Resonances for the ketone bodies 3-D-hydroxybutyrate, acetone and acetoacetate are readily detected in serum, plasma and urine samples from fasting and diabetic subjects by 1H n.m.r. spectroscopy at 400 MHz. Besides the simultaneous observation of metabolites, the major advantage of n.m.r. is that little or no pretreatment of samples is required. N.m.r. determinations of 3-D-hydroxybutyrate, acetoacetate, lactate, valine and alanine were compared with determinations made with conventional assays at six 2-hourly intervals after insulin withdrawal from a diabetic subject. The n.m.r. results closely paralleled those of other assays although, by n.m.r., acetoacetate levels continued to rise rather than reaching a plateau 4h after insulin withdrawal. The 3-D-hydroxybutyrate/acetoacetate ratio in urine during withdrawal gradually increased to the value observed in plasma (3.0 +/- 0.2) as determined by n.m.r. The acetoacetate/acetone ratio in urine (17 +/- 6) was much higher than in plasma (2.5 +/- 0.7). Depletion of a mobile pool of fatty acids in plasma during fasting, as seen by n.m.r., paralleled that seen during insulin withdrawal. These fatty acids were thought to be largely in chylomicrons, acylglycerols and lipoproteins, and were grossly elevated in plasma samples from a non-insulin-dependent diabetic and in cases of known hyperlipidaemia.

1239hydrate diet, reduced physical activity, and obesity may be the important factors implicated. And all these factors seem to operate in the Nauruan population.8This work was supported in part by a grant from the National Health and Medical Research Council of Australia. We thank the government of the Republic of Nauru for allowing the study to proceed, and Miss Roma Swan for typing the manuscript. ReferencesIPrior, I A M, et al, Lancet, 1966, 1, 333. 2 West, K M, Diabetes, 1974, 23, 841. 3 Zimmet, P, et al, Diabetologia, 1977 DeBoer, W, Collins, J, and Zimmet, P, Di'abetologi 'a, 1977, 13, 388. 5 Prior, I A M, and Davidson, F, New Zealand Journal of Medicine, 1966, 65, 375. 6 Bennett, P H, Burch, T A, and Miller, M, Lancet, 1971, 2, 125. 7 Summary and conclusions Six insulin-requiring diabetics were studied after insulin had been withheld for 24 hours. On three separate occasions each received a two-hour infusion of insulin at a low dose (2-6 U/h) and a high dose (10 6 U/h) and an infusion of saline as control. The rates of production and utilisation of glucose were measured isotopically. The rate of fall of plasma glucose concentration was faster on the hightdose infusion of insulin than on the low, whereas the fall in plasma free fatty acids, glycerol, and keton bodies was the same on both insulin infusions. The mechanism whereby the two rates of insulin administration lowered plasma glucose concentration differed: during the low-dose infusion the decrease in the glucose concentration was produced entirely by a fall of hepatic glucose output, whereas during the high-dose insulin infusion the glucose concentration fell because both the rate of glucose production fell and the rate of glucose utilisation rose. In all experiments there was a direct relation between a fall in serum potassium concentration and the fall in plasma glucose concentration irrespective of the mechanism that reduced the glucose concentration. These results indicate that in uncontrolled diabetics low-dose insulin infusions lower the blood glucose concentration entirely by reducing glucose production from the liver and that the effect of insulin on potassium transport is independent of its effect on glucose uptake.

