c-peptide and acetoacetic-acid

To determine the relative effects of growth hormone and insulin on ketogenesis during puberty.. We studied overnight changes in plasma ketones--3-hydroxybutyrate and acetoacetate--in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release.. Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 +/- 5 microM), reaching a peak at 0200 (103 +/- 16 microM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = -0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate.. We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adolescent; Adult; Age Factors; C-Peptide; Child; Circadian Rhythm; Diabetes Mellitus, Type 1; Female; Glucose Clamp Technique; Growth Hormone; Humans; Hydroxybutyrates; Insulin; Ketone Bodies; Male; Pirenzepine; Puberty; Reference Values

To compare the metabolic effects of elevated plasma concentrations of IGF-I and insulin, overnight-fasted normal subjects were studied twice, once receiving IGF-I and once insulin at doses that resulted in identical increases in glucose uptake during 8-h euglycemic clamping. Recombinant human IGF-I or insulin were infused in one group at high doses (30 micrograms/kg per h IGF-I or 0.23 nmol/kg per h insulin) and in another group at low doses (5 micrograms/kg per h IGF-I or 0.04 nmol/kg per h insulin). Glucose rate of disappearance (measured by [6,6-D2]-glucose infusions) increased from baseline by 239 +/- 16% during high dose IGF-I vs 197 +/- 18% during insulin (P = 0.021 vs IGF-I). Hepatic glucose production decreased by 37 +/- 6% during high dose IGF-I vs 89 +/- 13% during insulin (P = 0.0028 vs IGF-I). IGF-I suppressed whole body leucine flux ([1-13C]-leucine infusion technique) more than insulin (42 +/- 4 vs 32 +/- 3% during high doses, P = 0.0082). Leucine oxidation rate decreased during high dose IGF-I more than during insulin (55 +/- 4 vs 32 +/- 6%, P = 0.0001). The decreases of plasma concentrations of free fatty acids, acetoacetate, and beta-hydroxybutyrate after 8 h of IGF-I and insulin administration were similar. Plasma C-peptide levels decreased by 57 +/- 4% during high doses of IGF-I vs 36 +/- 6% during insulin (P = 0.005 vs IGF-I). The present data demonstrate that, compared to insulin, an acute increase in plasma IGF-I levels results in preferential enhancement of peripheral glucose utilization, diminished suppression of hepatic glucose production, augmented decrease of whole body protein breakdown (leucine flux), and of irreversible leucine catabolism but in similar antilipolytic effects. The data suggest that insulin-like effects of IGF-I in humans are mediated in part via IGF-I receptors and in part via insulin receptors.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adult; Blood Glucose; C-Peptide; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Glucose; Glucose Clamp Technique; Humans; Hydroxybutyrates; Insulin; Insulin-Like Growth Factor I; Kinetics; Leucine; Liver; Male; Recombinant Proteins

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 k

Topics: Acetoacetates; Adult; Blood Glucose; Blood Pressure; C-Peptide; Diabetes Mellitus, Type 1; Epinephrine; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Heart Rate; Humans; Infusions, Intravenous; Insulin; Ketone Bodies; Kinetics; Lipolysis; Male; Palmitic Acid; Palmitic Acids; Reference Values

The serum ketone response to glucagon was measured in 10 patients with IDDM and 37 with NIDDM. In both groups, serum 3-hydroxybutyrate increased significantly after intravenous injection of 1 mg glucagon. The difference between the serum level of 3-hydroxybutyrate at 30 min and basal level [delta 3-OHBA(30')] was 133 +/- 25 mumol/l in the patients with IDDM, 13 +/- 8 mumol/l in those with NIDDM treated by diet alone or with oral hypoglycemic agents and 23 +/- 13 mumol/l in those with NIDDM treated with insulin. The delta 3-OHBA(30') was significantly greater in IDDM patients than in both groups of NIDDM patients (P less than 0.001). The delta 3-OHBA(30') was greater than 87 mumol/l in eighty percent of IDDM patients, but smaller than 87 mumol/l in both groups of NIDDM patients. The delta 3-OHBA(30') was correlated with the difference between the plasma level of C-peptide at 6 min and basal level [delta CPR(6')] (r = -0.540, P less than 0.001). The delta 3-OHBA(30') was not correlated with fasting plasma levels of glucose, fructosamine or hemoglobin A1c. These observations show that measurement of the serum ketone response to glucagon is a useful marker of insulin dependency. In order to determine insulin dependency, the simultaneous measurement of concentrations of ketones and C-peptide is indicated during the glucagon stimulation test.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adult; Biomarkers; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Fructosamine; Glucagon; Hexosamines; Humans; Hydroxybutyrates; Ketone Bodies; Kinetics; Male; Middle Aged; Regression Analysis

To evaluate the relationship of blood ketone bodies with diabetic control and endogenous insulin secretion, fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), fasting serum C-peptide (CPR), blood total ketone-bodies (TKB), blood acetoacetate (AcAc) and blood 3-hydroxybutyrate (3-OHB) were compared in 78 outpatients with non-insulin-dependent diabetes mellitus (NIDDM) treated with diet (n = 13), sulfonylurea (n = 52) and insulin (n = 13). TKB, AcAc and 3-OHB in patients treated with insulin were significantly higher than in patients treated with diet or sulfonylurea. In patients given diet therapy, log 3-OHB showed significant negative correlations with FPG, HbA1c and CPR. In patients treated with sulfonylurea, log 3-OHB showed significant positive correlations with FPG and HbA1c, but not with CPR. In patients treated with insulin, there were no correlations of log 3-OHB with FPG, HbA1c and CPR. For evaluation of the metabolic state in diabetes mellitus, measurement of blood ketone bodies is useful, and moreover necessary, in addition to diabetic control or determination of the endogenous insulin level.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diet, Diabetic; Female; Glycated Hemoglobin; Humans; Hydroxybutyrates; Hypoglycemic Agents; Insulin; Insulin Secretion; Ketone Bodies; Male; Middle Aged

