Exercise under hyperinsulinaemic conditions increases whole-body glucose disposal without affecting muscle glycogen utilisation in type 1 diabetes.

AIMS/HYPOTHESIS: We examined whole-body and muscle metabolism in patients with type 1 diabetes during moderate exercise at differing circulating insulin concentrations. METHODS: Eight men (mean +/- SEM age 36.4 +/- 1.5 years; diabetes duration 11.3 +/- 1.4 years; BMI 24.6 +/- 0.7 kg/m(2); HbA(1c) 7.9 +/- 0.2% and VO(2) peak 44.5 +/- 1.2 ml kg(-1) min(-1)) with type 1 diabetes were studied on two occasions at rest (2 h) and during 45 min of cycling at 60% maximum VO(2) with insulin infused at the rate of either 15 (LO study) or 50 (HI) mU m(-2) min(-1) and blood glucose clamped at 8 mmol/l. Indirect calorimetry, insulin-glucose clamps and thigh muscle biopsies were employed to measure whole-body energy and muscle metabolism. RESULTS: Fat oxidation contributed 15 and 23% to total energy expenditure during exercise in the HI and LO studies, respectively. The respective carbohydrate (CHO) oxidation rates were 31.7 +/- 2.7 and 27.8 +/- 1.9 mg kg(-1) min(-1) (p < 0.05). Exogenous glucose utilisation rate during exercise was substantially greater (p < 0.001) in the HI study (18.4 +/- 2.1 mg kg(-1) min(-1)) than in the LO study (6.9 +/- 1.2 mg kg(-1) min(-1)). Muscle glycogen content fell by approximately 40% during exercise in both trials. Muscle glycogen utilisation, muscle intermediary metabolism, and phosphorylation of protein kinase B/Akt, glycogen synthase kinase 3alpha/beta and extracellular signal-regulated protein kinase 1 and 2 proteins were no different between interventions. CONCLUSIONS/INTERPRETATION: In patients with type 1 diabetes, exercise under peak therapeutic insulin concentrations increases exogenous glucose utilisation but does not spare muscle glycogen utilisation. A disproportionate increase in exogenous glucose utilisation relative to the increase in CHO oxidation suggests an increase in glucose flux through non-oxidative pathways.

An audit of lower limb arteriography in diabetic patients.

The outcome of 83 diabetic patients with peripheral vascular disease who underwent arteriography between 1984 and 1988 was reviewed. Angioplasty was possible in 42 legs and was technically successful in 31 but led directly to clinical improvement in only 15. Five of 20 patients referred for vascular surgery also improved. Factors associated with a clinically successful outcome were presentation with claudication, palpable pulses in the contralateral foot, and radiographic evidence of either a short proximal lesion or 2-3 vessel run-off. Median life expectancy following arteriography was 36 months. The median time to amputation was 21 months and median survival with both life and limb intact was only 13 months.

Megaduodenum due to hollow visceral myopathy successfully managed by duodenoplasty and feeding jejunostomy.

A 29 year old man with a history of childhood polymyositis developed insulin dependent diabetes and was found coincidentally to have chronic intestinal pseudo-obstruction due to visceral myopathy. Multiple full thickness biopsy specimens showed severe disease in the duodenum and the proximal jejunum only, with less involvement distally. Total parenteral nutrition has been avoided for more than a year by enteral feeding through a fine bore jejunostomy catheter positioned with its tip in the distal jejunum.

Defect in thermoregulation in malnutrition reversed by weight gain. Physiological mechanisms and clinical importance.

Previous studies in infants and in the elderly have shown that a low body weight is associated with a defect in thermoregulation and an increased risk of hypothermia. In the present study, thermoregulatory responses to a cooling stimulus were measured in 10 young and middle-aged patients who lost at least 10 per cent of their body weight during illness. Investigations were performed before and after restoration of body weight (mean weight gain 7.2 kg, SE 1.2 kg, p less than 0.001). The cooling stimulus was provided by a special suit perfused with water at 28 degrees C and then at 23 degrees C. Before weight gain, there was no increase in metabolic rate in response to cooling, despite a fall in core temperature. Following weight gain, the thermogenic response to cooling was restored towards normal. Peripheral vasoconstriction, the principal mechanism for heat conservation, was similar before and after weight gain. The thermogenic response to an infusion of adrenaline (25 ng/kg/min) was not abolished by weight loss, suggesting that the defect in cold-induced thermogenesis following weight loss is due to a change in central control mechanisms of thermoregulation, and not to tissue unresponsiveness. The phenomenon of abnormal thermoregulation following weight loss and the return to normal with subsequent weight gain may be clinically important, particularly in the elderly, since quite small falls in core temperature may impair both neuromuscular coordination and cerebral function.

