Biomedical subjects

R A DeFronzo

Publications and source records attributed to R A DeFronzo.

At least 73 records · Page 4Linked to original sources

PubMed1995

Basal plasma insulin levels exert a qualitative but not quantitative effect on glucose-mediated glucose uptake.

UNLABELLED: We assessed the effect of hyperglycemia on glucose uptake in the presence of normal basal insulin levels or somatostatin-induced hypoinsulinemia in seven normal volunteers during a 200-min hyperglycemic clamp (+ 9 mmol/l) carried out with [3-3H]glucose and indirect calorimetry. Hyperglycemia increased glucose uptake to 22.4 +/- 2.6 and 21.3 +/- 1.6 mumol.kg-1.min-1 with and without insulin replacement, respectively. Normoinsulinemia increased glucose oxidation (delta = + 4.5 +/- 0.6 mumol.kg-1.min-1) and nonoxidative glucose metabolism (delta = + 5.2 +/- 1.7 mumol.kg-1.min-1), whereas with insulinopenia, glucose oxidation did not change (delta = -0.3 +/- 0.6 mumol.kg-1.min-1), and nonoxidative glucose metabolism increased (delta = + 48.7 +/- 0.8 mumol.kg-1.min-1). Nonoxidative glucose metabolism was higher during insulinopenic (13.5 +/- 1.8 mumol.kg-1.min-1) than normoinsulinemic hyperglycemia (9.8 +/- 2.7 mumol.kg-1.min-1; P < 0.01). Plasma FFA concentration and lipid oxidation were higher with insulinopenia. Blood lactate and alanine concentrations were greater with normoinsulinemia. IN CONCLUSION: 1) hyperglycemia promotes glucose uptake by stimulating both nonoxidative and oxidative glucose disposal; 2) the ability of hyperglycemia to enhance total body glucose uptake is similar with and without normoinsulinemia; 3) although acute insulinopenia does not impair the ability of hyperglycemia to stimulate glucose uptake, it plays a critical role in determining the intracellular metabolic fate of glucose taken up in response to hyperglycemia.

Adult↗

PubMed1995

Bicarbonate kinetics in humans: identification and validation of a three-compartment model.

A model of bicarbonate kinetics is crucial to a correct interpretation of experiments for measuring oxidation in vivo of carbon-labeled compounds. The aim of this study is to develop a compartmental model of bicarbonate kinetics in humans from tracer data by devoting particular attention to model identification and validation. The data base consisted of impulse-dose studies of 14C-labeled bicarbonate in nine normal subjects. The decay curve of specific activity of CO2 in expired air (saRCO2) was frequently sampled for 4-7 h. In addition, endogenous production of CO2, VCO2, was measured by indirect calorimetry. A model of data, i.e., an exponential model, analysis of decay curves of saRCO2 showed first that three compartments are necessary and sufficient to describe bicarbonate tracer kinetics. Compartmental models were then used as models of system. To correctly describe the input-output configuration, labeled CO2 flux in the expired air, phi RCO2 (= saRCO2.VCO2), has been used as measurement variable in tracer model identification. A mammillary three-compartment model with a respiratory and a nonrespiratory loss has been studied. Whereas there is good evidence that respiratory loss takes place in the central compartment, whether nonrespiratory loss is taking place in the central compartment or in one of the two peripheral compartments is uncertain. Thus three competing tracer models were considered. Using a model-independent analysis of data, based on the body activity variable, to calculate mean residence time in the system, we have been able to validate a specific model structure, i.e., with the two irreversible losses taking place in the central compartment. This validated tracer model was then used to quantitate bicarbonate masses in the system. Because there is uncertainty about where endogenous production enters the system, lower and upper bounds of masses of bicarbonate in the body are derived.

Bicarbonates↗

PubMed1995

Regulation of hexokinase II and glycogen synthase mRNA, protein, and activity in human muscle.

