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Research of the last two decades showed that chronic low-grade inflammation, elevated blood glucose and insulin levels may play role in the onset of a number of non-communicable diseases such as type 2 diabetes and some forms of cancer. Regular exercise and fasting can ameliorate high blood glucose and insulin levels as well as increase the concentration of plasma ketone bodies. These, in consequence, may lead to reduction of inflammation. Exercise or severe restriction of caloric intake is not always advisable for patients, in particular those suffering from cancer. The ketogenic diet (KD), characterized by high fat, moderate protein and very low carbohydrate composition can evoke a physiological state similar to that triggered by exercise or fasting. These attributes of KD prompted its possible use in treatment of a number of metabolic diseases, including several types of malignancies. Although results from clinical studies employing KD in the treatment of cancer are still limited, the results obtained from animal models are encouraging and show that KD presents a viable option as an adjunct therapy for cancer.

Bacterial translocation is believed to occur during cardiopulmonary bypass (CPB) because serum endotoxin concentrations rise. Intestinal ischemia during CPB, however, has never been proven directly. The condition of the intestinal mucosa during CPB was studied by measuring serum diamine oxidase (DAO) activity, an index of intestinal ischemia. Serum DAO activity, blood lactate concentration, and the arterial ketone body ratio (AKBR) were measured intraoperatively in four successive patients who underwent aortic arch replacement by the open distal anastomosis method. DAO activity rose after restoration of blood flow to the lower half of the body, and continued to rise throughout CPB. The lactate concentration also rose, mirroring the change in DAO activity, and returned to nearly normal 12 h after the operation. The AKBR decreased during CPB, with a mean minimum vale of 0.16-0.07 immediately after the restoration of blood flow to the lower half of the body. The parallel rise in DAO activity and serum lactate concentration once blood flow to the lower half of the body was restored implies that ischemic injury to the mucosa of the small intestine occurs during CPB. The continued rise in these parameters throughout CPB is consistent with ongoing injury due to splanchnic hypoperfusion, as reflected in the decrease in the AKBR during the same period.

Aims/hypothesis: We investigated the relation between glucose transport/phosphorylation and glycogen synthase activation in individual rat skeletal muscles in response to moderate hyperinsulinaemia in the absence or presence of hyperglycaemia during pregnancy., Methods: Rats were studied on day 20 of pregnancy after 24-h starvation, with unmated rats as controls. Insulin and glucose were infused into conscious rats through an indwelling cannula as specified. Glucose transport/phosphorylation was assessed in vivo using 2-deoxy-[1-3H]glucose. Glycogen synthase activity was measured in muscle extracts < or = 10 mmol/l glucose-6-phosphate., Results: In unmated rats, stimulation of glucose transport/phosphorylation occurred in response to euglycaemic-hyperinsulinaemia in all muscles studied but activation of glycogen synthase was not observed. Muscle glucose transport/phosphorylation rates during euglycaemic-hyperinsulinaemia after 24-h starvation were lower in pregnant compared with unmated rats, whereas glycogen synthase activation by insulin occurred in two of three fast-twitch muscles of pregnant rats. When insulin and glucose concentrations were matched between the 24-h starved unmated and pregnant groups through variable glucose infusion (15 min), glycogen synthase activities in fast-twitch muscles did not differ between unmated and pregnant groups. The response of glycogen synthase to hyperglycaemia in slow-twitch muscle was, however, greater in the pregnant group., Conclusion/interpretation: Glycogen synthase activation in slow-twitch muscle in response to hyperinsulinaemia after 24-h starvation is enhanced in late pregnancy but the response is critically dependent on glycaemia. Pregnancy is, nevertheless, associated with reduced muscle glucose transport/phosphorylation. This disassociation ensures that available glucose is directed towards the fetus rather than the mother under conditions of moderate hyperinsulinaemia, for example during refeeding after starvation.

We examined whether the increased rates of protein catabolism (proteolysis and leucine oxidation) associated with moderate insulinopenia in subjects with IDDM would be accentuated by prior bicycle exercise (53% VO2max for 82 min). Insulin infusions maintained plasma glucose concentrations on one study day in "tight" control (TC: 6 mmol/l) and on a separate day in "loose" control (LC: 12 mmol/l). Elevations in serum ketone body, plasma NEFA, and whole-blood branched-chain amino acid concentrations on the loose control day during the basal period persisted throughout the post-exercise recovery period. Amino acid kinetics were estimated during a primed, constant infusion of L-[1-13C]leucine from plasma dilution of alpha-[1-13C]KIC and expired air 13CO2 enrichments. Loose control was associated with increased rates of whole-body leucine oxidation (LC 25 +/- 7 vs TC 21 +/- 8 mumol.kg-1.h-1) and protein degradation (LC 127 +/- 12 vs TC 118 +/- 18 mumol.kg-1.h-1) (both p < 0.05). During the 2-h post exercise recovery period, there were significant decreases in rates of leucine oxidation (LC 21 +/- 7, TC 16 +/- 7) and protein degradation (LC 112 +/- 13, TC 107 +/- 11), compared to the basal period (both p < 0.05, basal vs recovery). Rates of whole-body protein synthesis were unchanged by prior exercise. In conclusion, moderate insulinopenia is associated with significantly higher rates of protein degradation and leucine oxidation in the basal state. Following exercise, net protein catabolism is diminished due to reduced rates of protein degradation in the presence of maintained rates of protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: Abnormally elevated central venous pressure is considered to be an etiological factor in the onset of acute hepatic failure following modified Fontan operation. This paper hypothesises that an increase in inferior vena cava pressure (IVCP) after such an operation has adverse effects on hepatic energy status., Design: Various degrees of venous hypertension were produced in 10 mongrel dogs by clamping the thoracic IVC with an active veno-venous shunt and varying its flow rate from 60-2.5 ml/min/kg. Arterial ketone body ratio (KBR), reflecting the hepatic mitochondrial redox state, was measured as an index of hepatic energy status., Measurements and Results: The lower the flow rates of the shunt, the higher the pressures of IVC and portal vein, while systolic blood pressure was maintained above 100 mmHg. CO significantly decreased when the pump speed was less than 30 ml/min/kg. KBR showed a negative correlation to IVCP as well as a positive correlation to portal blood flow (p < 0.05)., Conclusion: From the simple regression line obtained between IVCP and KBR, it was determined that an upper safety limit of IVCP may lie at about 27 cmH2O (20.5 mmHg), and that a IVCP of 35 cmH2O (26.6 mmHg) seems to be the critical level for maintaining liver viability.

