Comparison of intraduodenal and intravenous glucose metabolism under clamp conditions in humans.

To determine whether the uptake and metabolic partition of glucose are influenced by its delivery route, 12 normal volunteers underwent two 3-h euglycemic (approximately 93 mg/dl) hyperinsulinemic (approximately 43 mU/l) clamps at a 3- to 5-wk interval, one with intravenous (i.v.) and the other with intraduodenal (i.d.) glucose labeled with [3-3H]- and [U-14C]glucose. Systemic glucose was traced with [6,6-2H2]glucose in eight subjects. During the last hour of the clamps, the average glucose infusion rate (5.85 +/- 0.37 vs. 5.43 +/- 0.43 mg.kg(-1).min(-1); P = 0.02) and exogenous glucose uptake (5.66 +/- 0.37 vs. 5.26 +/- 0.41 mg.kg(-1).min(-1); P = 0.04) were borderline higher in the i.d. than in the i.v. studies. The increased uptake was entirely accounted for by increased glycolysis (3H2O production), which was attributed to the stimulation of gut metabolism by the absorptive process. No difference was observed in glucose storage whether it was calculated as glucose uptake minus glycolysis (i.d. vs. i.v.: 2.44 +/- 0.28 vs. 2.40 +/- 0.31 mg.kg(-1).min(-1)) or as glucose uptake minus net glucose oxidation (2.86 +/- 0.33 vs. 2.81 +/- 0.35 mg.kg(-1).min(-1)). Because peripheral tissues were exposed to identical glucose, insulin, and free fatty acid levels under the two experimental conditions, we assumed that their glucose uptake and storage were similar during the two tests. We therefore suggest that hepatic glycogen storage (estimated as whole body minus peripheral storage) was also unaffected by the route of glucose delivery. On the other hand, in the i.d. tests, the glucose splanchnic extraction ratio calculated by the dual-isotope technique averaged 4.9 +/- 2.3%, which is close to the figures published for i.v. glucose. Despite the limitations related to whole body measurements, these two sets of data do not support the idea that enteral glucose stimulates hepatic uptake more efficiently than i.v. glucose.

Level of glycogen stores and amount of ingested glucose regulate net carbohydrate storage by different mechanisms.

The respective effects of the level of glycogen stores and the size of the glucose load on the pathways of carbohydrate (CHO) metabolism were compared over the 5-hour period following glucose ingestion in normal human subjects. For this purpose, labeling of the oral glucose load with [3-(3)H]- and [U(14)C] glucose was combined with indirect calorimetry. In group I, 75 g glucose was given to subjects who had either been "fed" with intravenous (IV) glucose or fasted for 13, 24, or 36 hours, or 4 days. In fed versus 4-day-fasted subjects, net CHO storage averaged approximately 15 versus 63 g/5 h (P <.001). About 83% of the increase in fasted subjects was due to suppression of glycogen breakdown, with only minimal stimulation of glycogen synthesis from oral glucose. Over the whole range of nutritional conditions tested, a strong positive correlation existed between basal CHO oxidation and glycogen breakdown occurring during the oral glucose tolerance test (OGTT), suggesting that the initial degree of repletion of hepatic glycogen stores is a major determinant of postprandial glycogen turnover. In group II, OGTTs with 33 and 100 g glucose were compared in 13-hour-fasted subjects. Net storage rose from approximately -6 to approximately 37 g/5 h (P <.001) solely because of an increase in glycogen synthesis with no inhibition of glycogen turnover. Overall, these results show that the initial dietary state and the size of the glucose load modulate postprandial net CHO accumulation by different mechanisms.

Metabolic handling of intraduodenal vs. intravenous glucose in humans.

