[Physiopathology of diabetes in famine].
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Blood Glucose↗
Biomedical subjects
E O Balasse
Publications and source records attributed to E O Balasse.
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.
3-Hydroxybutyric Acid↗
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)
Diabetes Mellitus↗
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.
Activity Cycles↗
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.
Adult↗
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.
Adult↗
Response of ketone body metabolism to exercise during transition from postabsorptive to fasted state.
This study examines the effects of a 2-h exercise of moderate intensity (50% of VO2 max) on the tracer-determined turnover rate of ketone bodies (KB) in 21 normal subjects fasted for 16 h, 5 days, whose basal ketonemia ranged between 0.09 and 6.16 mM. The KB response observed at the end of exercise is a function of the initial degree of ketosis. When basal ketonemia is below 0.6 mM, exercise enhances ketogenesis (Ra), the amplitude of this process being positively correlated with KB level. There is a concomitant acceleration of the metabolic clearance rate (MCR) of KB attaining 40-50%. When ketonemia exceeds 2.5 mM, the stimulatory effects of exercise on Ra and on MCR become less marked as basal ketonemia rises and are completely abolished or even reversed when initial KB level is higher than 3-4 mM. The pattern of changes in the concentration and in the overall disposal rate of KB were similar to that of Ra. It is suggested that the parallel inhibition of the stimulatory effect of work on hepatic ketogenesis and on muscular extraction of ketones associated with increasing degrees of fasting hyperketonemia has two physiological implications: it maintains the preferential utilization of KB by nonmuscular tissues (presumably the brain) and prevents the development of uncontrolled hyperketonemia, despite the intense catabolic situation created by the combination of exercise and starvation.
3-Hydroxybutyric Acid↗
Determination of ketone body kinetics using a D-(-)-3-hydroxy[4,4,4-2H3]butyrate tracer.
In studies where D-(-)-3-hydroxy[4,4,4-2H3]butyrate is employed as isotopic tracer in vivo, we have described a selected ion monitoring, gas-liquid chromatography-mass spectrometry micromethod which measures [2H3] tracer enrichment in 3-hydroxybutyrate and acetoacetate from 300-microliters blood samples. For plasma samples in the physiologic range, intra- and interassay precisions for each ketone averaged better than +/- 1% and +/- 2%, respectively. The use of the method was validated by comparing kinetic data obtained with the above tracer with simultaneous flux data obtained with conventional D-(-)-3-hydroxy[3-14C]butyrate tracer in five fasted rats.
3-Hydroxybutyric Acid↗
Alanine turnover in normal and diabetic dogs.
The rate of turnover of alanine was determined in normal and insulin-deprived pancreatectomized dogs using a primed constant infusion of U-14 C-alanine. In the diabetic group, alanine levels and turnover rates were closely correlated suggesting that alanine production is a major determinant of its concentration. Alanine metabolism varied according to the degree of hyperglycaemia: when glucose levels were less than 22 mmol/l, alanine fluxes and concentrations remained normal as observed in previously published studies. In contrast, when glucose levels exceeded 25 mmol/l, alanine concentrations and fluxes tended to be markedly elevated (up to 4-5 times the normal values). This finding suggests that in severely hyperglycaemic animals in which hepatic glucose production is likely to be strikingly elevated, an excessive rate of transport of alanine from muscle to the liver might contribute to the accelerated rate of gluconeogenesis.
Alanine↗
Ketone body production and disposal in diabetic ketosis. A comparison with fasting ketosis.
This work compares the metabolism of total ketone bodies in 13 insulin-deprived, type I diabetic subjects and 26 control subjects fasted for 15 h to 23 days, with the two groups showing a similar range of ketone body levels (1-12 mM). Ketone turnover rate was measured using a primed, constant infusion of either 14C-acetoacetate or 14C-beta-hydroxybutyrate, both tracers yielding comparable results. The major conclusions of this study are the following: the kinetics of ketone bodies are comparable in the two groups within the range of concentrations tested. The hyperketonemia of fasting and diabetes is primarily caused by an increased production of ketone bodies, but the phenomenon is amplified by a progressive limitation in the ability of tissues to remove ketones from blood as the concentration rises. The inverse relationship between the metabolic clearance and the plasma levels of ketones, which underlies this process, represents a general characteristic of ketone body metabolism that applies to both types of ketosis. A maximal metabolic disposal rate of about 2.3 mmol/min/1.73 m2 is attained in both groups at concentrations of 10-12 mM, which correspond to the highest ketone body levels encountered during prolonged fasting. Thus, up to these levels, there is no evidence for the existence of a ketone body removal defect specific to diabetes.
3-Hydroxybutyric Acid↗
Kinetics of ketone body metabolism in fasting humans.
