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Biomedical subjects

D J Chisholm

Publications and source records attributed to D J Chisholm.

At least 73 records · Page 4Linked to original sources
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

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

Impact of intensive educational approach to dietary change in NIDDM.

The aim of this study was to compare the effects of an intensive educational approach incorporating longer time, greater simplicity, repetition, and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus (NIDDM) whose weight, glycemic control, and diet were not optimal. Subjects were randomly allocated to intensive or conventional education. Of 350 subjects, 70 met the study criteria, which included established NIDDM (greater than or equal to 3 mo), suboptimal recent glycemic control, dietary fat intake greater than or equal to 35% of total energy intake, and body mass index greater than or equal to 25 kg/m2. The intensive approach was associated with significantly greater improvements in dietary compliance, dietary intake (complex carbohydrate, [P = 0.013], legumes [P less than 0.0001], fiber [P less than 0.0001], total fat [P less than 0.004], saturated fat [P less than 0.004]), and total cholesterol level (P = 0.007). The transient improvement in glycemic control was similar in both groups. An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one. These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control.

Aged↗
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

Factors in sexual dysfunction in diabetic female volunteer subjects.

The aetiology and management of diabetic impotence is well-documented; the effects of diabetes on female sexuality are not so clear. In this study, 48 diabetic women were assessed clinically and answered detailed sexual questionnaires during a semistructured interview with a sexual counsellor. Twenty-four of the women reported one-or-more sexual dysfunctions: decreased libido, slow arousal, inadequate lubrication, anorgasmia or dyspareunia. There was no significant relationship between the presence of dysfunction and recent glycaemic control, the duration of diabetes, the presence of clinical complications or of neuropathy alone, or the attitude to sexuality. The sexual dysfunction(s) were present at the onset of diabetes in the majority of those so affected (17 of 24 patients), or were attributed to other causes in the remainder. It is suggested that sexual dysfunction in diabetic women should be treated actively as in "normal" women, since diabetes is not the major aetiological factor.

Adult↗
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

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↗
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

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

Primary adrenal tumours--a ten-year experience.

The experience of 31 patients with primary adrenal tumours seen in one teaching hospital over a 10-year period is reviewed. There were 10 patients who had benign cortical adenomas; 11 had adrenal cortical carcinomas, and 10 had phaeochromocytomas, one of which was malignant. During the review period, a primary adrenal mass was discovered in 5% of 2951 autopsies performed in the study institution. The diagnosis and management of these uncommon tumours is reviewed.

Adenoma↗
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

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↗