Not all dietary fats may lead to obesity.
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Animals↗
Biomedical subjects
L H Storlien
Publications and source records attributed to L H Storlien.
Inducement by fat feeding of basal hyperglycemia in rats with abnormal beta-cell function. Model for study of etiology and pathogenesis of NIDDM.
Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogenous disorder characterized by defects in insulin action and secretion. This study was aimed at developing a rat model in which these pathogenic factors might be studied. Male Wistar rats were injected at 2 days of age with 45 or 30 mg/kg streptozocin (STZ) or vehicle (control). Fasting plasma glucose and insulin levels were not significantly different between the two groups between 5 and 8 wk of age. At 8 wk, half of each group was randomly assigned to isocaloric diets high in either fat (59% of calories) or starch (70% of calories). After 1 wk on the diets, 45-mg/kg-STZ-administered fat-fed animals displayed significant fasting hyperglycemia (8.6 +/- 0.2 mM; P less than 0.01), which was exacerbated by the stress of anesthesia and/or cannulation, whereas no changes were observed in any of the other groups before (STZ starch fed, 6.7 +/- 0.1 mM; control fat fed, 6.8 +/- 0.1 mM; control starch fed; 6.4 +/- 0.1 mM) or after anesthesia and/or cannulation. In the 30-mg/kg-STZ animals, fat feeding did not significantly elevate plasma glucose concentration, but a significant hyperglycemic response was seen with anesthesia and/or cannulation. In all STZ groups, substantial impairment of glucose-induced insulin secretion was observed, particularly early-phase insulin secretion. Further studies indicated that STZ animals on a diet conferring normal insulin sensitivity (starch) maintained basal normoglycemia and mildly impaired (i.v.) glucose tolerance despite this gross insulin secretory defect.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Tracer studies of in vivo insulin action and glucose metabolism in individual peripheral tissues.
The ability to study in vivo insulin action in specific muscle types and other individual tissues has been considerably enhanced following adaptation of the euglycemic clamp technique to the rat. The importance of this model derives particularly from its combination with administration of 3H-2-deoxyglucose and 14C-glucose. Analysis of the metabolic fate of these tracers at the conclusion of the clamp enables an assessment to be made of insulin action at both the whole body and the individual tissue level, the latter by estimating a tissue-specific glucose metabolic rate (from 3H-2-deoxyglucose phosphorylation). Information on stored vs utilised glucose can be obtained by simultaneously estimating 14C-glucose incorporation into glycogen and/or lipids. This review briefly considers the basis of the technique and its recent application. It has been used to demonstrate in the rat that in vivo insulin sensitivity differs widely among insulin target tissues, such as adipose tissue, red and white skeletal muscle, and cardiac muscle. The technique has provided a means to study how factors such as diet, exercise, pregnancy, stress hormones and pharmacological agents modify in vivo insulin action in muscle and other tissues, to compare insulin and exercise as stimuli to muscle glucose uptake, and to examine factors which might be important in the aetiology of muscle insulin resistance. These new tracer techniques for in vivo use with the glucose clamp have narrowed the gap that exists between established whole body and cellular in vitro approaches to the study of insulin action and glucose metabolism.
Animals↗
2-deoxy-D-glucose-induced hyperglycemia: role for direct sympathetic nervous system activation of liver glucose output.
The hypothalamus plays an important integrative role in the control of peripheral metabolism, achieved by modulation of autonomic outflow to the endocrine pancreas, the liver and the adrenal medulla. This study examines the role of direct sympathetic nervous system control of hepatic glucose output during neuroglycopenia induced by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG). Steady-state tracer methodology was used to directly measure hepatic glucose output (Ra) in pentobarbitone-anesthetised male Wistar rats (220-320 g). Administration of 500 mg/kg 2-DG i.p. produced an increase in Ra from a control value of 7.3 +/- 0.3 mg/kg.min (n = 4) to 15.2 +/- 2.2 mg/kg.min-1 (n = 8), corresponding to an increase in plasma glucose (PG) from 6.4 +/- 0.1 mmol/l to 10.1 +/- 0.4 mmol/l. This rise was countered by the sympathetic noradrenergic blocker guanethidine (100 mg/kg i.p.), reducing Ra to 10.4 +/- 0.9 mg/kg.min-1 and PG to 6.1 +/- 0.3 mmol/l (n = 8), despite markedly lower plasma insulin (PI) levels (2-DG: PI = 94.7 +/- 18.6 mU/l (n = 7), 2-DG + guanethidine: PI = 41.4 +/- 3.3 mU/l (n = 8). Hyperglycemia and elevated liver glucose output were maintained in ADX animals treated with 2-DG, indicating an absence of adrenal-medullary influence (2-DG: Ra = 15.2 +/- 2.2 mg/kg.min-1, 2-DG + ADX = 15.6 +/- 1.0 mg/kg.min-1). Elevated Ra in the 2-DG + ADX was maintained despite markedly elevated insulin levels 349.3 +/- 72.6 mU/l (n = 7)).(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic Fibers↗
Monoaminergic activity at the level of the hypothalamus and striatum: relationship to anticipated feeding and pancreatic insulin responses.
