Studies of Insulin Sensitivity Using the Euglycaemic Hyperinsulinaemic Clamp

Morris, Andrew David (1994) Studies of Insulin Sensitivity Using the Euglycaemic Hyperinsulinaemic Clamp. MD thesis, University of Glasgow.

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A series of studies which have utilised the euglycaemic hyperinsulinaemic clamp to measure insulin sensitivity is described. The methods for measuring insulin sensitivity have been evaluated and conclusions drawn about reproducibility and inherent limitations of the technique. The euglycaemic clamp has been used to examine the effects of angiotensin II and antihypertensive drugs on insulin sensitivity in normal subjects, patients with essential hypertension and patients with impaired glucose tolerance or non-insulin dependent diabetes mellitus (NIDDM). Each individual study was approved by the local Research and Ethical Committee and informed consent was obtained from each subject before participation in a study. (i) Evaluation of the euglvcaemic hvperinsulinaemic clamp technique. It was recognised that despite widespread use of the euglycaemic clamp in clinical research, key aspects of the technique remained to be validated. (a) The intra- and inter-subject variability in insulin sensitivity and the time for insulin mediated glucose disposal to reach steady state were evaluated in 18 healthy male subjects and 6 patients with essential hypertension who attended two study days when a euglycaemic hyperinsulinaemic clamp was performed. Measurements of insulin sensitivity derived from the euglycaemic hyperinsulinaemic clamp were expressed as whole body glucose uptake (M), and the insulin sensitivity index (SIP). M values at 120 mins were significantly less than at 180 mins in both the healthy subjects and in the hypertensive patients indicating a progressive increase in glucose utilisation over the 180 minutes. The intra subject coefficient of variation (c.v.) of M at 120 mins and 180 mins was 8% and 6% for healthy subjects and 14% and 5% for patients with essential hypertension respectively. The inter subject c.v. of M at 120 mins and 180 mins was 22% and 21% for healthy subjects and 43% and 38% for patients with essential hypertension. The intra subject c.v. of the insulin stimulus was 10% in both groups. The intra subject c.v. of the was 21% for healthy subjects and 16% for patients with essential hypertension. Thus, it was demonstrated that the clamp is highly reproducible within subjects but the inter subject variability is wide. Clamps of 120 min duration underestimate M by up to 10% and are not as reproducible in patients with essential hypertension. The SIP is poorly reproducible; my data suggest that the M value is a better index for comparison of possible changes in insulin sensitivity. (b) The need to arterialise venous blood with a heated hand box was evaluated in 6 healthy subjects. Each subject attended 2 study days when a euglycaemic hyperinsulinaemic clamp was performed and "arterialised" (AV; heated hand vein) and mixed venous blood (MV; antecubital fossa) were collected simultaneously for the measurement of plasma glucose and oxygen saturations It was demonstrated that AV blood was effectively arterialised achieving oxygen saturations of 95+2%, and that plasma glucose concentrations were less variable when compared with MV samples. (c) The haemodynamic and metabolic effects of hand warming were evaluated in 6 healthy male subjects who attended 2 study days when a euglycaemic hyperinsulinaemic clamp was performed. On the first day AV blood was used to adjust the glucose infusion rate required to maintain euglycaemia; on the second study day MV blood was used. The results demonstrate that there was a significant trend for M values to be higher when arterialised blood was used when compared with mixed venous blood. My results suggest that hand warming may induce a blood pressure lowering effect that is associated with a confounding increase in the derived measurement of insulin sensitivity. (ii) Evaluation of the effects of lacidipine on insulin sensitivity. The acute and chronic (2 weeks) effects of the dihydropyridine calcium antagonist, lacidipine (4 mg daily), on insulin mediated metabolic responses was evaluated in a double-blind placebo-controlled crossover study in 12 healthy subjects and 6 patients with essential hypertension. Each subject attended 4 study days when insulin sensitivity was evaluated using the euglycaemic hyperinsulinaeniic clamp. In the healthy subjects, reflex tachycardia was observed after lacidipine administration but neither first dose nor 2 weeks of lacidipine treatment altered insulin sensitivity when compared with placebo. A significant decrease in fasting triglyceride concentrations was observed after 2 weeks lacidipine treatment. 95% confidence intervals excluded a 15% change in whole body glucose uptake. In the hypertensive patients, lacidipine treatment was associated with reflex tachycardia and a trend towards decreased blood pressure but there was no significant effect on whole body insulin sensitivity. (Abstract shortened by ProQuest.).

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: Richard Donnelly
Keywords: Medicine
Date of Award: 1994
Depositing User: Enlighten Team
Unique ID: glathesis:1994-75661
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 19 Nov 2019 18:59
Last Modified: 19 Nov 2019 18:59

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