Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation

We tested whether FFAs influence glucose uptake by human peripheral tissues in vivo. Whole body glucose uptake, FFA turnover, energy expenditure and substrate oxidation rates, forearm glucose and FFA uptake, and nonoxidative glycolysis (net release of alanine and lactate) were measured in 14 normal male subjects in the basal state (0-240 min; serum insulin, approximately 5 microU/mL) and during euglycemic hyperinsulinemia (240-360 min; approximately 75 microU/mL) on 2 separate occasions, once during elevation of plasma FFA by infusions of Intralipid and heparin (plasma FFA, 4.6 +/- 0.1 vs. 4.2 +/- 0.4 mmol/L; 180-240 vs. 300-360 min) and once during infusion of saline (plasma FFA, 0.50 +/- 0.07 vs. 0.02 +/- 0.07 mmol/L, respectively). In the basal state, whole body glucose disposal remained unchanged, but the fate of glucose was significantly altered toward diminished oxidation (7.3 +/- 0.8 vs. 5.6 +/- 0.5 mumol/kg.min; P less than 0.05, saline vs. Intralipid) and increased nonoxidative glycolysis (P less than 0.05). Elevation of plasma FFA significantly increased forearm glucose uptake (1.0 +/- 0.6 vs. 2.4 +/- 0.7 mumol/kg.min; P less than 0.01) and nonoxidative glycolysis (net release of alanine and lactate, 0.4 +/- 0.5 vs. 1.2 +/- 0.4 mumol glucose equivalents/kg.min; P less than 0.05). During hyperinsulinemia, FFA decreased whole body glucose disposal (38 +/- 2 vs. 30 +/- 3 mumol/kg.min; P less than 0.001) due to a decrease in glucose oxidation (13 +/- 1 vs. 7 +/- 1 mumol/kg.min; P less than 0.01, saline vs. Intralipid), and forearm glucose uptake (31 +/- 4 vs. 24 +/- 6 mumol/kg.min; P less than 0.01, saline vs. Intralipid). Under these conditions, 7 +/- 2% and 3 +/- 1% (P less than 0.05) of forearm glucose uptake could be accounted for by nonoxidative glycolysis in the Intralipid and saline studies, respectively. In summary, 1) elevation of plasma FFA concentrations suppresses the rate of carbohydrate oxidation to a rate that, both basally and during hyperinsulinemia, is similar to that reported for insulin-independent glucose oxidation in the brain; 2) basally, forearm glucose uptake is increased by FFA; and 3) during hyperinsulinemia, FFA inhibit glucose uptake by forearm tissues. We conclude that the interaction between glucose and FFA fuels in human forearm tissues is dependent upon the ambient insulin concentration; the increase in basal glucose uptake would be compatible with the increase need of glucose for FFA reesterification; the decrease in insulin-stimulated glucose uptake supports operation of the glucose-FFA cycle in human forearm tissues.     

Metabolic control during total parenteral nutrition: use of an artificial endocrine pancreas

The metabolic impact of total parenteral nutrition (TPN) was evaluated in nine subjects who underwent esophagogastroplasty for esophageal carcinoma. On the second day after operation all subjects were connected to an artificial endocrine pancreas. In four patients only glucose was infused (5.5 mg/kg X min). The remaining five subjects received glucose (4.0 mg/kg X min), amino acid (0.5 mg/kg X min), and lipid emulsion (0.6 mg/kg X min). Plasma glucose concentration was kept constant over 24 hours. However, both insulin requirement (111 +/- 15 v 70 +/- 2 mU/kg X h) and plasma insulin level (99 +/- 15 v 30 +/- 7 microU/mL; P less than .01) were higher during combined TPN. Blood lactate concentration was higher during glucose infusion (P less than .05). No difference was found in blood concentrations of pyruvate, alanine, and ketone bodies. Both glycerol and FFA were higher during combined TPN. The ratio between glucose infusion rate and the average plasma insulin level was calculated as an index of insulin-mediated glucose metabolism; G/I X 100 was markedly reduced during combined TPN (4.5 +/- 0.8 v 20.7 +/- 3.7; P less than .05). Plasma FFA levels were positively correlated with plasma insulin concentration (r = .76) and inversely correlated to G/I X 100 (r = -.73; both P less than .05). In conclusion, during combined TPN a state of insulin resistance is induced and more insulin is required to achieve a normal glucose utilization.     