The present study examined monoaminergic activity at the level of the lateral hypothalamus (LH), ventromedial hypothalamus (VMH) and ventral striatum associated with the conditioned cephalic phase insulin release. Partially food-deprived male Wistar rats were divided into 3 groups. Two of the groups were conditioned to drink a 50% glucose solution each morning for 3 weeks; the control group received an amount of glucose equal to the amount drunk by the experimental animals with their afternoon meal. On test day, conditioned animals were sacrificed either just prior to glucose presentation or 2 min following consumption of the solution; control animals were sacrificed at the same time. Gas chromatography/mass spectrometry was used to determine the levels of the monoamines noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as their principal metabolites dihydroxyphenylethyleneglycol, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the LH and VMH. DA and DOPAC levels were assayed in the striatum. Although serum glucose levels were unchanged, animals conditioned to drink glucose had significantly higher serum insulin levels. This increased insulin was associated with increased content of 5-HT and 5-HIAA at the level of the LH and VMH, increased NA content in the LH, increased DOPAC levels in the VMH as well as increases in the ratio of DOPAC to DA in the striatum. A regression analysis showed that 5-HIAA at the level of the LH related closely to serum insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A potent in vivo effect of ciglitazone on muscle insulin resistance induced by high fat feeding of rats.
Ciglitazone (5-4-(1-methylcyclohexyfmethoxy)benzyl-thiazolidine-2,4-dione) is a hypoglycemic agent, which has been shown to improve blood glucose levels and in vitro insulin sensitivity in some genetically hyperglycemic rodents. Whether ciglitazone administration prevents the widespread peripheral insulin resistance induced by high fat feeding (HFF) of rats was examined. Insulin action (euglycemic clamp at 150 mU/L insulin, plus 3H-2-deoxyglucose tracer administration) was studied after 3 weeks on diet in control (high carbohydrate fed [HCF]) and HFF rats with or without a ciglitazone gavage (140 mg/k/d) for six days prior to study. HFF reduced the glucose infusion rate required to maintain euglycemia to 57% of control (P less than .01), but this was restored to 82% of control by ciglitazone treatment (P less than .01 v HFF alone). Estimated glucose disposal (Rd) and skeletal muscle glucose metabolic index (Rg', from accumulation of phosphorylated deoxyglucose) were reduced by HFF but restored to control values by concomitant ciglitazone treatment. Ciglitazone increased muscle Rg' by approximately twofold v HFF in all eight muscles sampled. However, in other tissues (white and brown adipose tissue, lung, and heart), ciglitazone did not alter responses from HFF alone. Thus, ciglitazone counteracts whole body insulin resistance in the HFF rat model mainly due to potent effects on insulin action in both oxidative and glycolytic skeletal muscle.
Animals↗
Mind over metabolism: the cephalic phase in relation to non-insulin-dependent diabetes and obesity.
The notion that a defect in hypothalamic function may be a critical factor in the aetiology of obesity and diabetes stems from observations of the important role that this brain region plays in both the behavioural and metabolic events related to feeding and energy balance. Sensory events associated with the beginning of a meal trigger a series of metabolic changes, the function of which is to prepare an organism to receive, and properly dispose of, the incoming nutrients. Insulin release and nervous control of hepatic glucose output are important components of these neural, or cephalic-phase, sensory-driven metabolic events. The present review firstly summarizes evidence for direct autonomic nervous system links between the hypothalamus and the pancreas and liver, that is, the physical basis for cephalic-phase reflexes. Secondly, an assessment is made of both the normal function of the cephalic phase and how derangements might be central to the aetiology of important disease states such as obesity and non-insulin-dependent diabetes mellitus. A central hypothesis in this article is that a primary failure of normal cephalic-phase responses, over time, leads to increased post-meal hyperglycaemia and decreased thermogenesis. The persistent hyperglycaemia (among other metabolic abnormalities) leads to insulin resistance (insulin not being effective in disposing of glucose). The reduced post-meal thermogenesis leads to weight gain through reduced energy expenditure rather than through increased intake. The obesity in turn leads to further insulin resistance and, in genetically predisposed individuals, on to frank diabetes.