The effect of low-molecular-weight heparin (LMWH) on hepatic mithocondrial metabolism was compared with that of unfractionated heparin (UH) after the intravenous administration of these two kinds of heparin to normal rabbits. The magnitude of decrease in blood triglyceride levels 5 min after administration of UH (200 U/kg) was significantly greater than after LMWH (200 U/kg). Free fatty acid levels in the blood were significantly higher after this dose of UH than after LMWH. Blood total ketone body levels (acetoacetate + 3-hydroxybutyrate) 15 min after injection of 50 U/kg of UH were significantly higher than those after a dose of 50 U/kg of LMWH, and levels after 200 U/kg of UH were significantly higher than those after 200 U/kg of LMWH at 15, 30, 45 and 60 min. Enhanced ketogenesis was not noted after LMWH at any of the doses, or after UH at 3 U/kg. Arterial ketone body ratio (AKBR; acetoacetate/3-hydroxybutyrate), which reflects the hepatic mitochondrial oxidation-reduction state (NAD+/NADH), was maintained above 1.0 in all groups except in the U-200 group, while AKBR in that group was significantly decreased to 0.99 +/- 0.14 at 30 min, and further decreased to 0.80 +/- 0.08 at 60 min. These results indicate that LMWH has less effect on lipolysis than UH and does not enhance ketogenesis, resulting in less deterioration of mitochondrial redox state.

It is controversial as to whether ketone bodies are utilized by the human brain as a fuel alternative to glucose during hypoglycaemia. To clarify the issue, we studied 10 normal volunteers during an experimental hypoglycaemia closely mimicking the clinical hypoglycaemia of patients with Type 1 (insulin-dependent) diabetes mellitus or insulinoma. Hypoglycaemia was induced by a continuous infusion of insulin (0.40 mU.kg-1.min-1 for 8 h, plasma insulin approximately 180 pmol/l) which decreased the plasma glucose concentration to approximately 3.1 mmol/l during the last 3 h of the studies. Subjects were studied on two occasions, i.e. spontaneous, counterregulatory-induced post-hypoglycaemic increase in 3-beta-hydroxybutyrate (from approximately 0.2 to approximately 1.1 mmol/l at 8 h), or prevention of post-hypoglycaemic hyperketonaemia (plasma beta-hydroxybutyrate approximately 0.1 mmol/l throughout the study) after administration of acipimox, a potent inhibitor of lipolysis. In the latter study, glucose was infused to match the hypoglycaemia observed in the former study. The glycaemic thresholds and overall responses of counterregulatory hormones, symptoms (both autonomic and neuroglycopenic), and deterioration of cognitive function (psychomotor tests) were superimposable in the control study in which ketones increased spontaneously after onset of hypoglycaemic counterregulation, as compared to the study in which ketones were suppressed (p = NS). The fact that responses of counterregulatory hormones, symptoms and deterioration in cognitive function were not exaggerated when posthypoglycaemic hyperketonaemia was prevented, indicate that during hypoglycaemia, the counterregulatory-induced endogenous hyperketonaemia does not provide the human brain with an alternative substrate to glucose. Thus, it is concluded that during hypoglycaemia, endogenous hyperketonaemia does not contribute to brain metabolism and function.

Oxido-reduction states of intramitochondrial pyridine nucleotide and cytochrome c oxidase and oxygen saturation of hemoglobin in the regenerating rabbit liver were studied with arterial ketone body ratio and tissue near-infrared spectroscopy. Arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate), which reflects the oxido-reduction states of the intramitochondrial pyridine nucleotide (NAD+/NADH), was reduced from the control value of 0.93 +/- 0.09 to 0.42 +/- 0.03 12 h after 70% hepatectomy, while the oxido-reduction states of cytochrome c oxidase and the oxygen saturation of hemoglobin did not change. The velocity of ATP synthesis, as measured by state 3 respiration and ADP/O ratio in isolated mitochondria, increased by 61.4% 24 h after hepatectomy. These results support the near-equilibrium theory that an increased span in oxido-reduction state between pyridine nucleotide and cytochrome c oxidase drives mitochondrial ATP synthesis.

This study was performed to verify: (1) the ability of different insulin concentrations to restrict the lipolytic and ketogenic responses to exogenous epinephrine administration; (2) whether the ability of insulin to suppress the lipolytic and ketogenic responses during epinephrine administration is impaired in Type 1 (insulin-dependent) diabetic patients. Each subject was infused on separate occasions with insulin at rates of 0.2, 0.4, and 0.8 mU.kg-1.min-1 while normoglycaemic. To avoid indirect adrenergic effects on endocrine pancreas secretions, the so-called "islet clamp" technique was used. Rates of appearance of palmitic acid, acetoacetate, and 3-hydroxybutyrate were simultaneously measured with an infusion of 13C-labelled homologous tracers. After a baseline observation period epinephrine was exogenously administered at a rate of 16 ng.kg-1.min-1. At low insulin levels (20 microU/ml) the lipolytic response of comparable magnitude was detected in normal and Type 1 diabetic patients. However, the ketogenic response was significantly higher in Type 1 diabetic patients. During epinephrine administration, similar plasma glucose increments were observed in the two groups (from 4.74 +/- 0.53 to 7.16 +/- 0.77 mmol/l (p less than 0.05) in Type 1 diabetic patients and from 4.94 +/- 0.20 to 7.11 +/- 0.38 mmol/l (p less than 0.05) in normal subjects, respectively). At intermediate insulin levels (35 microU/ml) no significant differences were found between Type 1 diabetic patients and normal subjects, whereas plasma glucose levels rose from 4.98 +/- 0.30 to 6.27 +/- 0.66 mmol/l (p less than 0.05) in Type 1 diabetic patients, and from 5.05 +/- 0.13 to 6.61 +/- 0.22 mmol/l (p less than 0.05) in normal subjects. At high insulin levels (70 microU/ml) the lipolytic response was detectable only in Type 1 diabetic patients; the ketogenic response was reduced in both groups. During the third clamp, a significant rise in plasma glucose concentration during epinephrine infusion was observed in both groups. In conclusion this study shows that at low insulin levels Type 1 diabetic patients show an increased ketogenic response to epinephrine, despite their normal nonesterified fatty acid response. Instead, high insulin levels are able to restrict the ketogenic response to epinephrine in both normal and Type 1 diabetic subjects, although there is a still detectable lipolytic response in the latter. In the presence of plasma free insulin levels that completely restrict the ketogenic response in the same group, there is still a distinct glycaemic response. Plasma insulin levels in Type 1 diabetic patients are a major determinant of the metabolic response to epinephrine.