Substrate availability other than glucose in the brain during euglycemia and insulin-induced hypoglycemia in dogs

Alternative substrates other than glucose could be used by the brain. In this study we hypothesized that lactate and ketone bodies can provide a significant portion of oxidative brain substrates in insulin-dependent diabetes mellitus (IDDM). Six control (C) and six insulin-treated streptozotocin diabetic (IDDM) dogs were studied during euglycemia (EU) and acute insulin induced hypoglycemia (HYPO). During EU for similar plasma glucose concentration (5.5 +/- 0.4 v 5.2 +/- 0.2 mmol/L in IDDM dogs showed a higher baseline lactate concentration (1.5 +/- 0.25 v 0.74 +/- 0.10 mmol/L; P less than .05). The ketone body concentrations were also increased in IDDM dogs but this increase was not statistically significant. The brain glucose uptake was 6.9 +/- 0.6 mumol/kg/min in C and 5.4 +/- 0.7 in IDDM. Lactate was released by the brain both in IDDM dogs (11.36 +/- 1.8 mumol/kg/min) and in C dogs (3.87 +/- 0.9; P less than .05). The brain ketones rate of disappearance (Rd) was 0.3 +/- 0.05 mumol/kg/min in IDDM dogs and 0.19 +/- 0.08 in C dogs. During HYPO the glucose uptake across the brain was 2.88 +/- 0.7 mumol/kg/min in IDDM and 3.12 +/- 0.5 in C dogs. We observed an overall brain lactate release (3.21 +/- 1.7 mol/kg/min) in C dogs and a net uptake (13.44 +/- 1.1; P less than .01) in IDDM (P less than .01). The brain ketones Rd was 0.1 +/- 0.2 mumol/kg/min in IDDM and 0.1 +/- 0.1 in C dogs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epinephrine directly antagonizes insulin-mediated activation of glucose uptake and inhibition of free fatty acid release in forearm tissues.

To determine whether the anti-insulin effect of epinephrine is due to a direct antagonism on target tissues or is mediated by indirect mechanisms (systemic substrate and/or hormone changes), insulin and epinephrine were infused intrabrachially in five normal volunteers using the forearm perfusion technique. Insulin (2.5 mU/min) was infused alone for 90 minutes and in combination with epinephrine (25 ng/min) for an additional 90 minutes, so as to increase the local concentrations of these hormones to physiological levels (60 to 75 microU/mL and 200 to 250 pg/mL for insulin and epinephrine, respectively). Systemic plasma glucose and free fatty acids (FFA) concentrations remained stable at their basal values during local hormone infusion. Forearm glucose uptake (FGU) increased in response to insulin alone from 0.8 +/- 0.2 mg.L-1.min-1 to 4.3 +/- 0.8. Addition of epinephrine completely abolished the insulin effect on FGU, which returned to its preinfusion value (0.7 +/- 0.2). Forearm lactate release was slightly increased by insulin alone, but rose markedly on addition of epinephrine (from 5.2 +/- 0.8 mumol.L-1.min-1 to 17 +/- 2; P less than .02). During infusion of insulin alone, forearm FFA release (FFR) decreased significantly from the postabsorptive value of 1.76 +/- 0.25 mumol.L-1.min-1 to 1.05 +/- 0.11 (P less than .01). Epinephrine addition reverted insulin suppression of FFR, which returned to values slightly above baseline (2.06 +/- 0.47 mumol.L-1.min-1; P less than .05 v insulin alone). The data demonstrate that epinephrine is able to antagonize directly insulin action on forearm tissues with respect to both stimulation of glucose uptake and inhibition of FFA mobilization.     

