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Biomedical subjects

A B Jenkins

Publications and source records attributed to A B Jenkins.

At least 55 records · Page 3Linked to original sources
PubMed1992

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly.

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.

Acromegaly↗
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

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

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

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

Pentobarbital reduces basal liver glucose output and its insulin suppression in rats.

Recent reports conflict on the effect that pentobarbital anesthesia has on basal glucose turnover in the rat. It is also unclear whether pentobarbital alters insulin suppressibility of hepatic glucose production (Ra). We examined these issues by performing basal and hyperinsulinemic euglycemic clamp studies in anesthetized and conscious animals. Ra and glucose utilization (Rd) were estimated using a steady-state infusion of 3-[3H]glucose. Pentobarbital anesthesia in normothermic rats transiently elevated plasma glucose but resulted in a sustained suppression of basal Ra (10.4 +/- 0.3 vs. conscious 13.2 +/- 0.9 mg.kg-1.min-1, P less than 0.05). In the insulin-stimulated state (110 mU/l), despite similar plasma glucose and insulin levels, clamp glucose infusion rate was significantly reduced in anesthetized animals (11.1 +/- 0.9 vs. conscious 23.6 +/- 1.3 mg.kg-1.min-1, P less than 0.001). This can be attributed to both a significantly lower insulin-stimulated Rd (15.4 +/- 1.3 vs. conscious 22.8 +/- 1.4 mg.kg-1.min-1, P less than 0.005) and reduced insulin suppression of Ra (4.3 +/- 0.8 vs. conscious -0.8 +/- 0.5 mg.kg-1.min-1, P less than 0.001; i.e., anesthetized 59% vs. conscious 100% reduction of basal Ra). Thus pentobarbital anesthesia significantly reduces basal Ra and induces hepatic insulin resistance (reduces Ra suppressibility). Pentobarbital effects are not dependent on induced hypothermia, but this exacerbates the metabolic perturbation. Caution should be used in extrapolating from the anesthetized to the conscious state.

Animals↗
PubMed1990

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1988

Regulation of hepatic glucose output during moderate exercise in non-insulin-dependent diabetes.

In normal subjects during moderate exercise there is a strong negative correlation between plasma glucose and hepatic glucose output (HGO) suggesting a negative feedback regulation of HGO by plasma glucose. Little information is available about HGO responses to exercise in non-insulin-dependent diabetes mellitus (NIDDM). To determine whether the same feedback relationship is operative, we have compared the glucose turnover responses to moderate exercise (50% Vo2max for 60 minutes) of nonobese non-insulin-dependent diabetic subjects (NIDDM, n = 7) with a group of age-matched controls (n = 5). Glucose turnover responses to exercise in NIDDM were heterogeneous. Plasma glucose showed sustained falls, no change, or sustained rises in different individuals. Similarly, HGO responses ranged from undetectable to responses comparable to those of normal subjects. The mean integrated HGO response in NIDDM was significantly reduced compared with controls (11 +/- 6 [SEM] v 33 +/- 7 mmol/h/70 kg, P less than .05); mean glucose utilization response was also reduced but not significantly different from controls (NIDDM 18 +/- 5 v control 35 +/- 6). In NIDDM there was no significant feedback-control relationship between plasma glucose and HGO (r = -0.20, P = NS) in contrast to controls (r = -0.87, P less than .01). We conclude that feedback control of HGO by plasma glucose during moderate exercise is impaired in NIDDM. This impairment may be due to defective nonpancreatic glucoregulatory mechanisms.

Aged↗
PubMed1988

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↗
PubMed1988

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↗
PubMed1988

Effect of insulin on [3H]deoxy-D-glucose pharmacokinetics in the rat.

Despite its increasing use in physiological animal investigations, there has been no systematic study of the whole body kinetics of 2-deoxy-D-glucose (2DG) or its modification by insulin. A previously proposed model that included processes representing transport across cell walls and intracellular phosphorylation of 2DG was investigated. The model predictions were compared with the plasma disappearance of 2DG observed in the rat following intravenous bolus injection. Experiments were performed during euglycemia at varying levels of hyperinsulinemia. The model was adequate to describe empirically the experimental data after a correction was made for urine loss. However, the variation in model parameters with plasma insulin concentration was not consistent with the expected action of insulin on cellular efflux. A possible explanation could be a shift in the rate-limiting step from glucose transport to another prephosphorylation process under conditions of high tissue uptake. This suggests that either intracellular or extracellular diffusion may constitute a significant barrier to 2DG (and glucose) uptake under some conditions.

Animals↗
PubMed1988

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↗
PubMed1988

Serum insulin and bone density in normal subjects.

A relationship between circulating insulin and bone mass has been postulated. To test this hypothesis we measured fasting serum insulin and quantitated bone density in the forearm, spine and femoral neck by single and dual photon absorptiometry of 70 normal women. There was no statistically significant relationship between insulin and bone density at any site by correlation or regression analysis. Although the relationship between a single measurement of a hormone (at one point in time) and bone density (the result of lifelong factors) should be interpreted with caution, our findings do not support the hypothesis that there is an association between serum insulin and bone mass.

Adult↗