Arterial blood ketone body ratio (KBR) and hepatic mitochondrial phosphorylation rate (PR) were investigated in partially (70%) hepatectomized rats treated with 100 micrograms/kg body weight prostacyclin (PGI2) analogue i.p. after operation and every 12 h thereafter up to 72 h. Sampling was performed at 12, 24, 48, and 72 h after operation. In sham-operated rats, KBR significantly increased from the preoperative values of 0.34 +/- 0.03 and 0.38 +/- 0.03, to 0.55 +/- 0.03 and 0.58 +/- 0.02 at 12 h in the groups with and without PGI2 treatment, respectively (P less than 0.001). KBR returned to the preoperative levels after 24 h in the PGI2-treated group, while it tended to be in the lower normal range in the untreated group. In the hepatectomized rats, KBR significantly decreased in the untreated group compared with the preoperative values and the values in the sham-operated group. It returned to the preoperative range within 72 h. In the PGI2-treated group, KBR increased significantly, to values above 0.54, after a 24-h delay and was maintained at those levels for 72 h. Concentrations of total ketone bodies (TKB) in the untreated groups remained in the upper range of preoperative values (above 200 nmol/ml) in the sham-operated rats and decreased significantly in the hepatectomized group (234 to 126 nmol/ml). TKB in the treated groups tended to decrease only in the sham-operated group (205 to 166 nmol/ml), and was massively reduced in the hepatectomized group (167 to 81 nmol/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

To investigate the pathophysiology of warm ischemia (WI) of the liver, the changes in hemodynamics and energy metabolism were studied during and after 60-min complete WI induced by total hepatic vascular exclusion (HVE) in the canine model. Hepatic arterial blood flow after WI was maintained at 76% of the pre-ischemic level, while portal blood flow was only 27% of the pre-ischemic level associated with increased portal vein pressure, which was twice the pre-ischemic level, resulting in a decrease of total hepatic blood flow to 46% of the pre-ischemic level. Concentration of tissue lipid peroxide increased after WI. Arterial blood ketone body ratio (AKBR), which reflects the hepatic mitochondrial redox state, could not recover to the pre-ischemic level after termination of WI. However, when 100 mg/kg of allopurinol (xanthine oxidase inhibitor) was administered intravenously 10 min prior to initiating WI, AKBR was restored to the pre-ischemic level at 30 min after WI in spite of the fact that allopurinol administration to one group produced no remarkable changes in the hepatic hemodynamics compared with the group without allopurinol treatment. Concentration of adenine nucleotides was significantly higher for the treated group at the end of and after WI than for the group without allopurinol treatment and was maintained at a higher level even after WI. Lipid peroxide production was suppressed. Electron microscopic examination revealed that allopurinol treatment could not prevent mitochondrial swelling. It is suggested that WI causes injury primarily to the portal sinusoidal circulation, resulting in portal congestion concomitant with high portal pressure after the release of WI. Allopurinol could prevent the deterioration of mitochondrial ATP metabolism, and was able to inhibit lipid peroxide production, resulting in the rapid recovery of mitochondrial redox state in spite of the fact that it produced no amelioration of hepatic hemodynamics and morphological alterations.

With current surgical techniques for pancreatic transplantation, the graft is anastomosed to the iliac vessels, resulting in delivery of insulin to the systemic circulation rather than to the portal vein as in healthy man. The possible influence of the altered route of insulin delivery on the regulation of splanchnic glucose metabolism was studied in four patients with Type 1 (insulin-dependent) diabetes mellitus at 6-19 months after combined pancreatic and kidney transplantation. Four non-diabetic, age-matched renal transplant recipients and two groups of age-matched healthy subjects served as controls. The studies were carried out in the basal state and during two rates of intravenous glucose infusion (2 and 4 mg.kg-1.min-1). Fasting arterial glucose and splanchnic glucose output was similar in all groups. Basal hyperinsulinaemia was present in pancreatic graft recipients compared to healthy subjects. During low rate intravenous glucose infusion splanchnic glucose output decreased to a similar extent in all groups. With the higher glucose infusion rate (4 mg.kg-1.min-1) a net glucose uptake was observed which was similar in all three groups. Peripheral glucose uptake was unchanged at the lower glucose infusion rate but increased by 45-55% at the higher rate. It is concluded that despite systemic insulin delivery from a heterotopic pancreatic graft, hepatic glucose metabolism appears normal both in the post-absorptive state and in response to glucose-stimulated endogenous insulin secretion. Portal insulin delivery is thus not necessary for normal hepatic glucose metabolism in the Type 1 diabetic patient.

Arterial blood ketone body ratio, reflecting hepatic mitochondrial redox state, was measured in 26 brain-dead patients who were hypotensive but hemodynamically stable. All of them had substantially normal hepatic function. In 18 of the patients, blood ketone body ratio was maintained within the normal range in spite of hypotension. This was in marked contrast to the markedly decreased blood ketone body ratio often observed in patients in shock. This phenomenon was especially conspicuous in those who had not received exogenous dopamine infusion. It is suggested that hepatic mitochondrial redox state can probably be maintained despite systemic hypotension in brain-dead patients. Dopamine administration, on the other hand, is suggested to be a contributing factor to the reduction of hepatic mitochondrial redox state in hypotensive brain-dead patients. This study may provide a guideline for effective preservation of hepatic function in the body of brain-dead patients.

A 24-h fasting test was performed in 48 control children, in 9 hypoketotic patients with inherited defects of fatty acid oxidation and in 2 hyperketotic patients with inherited defects of ketolysis. The control group was then divided into three age groups on the basis of different adaptation to fasting. Concentrations of blood glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate, acetoacetate and carnitine were measured after 15 h, 20 h and 24 h of fasting. Significant negative correlations were found in the control group between plasma total ketone bodies (KB) and plasma glucose (P less than 0.001), plasma carnitine (P less than 0.005) and the amplitude of glycaemic response to glucagon at the end of the fast (P less than 0.01). FFA/KB ratio and the product of final fasting values of glucose and ketones were useful to differentiate between hypoketotic or hyperketotic patients and normal subjects. In children with a suspected or definite hyperketotic or hypoketotic disorder, a fasting test must only be performed in healthy patients, in good nutritional condition with non-diagnostic basal biochemical investigations. Carefully supervised fasting should be continued sufficiently to allow ketogenesis and ketolysis to become activated.