Fuel metabolism in anorexia nervosa and simple obesity

To examine insulin sensitivity and the relative contribution of different fuels to energy metabolism in anorexia nervosa and obesity, we measured oxidation (indirect calorimetry) of glucose, lipids, and proteins in the basal state and during an insulin clamp (+45 mU/m2.min) in 11 women with anorexia nervosa (age, 25 +/- 3 years; body mass index [BMI], 13.6 +/- 0.4 kg/m2; fat mass, 15.7% +/- 1.6%), eight obese women (age, 31 +/- 3; BMI 36.0 +/- 1.5; fat mass, 47.1% +/- 1.9%), and eight controls (age, 26 +/- 3; BMI, 21.8 +/- 0.9; fat mass, 25.7% +/- 3.6%). Expressed per lean body mass, (LBM), glucose disposal was equally reduced in anorectics (7.53 +/- 0.62 mg/kg LBM.min) and obese (6.80 +/- 1.07 mg/kg LBM.min) compared with controls (10.64 +/- 0.69 mg/kg LBM.min; P less than .01). The reduction in glucose disposal in anorectics was primarily due to a significant (P less than .01) reduction in glucose storage, while glucose oxidation was normal. In obese women, both storage and oxidation of glucose were reduced compared with controls (P less than .01). Basal energy expenditure was similar in anorectic, obese, and control subjects (20.6 +/- 1.00, 23.7 +/- 0.56, 23.2 +/- 1.36 cal/kg LBM.min, respectively). However, the contribution of glucose, lipids, and proteins to basal energy expenditure differed between anorectic (62%, 16%, 22%), obese (26%, 58%, 16%), and control (30%, 54%, 16%) subjects (P less than .05 v all). In conclusion, in anorexia nervosa, insulin stimulates glucose oxidation more than storage. In obesity, both components of insulin-stimulated glucose metabolism are impaired.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolic response of the canine neonate to twenty-four hours of fasting

The metabolic effects of 24 hours of neonatal fasting in unanesthetized dogs were compared to fasting for three hours during the first day of life. Blood glucose, lactate, and ketones were unaltered while FFA (0.94 +/- 0.07 v 0.70 +/- 0.04 mmol/L, P less than .01), glycerol (0.21 +/- 0.01 v 0.12 +/- 0.01 mmol/L, P less than .01), and triglycerides (0.41 +/- 0.03 v 0.23 +/- 0.03 mmol/L, P less than .01) were lower at 24 hours. Glucose production and lactate and alanine turnover were unaffected while palmitate turnover declined (8.8 +/- 0.7 v 5.1 +/- 0.5 mumol/kg/min, P less than .01). Oxygen consumption decreased (6.9 +/- 0.4 v 6.0 +/- 0.3 mL/kg/min, P less than .02) while RQ increased (0.79 +/- 0.02 v 0.86 +/- 0.03, P less than 0.05) at 24 hours. Hepatic glycogen content declined (575 +/- 37 to 266 +/- 32 mumol/g, P less than .001) and could account for a GP of 12 mumol/kg/min between 3 and 24 hours of age. Both gluconeogenesis from lactate and alanine increased, together accounting for 7% and 21% of glucose production at 3 and 24 hours. The increment in gluconeogenesis may be facilitated by augmented hepatic cytosolic phosphoenolpyruvate carboxykinase at 24 hours (1.8 +/- 0.2 v 14.1 +/- 0.8 nmol/min mg protein, P less than .01). Despite the decline in VO2, hepatic ATP and energy charge were unaltered by 24 hours of fasting. These data suggest that FFA availability diminishes during a prolonged neonatal canine fast resulting in lower VO2. Furthermore, as FFA availability declines, glucose utilization becomes the predominant precursor for energy production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans.