Animals↗
Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats.
Insulin action was assessed by using the hyperinsulinemic (approximately 800 pmol/L) euglycemic clamp in rats fed equal amounts of glucose or fructose (35% of calories) for 4 wk. The glucose infusion rate required to maintain euglycemia was decreased in fructose-fed animals (14.6 +/- 1.4 vs 21.8 +/- 1.1 for glucose-fed rats, p less than 0.001) with this whole-body effect contributed to equally by an impairment in hepatic insulin action and a reduction in peripheral glucose disposal in a range of tissues. There was no difference in basal glucose turnover, energy expenditure, or postprandial blood glucose and insulin responses to the diets. In the fructose-fed rats there was an increase in fasting triglyceride levels by 2 wk. Euglycemic clamp glucose disposal correlated positively and clamp hepatic glucose output correlated negatively with fasting triglyceride levels. In summary, fructose but not glucose feeding led to impaired insulin action in both the liver and peripheral tissues, effects that may depend on antecedent circulating triglyceride levels.
Animals↗
Hypothalamic noradrenergic and sympathoadrenal control of glycemia after stress.
Central noradrenergic pathways play a significant role in mediating blood glucose levels after neuroglycopenia. To further investigate hypothalamic noradrenergic neuronal activity (NNA) and sympathoadrenal influences in glucoregulation, we studied the effects of acute stress on glycemia and insulin release in normal and adrenalectomized (ADRX) rats. Within 5 min of exposure of rats to ether or cold-swim stress, significant positive correlations were evident between hypothalamic NNA and serum glucose levels (r = 0.70, P less than 0.001; at 15 min r = 0.78, P less than 0.0001). Five minutes after stress in the intact rat, insulin release was inhibited and serum insulin levels inversely correlated to hypothalamic NNA (r = 0.45, P less than 0.05). This relationship between insulin and NNA was no longer present 15 min after stress, but the levels of insulin remained inappropriately low with respect to the elevated serum glucose levels (approximately 30% above basal). Blockade of sympathetic noradrenergic pathways by treatment of intact rats with guanethidine prevented the rise in glucose after cold-swim stress but did not prevent the inhibition of insulin release. Fifteen minutes after exposure of ADRX rats to cold-swim stress their hypothalamic NNA and serum glucose levels were similar to intact animals. However, in contrast to their intact counterparts, serum insulin levels were significantly elevated (P less than 0.01). These data are consistent with central noradrenergic neural pathways directly mediating hepatic glucose release and indirectly inhibiting pancreatic insulin release via activation of adrenal medullary catecholamines.
Adrenalectomy↗
Hypothalamic monoamines associated with the cephalic phase insulin response.
This study elucidated the hypothalamic monoamine systems associated with the cephalic phase insulin release. Male Wistar rats conditioned to drink a glucose solution were killed 2 min after the onset of their scheduled feeding; control rats were killed at the same time. The ventromedial (VMH) and lateral (LH) portions of the hypothalamus were analyzed for the monoamines and their principal metabolites. Serum was assayed for insulin and glucose. The results showed that the experimental animals had significantly higher serum insulin levels than did the control animals, although glucose levels were unchanged. In the LH, there were increased levels of norepinephrine, its metabolite dihydroxyphenylethylene glycol (DHPG), and serotonin [(5-hydroxytryptamine (5-HT)]. In the VMH, 5-HT, its metabolite 5-hydroxyindoleacetic acid, and the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were all higher in the conditioned animals. 5-HT levels in the LH and DOPAC levels in the VMH were closely associated with serum insulin (r = 0.80 and 0.71, respectively). This study has defined, in the normal animal, changes in monoamines in specific areas of the hypothalamus associated with the cephalic phase insulin release.
Animals↗
Chronic exercise compensates for insulin resistance induced by a high-fat diet in rats.