The use of 13C labelled glucose in human metabolic studies has been limited by the high cost of the tracer and the problems of measuring low 13C isotopic abundance in plasma glucose. In the present work we describe a new gas chromatograph-isotope ratio mass spectrometer allowing the measurement of a 0.001 atom % increase in 13C abundance over baseline, on a nanomole glucose sample. Studies were performed in rats and in human subjects. The rate of glucose appearance in 24 h fasted rats using D-[1-13C] glucose as tracer and analysed by this new method was found to be 10.4 +/- 0.7 mg.kg-1.min-1, a value 21% lower than that found using D-[6,6-2H2] glucose as tracer (13.1 +/- 1.1 mg.kg-1.min-1) analysed by classic gas chromatography-mass spectrometry. The new method was also used to trace, in combination with D-[6,6 2H2] glucose, the metabolic fate in human subjects of two oral glucose loads (0.5 g.kg.-1,1 g.kg.-1) labelled with 0.1% D-[U-13C] glucose. During the six hours following the glucose load, it was found that total glucose appearance was 0.97 +/- 0.04 g.kg.-1 and 1.2 +/- 0.04 g.kg.-1, exogenous glucose appearance was 0.51 +/- 0.02 g.kg.-1 and 0.84 +/- 0.04 g.kg.-1, endogenous glucose production was 0.44 +/- 0.04 g.kg.-1 and 0.35 +/- 0.06 g.kg.-1 after the 0.5 and 1 g.kg.-1 load respectively. These values are similar to those reported using glucose labelled with radioactive isotopes.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study aimed at investigating the hyperglycaemic, lipolytic and ketogenic effects of small doses of glucagon delivered continuously or in a pulsatile manner. The study was performed in eight healthy young volunteers (24.2 +/- 1.2 years) and in eight healthy aged subjects (69.4 +/- 2.0 years). In all the subjects, endogenous pancreatic hormone secretion was inhibited by somatostatin and only glucagon was replaced. Consequently, the effects of pulsatile and continuous glucagon delivery were studied in conditions of progressive somatostatin-induced insulin deficiency. In both the young and the aged subjects, pulsatile glucagon delivery resulted in increases in plasma glucose, non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels greater than those observed when the same amount of glucagon was delivered in a continuous manner. The net increases in plasma glucose, glycerol and non-esterified fatty acid levels were similar between the young and the aged subjects when glucagon was infused continuously; in contrast, the rise in plasma beta-hydroxybutyrate in the aged was only about half that observed in the young subjects. Surprisingly, when glucagon was infused in a pulsatile manner, the rises in plasma glycerol, non-esterified fatty acid and beta-hydroxybutyrate levels were all significantly smaller in the aged subjects, while no significant differences were observed in the blood glucose responses. We conclude that, in the presence of somatostatin-induced insulin deficiency, pulsatile glucagon exerts greater effects on blood glucose, plasma non-esterified fatty acid, glycerol and beta-hydroxybutyrate levels than its continuous delivery. In the elderly, the lipolytic and ketogenic, but not the hyperglycaemic, responses to pulsatile glucagon are significantly reduced.

The suitability of energy substrates used by the remnant liver after a 70% partial hepatectomy was studied in relation to the hepatic energy status in diabetic rats. Rats with streptozotocin-induced diabetes mellitus underwent 70% hepatectomy, and were divided into three groups receiving total parenteral nutrition (TPN) for 24h. One group received standard TPN without fat, while two other groups received standard TPN with medium-chain triglycerides (MCTs) or long-chain triglycerides (LCTs) as a 10% lipid emulsion. All rats of the TPN group without fat died within 24h. Blood ketone body ratios (aceto-acetate/beta-hydroxybutyrate), energy charge levels of the remnant liver, and cumulative amounts of 14CO2 in the expired breath during the 6h following 14C-labeled fat emulsion administration (MCT or LCT) were all significantly higher in the MCT group than in the LCT group 24h after hepatectomy. These findings suggest that medium-chain fatty acids (MCFAs) as an energy substrate are superior to long-chain fatty acids (LCFAs) during the immediate posthepatectomy phase in diabetics.

Serum levels of acetoacetate, 3-hydroxybutyrate and the 3-hydroxybutyrate/acetoacetate ratio were determined in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients by a new sensitive method. Efforts were made to differentiate Type 1 and Type 2 diabetes by serum levels of ketone bodies and to determine whether their measurement is a useful way of monitoring diabetic control. In Type 2 diabetes, serum levels of total ketone bodies did not exceed 2.0 mmol/l even if the patients were untreated or poorly controlled. In Type 1 diabetic subjects, treated with once or twice daily injections of insulin, morning serum levels of acetoacetate, 3-hydroxybutyrate and total ketone bodies were significantly elevated by four-, ten- and sevenfold, respectively. In Type 2 diabetic subjects treated with diet or sulphonylureas, serum levels of 3-hydroxybutyrate were highest before breakfast, next highest before dinner and decreased after each meal. The changes were roughly inversely proportional to serum insulin levels. In addition, insulin treatment normalized fasting serum levels of ketone bodies better than diet or sulphonylurea treatment. Acetoacetate was also significantly increased in both types of diabetes to a lesser extent, but no apparent diurnal rhythm was observed. Determination of serum levels of ketone bodies is useful for the diagnosis of Type 1 diabetes (those with total ketone bodies greater than 2 mmol/l) and for detecting insufficient insulin therapy.

A Latin Square design has been used to test the responses of 24 relatively fit young women to 200 minute bouts of exercise performed over 5 day trials under each of three different ambient conditions: 15 degrees C (warm-warm; (WW)); -20 degrees C while inhaling, from a facemask, air heated to 18 degrees C (cold-warm; (CW)); and -20 degrees C (cold-cold; (CC)). In both of the cold environments, special clothing and boots were provided (insulation 0.47 degree C X watt-1 X m-2 and 0.62 degree C X watt-1 X m-2; (4 and 3 CLO units)). All three trials led to a small (0.6-0.7 degree C) rise of rectal temperature, but in the two cold environments mean body temperatures fell by over 1.0 degree C. A large increase of serum ketones occurred under all conditions, and the exercise respiratory quotient suggested some increase of fat utilization, WW (0.85) through CW (0.84) to CC (0.83). A fat loss of about 0.5 kg over the five days was confirmed by hydrostatic weighing and measurement of skinfold thicknesses. This was much less than the change previously observed in men, and moreover, it seemed to be independent of ambient conditions. Possible reasons why cold did not increase fat loss in these women include: a lower relative intensity of exercise; a greater stability of fat stores in women; avoidance of caffeine; a possible translocation of subcutaneous fat to deep fat depots; and a greater desire to "lose weight" irrespective of environmental conditions.