To determine whether the route of glucose administration affects whole body glucose metabolism, 14 healthy volunteers were randomly infused with intraduodenal (id) or intravenous (iv) glucose at 6 mg x kg(-1) x min(-1) for 180 min. Infused glucose was labeled with [2-(3)H]glucose in a first series of paired experiments designed to characterize kinetic parameters to be used in a second series of experiments in which [3-(3)H]- and [U-(14)C]glucose labeling was used to characterize the metabolic fate of infused glucose. Experiments with [2-(3)H]glucose showed that, after a lag period of only 20 min, id absorption averaged 105 +/- 3% of infusion. During the final hour of id and iv infusion of [3-(3)H]glucose, tissue uptake averaged 98 +/- 3 and 107 +/- 4% of infusion, respectively, and was equally divided between glycolysis ((3)H(2)O production) and storage (uptake-glycolysis). Glucose oxidation ((14)CO(2)), total carbohydrate oxidation (indirect calorimetry), and net carbohydrate balance were also similar, but the thermic effect of glucose was significantly greater after id infusion. Because insulin and estimated portal vein glucose levels were similar during the final 80 min of both infusions, our results suggest that hepatic glucose storage (and therefore muscle storage estimated as whole body minus liver storage) is not affected by the route of glucose administration.

Effect of fasting on the intracellular metabolic partition of intravenously infused glucose in humans.

The effects of fasting on the pathways of insulin-stimulated glucose disposal were explored in three groups of seven normal subjects. Group 1 was submitted to a euglycemic hyperinsulinemic clamp ( approximately 100 microU/ml) after both a 12-h and a 4-day fast. The combined use of [3-(3)H]- and [U-(14)C]glucose allowed us to demonstrate that fasting inhibits, by approximately 50%, glucose disposal, glycolysis, glucose oxidation, and glycogen synthesis via the direct pathway. In group 2, in which the clamp glucose disposal during fasting was restored by hyperglycemia (155 +/- 15 mg/dl), fasting stimulated glycogen synthesis (+29 +/- 2%) and inhibited glycolysis (-32 +/- 3%) but only in its oxidative component (-40 +/- 3%). Results were similar in group 3 in which the clamp glucose disposal was restored by a pharmacological elevation of insulin ( approximately 2,800 microU/ml), but in this case, both glycogen synthesis and nonoxidative glycolysis participated in the rise in nonoxidative glucose disposal. In all groups, the reduction in total carbohydrate oxidation (indirect calorimetry) induced by fasting markedly exceeded the reduction in circulating glucose oxidation, suggesting that fasting also inhibits intracellular glycogen oxidation. Thus prior fasting favors glycogen retention by three mechanisms: 1) stimulation of glycogen synthesis via the direct pathway; 2) preferential inhibition of oxidative rather than nonoxidative glycolysis, thus allowing carbon conservation for glycogen synthesis via the indirect pathway; and 3) suppression of intracellular glycogen oxidation.

Mechanisms of whole-body glycogen deposition after oral glucose in normal subjects. Influence of the nutritional status.

It is known that prior fasting enhances whole-body glycogen retention after glucose ingestion. To identify the involved mechanisms, 33 normal volunteers underwent a total fast, varying between 14 h and 4 days, and ingested thereafter 75 g glucose labeled with [14C]glucose. Measurements of oral glucose oxidation (expired 14CO2, corrected for incomplete recovery) and total carbohydrate (CHO) oxidation (indirect calorimetry) were performed over the following 5 h. These data allowed us to calculate oral glucose storage (uptake oxidation), glycogen oxidation (CHO oxidation - oral glucose oxidation), and net CHO balance (oral glucose uptake - CHO oxidation). As compared with an overnight fast, prolonged fasting (4 days) inhibited the uptake (64.8 vs. 70.3 g/5 h; P < 0.01) and the oxidation (10.9 vs. 20.0 g/5 h; P < 0.001) of oral glucose and stimulated slightly its conversion to glycogen (53.9 vs. 50.3 g/5 h; P < 0.05). The latter effect played only a minor role in the marked increase in net CHO balance (52.3 vs. 25.2 g/5 h; P < 0.001), which was almost entirely related to a decrease in glycogen oxidation (1.6 vs. 25.1 g/5 h; P < 0.001). Considering the whole series of data, including intermediate durations of fast, it was observed that the modifications in postprandial CHO metabolism, induced by fasting, correlated strongly with basal CHO oxidation, suggesting that the degree of initial glycogen depletion is a major determinant of glycogen oxidation and net CHO storage. Thus, prior fasting stimulates postprandial glycogen retention, mainly through an inhibition of the glycogen turnover that exists in overnight-fasted subjects, during the absorptive period.