Insulin regulates the activity of key enzymes of glucose metabolism in skeletal muscle by altering transcription or translation or by producing activity-altering modifications of preexisting enzyme molecules. Because of the small size of percutaneous muscle biopsies, these phenomena have been difficult to study in humans. This study was performed to determine how physiological hyperinsulinemia regulates the activities of hexokinase (HK), glycogen synthase (GS), and GLUT-4 in human skeletal muscle in vivo. We determined mRNA abundance, protein content, and activities for these proteins in muscle biopsies before and after a hyperinsulinemic clamp in normal subjects. HK I, HK II, GS, and GLUT-4 were expressed in muscle. HK II accounted for 80% of total HK activity and was increased by insulin from a basal value of 2.11 +/- 0.26 to 3.35 +/- 0.47 pmol.min-1.mg protein-1 (P < 0.05); HK I activity was unaffected. Insulin increased GS activity from 3.85 +/- 0.82 to 6.06 +/- 0.49 nmol.min-1.mg-1 (P < 0.01). HK II mRNA was increased 3.3 +/- 1.3-fold (P < 0.05) by insulin infusion. HK I, GS, and GLUT-4 mRNA and protein were unaffected. Because insulin infusion increased HK II but not GS mRNA, we conclude that HK II and GS may be regulated by insulin by different mechanisms in human skeletal muscle.

Adult↗

PubMed1995

Acute effect of human recombinant insulin-like growth factor I on renal function in humans.

We examined the acute effects of insulin-like growth factor I (IGF-I) on renal function in 8 normal subjects who received a 3-hour intravenous infusion of IGF-I at a rate of 0.4 micrograms/kg.min. After starting the IGF-I infusion, the plasma IGF-I concentration rose quickly and achieved a plateau after 90 min that was threefold above the basal value. During IGF-I infusion, progressive rises in glomerular filtration rate (from 93 +/- 4 to 121 +/- 6 ml/173 m2.min; p < 0.01) and renal plasma flow (from 529 +/- 31 to 703 +/- 55 ml/1.73 m2.min; p < 0.01) were observed, with no change in filtration fraction. The plasma levels of potassium and phosphate decreased significantly during the last 90 min of the study, while the plasma sodium concentration remained unchanged. A significant decrease in the fractional excretion of sodium, potassium, and phosphate was observed during the last 90 min of the IGF-I infusion period. The heart rate rose modestly with no change in mean arterial pressure. These findings show that, when administered acutely, IGF-I is a potent renal vasodilator, but is antinatriuretic. IGF-I also enhances potassium and phosphate uptake by extrarenal tissues and reduces renal potassium and phosphate excretion.

Adult↗

PubMed1995

Bedtime insulin/daytime glipizide. Effective therapy for sulfonylurea failures in NIDDM.

Bedtime insulin (BI)/daytime sulfonylurea (DSU) therapy was studied double-blind in 30 non-insulin-dependent diabetes mellitus subjects in whom sulfonylurea (SU) therapy had failed. Subjects were switched to glipizide for 2 months (phase I) to confirm failure (fasting plasma glucose [FPG] 12.0 +/- 0.4 mmol/l) and then randomly assigned into three groups: BI-DSU; BI-no DSU; and DSU-no BI. During phase II (3 months), the BI dose was fixed (20 U/1.73 m2, low-dose). In phase III (3 months), BI was titrated up (high-dose) to achieve good control or until hypoglycemic symptoms prevented further dose increases. In phase IV (6 months), 25 of the 30 original subjects received open-labeled, high-dose BI-DSU. Low-dose BI-DSU markedly reduced FPG (13.6 +/- 0.8 to 8.0 +/- 0.6 mmol/l, P < 0.001), mean 24-h glucose (P < 0.001), HbA1c (8.9 +/- 0.7 to 7.6 +/- 0.3%, P = 0.07), and basal hepatic glucose production (HGP) (P < 0.005). A positive correlation (r = 0.69, P < 0.05) between the declines in FPG and HGP was observed. Neither low-dose BI alone nor DSU alone reduced FPG, mean 24-h glucose, HbA1c, or basal HGP. High-dose (40 +/- 5 U/day) BI plus DSU further reduced the FPG (6.3 +/- 0.6 mmol/l), HbA1c (7.1 +/- 0.3%), mean 24-h plasma glucose, and basal HGP (all P < 0.05 vs. phase II).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Effects of angiotensin-converting enzyme inhibitors, Ca2+ channel antagonists, and alpha-adrenergic blockers on glucose and lipid metabolism in NIDDM patients with hypertension.