Twelve insulin deficient Type 1 (insulin-dependent) diabetic subjects were studied over an 11 1/2 h period during both subcutaneous insulin therapy and closed loop insulin delivery, using a glucose controlled insulin system (Biostator) programmed to maintain normoglycaemia. Results were compared with those from 21 age and weight-matched normal subjects. Using the Biostator, normoglycaemia was achieved in all diabetic subjects within 3.5 h and normal profiles maintained thereafter. Blood metabolite and hormone values were evaluated during the subsequent 8 h normoglycaemic period. Subcutaneous therapy resulted in abnormal glucose levels throughout the study period (mean 8 h value 8.3 +/- 0.7 compared with 5.6 +/- 0.3 mmol/l on feedback control and 5.5 +/- 0.1 mmol/l in normal subjects). The mean value of lactate and pyruvate over the final 8 h period was 25% higher in diabetic patients than in normal subjects with no difference between the two insulin treatments (blood lactate: 0.94 +/- 0.04 on subcutaneous insulin, 0.91 +/- 0.04 on feedback control and 0.74 +/- 0.03 mmol/l in control subjects). The pre-prandial peaks of blood glycerol and plasma non-esterified fatty acids were significantly decreased or absent during both feedback control and subcutaneous therapy in comparison with the normal subjects, whereas after the midday and evening meals, total ketone body levels were significantly higher in the diabetic patients. Peripheral serum free insulin levels were two-to fourfold greater in the diabetic than in the normal subjects. There were no significant differences between levels in diabetic patients receiving subcutaneous insulin or on the Biostator. Glucose turnover (1600-1800 h) was normal on feedback control (1.41 +/- 0.20 versus 1.55 +/- 0.18 mg X kg-1 X min-1 in the normal subjects) but was significantly decreased during subcutaneous insulin (1.04 +/- 0.09 mg X kg-1 X min-1). There was, in addition, a decrease in glucose recycling during both subcutaneous insulin therapy and feedback control in the diabetic subjects. These data suggest that although fine control of glucose metabolism both in terms of circulating concentrations and rates of production can be achieved by feedback-control, insulin infusion by the peripheral route is associated with significant metabolic abnormalities, at least in the short term. Longer term studies and examination of portal insulin delivery seem warranted.

The metabolism of the snail Biomphalaria glabrata stressed by five days' starvation as well as by infection with Schistosoma mansoni was examined with regard to the metabolism of ketone bodies. Previous studies in the metabolism of this host--parasite relationship always resulted in changes in the same direction with starvation as well as with infection. Contrary to that the concentration of acetoacetate and beta-hydroxybutyrate measured in the hemolymph decreased significantly with starvation but increased significantly with infection. The following problems concerning the ketone body metabolism are discussed: on the one hand the differences between infected and starved snails, and on the other hand the differences between the snails and the mammals as well as in the invertebrates so far investigated.

The purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657 +/- 88 to 762 +/- 81 ml X min-1. 1.73 m-2 in diabetic patients (p less than 0.01) and from 590 +/- 71 to 691 +/- 135 in control subjects (p less than 0.01). Glomerular filtration rate increased from 135 +/- 9 to 180 +/- 8 ml X min-1. 1.73 m-2 in diabetic patients (p less than 0.001) and from 117 +/- 8 to 145 +/- 7 in control subjects (p less than 0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, beta 2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and causes a tubular proteinuria.

Thirty-five freshly presenting, diabetic patients received 5 hour, 100 g oral glucose tolerance tests when first seen and after a period of carbohydrate and energy restriction. After treatment, the significant improvement in glucose tolerance was accompanied by increased insulin secretion and lower concentrations of blood ketone bodies, lactate, glycerol, FFA, triglycerides, cholesterol and pre-beta lipoprotein. There were no significant changes in serum growth hormone or blood pyruvate concentrations. Improvement in glucose tolerance was greater in patients who were obese (greater than 115% of desirable body weight for height) on presentation and was related to the improvement in insulin secretion and the diminished lipolysis. An hypothesis to explain the changes in insulin secretion is prosposed. Eleven out of the 35 patients showed sufficient improvement in glucose tolerance to require no treatment other than diet.

After 5 years of cyclic vomiting an 8 year old boy was presented with coma and hyponatremia. ACTH and renin plasma concentrations were elevated, cortisol concentrations did not rise after ACTH-stimulation. Behavioural abnormalities including secondary enuresis and dysarthria drew attention to the possibility of an association of adrenal insufficiency with leucodystrophy. NMR tomography of the brain showed symmetrical demyelinated areas in the parieto-occipital regions. Very long chain fatty acids were elevated. The mother showed discrete neurological symptoms and elevated long chain fatty acids. Cyclic vomiting might suggest adrenoleukodystrophy.

Between 1969 and 1976, 317 adults were admitted to hospital in Nottingham with severely uncontrolled diabetes (plasma glucose over 33 mmol/l and/or venous bicarbonate less than 14 mmol/l). A third of episodes were in patients over the age of 50 years, of which 43% were fatal. In contrast, only 3.4% of episodes in patients under 50 years were fatal. In the older group, 65% of deaths occurred within 48 h of admission and in 44% no cause was found other than uncontrolled diabetes. Later deaths were due to underlying disease, infection or thromboembolism. Amongst older patients 38% were not previously known to have diabetes. Presentation to hospital was late and we conclude that many deaths were potentially avoidable by earlier detection in the community.

Metabolic defects resulting in hypoketotic hypoglycemia can lead to hepato-encephalopathy and can be lethal. Recognition of the association of hypoglycemia with hypoketonemia is essential for efficient diagnostic and therapeutic procedures. The pattern of urinary excretion of organic acids is useful in differential diagnosis between the possible metabolic defects, viz. carnitine deficiency, carnitine palmitoyl transferase deficiency, medium-chain, long-chain and multiple acyl-CoA dehydrogenase deficiencies, and HMG-CoA lyase deficiency. These (except for carnitine deficiency) can be confirmed by enzyme activity measurements in cultured fibroblasts and tissue biopsies and prenatally. Treatment is available for all of them except some cases of multiple acyl-CoA dehydrogenase deficiency. Genetic counselling of the families must be based on a precise biochemical diagnosis.