Inhibition of lipolysis stimulates whole body glucose production and disposal in normal postabsorptive subjects.

The role played by circulating free fatty acids (FFA) and fat oxidation in the regulation of whole body glucose production and uptake in the basal state is still a matter of debate. This question was analyzed in nine normal overnight fasted volunteers in whom glucose kinetics ([3-3H]glucose infusion) and substrate oxidation rates (indirect calorimetry) were measured during 10.5 h both under placebo conditions and during experimental antilipolysis induced by Acipimox given orally during the last 8 h of the study. During the last 2 h of the tests, the following mean changes (delta) from baseline were recorded in Acipimox vs. placebo studies: delta FFA, -0.26 +/- 0.08 vs. +0.29 +/- 0.06 mmol/L (P < 0.001); delta glucose, -12 +/- 2 vs. -12 +/- 1 mg/dL (P > 0.05); delta glucose production, +16 +/- 5 vs. -15 +/- 3 mg/min (P < 0.001); delta C peptide, -1.11 +/- 0.10 vs. -0.66 +/- 0.10 ng/mL (P < 0.001); delta glucagon, +64 +/- 25 vs. +21 +/- 9 pg/mL (P < 0.05); delta GH, +37 +/- 9 vs. +4 +/- 2 ng/mL (P < 0.007); delta cortisol, +37 +/- 25 vs. -30 +/- 26 ng/mL (P < 0.04). Acipimox inhibited fat oxidation (-18 +/- 4 vs. +19 +/- 4 mg/min; P < 0.001) and enhanced carbohydrate oxidation (+18 +/- 8 vs. -24 +/- 11 mg/min; P < 0.02). Protein catabolism calculated over the 8-h study period was significantly stimulated (+5.7 +/- 2.5 vs. -1.9 +/- 1.7 g/8 h; P < 0.02). During the Acipimox studies, the increased protein breakdown could theoretically account for about 75% of the increased glucose production. Thus, contrary to current opinion, FFA suppression stimulates glucose production and whole body glucose disposal in normal overnight fasted subjects.

Effects of metformin on the pathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients.

To analyze the effects of metformin (M) on the kinetics and pathways of glucose utilization after glucose ingestion, nine non-insulin-dependent diabetes mellitus (NIDDM) patients underwent two 5-hour oral glucose tolerance tests (OGTTs) preceded in random order by a 3-week treatment with either M (850 mg twice per day) or placebo. Each test included intravenous infusion of 3-3H-glucose and labeling of the oral dose (75 g) with 1-14C-glucose, with measurements of glucose kinetics, glycolytic flux (3H2O production), and glucose oxidation (indirect calorimetry and expired 14CO2). Basal glycemia was decreased by M (6.6 v 8.2 mmol/L, P < .01) with no changes in insulin levels, with the hypoglycemic effect correlating strongly (P < .001) with a decrease in glucose production. Mean 0- to 5-hour postprandial glycemia was also decreased by the drug (9.9 v 12.2 mmol/L, P < .04), lactate concentration was increased (1.79 v 1.44 mmol/L, P < .01), and absolute insulin levels were increased, but not to a significant extent. The rates of appearance (Ra) of exogenous and endogenous glucose were not modified, and the hypoglycemic effect of M in the postprandial state was entirely related to an increase in systemic glucose disposal (85.1 v 77.5 g/5 h, P < .001). Carbohydrate oxidation was unchanged, and glycolytic flux and nonoxidative glycolysis were increased by approximately 13 g/5 h (P < .01), with the excess lactate produced probably being converted to glycogen in the liver. Whole-body glycogen synthesis through the direct pathway tended to be reduced (-8 g/5 h, P > .05). Thus, M decreases postprandial glycemia by increasing glucose disposal and stimulates lactate production. The data also suggest that the drug increases the proportions of glycogen deposited through the indirect rather than the direct pathway.

[Pharmacology of hypolipidemic agents]. / Pharmacologie des agents hypolipidémiants.

