Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulin-dependent diabetic subjects

The relationships between insulin secretion, insulin action, and fasting plasma glucose concentration (FPG) were examined in 34 southwest American Indians (19 nondiabetics, 15 noninsulin-dependent diabetics) who had a broad range of FPG (88-310 mg/100 ml). Fasting, glucose-stimulated, and meal-stimulated plasma insulin concentrations were negatively correlated with FPG in diabetics but not in nondiabetics. In contrast, fasting and glucose-stimulated plasma C-peptide concentrations did not decrease with increasing FPG in either group and 24-h urinary C-peptide excretion during a diet of mixed composition was positively correlated with FPG for all subjects (r = 0.36, P less than 0.05). Fasting free fatty acid (FFA) was correlated with FPG in nondiabetics (r = 0.49, P less than 0.05) and diabetics (r = 0.77, P less than 0.001). Fasting FFA was also correlated with the isotopically determined endogenous glucose production rate in the diabetics (r = 0.54, P less than 0.05). Endogenous glucose production was strongly correlated with FPG in the diabetics (r = 0.90, P less than 0.0001), but not in the nondiabetics. Indirect calorimetry showed that FPG was also negatively correlated with basal glucose oxidation rates (r = -0.61, P less than 0.001), but positively with lipid oxidation (r = 0.74, P less than 0.001) in the diabetics. Insulin action was measured as total insulin-mediated glucose disposal, glucose oxidation, and storage rates, using the euglycemic clamp with simultaneous indirect calorimetry at plasma insulin concentrations of 135 +/- 5 and 1738 +/- 59 microU/ml. These parameters of insulin action were significantly, negatively correlated with FPG in the nondiabetics at both insulin concentrations, but not in the diabetics although all the diabetics had markedly decreased insulin action. We conclude that decreased insulin action is present in the noninsulin-dependent diabetics in this population and marked hyperglycemia occurs with the addition of decreased peripheral insulin availability. Decreased peripheral insulin availability leads to increased FFA concentrations and lipid oxidation rates (and probably also increased concentrations of gluconeogenic precursors) that together stimulate gluconeogenesis, hepatic glucose production, and progressive hyperglycemia.     

Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.

To characterize glucose counterregulatory mechanisms in patients with noninsulin-dependent diabetes mellitus (NIDDM) and to test the hypothesis that the increase in glucagon secretion during hypoglycemia occurs primarily via a paracrine islet A-B cell interaction, we examined the effects of a subcutaneously injected therapeutic dose of insulin (0.15 U/kg) on plasma glucose kinetics, rates of glucose production and utilization, and their relationships to changes in the circulating concentrations of neuroendocrine glucoregulatory factors (glucagon, epinephrine, norepinephrine, growth hormone, and cortisol), as well as to changes in endogenous insulin secretion in 13 nonobese NIDDM patients with no clinical evidence of autonomic neuropathy. Compared with 11 age-weight matched nondiabetic volunteers in whom euglycemia was restored primarily by a compensatory increase in glucose production, in the diabetics there was no compensatory increase in glucose production (basal 2.08 +/- 0.04----1.79 +/- 0.07 mg/kg per min at 21/2 h in diabetics vs. basal 2.06 +/- 0.04----2.32 +/- 0.11 mg/kg per min at 21/2 h in nondiabetics, P less than 0.01) despite the fact that plasma insulin concentrations were similar in both groups (peak values 22 +/- 2 vs. 23 +/- 2 microU/ml in diabetics and nondiabetics, respectively). This abnormality in glucose production was nearly completely compensated for by a paradoxical decrease in glucose utilization after injection of insulin (basal 2.11 +/- 0.03----1.86 +/- 0.06 mg/kg per min at 21/2 h in diabetics vs. basal 2.08 +/- 0.04----2.39 +/- 0.11 mg/kg per min at 21/2 h nondiabetics, P less than 0.01), which could not be accounted for by differences in plasma glucose concentrations; the net result was a modest prolongation of hypoglycemia. Plasma glucagon (area under the curve [AUC] above base line, 12 +/- 3 vs. 23 +/- 3 mg/ml X 12 h in nondiabetics, P less than 0.05), cortisol (AUC 2.2 +/- 0.5 vs. 4.0 +/- 0.7 mg/dl X 12 h in nondiabetics, P less than 0.05), and growth hormone (AUC 1.6 +/- 0.4 vs. 2.9 +/- 0.4 micrograms/ml X 12 h in nondiabetics, P less than 0.05) responses in the diabetics were decreased 50% while their plasma norepinephrine responses (AUC 49 +/- 12 vs. 21 +/- 5 ng/ml X 12 h in nondiabetics, P less than 0.05) were increased twofold (P less than 0.05) and their plasma epinephrine responses were similar to those of the nondiabetics (AUC 106 +/- 17 vs. 112 +/- 10 ng/ml X 12 h in nondiabetics). In both groups of subjects, increases in plasma glucagon were inversely correlated with plasma glucose concentrations (r = -0.80 in both groups, P less than 0.01) and suppression of endogenous insulin secretion (r = -0.57 in nondiabe     

Effect of insulin-glucose infusions on plasma glucagon levels in fasting diabetics and nondiabetics.