Arterial ultrastructure was examined in twelve untreated streptozotocin-diabetic rats. Five showed severe changes in muscular (coronary, tibial, pulmonary) arteries two months after induction of diabetes. The basement membrane of smooth muscle cells was patchily thickened in these arteries. No similar changes were seen in muscular arteries of the other seven diabetic rats or in 10 control rats. No lesions were found in elastic arteries (aorta, main pulmonary artery) of any diabetic or control animals. Plasma non-esterified fatty acids, total ketone bodies, and glucose levels were higher in the diabetic rats with arterial changes (p less than 0.01) than in the diabetic animals without such changes. The molar ratio of non-esterified fatty acid to albumin in plasma ranged between 2.3-3.3 in the diabetic rats with arterial lesions, 1.4-1.8 in those without such features, and 0.6-1.1 in the controls. The excess of non-esterified fatty acid in plasma during insulin deficiency could be an important factor in the initiation of arterial changes in this model of experimental diabetes.

The changes in arterial blood levels of glucose, free fatty acids, ketone bodies, and amino acids were investigated after 70% hepatectomy in rabbits in relation to the changes in adenylate energy charge of the remnant liver and ketone body ratio of arterial blood. Hepatic energy charge decreased to 0.767 +/- 0.008 within 24 h (p less than 0.001), and arterial blood ketone body ratio decreased to 0.415 +/- 0.041 within 12 h (p less than 0.001). Plasma free fatty acid concentrations increased to about twice the original values within 12 h (p less than 0.01), total amino acid concentrations also doubled within 24 h (p less than 0.01), and blood glucose levels decreased to below 100 mg/dl at 12 and 24 h (p less than 0.05). Afterward, at 96 h postoperatively (p.o.), blood ketone body ratio and energy charge levels were restored to near normal levels with the normalization of blood glucose, plasma free fatty acids, and plasma amino acids. These findings suggest that the decreased energy charge of the remnant liver concomitant with a fall in blood ketone body ratio may be the basis of the sequential changes in the blood concentration of fuels after massive hepatectomy.

Medium-chain triglycerides (MCT) are known to be rapidly digested and oxidized. Their potential value as a source of dietary energy during exercise was compared with that of maltodextrins (MD). Twelve subjects exercised for 1 h on a bicycle ergometer (60% VO2 max), 1 h after the test meal (1MJ). The metabolism of MCT was followed using 1-13C-octanoate (Oc) as tracer and U-13C-glucose (G) was added to the 13C-naturally enriched MD. After MCT ingestion no insulin peak was observed with some accumulation of ketone bodies (KB), blood levels not exceeding 1 mM. Total losses of KB during exercise in urine, sweat and as breath acetone were small (less than 0.2 mmol X h-1). Hence, the influence of KB loss and storage on gas exchange data was negligible. The partition of fat and carbohydrate utilization during exercise as obtained by indirect calorimetry was practically the same after the MCT and the CHO meals. Oxidation over the 2-h period was 30% of dose for Oc and 45% for G. Glycogen decrements in the Vastus lateralis muscle were equal. It appears that with normal carbohydrate stores, a single meal of MCT or CHO did not alter the contribution of carbohydrates during 1 h of high submaximal exercise. The moderate ketonemia after MCT, despite substantial oxidation of this fat, led to no difference in muscle glycogen sparing between the diets.

The ultrastructure of myocardium was examined in short-term diabetic rats. Morphometric analysis showed the volume of myocytic mitochondria, sarcoplasmic reticulum and lipid droplets to be significantly increased compared with those of control animals. Further measurements of mitochondria and sarcoplasmic reticulum indicated that the augmentation of these compartments was accountable by the enlargement of pre-existing mitochondria, which were swollen, and of pre-existing tubules of sarcoplasmic reticulum, the lumen of which was dilated. After insulin treatment the morphological changes were returned to normal which indicates that they were not due to the toxic effect of streptozotocin but were caused by the diabetic state per se. This suggestion is further supported by the finding that experimentally induced metabolic acidosis without diabetes did not cause any morphologically detectable changes in the heart muscle. It is concluded that short-term diabetes in the rat causes mitochondrial swelling, dilatation of sarcoplasmic reticulum and accumulation of lipid in cardiac myocytes, and that these changes are preventable with insulin treatment. We suggest that insulin may have an important role in the maintenance of metabolism in heart muscle.

The effects of moderate exercise of 2-h duration on the concentration and turnover rate of total ketone bodies were assessed in 7 acutely insulin-deprived Type 1 (insulin-dependent) diabetic patients with an isotope tracer technique using a constant infusion of 14C-beta-hydroxybutyrate. These results were compared to those obtained in 13 normal control subjects in whom a similar range of hyperketonaemia (approximately 1-6 mmol/l) was induced by fasting. In all subjects, the concentration and the rate of production of ketone bodies followed a biphasic pattern with an initial fall lasting for about 20 min followed by a secondary rise. When integrated over the entire working period, the exercise-induced changes in ketone turnover were markedly dependent on the initial ketone body concentrations in both groups: at low ketonaemia (approximately 1 mmol/l), exercise increased the rate of production and disposal of ketones. These effects were progressively attenuated as basal ketonaemia rose and were reversed to an inhibitory action in markedly ketotic subjects (greater than 4 mmol/l). Despite the finding that, at high ketosis, exercise inhibited ketogenesis to a similar degree in control subjects and diabetic patients, the changes in concentration recorded at the end of exercise were different in the 2 groups: ketonaemia was reduced in fasted control subjects and increased in the diabetic patients. These data suggest that, contrary to a widely accepted opinion, the hyperketonaemic effect of prolonged exercise in ketotic diabetic patients does not result from an exaggerated stimulation of ketogenesis, but from some defect in their removal capacities for ketones, possibly related to insulinopenia.