This review article examines the mode of action, the efficacy and the side effects of the various types of hypolipidemic agents (fibrates, bile acid sequestrants, statins, nicotinic acid and acipimox) currently available in Belgium. It also summarizes the recent guidelines recommended by the Belgian Lipid Club in the management of hyperlipidemia for the primary and secondary prevention of cardiovascular diseases as well as the therapeutic strategy.

Role of fat-derived substrates in the regulation of gluconeogenesis during fasting.

To determine the role of fat-derived substrates in the regulation of glucose metabolism during fasting, glucose turnover, urea nitrogen production, alanine conversion to glucose, and substrate oxidation rates were measured in 34 normal 4-day-fasted volunteers treated with the antilipolytic drug acipimox or placebo for 8 h. The approximately 50% inhibition of lipolysis induced by acipimox increased glucose concentration and production, respectively, by approximately 35 and approximately 30%, whereas the protein breakdown and the amount of alanine converted to glucose were increased, respectively, by approximately 70 and approximately 85%. Insulin levels were reduced by approximately 40%, cortisol levels doubled, and growth hormone concentration increased sevenfold. The relative contribution of free fatty acid (FFA) and ketone body lowering to the observed response was evaluated in nine acipimox-treated subjects in whom ketone body concentration was clamped with an intravenous beta-hydroxybutyrate infusion. The results of these experiments suggest that, during fasting, both FFA and ketone bodies tend to suppress gluconceogenesis and to protect the protein stores. FFA seem to exert their effects mainly through their ability to modulate the hormonal milieu (especially insulin), whereas ketone bodies seem to act mainly by other mechanisms. Thus the widespread view according to which FFA exert a stimulatory role on gluconeogenesis does not apply to the fasting state in vivo.

Glucose metabolism during the starved-to-fed transition in obese patients with NIDDM.

To analyze the effects of short-term fasting on postprandial glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM), two groups of nine obese NIDDM patients and two comparable groups of control subjects underwent a 5-h oral glucose tolerance test after either 14 h or 4 days of fasting. The fluxes and the rates of oxidation and storage of glucose were measured using a dual isotope technique combined with indirect calorimetry. The effect of fasting on insulin action and beta-cell responsiveness was tested in an additional group of six obese NIDDM patients with a euglycemic hyperinsulinemic clamp followed by an intravenous glucagon test. In the diabetic patients, fasting enhanced beta-cell response to glucose and glucagon and did not modify insulin action. This response differs from that of nondiabetic subjects in whom fasting is known to impair insulin secretion and action. Regarding glucose fluxes, it was observed that in the overnight-fasted state, the incremental tissular disposal following glucose ingestion was reduced by approximately 50% in the diabetic versus control subjects in relation to an approximately 62% impairment in glucose storage. After fasting, incremental tissular disposal was restored to normal, glucose oxidation was virtually abolished, and storage was increased approximately threefold. Thus, in NIDDM patients, fasting corrects the defect in glycogen storage without modifying the action of insulin on glucose uptake and improves beta-cell responsiveness, the latter two effects being opposite to those observed in nondiabetic subjects.

Glucose fluxes and oxidation after an oral glucose load in patients with non-insulin-dependent diabetes mellitus of variable severity.

The relative contribution of liver and peripheral tissues to the postprandial glucose response has been examined in 19 obese non-insulin-dependent diabetes mellitus (NIDDM) patients and 11 matched nondiabetic control subjects during a 5-hour oral glucose tolerance test (OGTT) performed with a load of 75 g, corresponding to approximately 67 g/1.73 m2. A dual-tracer technique was used to measure exogenous and endogenous glucose fluxes separately. Glucose oxidation was measured by indirect calorimetry. Diabetic patients were subdivided into two subgroups designated as "mild" (n = 7) and "severe" (n = 12) NIDDM according to postabsorptive glucose concentration with a cut-off point of 140 mg/dL. In the basal state, glucose concentrations averaged 99, 117, and 194 mg/dL, respectively, in control subjects and in the two diabetic subgroups, but insulin concentrations were not significantly different between groups. In comparison to control subjects, the basal hyperglycemia of mildly diabetic patients was entirely caused by a reduced metabolic clearance rate (118 v 144 mL/min; P < .05), whereas in severely diabetic patients basal hyperglycemia resulted from a combination of increased hepatic glucose output (187 v 139 mg/min; P < .001) and decreased metabolic clearance rate (97 v 144 mL/min; P < .001). A similar situation prevailed during the initial 2 hours after glucose ingestion. In patients with mild NIDDM, glucose concentration increased by 121 +/- 10 mg/dL as compared with 36 +/- 7 mg/dL in control subjects (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of starvation diabetes: a study with double tracer and indirect calorimetry.