To examine mechanisms of insulin resistance, nine patients (age 33 +/- 4 yr, body mass index 22 +/- 1 kg/m2) with acute bacterial or viral infections and in six matched normal subjects were studied. Endogenous glucose appearance (Ra), glucose disappearance (Rd), and recycling, the percentage of plasma lactate originating from plasma glucose, total glucose oxidation, and whole body and forearm muscle Rd were measured after an overnight fast in the basal state and during physiological hyperinsulinemia (serum insulin approximately 215 pmol/L). Basally Ra, Rd, glucose recycling, and oxidation were similar in both groups. During hyperinsulinemia, insulin stimulated plasma Rd approximately 35% less (17.6 +/- 1.3 vs. 26.8 +/- 3.6 mumol/kg.min, P less than 0.01, patients vs. normal subjects), and inhibited endogenous Ra less in the patients (from 13.3 +/- 0.8 to 5.3 +/- 0.8 mumol/kg.min) than in the normal subjects (from 12.8 +/- 1.0 to 2.1 +/- 1.2 mumol/kg.min, P less than 0.01). The decrease in whole body Rd was largely explained by a approximately 75% reduction in muscle Rd (5.6 +/- 1.5 vs. 20.8 +/- 3.3 mumol/kg muscle.min, P less than 0.01, patients vs. normal subjects). The defect in Rd was confined to nonoxidative (4.8 +/- 1.1 vs. 11.0 +/- 3.0 mumol/kg.min, P less than 0.01, patients vs. normal subjects) but not to oxidative glucose metabolism. The percentage of plasma lactate derived from plasma glucose during hyperinsulinemia averaged 63 +/- 6% in the patients and 79 +/- 5% in the normal subjects, indicating that glycogenolysis did not excessively dilute glycolytic carbons in the patients. We conclude that during natural infections in humans, abnormal glucose metabolism is confined to the insulin-stimulated state and involves a marked defect in muscle glucose uptake and glycogen synthesis, as well as a less marked hepatic defect.     

Role of impaired intracellular glucose metabolism in the insulin resistance of aging.

The insulin resistance of aging is characterized by both reduced glucose uptake and impaired intracellular glucose metabolism. The aim of this study was to determine whether impaired intracellular glucose metabolism contributes to insulin resistance in the elderly independent of reduced glucose uptake. To address this question, glucose uptake in non-obese elderly males was matched to controls using the glucose clamp technique, and intracellular glucose metabolism was assessed in vivo by indirect calorimetry and in vitro by skeletal muscle biopsy for glycogen synthase activity. When elderly subjects were compared with controls at an equivalent basal glucose uptake of approximately 2.5 mg/kg fat-free mass (FFM)/min, muscle glycogen synthase activity was similar (fractional velocity of glycogen synthase at 0.1 mmol/L glucose-6-phosphate [FV0.1], 0.06 +/- 0.1 and 0.07 +/- 0.1), but whole-body rates of glucose oxidation were reduced (1.36 +/- 0.12 v 1.90 +/- 0.11 mg/kg FFM/min, P less than .05). During 40-mU/m2/min hyperinsulinemic clamps at matched rates of glucose uptake (approximately 10.7 mg/kg FFM/min in both groups), glycogen synthase activity was again similar (FV0.1, 0.15 +/- 0.02 and 0.14 +/- 0.02), and glucose oxidation remained reduced in the elderly (4.18 +/- 0.25 v 4.77 +/- 0.17 mg/kg FFM/min, P less than .05). Only during clamps in the maximal range of glucose uptake (approximately 29.5 mg/kg FFM/min) was glucose oxidation between the groups comparable (5.97 +/- 0.50 and 5.75 +/- 0.31 mg/kg FFM/min). Plasma free fatty acid (FFA) concentrations, fat oxidation, and protein oxidation were similar under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus

This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM, and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose, insulin, TG, and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly, plasma glucose, insulin, HGP, concentrations fell significantly, plasma glucose, insulin, HGP, and glucose MCR did not change. However, when patients were divided into two groups, those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control), a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001), insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001), FFA (652 +/- 150 to 504 +/- 76 mumol/L), and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005), and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05), the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001), neither insulin, FFA, HGP, nor glucose MCR changed in patients in good control. Furthermore, the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02), but, as before, the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).     