We examined whether chronic exercise prevents insulin resistance developing in the high-fat-fed (HFF) rat, a model that otherwise develops profound peripheral insulin resistance. Insulin action (euglycemic clamp plus 2-[3H]deoxy-D-glucose-[14C]glucose tracer technique) was examined after 3 wk in sedentary control and sedentary or wheel cage exercise-trained HFF rats. At the whole body level, a reduction in peripheral insulin potency in HFF rats was prevented by concomitant chronic exercise; the 30-40% reduction in insulin-stimulated whole body net glucose utilization in sedentary HFF rats was abolished. Responses in individual muscles, however, suggested that the chronic exercise effect may be a compensation for, rather than a correction of insulin resistance induced by a high-fat diet; in six of eight muscles examined it produced an upward additive shift rather than a left shift in insulin dose response. Chronic exercise increased both muscle glycolytic flux and glycogen storage rates in the HFF rats, suggesting that glucose transport may be involved. We conclude that increased physical activity is beneficial in counteracting high-fat diet-induced insulin resistance. Different processes appear to be involved in the development of diet-induced insulin resistance in muscle and its amelioration by regular exercise.
Animals↗
Effects of fish oil supplementation on glucose and lipid metabolism in NIDDM.
Fish oils, containing omega-3 fatty acids (omega 3FAs), favorably influence plasma lipoproteins in nondiabetic humans and prevent the development of insulin resistance induced by fat feeding in rats. We studied the effects of fish oils in 10 subjects (aged 42-65 yr) with mild non-insulin-dependent diabetes mellitus (NIDDM). Subjects were fed a standard diabetic diet plus 1) no supplementation (baseline), 2) 10 g fish oil concentrate (30% omega 3FAs) daily, and 3) 10 g safflower oil daily over separate 3-wk periods, the latter two supplements being given in radom order by use of a double-blind crossover design. At the end of each diet period, fasting blood glucose (FBG), insulin, and lipids were measured, and insulin sensitivity was assessed with a hyperinsulinemic-euglycemic clamp performed with [3-3H]glucose. FBG increased 14% during fish oil and 11% during safflower oil supplementation compared with baseline (P less than .05), whereas body weight, fasting serum insulin levels, and insulin sensitivity were unchanged. The absolute increase in FBG during each supplementation period correlated with the baseline FBG (fish oil, r = .83, P less than .005); safflower oil, r = .75, P = .012). Fasting plasma triglyceride levels decreased during fish oil supplementation in the 4 subjects with baseline hypertriglyceridemia (greater than 2 mM) but were not significantly reduced overall. There was no significant change in fasting plasma total, high-density lipoprotein, and low-density lipoprotein cholesterol levels. In summary, dietary fish oil supplementation adversely affected glycemic control in NIDDM subjects without producing significant beneficial effects on plasma lipids. The effect of safflower oil supplementation was not significantly different from fish oil, suggesting that the negative effects on glucose metabolism may be related to the extra energy or fat intake.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood Glucose↗
Effect of d-fenfluramine on basal glucose turnover and fat-feeding-induced insulin resistance in rats.
There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.
Adipose Tissue↗
Effect of procaine injection into the ventromedial hypothalamic area (VMH) of the rat on serum insulin, glucose and corticosterone and gastric emptying rate.
Bilateral injection of procaine into the VMH resulted in a decrease in serum glucose and immunoreactive insulin levels in both food-deprived rats and meal-fed rats. Corticosterone levels and gastric emptying rate were unaffected by these VMH procaine injections. Since it is likely that the procaine disrupted only those neurons whose cell bodies and synapses lay in the region of the VMH, the results suggest that the two major factors in the etiology of the 'VMH syndrome' following electrolytic lesions, rapid emptying and insulin hyperresponsivity, are dependent upon destruction of fibers of passage through the VMH. Finally, the results further support the proposal that the VMH exerts tonic excitatory control over liver glucose output.
Animals↗
Effect of fructose on phenylephrine-induced glucose output in perfused rat liver.
Glucose output induced by phenylephrine in perfused livers of fed rats was decreased by 34% during an infusion of fructose, but was increased by 30% (compared to controls) following cessation of fructose infusion. Corresponding changes in hepatic inorganic phosphate (Pi) were also observed with a 40% decrease and a 48% increase in Pi concentration being measured during and following fructose infusion, respectively. The data suggest that the glycogenolytic response to phenylephrine is dependent on the hepatic Pi concentration. It is also suggested that enhanced hepatic Pi concentrations and glycogenolytic responses observed following fructose infusion may antagonize insulin-induced suppression of hepatic glucose output and thus play a role in the glucose intolerance and insulin resistance associated with sucrose or fructose feeding.
