheral tissues. The use of a highly purified preparation of the hormone allowed us to examine the isolated effects of 22K hGH. The euglycemic hyperinsulinemic (approximately 100 mU/L) clamp plus 3H-2-deoxyglucose technique was used to quantitate the effects of hGH on insulin action in vivo. Administration of biosynthetic hGH at a dose of 10 IU/kg/24 h for 48 hours in male Wistar rats (approximately 340 g) produced a highly significant decrease in the steady state clamp glucose infusion rate (GIR) when compared with controls (8.1 +/- 0.6 v 18.7 +/- 0.7 mg/kg/min, P less than .001), reduced insulin-mediated suppression of hepatic glucose output (Ra) (3.9 +/- 0.6 v 0.7 +/- 0.3 mg/kg/min, P less than .05) and a decreased clamp glucose disposal rate (Rd) (12.0 +/- 0.4 v 18.10 +/- 1.1 mg/kg/min, P less than .001). There was a significant decrease in insulin-mediated glucose uptake as indicated by tissue accumulation of [3H]-2-deoxyglucose phosphorylation in diaphragm and hindlimb muscles. Insulin action was more substantially reduced in muscles (approximately 50%) than in adipose tissues (approximately 20%). These studies confirm that the diabetogenic action of hGH in the rat is due to a combination of inhibition of insulin suppression of hepatic glucose output and inhibition of the uptake and subsequent utilization of glucose in skeletal muscles.

Adipose Tissue↗