We compared the effects of captopril, nifedipine, and doxazosin on glucose and lipid metabolism in 30 hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients (age = 50 +/- 3 years; body mass index = 30 +/- 1 kg/m2). Of these patients, 9 were treated with captopril, 11 with nifedipine, and 10 with doxazosin for 12 weeks. Blood pressure, fasting plasma glucose (FPG) concentration, HbA1c, oral glucose tolerance test (OGTT), euglycemic insulin clamp, and plasma lipids were measured before and after a 3-month period. Mean arterial blood pressure (114 +/- 2 mmHg) was similar in all groups before initiating antihypertensive therapy and declined to 102 +/- 2 (captopril), 103 +/- 1 (nifedipine), and 103 +/- 2 (doxazosin) mmHg (P < 0.001). Baseline FPG (148 +/- 11 mg/dl) and HbA1c (6.3 +/- 1%) were similar in all groups and did not change significantly with treatment. Plasma glucose, insulin, and free fatty acid (FFA) concentrations during the OGTT were similar in all groups before antihypertensive treatment and did not change with captopril and nifedipine; after doxazosin, plasma glucose and FFA concentrations during the OGTT decreased (both P < 0.05) without change in plasma insulin response. Insulin-mediated glucose uptake (144 +/- 11 mg.m-2.min-1), glucose oxidation (76 +/- 4 mg.m-2.min-1), and nonoxidative glucose disposal (71 +/- 6 mg.m-2.min-1) were similar in all groups before the start of antihypertensive treatment and did not change in captopril and nifedipine groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1995

Insulin sensitivity is not impaired in Mexican-American women without a family history of diabetes.

OBJECTIVE: The purpose of this research was to compare insulin sensitivity in Mexican-Americans and non-Hispanic whites without a family history of diabetes to establish whether insulin resistance is a defect intrinsically related to subjects of Mexican origin. RESEARCH DESIGN AND METHODS: In study A, we compared insulin sensitivity in 12 Mexican-American and 12 non-Hispanic white women with normal glucose tolerance and no family history of diabetes. In study B, we compared insulin sensitivity in two groups of normal glucose-tolerant Mexican-Americans, nine with a positive (FHD+) and nine with a negative (FHD-) family history of diabetes. In both studies, the groups were closely matched for age, total body fat content, and fat topography. Insulin sensitivity was assessed with the euglycemic insulin clamp (20 microU.min-1.m2 surface area) which was performed in combination with tritiated glucose infusion and indirect calorimetry. Total fat mass and fat-free mass (FFM) were assessed by a tritiated water dilution technique, and regional fat distribution was evaluated by anthropometry and magnetic resonance imaging. RESULTS: During a 4-h euglycemic insulin clamp (study A), rates (mg.min-1.kg FFM-1) of total (6.32 +/- 0.64 vs. 6.62 +/- 0.81), oxidative (3.54 +/- 0.24 vs. 3.51 +/- 0.19), and nonoxidative (2.78 +/- 0.48 vs. 3.11 +/- 0.75) glucose utilization were similar in Mexican-Americans and non-Hispanic whites; hepatic glucose production (0.33 +/- 0.13 vs. 0.35 +/- 0.13) was suppressed similarly in both groups. During a 2-h euglycemic insulin clamp (study B), Mexican-Americans with FHD+ had lower rates of insulin-mediated total (3.55 +/- 0.39 vs. 5.93 +/- 0.59, P < 0.001), oxidative (3.31 +/- 0.25 vs. 4.32 +/- 0.17, P < 0.01), and nonoxidative (0.24 +/- 0.28 vs. 1.61 +/- 0.49, P < 0.01) glucose disposal than subjects with FHD-; suppression of hepatic glucose production (0.24 +/- 0.14 vs. 0.18 +/- 0.12) was similar in both groups. CONCLUSIONS: These results indicate that in the absence of a family history of non-insulin-dependent diabetes mellitus, Mexican-American women are not less sensitive to insulin than non-Hispanic white women.