The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats

The effect of a new drug (CP 68,722, Pfizer) on parameters of insulin sensitivity in an established insulin-resistant animal model was examined. Rates of hepatic glucose production (HGP) and peripheral glucose uptake in obese Zucker (fa/fa) rats treated with a 10-day course of the medication using a two-step (2 and 10 mU/kg/min) euglycemic hyperinsulinemic clamp technique were measured. In addition, changes in substrate concentrations after drug treatment were examined. Basal HGP rates were similar in the lean versus the obese animals (37 +/- 3 v 39 +/- 3 mumol/kg/min); however, the obese animals had impaired insulin-induced suppression of HGP at both 2 mU/kg/min (36 +/- 3 v 23 +/- 4 mumol/kg/min) and 10 mU/kg/min (18 +/- 5 v 2 +/- 1 mumol/kg/min). Insulin stimulation of glucose disposal was also defective in the obese animals (37 +/- 2 v 88 +/- 7 mumol/kg/min at 2 mU/kg/min and 98 +/- 9 v 219 +/- 18 mumol/kg/min at 10 mU/kg/min). In addition, obese animals had elevated free fatty acid (FFA) and ketone levels, both of which were resistant to insulin-induced suppression. After drug treatment, few alterations in glucose or lipid metabolism were found in the lean animals. In the obese animals, insulin suppression of HGP was normalized during the higher insulin infusion rate (0 v 18 +/- 5 mumol/kg/min at 10 mU/kg/min), and peripheral glucose disposal was enhanced at both steps of the insulin clamp (54 +/- 4 v 37 +/- 2 mumol/kg/min at 2 mU/kg/min and 134 +/- 12 v 98 +/- 9 mumol/kg/min at 10 mU/kg/min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of the rise in FFA by Acipimox partially prevents GH-induced insulin resistance in GH-deficient adults.

To test the hypothesis that GH-induced insulin resistance is mediated by an increase in FFA levels we assessed insulin sensitivity after inhibiting the increase in FFA by a nicotine acid derivative, Acipimox, in nine GH-deficient adults receiving GH replacement therapy. The patients received in a double blind fashion either Acipimox (500 mg) or placebo before a 2-h euglycemic (plasma glucose, 5.5 +/- 0.2 mmol/liter) hyperinsulinemic (serum insulin, 28.7 +/- 6.3 mU/liter) clamp in combination with indirect calorimetry and infusion of [3-(3)H]glucose. Acipimox decreased fasting FFA by 88% (P = 0.012) and basal lipid oxidation by 39% (P = 0.015) compared with placebo. In addition, the insulin-stimulated lipid oxidation was 31% (P = 0.0077) lower during Acipimox than during placebo. Acipimox increased insulin-stimulated total glucose uptake by 36% (P = 0.021) compared with placebo, which mainly was due to a 47% (P = 0.015) increase in glucose oxidation. GH induced insulin resistance is partially prevented by inhibition of lipolysis by Acipimox.     

Severity, duration, and mechanisms of insulin resistance during acute infections

Acute infections provoke insulin resistance. These experiments were designed to study the severity, duration, and mechanisms of insulin resistance caused by acute infections. First, we studied eight patients [mean age, 29 +/- 11 (+/- SD) yr; body mass index, 23 +/- 2 kg/m2] with acute viral or bacterial infections during the acute stage of their infection and 1-3 months after recovery. The rate of glucose infusion required to maintain normoglycemia during hyperinsulinemia (approximately 500 pmol/L) was used as a measure of insulin action. During infection, the glucose requirements in the patients [21 +/- 2 (+/- SE) mumol/kg.min] were 52% less than those in weight- and age-matched normal subjects (44 +/- 2 mumol/kg.min; P less than 0.001). Compared to data from a large group of normal subjects, the resistance to insulin during infection corresponded to that predicted for a weight-matched 84-yr-old normal person or an age-matched obese person with a body mass index of 37 kg/m2. One to 3 months after recovery, the patients' glucose requirements were still significantly lower (37 +/- 3 mumol/kg.min; P less than 0.02) than those in matched normal subjects. To assess the mechanism of insulin resistance, seven additional patients were studied during the acute stage of infection using a low dose insulin infusion (plasma insulin, 215 pmol/L) combined with a [3-3H]glucose infusion and indirect calorimetry. Again, the glucose requirements were 59% lower in the patients (14 +/- 2 mumol/kg.min) than in matched normal subjects (34 +/- 2 mumol/kg.min; P less than 0.001). This decrease was due to a defect in glucose utilization (18 +/- 2 vs. 37 +/- 1 mumol/kg.min; P less than 0.001, patients vs. normal subjects) rather than impaired suppression of glucose production (4 +/- 1 vs. 3 +/- 1 mumol/kg.min, respectively). Total carbohydrate oxidation rates were similar in both groups (16 +/- 2 vs. 14 +/- 1 mumol/kg.min, respectively), whereas the apparent glucose storage was neglible in the patients (2 +/- 1 mumol/kg.min) compared to that in normal subjects (22 +/- 2 mumol/kg.min; P less than 0.001). We conclude that acute infections induce severe and long-lasting insulin resistance, which is localized to glucose-utilizing pathways. The rate of carbohydrate oxidation is normal during infections, whereas the rate of nonoxidative glucose disposal, as determined by indirect calorimetry, is nearly zero. The apparent blockade in glucose storage could result from diminished glycogen synthesis, accelerated glycogenolysis, or both.     