The ability of ketone bodies to suppress elevated hepatic glucose output was investigated in eight postabsorptive subjects with non-insulin-dependent diabetes mellitus (NIDDM). Infusion of sodium acetoacetate alone (20 mumols/kg/min) for 3 hours increased total serum ketones (beta-hydroxybutyrate and acetoacetate) to approximately 6 mmol/L, but did not reduce plasma glucose (14.0 +/- 0.8 to 12.3 +/- 0.9 mmol/L) or isotopically determined hepatic glucose output (17.5 +/- 1.4 to 12.7 +/- 1.0 mumols/kg/min) more than saline alone. Plasma C-peptide concentrations were unchanged, while serum glucagon increased from 131 +/- 13 to 169 +/- 24 ng/mL (P less than .015) and free fatty acids were suppressed by 43% (0.35 +/- 0.08 to 0.20 +/- 0.06 mmol/L, P less than .025). When sodium acetoacetate was infused with somatostatin (0.10 micrograms/kg/min) to suppress glucagon and insulin secretion, the decrease in both plasma glucose (13.3 +/- 0.9 to 10.2 +/- 0.7 mmol/L) and hepatic glucose output (17.2 +/- 1.6 to 9.4 +/- 0.6 mumols/kg/min) was greater than either acetoacetate or somatostatin infusion alone. Infusion of equimolar amounts of sodium bicarbonate had no effect on glucose metabolism. In conclusion, these results demonstrate that ketone bodies can directly suppress elevated hepatic glucose output in NIDDM independent of changes in insulin secretion, but only when the concomitant stimulation of glucagon secretion is prevented. Ketone bodies also suppress adipose tissue lipolysis in the absence of changes in plasma insulin and may serve to regulate their own production.

Topics: Acetoacetates; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucagon; Glucose; Humans; Ketone Bodies; Liver; Male; Middle Aged; Radioisotope Dilution Technique; Somatostatin; Tritium

To compare cortisol and epinephrine action on oral glucose tolerance, healthy humans were infused with either cortisol (0.1 mg X kg-1 X h-1), epinephrine (5.4 micrograms X kg-1 X h-1), or saline before and after a 75-g glucose load, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, beta-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and beta-hydroxybutyrate and splanchnic FFA more than cortisol. Postprandially, C-peptide release and hyperinsulinemia were blunted by epinephrine initially and increased less thereafter than during cortisol infusion. The rise in arterial glucose after glucose ingestion as calculated by the area under the curve was more marked (P less than .01) after epinephrine [( 1.90 +/- 0.08 M) 150 min] and cortisol [( 1.41 +/- 0.05 M) 150 min] than in the control study [( 1.07 +/- 0.04 M) 150 min]. In parallel, the stress hormones induced an almost identical 24 and 31% rise in mean splanchnic glucose output versus control values (normal, 44.8 +/- 2.5; cortisol, 55.3 +/- 3.3; epinephrine, 58.9 +/- 6.9 g/150 min). The associated rise in arterial concentrations and splanchnic output of insulin above control values was considerably greater during cortisol but unchanged during epinephrine exposure. Epinephrine but not cortisol induced a rise versus the control study in splanchnic uptake of lactate and FFA, as well as in pyruvate output, whereas plasma beta-hydroxybutyrate and acetoacetate remained unchanged. The postprandial splanchnic glucose output-to-splanchnic C-peptide output ratio did not differ from normal during epinephrine but was reduced (P less than .01) during cortisol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adult; Blood Glucose; C-Peptide; Epinephrine; Fatty Acids, Nonesterified; Glucose Tolerance Test; Humans; Hydrocortisone; Hydroxybutyrates; Insulin; Insulin Resistance; Intestinal Mucosa; Lactates; Lactic Acid; Male

The effect of alanine on ketone body levels, independent of hormonal changes, in normal man has been investigated. Five normal subjects were given somatostatin infusions (200 micrograms/hour) for 3 hr. After 1 hr alanine or isotonic saline was infused for 2 hr. With saline blood beta-hydroxybutyrate and acetoacetate levels rose steadily to a peak of 0.230 plus or minus 0.053 and 0.112 plus or minus 0.023 mmole/l respectively. With alanine beta-hydroxybutyrate and acetoacetate levels plateaued at 0.099 plus or minus 0.020 and 0.055 plus or minus 0.006 mmole/l respectively. Alanine levels reached nearly 1 mmole/l but a significant effect on ketone body levels was apparent at physiologic levels (less than 0.6 mmole/l). Plasma fatty acid and glycerol levels did not change significantly. Insulin C-peptide and glucagon levels were suppressed to a similar extent in both experiments. These results support the view that alanine suppresses ketogenesis in man by a direct hepatic effect independent of insulin and glucagon. It is suggested that this forms part of a negative feedback substrate cycle between alanine and ketone bodies.

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Adult; Alanine; Blood Glucose; C-Peptide; Glucagon; Humans; Hydroxybutyrates; Insulin; Keto Acids; Ketone Bodies; Kinetics; Male; Somatostatin