Adipose Tissue↗

PubMed1994

Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man.

Two study protocols to examine the effects of chronic (72-96 h) physiologic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hyperglycaemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensitivity and insulin secretion were performed in 15 healthy young subjects. Subjects received a three-step euglycaemic insulin (insulin infusion rates = 1.5, 3, and 6 nmol.kg-1.min-1) clamp and a hyperglycaemia (6.9 mmol/l) clamp before and after chronic insulin or glucose infusion. Following 4 days of sustained euglycaemic hyperinsulinaemia whole body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non-oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsulinaemia did not alter insulin-mediated suppression of hepatic glucose production. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 72 h of chronic glucose infusion (combined hyperglycaemic hyperinsulinaemia), there was no change in whole body glucose disposal. However, glucose oxidation during each insulin clamp step was significantly increased and there was a reciprocal decline in non-oxidative glucose disposal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Chronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chronic, physiologic hyperinsulinaemia, whether created by exogenous insulin infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a specific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not only as a compensatory response to insulin resistance, but also as a self-perpetuating cause of the defect in insulin action.

Adult↗

PubMed1994

Glucose absorption and production following oral glucose: comparison of compartmental and arteriovenous-difference methods.

Both whole-body models and the regional arteriovenous (AV)-difference method have been used to calculate systemic glucose rates of appearance (Ras) under non-steady-state conditions. Although whole-body models have been experimentally validated in the dog, direct comparison of the whole-body and regional-balance approach has not been made in man. We reanalyzed published data obtained by combining the double-tracer technique ([3H]glucose infusion with ingestion of a [14C]glucose-labeled load) with hepatic vein catheterization. Steele's monocompartmental model underestimated the Ra of oral glucose ([RaO] by 12%, P < .0001) and overestimated the Ra of endogenous glucose ([RaE] by 19%, P < .0001) in comparison to a two-compartment (2-c) model calculation. Splanchnic balance data were used to compute the total glucose Ra (RaT) with either steady-state or non-steady-state equations (the latter by estimating splanchnic transit times). Except for one early time point (15 minutes), the two calculations agreed well with one another. The glucose RaT by the balance method was well correlated with that calculated by the 2-c whole-body model (r = .72, P < .0001 on all data points); however, the former significantly underestimated the latter by 0.62 mg.min-1.kg-1 (or 13%, P < .01) on average throughout the absorptive period. This bias was small in comparison to the estimated random error affecting the calculation of glucose RaT by the model, which averaged 1.4 mg.min-1.kg-1 (corresponding to a variation coefficient of approximately 30%).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Glycogen turnover during refeeding in the postabsorptive dog: implications for the estimation of glycogen formation using tracer methods.

Recent 13C nuclear magnetic resonance (13C-NMR) studies in the anesthetized rat and perfused liver suggest that hepatic glycogen is simultaneously synthesized and degraded, even during combined hyperglycemia and hyperinsulinemia. The presence of glycogen turnover would confound efforts to study glycogen repletion with the use of tracer methods during feeding, particularly if the liver is not glycogen-depleted. To ascertain whether glycogen turnover occurs during normal feeding, we measured liver uptake of glucose in 10 awake, healthy, postabsorptive dogs with long-term arterial, portal, and hepatic venous catheters before and for 3 hours after a meal of either glucose alone (1.5 g/kg) or glucose supplemented with crystalline amino acids (0.7 g/kg); the meal was labeled with D-[3-3H]glucose and [U-14C]alanine. Liver glycogen level was measured in biopsies obtained before and at 180 minutes after the meal. The postabsorptive liver glycogen content was 4.3 +/- 0.9 g/100 g, and net hepatic glucose release averaged 1.8 +/- 0.3 mg/min/kg. Over the 3 hours following feeding, the liver took up glucose (0.37 +/- 0.14 and 0.33 +/- 0.16 g/kg body weight in dogs receiving glucose and glucose with amino acids, respectively). At 3 hours, glycogen synthesis from D-[3-3H]glucose in the two groups averaged 0.24 +/- 0.09 and 0.22 +/- 0.05 g/kg, or approximately 15% of the ingested glucose load. 14C-glucose also was found in liver glycogen, demonstrating ongoing hepatic gluconeogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Free fatty acid and glucose metabolism in human aging: evidence for operation of the Randle cycle.