The effect of elevated plasma insulin concentration (55 +/- 2 mU/l) on peripheral clearance and production of total ketone bodies was determined using 3-14C-acetoacetate tracer infusions. Nine normal subjects were studied twice, once during insulin infusion (20 mU.m-2.min-1), once during basal plasma insulin concentrations (controls). Blood total ketone body concentrations (sum of acetone, acetoacetate and beta-hydroxybutyrate) were maintained in both studies at 2 mmol/l by feedback-controlled sodium acetoacetate infusions. The coefficient of variation of total ketone body concentrations during the two clamp studies was 10 and 11% respectively. The sodium acetoacetate infusion rate required during the clamp was 55 +/- 4% higher during hyperinsulinaemia than in controls (p less than 0.005). This was due to increased total ketone body clearance (8.4 +/- 0.7 vs 6.7 +/- 0.4 ml.kg-1.min-1, p less than 0.015), and to enhanced suppression of ketone body production (p less than 0.01). Hyperketonaemia alone decreased ketone body production by 42% and diminished ketone body clearance by 46%, the former being enhanced, the latter being in part antagonised by insulin. Since the plasma insulin concentrations were within those observed in patients treated for diabetic ketoacidosis, the data suggest that the antiketotic effect of insulin therapy results in part from an increase in peripheral ketone body disposal.

The relationship between non-esterified fatty acid (NEFA) mobilization and hepatic conversion to plasma triglycerides (TG), as modulated by diazoxide-induced effects upon endogenous catecholamine, glucagon, and insulin secretion, was examined in vivo in the rat. Thyrotropin (TSH)-induced NEFA mobilization provided the control study.--In all control experiments, TSH (1.5 IU/100 g) induced a 110% increase in NEFA availability, which was associated with a subsequent 52% increase in plasma TG concentration and a 73% increase in plasma ketone bodies. Following diazoxide administration (30 mg/kg), endogenous secretion of both catecholamines and glucagon was observed, resulting in a comparable 100% increase in NEFA availability, with the appropriate ketonaemic response. However, in contrast to the control TSH study, plasma triglyceride concentration did not increase. This suppression was secondary, at least in part, to a direct 40% inhibition of hepatic secretion of triglycerides.--Although plasma NEFA concentration is an important determinant of plasma triglyceride levels, the concurrent concentration of endogenous catecholamines, glucagon, and insulin modulate the hepatic conversion of NEFA to triglycerides in vivo.

Hepatic energy charge ((ATP + 1/2ADP)/(ATP + ADP + AMP)) and arterial blood ketone body ratio (acetoacetate/3-hydroxybutyrate) were measured after hepatic artery embolization in carbon-tetrachloride-induced cirrhotic rats. In normal livers, energy charge slightly decreased at 3 h and returned to normal levels at 6 h. By contrast, in cirrhotic livers, energy charge was drastically decreased at 3 h after embolization and was not completely recovered at 6 h. Blood ketone body ratio, reflecting hepatic mitochondrial redox (NAD+/NADH) state, also decreased at 3 h after embolization in both groups, and its recovery was not observed in cirrhotic group at 6 h.

Twenty-four hour metabolic profiles were performed in the third trimester of pregnancy in seven diabetic women; first when optimally controlled using conventional insulin regimes and subsequently when controlled with continuous subcutaneous insulin infusion. Seven non-diabetic women also studied. Mean +/- SD 24 h metabolite levels in the diabetics before and during continuous subcutaneous insulin infusion and in the controls were respectively: glucose-5.8 +/- 1.2;5.0 +/- 0.9;4.7 +/- 0.8 mmol/l; total ketone bodies -0.2 +/- 0.06; 0.15 +/- 0.05; 0.11 +/- 0.04 mmol/l; lactate - 0.90 +/- 0.33;0.90 +/- 0.24; 1.05 +/- 0.18 mmol/L; alanine - 0.29 +/- 0.06; 0.30 +/- 0.06; 0.31 +/- 0.03 mmol/l. Total ketone body levels were significantly elevated (p less than 0.05) on conventional therapy but not on continuous subcutaneous insulin infusion compared with controls. Variations in metabolites over 24 h, as measured by mean standard deviations, were increased for glucose (p less than 0.001) and for total ketone bodies (p less than 0.05) on the conventional regimes we employed compared with controls. On continuous subcutaneous insulin infusion variations of blood glucose were not affected whereas variations in total ketone bodies were no different from controls. The best possible maternal metabolic control is necessary for normal foetal development and continuous subcutaneous insulin infusion provides a method of achieving this.

Children with symptomatic hypoglycemia and asymptomatic hypoglycemia-prone children were shown to differ in the degree of ketosis after a 20 h fast. In the latter children the close negative correlation between ketone body levels and glucose levels yielded a regression line against which the former children's data could be compared. Half of the patients were found to be hypoketotic during hypoglycemia. The significance of this hypoketosis in the symptomatology is discussed. The finding of other abnormal responses to fasting, particularly in the patients' nitrogen metabolism, suggests that all these aberrations have a common cause which may be of hepatic origin.

Twelve hour metabolic rhythms have been performed on six maturity-onset diabetic subjects during successive periods of therapy with phenformin, metformin, and glibenclamide. Moderate control of blood glucose concentration was achieved with phenformin and metformin, the lowest concentrations being found with glibenclamide. Mean blood lactate concentration was grossly elevated during phenformin therapy, moderately elevated with metformin and normal during glibenclamide treatment. Similar patterns were found for the lactate/pyruvate ratio, alanine, glycerol and ketone bodies. Serum triglyceride concentrations were significantly higher during phenformin treatment than with the other two regimes. Serum insulin concentration was higher on glibenclamide than with either biguanide. Most of these effects of the biguanides could be accounted for by an inhibitory effect on hepatic gluconeogenesis. It is concluded that the use of biguanides as hypoglycaemic agents in diabetes is associated with the production of multiple metabolic abnormalities.

Normoglycaemia, peripheral normoinsulinaemia, and normoglucagonaemia were restored acutely in chronically diabetic dogs, using an extracorporal artificial B cell with peripheral venous insulin administration. Glucose metabolism was analysed by a non-steady-state tracer technique with double-labelled glucose (6-3H- and U-14C-glucose), and the incorporation of the 14C label into plasma lactate was determined. In the basal state, glucose turnover rates were not different from those in non-diabetic controls; but recirculation of the glucose-C label through the Cori cycle, and lactate labelling from glucose utilization were decreased. The glycaemic response to an intravenous infusion of non-labelled glucose was distinctly enhanced. This was based on a reduction in the rates of glucose disappearance. Its rates of appearance (total endogenous glucose production) were, however, suppressed to a normal extent by the exogenous glucose. Accordingly carbon recycling was nearly totally suppressed during the glucose infusion as in the controls. It is concluded that metabolic recompensation in these fasting, resting diabetic dogs remained incomplete because the interval of normoinsulinaemia, which obviously applied only to the peripheral circulation, was not long enough.