To analyze the mechanisms of fasting-induced glucose intolerance, glucose metabolism was studied before and after the ingestion of 75 g glucose in 24 normal subjects fasted for either 14 h (n = 12) or 4 days (n = 12). The techniques included intravenous infusion of [6-3H]glucose and oral administration of [1-14C]glucose combined with indirect calorimetry. Compared with the controls, the starved subjects exhibited the following differences in glucose metabolism during the 5 h after glucose ingestion. 1) Mean incremental levels were fourfold higher for glucose and 40% higher for insulin. 2) Absorption of oral glucose was delayed and prolonged, but total amount reaching systemic circulation in 5 h was identical in the two groups (approximately 63 g). 3) Suppression of hepatic glucose output was reduced (-12 +/- 1 vs. -22 +/- 2 g). 4) Consequently, the increment in peripheral appearance of total glucose (exogenous plus endogenous) was augmented (+ 52 +/- 2 vs. +41 +/- 2 g). 5) Mean glucose clearance increased significantly less (+28 +/- 7 vs. +96 +/- 10 ml/min). 6) Oxidation of oral glucose was reduced (9 +/- 2 vs. 36 +/- 3 g), and nonoxidative disposal (presumably storage) was enhanced (56 +/- 2 vs. 36 +/- 3 g) in the presence of an elevated fat oxidation (35 +/- 2 vs. 22 +/- 4 g). Thus the alterations in glucose homeostasis responsible for the starvation-induced glucose intolerance are located both at the splanchnic (hepatic) and peripheral levels.

Effect of short term fasting on glucose tolerance and insulin secretion: influence of the initial glucose level.

To evaluate the effect of fasting on glucose tolerance (GT) and insulin secretion, a 5 h oral glucose tolerance test was performed after an overnight fast and after 3-6 days of fasting in 66 obese subjects presenting a normal (n = 22), impaired (n = 23) or diabetic (n = 21) GT. Insulin secretory capacity was assessed using two glucose-independent parameters of beta cell function. In the normal group, fasting induced a fall in basal glycemia from 84 +/- 1 to 58 +/- 2 mg/dl (P less than 0.001) and an increase in the area of glucose (+58 +/- 8%, P less than 0.001), insulin (+75 +/- 10%; P less than 0.001) and C-peptide (+58 +/- 10%; P less than 0.001) during OGTT, these responses were consistent with the emergence of insulin resistance. The insulin secretory capacity was significantly decreased. In the diabetic group, fasting was associated with an increase in insulin (+34 +/- 10%; P less than 0.005) and C-peptide (+34 +/- 8%; P less than 0.001) responses to OGTT despite a reduction in basal glycemia from 174 +/- 11 to 86 +/- 4 mg/dl (P less than 0.001) and in glucose response (-20 +/- 3%; P less than 0.001), indicating an improvement of insulin secretory capacity. In the group with impaired GT, basal glycemia decreased from 97 +/- 2 to 70 +/- 2 mg/dl (P less than 0.001) but glucose, insulin and C-peptide curves were not significantly affected by fasting.(ABSTRACT TRUNCATED AT 250 WORDS)

Nocturnal decrease in glucose tolerance during constant glucose infusion.

