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Biomedical subjects

D J Chisholm

Publications and source records attributed to D J Chisholm.

At least 19 recordsLinked to original sources
PubMed1995

Importance of early insulin levels on prandial glycaemic responses and thermogenesis in non-insulin-dependent diabetes mellitus.

To examine the effect of different profiles of insulin administration on glycaemia and thermogenesis, we studied 10 subjects with mild non-insulin-dependent diabetes mellitus on four occasions after a standard mixed meal: (1) with no supplementary insulin (control), (2) with intravenous insulin (1.8U over 15 min = short), (3) as for short but extended over 30 min to simulate the normal initial rise in portal vein insulin levels (medium), (4) as for medium with additional insulin to normalize the profile from 30-60 min (3.6U over 60 min, long). All studies in which supplemental insulin was administered lowered the integrated glucose response above baseline versus the control study (short 76%, medium 71%, and long 56% of control, p = 0.003). The insulin infusions also increased the non-protein respiratory quotient in the first hour following the meal (0.82 +/- 0.01 (control) vs 0.87 +/- 0.01 (short), 0.86 +/- 0.01 (medium) and 0.87 +/- 0.01 (long), p = 0.003) and augmented thermogenesis (7.6 +/- 1.5 (control) vs 10.5 +/- 2.9 (short), 13.0 +/- 1.9 (medium) and 13.2 +/- 2.8% (long), p = 0.02). Total integrated insulin area above baseline was significantly greater in the long study (short 121, medium 111 vs long 179% of control, p = 0.02). Thus the greatest glycaemic benefit in relation to insulinaemia was obtained with the two shorter insulin infusions (short and medium). In conclusion, this study confirms the role of early prandial insulin secretion (or delivery) in limiting prandial glycaemia in NIDDM and increasing thermogenesis and highlights the pivotal role of the timing of elevation of insulin levels in modulating hyperglycaemia and hyperinsulinaemia.

Aged↗
PubMed1993

Potent effects of human galanin in man: growth hormone secretion and vagal blockade.

Human galanin (hGAL) is a 30-amino acid neurohormone that has recently been shown to differ significantly from porcine and rat GAL. We investigated the endocrine and cardiovascular effects of hGAL in eight male volunteers. On three separate occasions, each received a 90-min infusion of saline, low dose (33 pmol/kg.min) and high (132 pmol/kg.min) dose hGAL, combined with an iv glucose bolus (to assess effects on insulin and GH release). hGAL was undetectable, 1.4 +/- 0.2 nmol/L, and 3.7 +/- 0.5 nmol/L during control, low dose, and high dose studies, respectively. The half-life of hGAL was 3.5 +/- 0.5 min. GH levels rose significantly in both studies (vs. control) and were not suppressed by hyperglycemia [low dose area under the curve (AUC), 1827 +/- 348 micrograms/min.L (P < 0.05); peak, 19.5 +/- 5.3 micrograms/L; high dose AUC, 1896 +/- 401 micrograms/min.L (P < 0.005); peak, 28.0 +/- 7.5 micrograms/L]. PRL levels rose significantly with the high dose study only (AUC, 12.8 +/- 1.1 micrograms/min.L; P < 0.01). FSH, LH, and catecholamine levels were unchanged. Glucose-stimulated insulin release was not inhibited. There was a dose-dependent increase in pulse rate and a profound decrease in sinus arrhythmia, but no change in blood pressure. These cardiovascular effects have not been reported with studies in humans using GAL of other species. We conclude that hGAL may play an important role in man in modulating GH secretion and cardiac vagal tone, but not insulin release.

Adolescent↗
PubMed1992

White coat hyperglycaemia: disparity between diabetes clinic and home blood glucose concentrations.

OBJECTIVES: To identify patients with discrepantly high clinic blood glucose concentrations compared with self reported values and to assess whether such patients have errors in self monitoring technique. To determine whether, in patients with good technique, the discrepancy is a transient phenomenon related to clinic attendance. DESIGN: Prospective study of diabetes clinic patients recruited over six months. SETTING: Outpatient diabetes clinic of a teaching hospital. SUBJECTS: 34 consecutive patients with non-insulin dependent diabetes who had had at least two consecutive clinic blood glucose concentrations more than 5 mmol/l higher than the mean self reported concentration. MAIN OUTCOME MEASURES: Assessment of monitoring technique; presence of cognitive or physical impairment; serum fructosamine concentration; home and clinic blood glucose concentrations. RESULTS: 15 of 34 patients had errors in monitoring technique, 12 of whom had cognitive or physical impairment. In the remaining 19, the mean (SD) blood glucose concentrations of capillary and venous samples taken at home (10.2 (0.6) and 12.2 (1.1) mmol/l respectively) were significantly lower than in those taken at the clinic (16.8 (1.6) mmol/l, p < 0.0002). The fructosamine concentration was significantly higher in patients with monitoring errors than those without (2.4 (0.4) v 1.8 (0.4) mmol/l, p < 0.0001). CONCLUSIONS: "White coat" hyperglycaemia was detected in about half the patients but errors in technique accounted for the rest of the discrepancies. Patients' ability should be assessed before teaching self monitoring and the technique checked regularly.

Aged↗
PubMed1992

Will computers replace or complement the diabetes educator?

Computer programs are playing an increasingly important role in the management of diabetes and fall into various categories. Instructional programs are used to teach patients about diabetes. They cover the principles of blood glucose monitoring, diet, exercise, foot care and so on. Statistical and graphical analysis programs are used in diabetes clinics to help the physician, diabetes educator and patient detect patterns and trends in the patient's home blood glucose readings. Hand-held insulin dosage computers have been used by patients to advise them on insulin dosage adjustment on a day-to-day basis. The diabetes simulator we have recently developed allows patients to practise, and gain experience with insulin dosage adjustment; the patient decides on alterations to insulin dose, diet or the amount of exercise and the computer program demonstrates the resulting effect on blood glucose levels. Overall, computers complement and enhance, rather than replace the functions of the diabetes educator.

Blood Glucose Self-Monitoring↗
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

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↗
PubMed1992

Assessment of experts' approach to insulin therapy and development of a simulator for diabetes insulin adjustment.

OBJECTIVE: To develop a computer program (Macintosh) to predict changes in blood glucose after changes in insulin dose, timing, and regimen. RESEARCH DESIGN AND METHODS: We established program parameters (apparent insulin action profiles; different for insulin-dependent and non-insulin-dependent diabetes mellitus) to match predictions by five diabetes specialists at our hospital of blood glucose changes after insulin-dose adjustment in 22 hypothetical patient cases. We compared the action profiles, which represent the blood glucose changes predicted by the experts with glucose-clamp studies of insulin action. We tested the program's performance in 22 different hypothetical cases against the responses of 15 specialists from outside our hospital. RESULTS: The specialists, when predicting effects of insulin dose adjustment, integrate numerous processes (insulin action, diet, sequential blood glucose interactions). They could not specify algorithms for determining these individual factors, but they could easily predict the overall effect in the context of patient cases. The computer program's insulin-action profiles simulate this "composite" approach. The developed program incorporates multiple insulin regimens, which may be changed during the stimulation, and adjusts predicted responses according to the patient's estimated sensitivity to insulin. Its predicted change in 172 blood glucose levels (22 cases) correlated well with the corresponding means of the outside specialists (r = 0.83, P = 0.0001). Comparing this correlation with that of individual specialists ranked the program third. CONCLUSIONS: A computer program can simulate specialists' "composite" approach (not based purely on conscious application of physiological data) to insulin adjustment.

Blood Glucose↗
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↗