We assessed insulin effects on plasma free fatty acid (FFA) and glucose metabolism in seven elderly (71 +/- 2 yr) and in seven younger (21 +/- 1 yr) subjects matched for body weight and body mass index but not for percent body fat (32.4 +/- 3.8% in elderly vs. 20.4 +/- 3.5% in young, P < 0.05), by performing sequential euglycemic clamps at five insulin doses (0.6, 1.5, 3, 6, and 15 pmol.min-1.kg-1) in combination with indirect calorimetry and [1-14C]palmitate plus [3-3H]glucose infusion. At baseline, plasma FFA concentration, turnover infusion. At baseline, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were all increased in the elderly (897 +/- 107 vs. 412 +/- 50 mumol/l and 11.2 +/- 1.4 vs. 5.14 +/- 0.86, 3.45 +/- 0.65 vs. 1.37 +/- 0.25, and 4.63 +/- 0.72 vs. 3.01 +/- 0.33 mumol.min-1.kg-1 lean body mass, P < 0.05 for all comparisons), whereas glucose turnover was similar as a result of decreased glucose oxidation (8.2 +/- 1.4 vs. 13 +/- 1.9 mumol.min-1.kg-1 lean body mass, P < 0.05) and increased glucose storage (6.6 +/- 1.4 vs. 1.7 +/- 1.3 mmol.min-1.kg-1 lean body mass, P < 0.05). At all insulin infusions, plasma FFA concentration, turnover and oxidation, and total lipid oxidation were higher in the elderly than in the younger group (P < 0.05). However, if normalized per fat mass, all FFA and lipid metabolic fluxes, both in the postabsorptive state and during hyperinsulinemia, were comparable in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Time-dependent regulation by insulin of leucine metabolism in young healthy adults.

The long- and short-term effects of insulin on leucine turnover were investigated in six young healthy volunteers using [1-14C]leucine in combination with indirect calorimetry. After baseline measurement of leucine turnover (44.9 +/- 2.7 mumol.m-2.min-1), the plasma insulin concentration was raised by 10 microU/ml above baseline while maintaining euglycemia for 24 h. Repeat determinations of leucine turnover were carried out at 3 and 24 h. On a separate day, in three of the six subjects, leucine turnover also was quantitated after 13 h of equivalent hyperinsulinemia. Insulin significantly suppressed plasma leucine and ketoisocaproate (KIC) concentrations during short-term (3 h) infusion, and this reduction persisted after 13 and 24 h of insulin administration. Endogenous leucine flux (an index of protein degradation) was decreased similarly by hyperinsulinemia at 3 h (34.2 +/- 2.9 mumol.m-2.min-1, P < 0.001) and at 13 h (29.2 +/- 2.6 mumol.m-2.min-1, P < 0.05 vs. baseline) but returned to the basal preinsulin rate after 24 h of insulinization (40.4 +/- 2.9 mumol.m-2.min-1; P = not significant vs. baseline, P < 0.001 vs. 3 h, and P < 0.05 vs. 13-h studies). Leucine oxidation did not change significantly after either 3, 13, or 24 h of insulin infusion. Similar results were obtained whether the calculations were carried out using the [14C]KIC or [14C]leucine specific activities. Four separate subjects, treated in a similar manner to the experimental group, received a 24-h infusion of saline and thus served as the controls for time, nutritional status, and level of physical activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Effect of amino acid infusion on renal hemodynamics in humans: a dose-response study.