Low anthropometric indices in elderly females with fractured neck of femur.

Anthropometric measurements were made in 3 groups of elderly females (1) with fractured neck of femur, (2) those admitted to acute medical and geriatric wards, and (3) healthy women in the community. Mid-arm circumference was different in the three groups with mean values of 22.8 +/- 0.21 cm, 25.9 +/- 0.41 cm and 28.6 +/- 0.27 cm respectively; (p < 0.001 for all comparisons). Triceps skinfold thickness was 24.7 +/- 0.70 mm in the healthy elderly but only 13.0 +/- 0.59 mm in the fracture group (p < 0.001). Fractured femur patients are therefore thinner than both healthy controls and unselected elderly female medical in-patients. These differences are most apparent in anthropometric indices dependent on body fat and this may be significant in terms of the aetiology of fractured femur.

Reappraisal of the Weir equation for calculation of metabolic rate.

In 1949 Weir (3) demonstrated that the metabolic rate calculated from respiratory gas exchange measurements is to a close approximation proportional to the difference in percentage oxygen content between inspired and expired air. Although values for the energy equivalent of oxygen consumed and for the respiratory quotient for the oxidation of various nutrients have been revised since 1949, we show that the error in the calculation remains generally below 0.5% for the oxidation of dietary carbohydrate, fat, and protein. Where the original equation is uncritically applied to situations in which other nutrients are being oxidized, the error may reach 3%, although alternative methods for calculating the metabolic rate may be similarly in error. We give the derivation from first principles of the general mathematical solution to the calculation of the metabolic rate following Weir's method. Examples are provided of the subsequent derivation of specific equations for the more precise calculation of the metabolic rate where different combinations of nutrients are being oxidized.

The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans.

The effect of 48-hour starvation on glucose metabolism was studied in six non-diabetic, normal weight men using a hyperinsulinemic (100 mU/min/m2) glucose clamp (3.5 mmol/L). The rate of glucose oxidation was calculated from measurements of respiratory gas exchange, after allowing for the oxidation of ketones and of protein. During the glucose clamp, the whole body glucose disposal rate decreased from 39.8 (SEM 4.6) mumol/kg/min in the fed state to 24.1 (2.1) mumol/kg/min in the starved state (P less than .01), consistent with insulin "resistance." The glucose oxidation rate decreased from 21.8 (1.3) to 3.9 (1.4) mumol/kg/min with starvation (P less than .001), but the nonoxidative glucose disposal rate was unchanged (18.0 [3.9] mumol/kg/min normally fed, and 20.2 [1.2] mumol/kg/min starved). With starvation, the rate of glucose uptake in the forearm during the glucose clamp was reduced from 59.4 to 15.4 mumol/min/L forearm (SE 5.6, P less than .01, ANOVA). There was a significant net increase in thermogenesis during the glucose clamp in the normally fed state (0.27 [0.08] kJ/min, P less than .01, ANOVA), but not following starvation (0.11 [0.09] kJ/min, NS, ANOVA). Therefore, starvation caused decreases in oxidative glucose disposal and in forearm glucose uptake; despite the whole body nonoxidative disposal rate of glucose being unchanged, the associated net thermogenic response was diminished.

The effect of a 48 h fast on the physiological responses to food ingestion in normal-weight women.

The thermogenic, cardiovascular and metabolic responses to a 30 kJ/kg body-weight test meal were studied in eight normal-weight, healthy female subjects after a 6 or 48 h fast. There was no significant change in metabolic rate following the 48 h fast, but plasma glucose, insulin, noradrenaline and respiratory exchange ratio were all reduced, and plasma beta-hydroxybutyrate was increased. Forearm blood flow was increased, with reduction in diastolic blood pressure. After the 48 h fast, there was a reduction in the metabolic rate response 40-90 min after food (control + 0.54 (SE 0.05), 48 h fast + 0.27 (SE 0.12) kJ/min, P less than 0.01), and in forearm blood flow and diastolic blood pressure responses, but increases in heart rate, blood glucose and plasma insulin responses to the ingestion of the test meal. There was no significant relationship between plasma catecholamine concentration and food ingestion or metabolic rate. Fasting induced considerable adaptation in these subjects and altered some of the physiological responses to food ingestion.