Role of the splanchnic tissues in the pathogenesis of altered carbohydrate metabolism in patients with chronic renal failure

To evaluate the contribution of the splanchnic area to the carbohydrate abnormalities associated with chronic uremia, the splanchnic exchange of glucose and gluconeogenic substrates was quantitated basally and after an iv glucose load in nine uremic patients with impaired glucose tolerance and seven control subjects. In the basal state, blood glucose and splanchnic glucose production were similar in the two groups. During glucose infusion (33 mumol/kg.min for 90 min), blood glucose reached significantly higher levels in the uremic patients than in controls (P less than 0.02). Plasma insulin increased slightly more in uremic patients than in controls (P less than 0.05 at 15 min). Both basal and postglucose glucagon levels were 2- to 3-fold higher in uremic patients than in normal subjects (P less than 0.05-0.02). In both groups, splanchnic glucose balance switched from net output in the basal state (-9.4 +/- 0.5 and -8.0 +/- 1.1 mumol/kg.min in normals and uremics, respectively) to net uptake with glucose infusion. However, this response was less marked in the uremic patients than in normal subjects (P less than 0.05-0.02 at 30 and 90 min). The cumulative net splanchnic glucose balance over the 90-min study period was 538 +/- 55 mumol/kg in normal subjects and 279 +/- 89 in uremic subjects (P less than 0.05). A net splanchnic lactate uptake was present in the basal state in normal (4.2 +/- 0.5 mumol/kg.min) and uremic subjects (3.4 +/- 0.5). During glucose infusion, in normal subjects splanchnic lactate exchange switched to a net output (-4.0 +/- 1.6 mumol/kg.min), whereas in the uremic group it remained as a net uptake (1.1 +/- 0.7) throughout the study period. Splanchnic gluconeogenic amino acid uptake was similar in the two groups in the basal state (1.8 +/- 0.1 mumol/kg.min and 2.2 +/- 0.2 in normal and uremic subjects, respectively). Glucose infusion caused a marked fall in amino acid uptake by liver in normal subjects, whereas no change was observed in the uremic group (0.9 +/- 0.3 and 1.9 +/- 0.2 mumol/kg.min, respectively). Splanchnic glycerol uptake was not different in the two groups in the basal state (0.75 +/- 0.2 and 1.1 +/- 0.2 mumol/kg.min) and decreased to a similar extent during glucose infusion. We conclude the following. 1) In uremic patients with glucose intolerance but normal fasting glycemia, the splanchnic metabolism of glucose and gluconeogenic substrates is normal in the postabsorptive state.(ABSTRACT TRUNCATED AT 400 WORDS)     

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.     