Myocardial substrate extraction, coronary sinus flow, cardiac output, and left ventricular pressure were measured at increasing pacing rates before and after propranolol (0.2 mg/kg) in 13 patients with hypertrophic obstructive cardiomyopathy (HOCM) during diagnostic cardiac catheterisation. At the lowest pacing rate myocardial oxygen consumption varied considerably between patients and very high values were found in several individuals (range 10.1 to 57.5 ml/min). These large differences between patients were not explicable by differences in cardiac work; consequently, cardiac efficiency, estimated from the oxygen cost of external work, varied between patients and was lower than normal in all but two. The pattern of substrate extraction at the lowest pacing rate was similar to results reported for the normal heart, and measured oxygen consumption could be accounted for by complete oxidation of the substrates extracted; thus there was no evidence of a gross abnormality of oxidative metabolism, suggesting that low efficiency lay in the utilisation rather than in the production of energy. Each of the four patients with the highest myocardial oxygen consumption and lowest values of efficiency sustained progressive reductions in lactate and pyruvate extraction as heart rate increased, and at the highest pacing rate had low (< 3%) or negative lactate extraction ratios. In three of these four, coronary sinus flow did not increase progressively with each increment in heart rate. One patient with low oxygen consumption and normal efficiency also failed to increase coronary flow with the final increment in heart rate, and produced lactate at the highest pacing rate. Thus the five patients in whom pacing provoked biochemical evidence of ischaemia all had excessive myocardial oxygen demand and/or limited capacity to increase coronary flow. Propranolol did not change lactate extraction significantly at any pacing rate in either the ischaemic or non-ischaemic groups. In only one patient was ischaemia at the highest pacing rate abolished after propranolol, and this was associated with a 30 per cent reduction in oxygen consumption. These results do not demonstrate a direct effect of propranolol upon myocardial metabolism in patients with HOCM, but emphasise the potential value of beta-blockade in protecting these patients from excessive increases in heart rate.

SUMMARY When a decrease in left ventricular isovolumic pressure is considered as an exponential, the rate of relaxation can be defined by a time constant (T). Previously, T has been calculated from the slope of In (pressure) against time, but this method is valid only when the asymptote of the exponential is zero. In this study two estimates of T were made: Tin from the slope of In (pressure) against time, and TEXP by a method of exponential analysis that also estimated the asymptote. These techniques were applied to measurements of left ventricular pressure made at increasing pacing rates in three groups of patients catheterized for chest pain: group 1 (n = 9) normal coronary arteriograms; group 2 (n = 9) -coronary artery disease (CAD) but no angina or lactate production during pacing; and group 3 (n = 9) CAD and angina during pacing. Tjn was always shorter than TEXP, and in groups 1 and 2 TEXP was dependent on heart rate, whereas Tin was not. The asymptote was negative, and increased toward zero during pacing in groups 1 and 2. The difference between TEXP and Tin could be related to the value of the asymptote. In 18 of 20 beats tested, pressures calculated from TEXP and the asymptote were in closer agreement with measured pressures than were the pressures predicted by T1n. Despite their different values, TEXP and Tin each distinguished between the three groups. Although the choice of an exponential model is arbitrary, isovolumic pressure decrease approximates to a single expontial; but this study suggests that both T and the asymptote are variable.THE STUDY of the decrease in left ventricular pressure during isovolumic relaxation is hindered by the lack of a method of quantifying pressure decrease that can be used to compare individual subjects. The maximal rate of pressure decrease (dP/dt min) can decrease during ischemia,l but dependence on endsystolic pressure and fiber length limits its value.2' More recently, a pressure decrease from the point of dP/dt min has been treated as a single exponential, which allows derivation of a time constant that describes relaxation.4 6 The time constant is calculated as the negative reciprocal of the slope of ln (pressure) against time, and the correlation coefficient is used to test the validity of the monoexponential model.4-6 The time constant so derived is relatively insensitive to heart rate, ventricular volume and the level from which pressure decreases,4 7 8 but is prolonged during ischemia.6' This semilogarithmic method of estimating the time constant of an exponential is valid only when the asymptote of the exponential is zero. The zero reference for pressure measurement is an external point; one cannot assume that it corresponds to the asymptote of ventricular pressure decrease or that the asymptote remains constant under different conditions. In this study, we estimated the time constant of isovolumic pressure decrease both from the plot of In (pressure) against time and by a method of exponential analysis that also estimates the asymptote. We used these techn...

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