Enhanced thermogenic response to epinephrine after 48-h starvation in humans.

The effects of 48-h starvation on the physiological responses to a 30-min infusion of epinephrine at 25 ng.min-1.kg body wt-1 were studied in 11 normal-weight healthy young subjects. Starvation led to considerable alterations in basal metabolism including a significant (mean 3.6%) increase in resting metabolic rate. During the infusions, plasma epinephrine concentration rose less in the starved state (+1.47 nmol/l) than in the normally fed state (+1.73 nmol/l) (SE 0.06 nmol/l; P less than 0.05). The maximum increments (mean +/- SE) in heart rate induced by epinephrine were 11.9 +/- 1.3 beats/min in the normally fed state and 20.1 +/- 2.0 beats/min in the starved state (P less than 0.001); the corresponding mean increments in blood glycerol concentration were 0.07 and 0.14 mmol/l (SE 0.01 mmol/l; P less than 0.01). The increase in the metabolic rate above base line during the final 10 min of the epinephrine infusion was 0.58 +/- 0.18 kJ/min in the normally fed state and 0.78 +/- 0.14 kJ/min in the starved state (P less than 0.01). The chronotropic, lipolytic, and thermogenic effects of infused epinephrine were therefore enhanced by prior starvation, despite the lower plasma epinephrine levels.

Clinical effects and adequacy of a new all-in-one dextrose-electrolyte-trace element preparation in patients on prolonged TPN.

We have devised a new all-in-one dextrose/electrolyste/trace element mixture (Polyfusor DY) and tested its efficacy in clinical practice. Polyfusor DY was designed to be combined with an amino-acid preparation and to be infused with lipid in a standard total parenteral nutrition (TPN) regimen. This standard regimen was formulated to provide minimum nitrogen, energy, fluid, electrolyte, vitamin and trace element requirements for the stable patient. The adequacy of currently recommended levels of provision of trace elements was tested in patients receiving long periods of intravenous nutrition. Eleven consecutive patients were fed from 13 to 280 days using TPN prescriptions based on this standard regimen. Two patients died but the nutritional state of the remainder improved. Serum concentrations of zinc, copper, chromium and manganese remained largely within or above the reference ranges, however the selenium content of Polyfusor DY (500 nmol/l) was marginally inadequate to maintain normal biochemistry. Pharmacy compounding time for the standard TPN regimen based on Polyfusor DY was 10.6 +/- 0.19 min (mean +/- SEM) compared with 22.5 +/- 0.30 min for non-standard TPN regimens prescribed independently by other clinicians (P < 0.001). A standard TPN regimen based on Polyfusor DY was clinically effective, in particular giving generally adequate trace element provision with a reduction in pharmacy time and costs.

Effects of underfeeding and of starvation on thermoregulatory responses to cooling in women.

1. The effects of acute alterations in energy intake on the thermoregulatory responses to a cooling stimulus were studied in healthy, normal weight, young female subjects. On separate occasions, seven subjects were underfed for 7 days at 60 kJ day-1 kg-1 ideal body weight and six subjects were starved for 48 h. The cooling stimulus was provided by a coverall perfused with water at 16 degrees C. 2. After the application of the cooling stimulus, central body (auditory canal) temperature rose initially in both studies. After underfeeding, the magnitude of this rise in temperature was not significantly different from that seen in the normally fed state. After 48 h starvation, the rise in temperature on cooling was reduced from 0.30 (SEM 0.03) to 0.10 (0.04) degrees C (P less than 0.01). In two subjects in whom central body temperature had been maintained in the normally fed state, a fall occurred after starvation. 3. Underfeeding for 7 days did not affect thermogenesis or the degree of vasoconstriction in the forearm or hand in response to cooling. 4. After 48 h starvation, the thermogenic response to cooling was abolished and blood flow in the forearm remained higher than in the normally fed state. 5. In normal weight young females, thermoregulatory responses to a cooling stimulus were therefore substantially affected by 48 h starvation but not by 7 days underfeeding.