Studies comparing glucose tolerance in the morning vs. that in the evening have suggested that time of day may influence glucose regulation. To examine the variation in glucose tolerance throughout the 24-h span, normal subjects were given an iv glucose infusion at a constant rate of either 5 or 8 g/kg.24 h during 30 h, and plasma levels of insulin and glucose were measured at 15-min intervals for the last 24 h of the infusion. The timing of initiation of the infusion was varied to differentiate effects of time of day from effects of duration of the infusion. A nocturnal elevation of glucose levels, culminating around midsleep and corresponding to an increase of about 15% above daytime levels, was observed in all subjects. The timing of this nocturnal maximum was not dependent on the rate of the infusion or on the time elapsed since the beginning of the infusion. Insulin levels did not show a consistent diurnal pattern. Both insulin and glucose exhibited large ultradian oscillations recurring at 100- to 150-min intervals. The amplitude of these oscillations increased with the rate of glucose infusion. These ultradian oscillations of glucose and insulin levels were temporally correlated, with a tendency for glucose pulses to lead insulin pulses by 15-30 min. These results demonstrate in normal subjects the existence of a diurnal variation in glucose tolerance distinct from the dawn phenomenon observed in diabetic subjects and indicate that spontaneous 100- to 150-min oscillations in peripheral glucose and insulin levels characterize stimulated pancreatic function, with the amplitude of the oscillations being dependent on the size of the stimulus.

Ketone body production and disposal: effects of fasting, diabetes, and exercise.

Turnover studies performed during progressive fasting in normal subjects indicate that the production rate and the concentration of KB rise markedly during the early phase of fasting and start reaching a plateau after about 5 days. In addition to increased production, a reduction in the metabolic clearance rate of KB contributes to the hyperketonemia. This reduced metabolic clearance rate reflects essentially the progressive saturation of muscular ketone uptake that occurs with increasing ketonemia. The hormonal and metabolic environment of fasting plays only a minor role in this process, since a fall in KB metabolic clearance similar to that observed during fasting is observed if hyperketonemia is artificially induced in the postabsorptive state by the infusion of exogenous ketones. As extraction of KB by muscle becomes limited during ongoing fasting, KB are preferentially taken up by the brain to serve as a substrate replacing glucose. The remarkable stability of ketonemia during prolonged fasting is maintained through the operation of a negative feedback mechanism whereby KB tend to restrain their own production rate. The antilipolytic and insulinotropic effects of KB are instrumental in this process. This homeostatic mechanism maintains ketogenesis only slightly above the maximal metabolic disposal rate, the difference corresponding to urinary excretion, which is always below 10% of total turnover under physiologic conditions. When type I insulin-deprived diabetic patients are compared at the same KB concentration with control subjects with fasting ketosis, the characteristics of KB kinetics are comparable in the two groups. The maximal KB removal capacity is identical in the two situations, and it is not possible to identify a ketone removal defect specific to diabetes. Thus, these data favor the concept that excessive production of KB represent the main factor leading to uncontrolled hyperketonemia. It should be realized that a production exceeding only slightly that prevailing during prolonged fasting is sufficient to cause a progressive build-up in concentration, leading to uncontrolled diabetic ketosis. In the overnight-fasted state, a prolonged exercise (2 h) performed at moderate intensity (50% VO2 max) stimulates the capacity of muscle to extract ketones from blood as evidenced by a stimulation of the metabolic clearance rate.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of exercise on the disposal of infused ketone bodies in humans.

We previously reported that the stimulatory effect of exercise on the metabolic clearance of ketone bodies in postabsorptive subjects is abolished when plasma ketone body concentrations are elevated above 4 mmol/L by prior fasting. In this study we determined whether this process is related to fasting or to hyperketonemia itself. Eight normal postabsorptive subjects were rendered artificially hyperketonemic (approximately 6 mmol/L) by a constant infusion of acetoacetate and exercised moderately for 2 h. The kinetics of ketone bodies were determined with [14C]acetoacetate or beta-[14C]hydroxybutyrate. The metabolic clearance was slightly increased (approximately 25%) at the beginning of exercise, but this phenomenon was subsequently amplified by the progressive fall in ketonemia, which decreased to about 4 mmol/L at the end of exercise. Taking into account the fact that the metabolic clearance of ketones is inversely related to their concentration, it could be estimated that the direct effect of exercise on the metabolic clearance is negligible. Thus, the inability of exercise to enhance the metabolic clearance of ketones at high physiological plasma ketone levels is a general phenomenon that applies to both endogenous and exogenous ketosis.

Mechanism of the hyperketonaemic effect of prolonged exercise in insulin-deprived type 1 (insulin-dependent) diabetic patients.

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.