We evaluated the dose-response relationship between the plasma amino acid (AA) concentration and renal hemodynamics in eight normal subjects. After an overnight fast, a balanced 10% AA solution was infused for 180 min at five separate infusion rates: 0.5 (group I), 1.0 (group II), 2.0 (group III), 4.0 (group IV), and 6.0 (group V) ml.kg-1.min-1 on separate days. Basal plasma AA concentration was 1.87 +/- 0.1 mmol/l and increased to 2.26 +/- 0.1 (group I), 2.66 +/- 0.2 (group II), 3.79 +/- 0.5 (group III), 5.81 +/- 0.4 (group IV), and 7.41 +/- 0.4 mmol/l (group V). Basal glomerular filtration rate (GFR) and renal plasma flow (RPF) averaged 95 +/- 4 and 476 +/- 29 ml.1.73 m-2.min-1, respectively, and rose to 98 +/- 5 and 506 +/- 40 (group I) [P = not significant (NS)], 102 +/- 3 and 533 +/- 30 (group II) (P < 0.05 vs. basal), 110 +/- 4 and 567 +/- 29 (group III), 115 +/- 7 and 610 +/- 55 (group IV), and 117 +/- 7 and 614 +/- 66 ml.1.73 m-2.min-1 (group V) (P = NS vs. group IV). Basal plasma glucagon concentration averaged 68 +/- 10 pg/ml and increased to 74 +/- 10 (group I), 83 +/- 11 (group II) (P < 0.05 vs. basal), 100 +/- 14 (group III), 121 +/- 14 (group IV), and 229 +/- 35 pg/ml (group V) (P < 0.01 vs. basal). Increases in plasma growth hormone (GH) and insulin levels were observed only during groups IV and V.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Diabetic nephropathy.

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Adrenergic beta-Antagonists↗

PubMed1993

Contribution of muscle and liver to glucose-fatty acid cycle in humans.

To examine the influence of elevated free fatty acid (FFA) levels on hepatic glucose production (HGP) and oxidative and nonoxidative pathways of glucose metabolism, 12 healthy subjects participated in two euglycemic insulin-clamp studies performed with and without infusion of Intralipid plus heparin. To elucidate the role of skeletal muscle in this putative interaction, we performed muscle biopsies for the measurement of activities of glycogen synthase (GS), pyruvate dehydrogenase (PDH), and carnitine palmitoyltransferase (CPT). Infusion of Intralipid plus heparin caused an increase in plasma FFA concentrations and rate of lipid oxidation (measured by indirect calorimetry) that was not inhibited by insulin. Suppression of HGP by insulin was impaired by elevated plasma FFA levels. Furthermore, the increase in plasma FFA was associated with a 20% reduction in total glucose metabolism (P < 0.01), which was completely accounted for by a reduction in the rate of glucose oxidation. Although the fractional activity of GS was increased by insulin, elevation of plasma FFA had no influence on this key enzyme of glycogen synthesis. In addition, the activities of PDH and CPT were uninfluenced by the elevation of FFA, suggesting that oxidative processes in skeletal muscle were not a major target for the operative glucose-fatty acid cycle under the current conditions. Taken together, the data indicate that the interaction between FFA and glucose metabolism also involves impaired suppression of HGP by insulin.

Adult↗

PubMed1993

Effects of physiological hyperinsulinemia on the intracellular metabolic partition of plasma glucose.