Animals↗
Effects of sucrose vs starch diets on in vivo insulin action, thermogenesis, and obesity in rats.
High intake of simple sugars is generally seen as a detrimental factor in the etiology of both obesity and insulin resistance. To examine possible deleterious effects of sucrose, independent of changes in energy intake, rats were fed equal amounts of high-sucrose or high-starch diets over 4 wk. Energy expenditure was assessed by open-circuit respirometry and carcass analysis. In vivo insulin action in individual tissues was assessed with the hyperinsulinemic (1 nmol/L), euglycemic clamp combined with tracer glucose and 2-deoxyglucose administration. Whole-body glucose disposal was impaired by sucrose feeding (clamp glucose infusion rate of 77 +/- 4 vs 124 +/- 6 mumol/[kg.min], p less than 0.001, for sucrose and starch, respectively) because of a major impairment of insulin action at the liver with a smaller contribution from peripheral tissues. Sucrose feeding affected neither basal or stimulated energy expenditure nor accumulation of body fat. In conclusion, sucrose feeding produces a major impairment of insulin action, predominantly because of an effect at the liver.
Animals↗
Effects of nonesterified fatty acid availability on tissue-specific glucose utilization in rats in vivo.
The pathophysiological significance of the glucose-fatty acid cycle in skeletal muscle in vivo is uncertain. We have examined the short term effects of increased availability of nonesterified FFA on tissue-specific glucose uptake and storage in rat tissues in vivo basally and during a hyperinsulinemic (150 mU/liter) euglycemic clamp. Circulating FFA were elevated to 2 mmol/liter (FFA 1) or 4 mmol/liter (FFA 2). Elevated FFA produced a dose-dependent inhibition of myocardial glucose utilization in both basal (FFA1, 42%; FFA2, 68%; P less than 0.001, by analysis of variance) and clamp groups (FFA1, 39%; FFA2, 49%; P less than 0.001) and also suppressed brown adipose tissue glucose utilization during the clamp (-42%, P less than 0.001). In contrast to heart, glucose utilization in skeletal muscle was suppressed by FFA only in the FFA1 basal group (-36%, P less than 0.001); in other groups (e.g., FFA2 clamp) elevated FFA produced increased skeletal muscle glucose utilization (+68%, P less than 0.001) that was directed toward glycogen (+175%, P less than 0.05) and lipid deposition (+125%, P less than 0.005). FFA stimulated basal glucose utilization in white (e.g., FFA2, +220%, P less than 0.005) and brown adipose tissue (e.g., FFA2, +200%, P less than 0.005). Thus elevated FFA can acutely inhibit glucose utilization in skeletal muscle in addition to cardiac muscle in vivo supporting a possible role for the glucose-fatty acid cycle in skeletal muscle in acute insulin resistance. However, at high levels or with elevated insulin, FFA stimulates glucose utilization and storage in skeletal muscle. By promoting accumulation of glucose storage products, chronic elevation of FFA may lead to skeletal muscle (and therefore whole body) insulin resistance.
Adipose Tissue↗
Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent diabetes.
Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a deficiency in early prandial insulin secretion. To determine the contribution of this early deficiency to prandial hyperglycemia, exogenous intravenous insulin (1.8 U over 30 min) was delivered to eight NIDDM subjects in a profile designed to simulate the normal initial rise in insulin levels. The same dose of insulin was also administered 1) in the same profile but delayed by 30 min and 2) as a constant infusion over 180 min. Augmentation of the early insulin response caused a 33 +/- 4% reduction in the glycemic response to a mixed meal (P less than .005); the peak blood glucose increment above baseline was reduced by 1.4 mM (P less than .005) to an increment identical to nondiabetic subjects (3.3 +/- 0.3 vs. 3.2 +/- 0.2 mM), and blood glucose levels were still 0.9 mM lower after 180 min (P less than .05). In contrast, the delayed profile or constant infusion did not significantly alter the glycemic response to the meal. Early insulin augmentation resulted in elevated peripheral insulin levels initially (peak level 81 +/- 11 mU/L), but subsequent insulin and C-peptide levels were lower than in the control study (at 180 min after the meal, 22 +/- 5 vs. 33 +/- 8 mU/L, P less than .05, and 4.0 +/- 0.5 vs. 5.3 +/- 0.6 micrograms/L, P less than .02, respectively). Early insulin delivery caused free-fatty acid (FFA) levels to fall at a faster rate after the meal and also attenuated the initial rise in glucagon levels typical of NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