Underfeeding and the physiological responses to infused epinephrine in lean women.

Undernutrition leads to a reduction in sympathetic nervous system activity, but it is not established whether whole body responsiveness to catecholamines is also affected. The physiological responses to a 30-min infusion of epinephrine at 25 ng.kg-1.min-1 were studied in seven healthy, lean female subjects who had reduced their daily food intake to 60 kJ/kg ideal body weight for 7 days. Underfeeding led to greater epinephrine-induced increases in blood glycerol [peak increment 0.14 +/- 0.02 (SE) vs. 0.08 +/- 0.01 mmol/l, P less than 0.05] and beta-hydroxybutyrate concentrations (mean increment 0.30 +/- 0.05 vs. 0.13 +/- 0.04 mmol/l, P less than 0.05, analysis of variance). Compared with the normally fed state, in the underfed state epinephrine also caused greater increases in skin temperatures measured over the abdomen (0.94 +/- 0.08 vs. 0.67 +/- 0.06 degrees C, P less than 0.05) and over the thigh (1.00 +/- 0.07 vs. 0.61 +/- 0.12 degrees C, P less than 0.01). Underfeeding did not, however, affect the chronotropic, thermogenic, or other measured responses to epinephrine. Underfeeding therefore caused an enhancement of some but not all physiological responses to infused epinephrine.

Metabolic and cardiovascular effects of infusions of low doses of isoprenaline in man.

1. The cardiovascular and metabolic responses to low doses of isoprenaline (15 and 5 ng min-1 kg-1 body weight infused over 30 min) were determined in six healthy males. The study was performed to investigate whether there were sustained effects after the termination of the isoprenaline infusion, as has been observed previously after the infusion of adrenaline. 2. The isoprenaline infusions produced dose-dependent increases in heart rate, systolic blood pressure and metabolic rate, but similar increases in calf blood flow and decreases in diastolic blood pressure for the two infusion rates. Finger tremor was increased in amplitude by the 15 ng min-1 kg-1 infusion only. The changes in each of these physiological variables largely resolved within a few minutes of discontinuing the isoprenaline infusions. 3. There were no changes in arterialized venous plasma adrenaline or noradrenaline levels during the isoprenaline infusions. Mean peak plasma isoprenaline levels were 0.16 +/- 0.02 nmol/l during the 5 ng min-1 kg-1 infusion and 0.71 +/- 0.05 nmol/l during the 15 ng min-1 kg-1 infusion. 4. Plasma insulin levels increased with isoprenaline but blood glucose concentrations were unchanged, consistent with a direct effect of isoprenaline on beta 2-adrenoceptors mediating insulin release from pancreatic beta-cells. Blood glycerol concentration also increased with isoprenaline but blood lactate concentration was unaltered. 5. The present study demonstrates pronounced cardiovascular and metabolic effects of low dose isoprenaline infusions. Differences in the rate of resolution of the changes induced by isoprenaline and by adrenaline seen in previous studies may result from a significant difference in their metabolism.

The effect of underfeeding on the physiological response to food ingestion in normal weight women.

1. The thermogenic, cardiovascular and metabolic responses to the ingestion of a 30 kJ/kg body-weight test meal were studied in six normal weight, female subjects before and after a 7 d period of underfeeding at 60 kJ/kg ideal body-weight per d. 2. With underfeeding there were decreases in body-weight, plasma insulin and 3,5,3'-triiodothyronine concentrations, resting metabolic rate and respiratory exchange ratio, with increased blood ketone levels. Baseline 'arterialized' venous plasma noradrenaline and adrenaline concentrations were not affected by underfeeding. 3. Ingestion of the test meal caused similar increases in heart rate and calf blood flow and changes in blood pressure in the fed and underfed states. There was a greater glycaemic response to the test meal in the underfed state compared with the fed state although the rise in plasma insulin concentration was similar and ketogenesis was suppressed. The increases in metabolic rate and plasma noradrenaline concentrations following the test meal were similar in the fed and underfed states. 4. Although the period of underfeeding in the present study led to considerable metabolic adaptation, and some alteration in physiological responses to ingestion of a test meal, there was no evidence that there were associated changes in sympathetic nervous system activation.