The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans

The effect of 48-hour starvation on glucose metabolism was studied in six non-diabetic, normal weight men using a hyperinsulinemic (100 mU/min/m2) glucose clamp (3.5 mmol/L). The rate of glucose oxidation was calculated from measurements of respiratory gas exchange, after allowing for the oxidation of ketones and of protein. During the glucose clamp, the whole body glucose disposal rate decreased from 39.8 (SEM 4.6) mumol/kg/min in the fed state to 24.1 (2.1) mumol/kg/min in the starved state (P less than .01), consistent with insulin "resistance." The glucose oxidation rate decreased from 21.8 (1.3) to 3.9 (1.4) mumol/kg/min with starvation (P less than .001), but the nonoxidative glucose disposal rate was unchanged (18.0 [3.9] mumol/kg/min normally fed, and 20.2 [1.2] mumol/kg/min starved). With starvation, the rate of glucose uptake in the forearm during the glucose clamp was reduced from 59.4 to 15.4 mumol/min/L forearm (SE 5.6, P less than .01, ANOVA). There was a significant net increase in thermogenesis during the glucose clamp in the normally fed state (0.27 [0.08] kJ/min, P less than .01, ANOVA), but not following starvation (0.11 [0.09] kJ/min, NS, ANOVA). Therefore, starvation caused decreases in oxidative glucose disposal and in forearm glucose uptake; despite the whole body nonoxidative disposal rate of glucose being unchanged, the associated net thermogenic response was diminished.     

Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment.We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.     

Failure of carbohydrate to spare leucine oxidation in obese subjects

Leucine kinetics were studied in six obese subjects (W/H2 = 39 +/- 4) and six normal subjects (W/H2 = 21 +/- 3) before and after an oral load of 150 g glucose. An intravenous infusion of 1(-13)C leucine was given to the fasting subjects for 450 min: a steady state of plasma leucine enrichment was established 90 min after the start of the infusion, and the glucose load was given 220 min after the start of the infusion. Compared with the lean controls the obese subjects showed a greater area under the curve of blood glucose after the glucose load (P less than 0.025) and higher insulin and glucagon levels both before and after the meal (P less than 0.05), thus indicating the well-known insulin insensitivity of obese (but not diabetic) subjects with respect to glucose metabolism. After the glucose load the lean subjects showed a significant and sustained decrease in leucine oxidation (from 20.0 +/- 2.2 to 13.3 +/- 1.5 mumol/kg LBM/h: P less than 0.01). This response is similar to that observed when insulin-dependent diabetic subjects are given insulin. However the obese subjects showed no decrease in leucine oxidation after the glucose meal (20.3 +/- 1.9 before, and 21.2 +/- 3.6 after). This indicates that obese subjects show insensitivity to the action of insulin with respect to protein metabolism as well as carbohydrate metabolism.     

Effect of steroid-therapy on insulin sensitivity in insulin-dependent diabetic patients after kidney transplantation

Little information is available on glucose and energy metabolism in insulin-dependent diabetes mellitus (IDDM) patients receiving immunosuppression after kidney transplantation. We therefore measured insulin sensitivity (euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) in (a) eight steroid-treated IDDM patients after kidney transplantation, (b) ten IDDM patients without nephropathy, (c) ten nondiabetic patients after kidney transplantation, and (d) ten healthy control subjects. Hepatic glucose production was enhanced in both steroid-treated transplanted IDDM patients [4.8 ± 0.6 mg/kg lean body mass (LBM)·min] and IDDM patients without complications (3.8 ± 0.2 mg/kg LBM·min) compared with nondiabetic renal graft recipients and with healthy controls (2.8 ± 0.2 and 2.7 ± 0.1 mg/kg LBM·min; p < 0.01). Insulin-stimulated glucose disposal was reduced in transplanted and non-transplanted IDDM patients and nondiabetic transplanted patients versus healthy controls (6.6 ± 0.8, 5.7 ± 0.7, and 7.5 ± 0.6 versus 9.3 ± 0.6 mg/kg LBM·min; p < 0.05). This reduction was mainly due to an impairment in nonoxidative glucose metabolism, i.e., glycogen synthesis (3.1 ± 0.6, 2.7 ± 0.4, and 3.3 ± 0.5 versus 5.0 ± 0.5 mg/kg LBM·min; p < 0.05 versus healthy controls). It is concluded that IDDM patients without nephropathy show both hepatic and peripheral insulin resistance. In IDDM patients a further increase of insulin resistance caused by treatment with corticosteroids can be corrected by increased insulin doses. However, nondiabetic steroid-treated renal graft recipients show insulin resistance comparable to IDDM patients.     

Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects

We studied the effects of hypocaloric diet (500 kcal/d) and insulin therapy in 15 obese (body mass index greater than 30.0 kg/m2) non-insulin-dependent diabetic patients with secondary drug failure and poor metabolic control. The patients were randomly allocated either to hypocaloric diet (n = 8) or to insulin treatment (n = 7). After 2 weeks of treatment there was a significant improvement in the fasting blood glucose, in the mean diurnal glucose, in glucosuria, and in glucose response to a 75-g oral glucose load in both groups. No change in insulin secretion was seen in either group. Glucose disposal rates (GDR) improved significantly both in the diet-treated group (from 2.34 +/- 0.15 to 4.01 +/- 0.40 mg/kg/min, P less than .01) and in the insulin-treated group (from 2.46 +/- 0.33 to 2.77 +/- 0.29 mg/kg/min, P less than .01). The improvement was greater in the diet-treated group (71%) than in the insulin-treated group (13%, P less than .05). The increase of GDR in the diet-treated group was due to an increase of nonoxidative GDR (from 1.18 +/- 0.17 to 2.98 +/- 0.39 mg/kg/min, P less than .001) as assessed by indirect calorimetry. In the insulin-treated group there was a small increase both in oxidative and nonoxidative GDR, but the changes were not statistically significant. Hepatic glucose output (HGO) in a postabsorptive state decreased significantly both in the diet-treated group (from 2.49 +/- 0.15 to 2.04 +/- 0.10 mg/kg/min, P less than .01) and in the insulin-treated group (from 2.63 +/- 0.23 to 2.05 +/- 0.12 mg/kg/min, P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of superphysiologic hyperinsulinemia on glucose and lipid metabolism in glucose-tolerant offspring of patients with non-insulin-dependent diabetes mellitus (NIDDM).

First-degree relatives of patients with NIDDM manifest severe insulin resistance despite normal glucose tolerance test. To examine the mechanisms underlying the normal glucose tolerance, we evaluated the serum glucose/C-peptide/insulin dynamics and free fatty acid (FFA) as well as substrate oxidation rates and energy expenditure (EE) (indirect calorimetry) in nine young offspring of NIDDM patients (mean +/- SEM age 30 +/- 2.3 years, body mass index 24.2 +/- 1.2 kg/m2). Nine age-, sex- and weight-matched, normal subjects with no family history of diabetes served as the controls. Metabolic parameters were measured before, during and after a two-step glucose infusion (2 and 4 mg/kg.min) for 120 min. Mean basal serum glucose, insulin and C-peptide levels were similar in both groups. During 2 mg/kg.min glucose infusion, mean serum insulin and C-peptide rose to significantly (P less than 0.05-0.02) greater levels in the offspring vs. controls, while serum glucose levels were similar. With the 4 mg/kg.min glucose infusion, mean serum glucose, insulin and C-peptide levels were significantly (P less than 0.02-0.001) greater in the offspring at 100-120 min. Isotopically-derived (D[3-3H]glucose), basal hepatic glucose output (HGO) was not significantly different between the offspring vs. controls (1.86 +/- 0.30 vs. 1.78 +/- 0.06 mg/kg.min). During glucose infusion, basal HGO was partially suppressed by 66% at 60 min and by 100% at 120 min in the offspring. In contrast, HGO was completely (100%) suppressed at both times in the controls. Following cessation of glucose infusion, HGO rose to 1.64 +/- 0.12 mg/kg.min in the offspring and 1.46 +/- 0.05 mg/kg.min in the controls (P less than 0.05) between 200 and 240 min. These were 88% and 82% of the respective basal HGO values. At low glucose infusion (t = 0-60 min), the mean absolute, non-oxidative glucose disposal remained 1.5-fold greater in the offspring while at higher glucose infusion, nonoxidative glucose metabolism was not different in both groups. Throughout the study period, oxidative glucose disposal rate was not significantly different in both groups. The mean basal FFA was significantly greater in the offspring vs. controls (865 +/- 57 vs. 642 +/- 45 microEq/l). It was appropriately suppressed during glucose infusion to a similar nadir in both groups (395 +/- 24 vs. 375 +/- 33 microEq/l). The mean basal lipid oxidation was also significantly greater in the offspring than controls (1.06 +/- 0.05 vs. 0.75 +/- 0.04 mg/kg.min, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)