The rates of production of total ketone bodies (acetoacetate + beta-hydroxybutyrate) were determined using an isotope tracer technique in 23 obese subjects submitted to a fast of variable duration (15 hr--23 days). Constant infusions of 14C-acetoacetate were used in most studies, but similar results were obtained with pulse injections of this tracer or with constant infusions of 14C-D(-)-beta-hydroxybutyrate. Blood concentration, production rate, and urinary elimination of total ketones rose during approximately the first 3 days of fast and plateaued thereafter at values amounting, respectively, to 7.09 +/- 0.32 mumole/ml, 1908 +/- 80 mumole/min and 167 +/- 14 mumole/min. The rates of ketogenesis are significantly higher than those usually reported in the literature. Ketonemia was an exponential function of production rate suggesting that tissue uptake becomes progressively saturated as inflow rate rises. The same type of relationship between concentration and inflow rate was observed in nine control overnight fasted obese subjects rendered hyperketonemic with infusions of variable amounts of unlabeled acetoacetate. The comparison between the fasted and the control subjects at ketone concentrations of 3--10 mumole/ml showed that on an average, starvation is associated with a 35% decrease in the metabolic clearance rate of ketones. These data suggest that fasting is associated with an impairment of mechanisms for utilizing ketones, this defect contributing to the hyperketonemia of food deprivation.
Acetoacetates↗
[Do ketone bodies exert control over protein metabolism?].
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Amino Acids↗
[Physiopathology of chronic complications in diabetes: therapeutic implications].
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Adult↗
Changes induced by exercise in rates of turnover and oxidation of ketone bodies in fasting man.
Seven normal subjects fasted for 3 days were exercised for 30 min on a bicycle ergometer at 60 +/- 30% (mean +/- SE) of their maximal aerobic capacity. Rates of transport and oxidation of ketone bodies were determined at rest and during exercise using a primed constant infusion of [14C]acetoacetate. During the initial 7.5 min of exercise, ketone concentration abruptly decreased (-19.4 +/- 3.1%; P less than 0.001) as the result of a 22.2 +/- 7.0% reduction (P less than 0.05) in ketone production rate (Ra) and a 30.4 +/- 7.5% increase (P less than 0.01) in the rate of uptake (Rd) of ketones. As work progressed, blood ketones continued to fall slowly until the 15th min of exercise and thereafter plateaued at a level which was 21.9 +/- 4.1% lower (P less than 0.005) than resting values. During this apparent new steady state, both Ra and Rd were below control values but tended to be equal and to return simultaneously to their preexercise level. The metabolic clearance rate was increased throughout the entire period of exercise, the rise being more marked during the initial 7.5 min (+40.7 +/- 7.5%; P less than 0.01) than at later periods (+19.0 +/- 7.4%; P less than 0.05). Exercise greatly enhanced ketone oxidation which became virtually complete; despite this, the %CO2 derived from ketones, which averaged 17.6 +/- 1.6% at rest, decreased to 10.1 +/- 0.6% (P less than 0.01) after 30 min of work. This indicates that even during the hyperketonemia of fasting, the increased energy needs related to exercise are met primarily by fuels other than ketones.
Acetoacetates↗
Influence of short-term administration of clofibrate on insulin and glucagon response to protein ingestion in man.
Nine normal and two mildly hypertriglyceridemic subjects were treated with 2 g of clofibrate per day for 8 days. A significant fall in serum triglyceride and cholesterol concentration was observed from the second day onwards whereas free fatty acid levels were minimally affected. Insulin and glucagon responses to the ingestion of 200 g of meat were tested before and at the end of clofibrate treatment. Insulin response was significantly depressed (-28 +/- 12%) by the drug whereas glucagon response was enhanced but not to a significant degree. The ratio between insulin response and glucagon response was decreased by 38 +/- 11% (p less than 0.01) after treatment. A positive correlation was observed between the effects of clofibrate on basal triglyceride concentration on one hand and the effects of the drug on insulin and insulin/glucagon response to the protein meal on the other hand. Since insulin and glucagon are known to influence triglyceride metabolism, our data are compatible with the concept that the hypotriglyceridemic effect of clofibrate is--at least partly--related to the observed changes in insulin and glucagon reactivity.
Adult↗
Lactic acidosis complicating diabetic ketosis in a patient with hyperthyroidism.
The present report describes a patient with insulin-dependent diabetes who developed simultaneously lactic acidosis and ketoacidosis following insulin deprivation. Administration of insulin at low doses rapidly corrected both ketosis and lactic acidosis. There had been neither circulatory collapse, nor phenformin intake, and hepatic function was normal. The development of lactic acidosis in this case was possibly precipitated by hyperthyroidism. A review of the literature indicates that lactic acidosis is a very rare complication of diabetic ketosis per se.
Acidosis↗
Treatment of diabetic coma with small intravenous insulin boluses.
The clinical efficacy of small intravenous boluses of insulin in treating diabetic decompensation was tested in 23 patients presenting in either a ketoacidotic or a nonketotic diabetic coma. In addition to the usual ionic and fluid replacement, the patients received hourly intravenous injections of insulin 5 IU. This dose lowered blood glucose levels in all but two patients. In the patients who responded the percentage decrease in glycaemia was similar whatever the initial glucose concentration and averaged (+/-SE of mean) 50+/-3% in five hours. Close monitoring of insulin and glucose concentrations after intravenous insulin in three patients showed that despite the short half life of insulin the effect of the intravenous bolus lasted for about 60 minutes. The overall clinical effectiveness of this type of treatment is comparable to that of the other low-dose regimens. Owing to its simplicity, this technique of insulin administration seems most suitable for the routine treatment of diabetic coma.
Blood Glucose↗
[Physiolopathologic aspects of diabetic ketosis and the ketosis of fasting].
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Acetoacetates↗