Methodology for assessing the glycolytic and oxidative fluxes from plasma glucose, by measuring 3H2O and 14CO2 rates of production during [3-3H]- and [U-14C]glucose infusion, was tested in healthy subjects. In study 1, during staircase 3H2O infusion in six subjects, calculated rates of 3H2O appearance agreed closely with 3H2O infusion rates. In study 2, when [2-3H]glucose and NaH14CO3 were infused in four subjects in the basal state and during a 4-h euglycemic insulin (approximately 70 microU/ml) clamp, accurate estimates of the rates of [2-3H]glucose detritiation were obtained (94-97% of the expected values), and the recovery factor of NaH14CO3 did not change during hyperinsulinemia. In study 3, 11 subjects underwent a 4-h euglycemic insulin (approximately 70 microU/ml) clamp with [3-3H]- and [U-14C]glucose infusion and measurement of gaseous exchanges by indirect calorimetry to estimate the rates of total glycolysis, glycogen synthesis, glucose oxidation, nonoxidative glycolysis, hepatic glucose production, glucose recycling, and glucose conversion to fat. Hyperinsulinemia stimulated glycogen synthesis above baseline more than glycolysis [increment of 4.78 +/- 0.37 vs. 2.0 +/- 0.17 mg.min-1 x kg-1 of lean body mass (LBM), respectively, P < 0.01] and incompletely suppressed (approximately 87%) hepatic glucose production. The major component of nonoxidative glycolysis shifted from glucose recycling in the postabsorptive state (approximately 57% of nonoxidative glycolysis) to glucose conversion to fat during hyperinsulinemia (approximately 59% of nonoxidative glycolysis). Lipid oxidation during the insulin clamp was negatively correlated with both isotopic glucose oxidation (r = -0.822, P < 0.002) and glycolysis (r = -0.582, P < 0.07). In conclusion, in healthy subjects, glycogen synthesis plays a greater role than glycolysis and glucose oxidation in determining insulin-mediated glucose disposal. Part of insulin-mediated increase in glycolysis/oxidation might be secondary to the relief of the competition between fat and glucose for oxidation.

Adult↗

PubMed1993

Characterization of cellular defects of insulin action in type 2 (non-insulin-dependent) diabetes mellitus.

Seven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia.

Adult↗

PubMed1993

Effect of insulin on system A amino acid transport in human skeletal muscle.

Transmembrane transport of neutral amino acids in skeletal muscle is mediated by at least four different systems (system A, ASC, L, and Nm), and may be an important target for insulin's effects on amino acid and protein metabolism. We have measured net amino acid exchanges and fractional rates of inward (k(in), min-1) and outward (kout, min-1) transmembrane transport of 2-methylaminoisobutyric acid (MeAIB, a nonmetabolizable amino acid analogue, specific for system A amino acid transport) in forearm deep tissues (skeletal muscle), by combining the forearm perfusion technique and a novel dual tracer ([1-H3]-D-mannitol and 2-[1-14C]-methylaminoisobutyric acid) approach for measuring in vivo the activity of system A amino acid transport. Seven healthy lean subjects were studied. After a baseline period, insulin was infused into the brachial artery to achieve local physiologic hyperinsulinemia (76 +/- 8 microU/ml vs 6.4 +/- 1.6 microU/ml in the basal period, P < 0.01) without affecting systemic hormone and substrate concentrations. Insulin switched forearm amino acid exchange from a net output (-2,630 +/- 1,100 nmol/min per kig of forearm tissue) to a net uptake (1,610 +/- 600 nmol/min per kg, P < 0.01 vs baseline). Phenylalanine and tyrosine balances simultaneously shifted from a net output (-146 +/- 47 and -173 +/- 34 nmol/min per kg, respectively) to a zero balance (16.3 +/- 51 for phenylalanine and 15.5 +/- 14.3 nmol/min per kg for tyrosine, P < 0.01 vs baseline for both), showing that protein synthesis and breakdown were in equilibrium during hyperinsulinemia. Net negative balances of alanine, methionine, glycine, threonine and asparagine (typical substrates for system A amino acid transport) also were decreased by insulin, whereas serine (another substrate for system A transport) shifted from a zero balance to net uptake. Insulin increased k(in) of MeAIB from a basal value of 11.8.10(-2) +/- 1.7.10(-2).min-1 to 13.7.10(-2) +/- 2.2.10(-2).min-1 (P < 0.02 vs the postabsorptive value), whereas kout was unchanged. We conclude that physiologic hyperinsulinemia stimulates the activity of system A amino acid transport in human skeletal muscle, and that this effect may play a role in determining the overall concomitant response of muscle amino acid/protein metabolism to insulin.

Adult↗