The effects of hepatic warm ischemia and portal pooling on the viability of the liver were investigated with respect to hepatic energy metabolism by performing intermittent portal triad cross-clamping (Pringle's maneuver) on dogs with or without portosystemic shunt. The dogs were divided into two groups of five: Group 1, non-shunt group, underwent Pringle's maneuver performed for 30 min and declamping for 30 min, a process that was repeated five times; and Group 2, shunt group, underwent the same procedure as Group 1, except for portosystemic shunt using a heparinized hydrophilic catheter between the splenic and jugular veins. The shunt was opened during Pringle's maneuver and was closed immediately at declamping. In the non-shunt group, portal pooling increased and systemic blood pressure decreased when Pringle's maneuver was performed, but in the shunt group portal and systemic blood pressures remained within the normal range. In the non-shunt group, the initial velocity of arterial blood ketone body ratio (KBR) recovery after each declamping significantly (P less than 0.01) decreased from 0.122 +/- 0.016 (per min) after the first declamping to 0.028 +/- 0.017 (per min) after the fifth declamping. Hepatic energy charge [= (ATP + 1/2 ADP)/(ATP + ADP + AMP)] decreased from 0.840 +/- 0.003 before ischemia to 0.749 +/- 0.003 30 min after the fifth declamping (P less than 0.001). The concentrations of lactate and total amino acids in arterial blood increased. On the other hand, in the shunt group, the initial velocity of KBR recovery and hepatic energy charge showed little change even after the fifth declamping (0.081 +/- 0.016 per min and 0.851 +/- 0.009, respectively). The concentrations of lactate and total amino acids showed almost no increase. The impairment of hepatic energy metabolism by intermittent portal triad cross-clamping is mainly due to reinflow of pooled-portal blood to the previously ischemic liver, rather than hepatic warm ischemia. The KBR may be useful for determining the degree of impairment of hepatic energy metabolism.

To assess the role of glucagon and insulin in the acute regulation of ketone body kinetics in man, somatostatin was administered with various combinations of these hormones by replacement infusions in groups of six to seven normal subjects. Somatostatin-induced insulin and glucagon deficiency produced a threefold increase in total ketone body concentrations within 2 h. This increase was the combined result of enhanced production (71%), and decreased metabolic clearance (32%), as determined by 14C-acetoacetate infusions. An associated elevation of non-esterified fatty acids (66%) and glycerol levels occurred. Glucagon replacement (2 ng . kg-1 . min-1) during insulin deficiency failed to enhance ketogenesis or lipolysis but lowered the beta-hydroxybutyrate/acetoacetate concentration ratios. Hyperglycaemia, observed during glucagon administration and insulin deficiency, did not diminish ketone body production or lipolysis. In contrast, insulin replacement (150 microunits . kg-1 . min-1) diminished lipolysis, lowered ketone production, and elevated the metabolic clearance rate of ketone bodies. Glucagon infusions (2 and 4 ng . kg-1 . min-1) during somatostatin and insulin replacement did not accelerate ketone body production or raise non-esterified fatty acid levels, but produced a dose-dependent elevation of blood glucose levels. The results suggest that glucagon is not an important ketogenic hormone under the conditions studied.

The metabolic and hormonal effects of stable hyperglycaemia (10-12 mmol/l) have been examined in five insulin-dependent diabetics and compared with the results of 8 h (1200 to 2000 h) normoglycaemic (5-6 mmol/l) clamping. Glucose levels were maintained using a glucose controlled insulin infusion system. Mean blood lactate, pyruvate, total ketone bodies, glycerol and plasma non-esterified fatty acids were similar during the period of stable glycaemia at the two glucose levels. In contrast mean blood alanine was markedly elevated during hyperglycaemic clamping (0.384 +/- 0.008 vs 0.298 +/- 0.021 mmol/l) and 3-hydroxybutyrate was slightly decreased (0.068 +/- 0.007 vs 0.084 +/- 0.008 mmol/l). Plasma glucagon levels were raised during hyperglycaemic clamping and growth hormone slightly decreased. There was a close positive correlation between mean blood alanine and mean blood glucose (r = 0.79, p less than 0.01), and a negative correlation of alanine with the amount of insulin infused (r = -0.72, p less than 0.01). It is suggested that the raised alanine results from increased peripheral glucose utilisation. In general a short period of stable hyperglycaemia is not associated with a worsening of metabolic abnormalities in insulin-dependent diabetic subjects.

In 24 normal and 24 obese subjects of both sexes circulating substrates (blood sugar, free fatty acids, ketone bodies) and hormones (insulin, growth hormone, pancreatic glucagon) were determined during 6 days of total fast. In normals the blood sugar fell to lower levels than in the obese. Plasma free fatty acids and ketone concentrations rose faster in normal than in obese subjects, and faster in females than in males. Plasma insulin concentrations declined to a greater extent in obese than in normal subjects. In all groups studied a significant increase of the pancreatic glucagon level within 1-3 days of fasting was observed, however, its rise occurred faster in normal females than in males. Growth hormone (GH) rose significantly in normal males but not in obese males. Following high overnight fasting values in some normal females showed no significant increase in GH levels but significantly higher GH values than obese females after 1-6 days of fasting. After summarizing starvation-induced metabolic changes common to all study groups the respective differences found between males and females and between normal and obese subjects are discussed.

Post-exercise ketosis is known to be suppressed by physical training and by a high carbohydrate diet. As a result it has often been presumed, but not proven, that the development of post-exercise ketosis is closely related to the glycogen content of the liver. We therefore studied the effect of 1 h of treadmill running on the blood 3-hydroxybutyrate and liver and muscle glycogen concentrations of carbohydrate-loaded trained (n = 72) and untrained rats (n = 72). Resting liver and muscle glycogen levels were 25%-30% higher in the trained than in the untrained animals. The resting 3-hydroxybutyrate concentrations of both groups of rats were very low: less than 0.08 mmol.l-1. Exercise did not significantly influence the blood 3-hydroxybutyrate concentrations of trained rats, but caused a marked post-exercise ketosis (1.40 +/- 0.40 mmol.l-1 h after exercise) in the untrained animals, the time-course of which was the approximate inverse of the changes in liver glycogen concentration. Interpreting the results in the light of similar data obtained after a normal and low carbohydrate diet it has been concluded that trained animals probably owe their relative resistance to post-exercise ketosis to their higher liver glycogen concentrations as well as to greater peripheral stores of mobilizable carbohydrate.