The effect of the intravenous infusion of insulin plus glucose on plasma glucagon levels was studied in hyperglycemic fasting adult-type and juvenile-type diabetics and compared with fasting nondiabetics. Adult-type diabetics were given insulin for 2 h at a rate of 0.03 U/kg-min, raising their mean insulin to between 25 and 36 muU/ml; glucagon declined from a base-line value of 71+/-2 (SEM) to 56+/-1 pg/ml at 120 min (P less than 0.001). In juvenile-type diabetics given the same insulin-glucose infusion, glucagon declined from a base-line level of 74+/-8 to 55+/-5 pg/ml at 120 min (P less than 0.05). The absolute glucagon values in the diabetic groups did not differ significantly at any point from the mean glucagon levels in nondiabetics given insulin at the same rate plus enough glucose to maintain normoglycemia. When glucagon was expressed as percent of baseline, however, the normoglycemic nondiabetics exhibited significantly lower values than adult-type diabetics at 90 and 120 min and juvenile-type diabetics at 60 min. In nondiabetics given insulin plus glucose at a rate that caused hyperglycemia averaging between 134 and 160 mg/dl, glucagon fell to 41+/-7 pg/ml at 120 min, significantly below the adult diabetics at 90 and 120 min (P less than 0.01 and less than 0.05) and the juvenile group at 60 min (P less than 0.01). The mean minimal level of 39+/-2 pg/ml was significantly below the adult (P less than 0.001) and juvenile groups (P less than 0.05). When insulin was infused in the diabetic groups at a rate of 0.4 U/kg-min together with glucose, raising mean plasma insulin to between 300 and 600 muU/ml, differences from the hyperglycemic nondiabetics were no longer statistically significant. It is concluded that, contrary to the previously reported lack of insulin effect in diabetics during carbohydrate meals, intravenous administration for 2 h of physiologic amounts of insulin plus glucose is accompanied in unfed diabetics by a substantial decline in plasma glucagon. These levels are significantly above hyperglycemic nondiabetics at certain points but differ from normoglycemic nondiabetics only when expressed as percent of the baseline. At a supraphysiologic rate of insulin infusion in diabetics, these differences disappear.     

Relationship between insulin-mediated glucose disposal and lipid metabolism in man.

To assess the possible effects of lipid metabolism on insulin-mediated glucose disposal, 18 nondiabetic Pima Indian women (age 18-35 yr) were studied using 1-14C-palmitate infusion to measure free fatty acid turnover rate followed by a euglycemic clamp (clamp) to measure in vivo insulin-mediated glucose disposal (M). Indirect calorimetry was performed in the basal state and during the clamp. This was used to assess glucose oxidation rate, lipid oxidation rate, and to calculate nonoxidative glucose disposal (storage). Basal and clamp lipid oxidation rate correlated with basal plasma free fatty acid concentration (r = 0.81, P less than or equal to 0.0001, r = 0.67, P less than 0.003, respectively). The fall in lipid oxidation was highly correlated with the increase in glucose oxidation during the insulin infusion (r = 0.96, P less than or equal to 0.0001). The clamp lipid oxidation rate negatively correlated with the glucose oxidation rate (r = -0.85, P less than 0.0001) and with the M value (r = -0.60, P less than 0.01) but was not correlated with the clamp glucose storage (r = -0.2, P = 0.4). On the other hand, glucose storage appeared to make a greater contribution to the difference in M value between the upper and lower extremes of M than did glucose oxidation, as evidenced by an increase in glucose storage of 0.59 mg/kg fat-free mass times minute per 1 mg/kg fat-free mass times minute increase in glucose disposal. The M value was negatively correlated with obesity as measured by percent body fat (r = -0.64, P less than 0.004), but neither basal free fatty acid concentration, basal free fatty acid turnover, basal lipid oxidation, nor clamp lipid oxidation correlated with percent body fat. We conclude that an interaction of lipid and glucose metabolism in a glucose fatty acid cycle, as proposed by Randle et al. (1), may be operative in the regulation of glucose oxidation in man. The disposal of glucose however has two components. The storage component does not appear to be associated with lipid oxidation in the way that the oxidative component is and may be regulated by a different mechanism. Since the results show that the glucose storage component plays a significant role in distinguishing between those with low and high M values, we suggest that the glucose fatty acid cycle can, at best, only partially explain impaired in vivo insulin-mediated glucose disposal. Furthermore, the data suggest that the impact of obesity on in vivo insulin resistance appears to be mediated by factors other than changes in lipid availability or metabolism.     

Hyperglucagonemia and insulin-mediated glucose metabolism.

The effect of chronic physiologic hyperglucagonemia on basal and insulin-mediated glucose metabolism was evaluated in normal subjects, using the euglycemic insulin clamp technique (+50, +100, and +500 microU/ml). After glucagon infusion fasting glucose increased from 76 +/- 4 to 93 +/- 2 mg/dl and hepatic glucose production (HGP) rose from 1.96 +/- 0.08 to 2.25 +/- 0.08 mg/kg X min (P less than 0.001). Basal glucose oxidation after glucagon increased (P less than 0.05) and correlated inversely with decreased free fatty acid concentrations (r = -0.94; P less than 0.01) and decreased lipid oxidation (r = -0.75; P less than 0.01). Suppression of HGP and stimulation of total glucose disposal were impaired at each insulin step after glucagon (P less than 0.05-0.01). The reduction in insulin-mediated glucose uptake was entirely due to diminished non-oxidative glucose utilization. Glucagon infusion also caused a decrease in basal lipid oxidation and an enhanced ability of insulin to inhibit lipid oxidation and augment lipid synthesis. These results suggest that hyperglucagonemia may contribute to the disturbances in glucose and lipid metabolism in some diabetic patients.     

Acute metabolic and hormonal responses to the inhibition of lipolysis in non-obese patients with non-insulin-dependent (type 2) diabetes mellitus: effects of acipimox.

1. Increased rates of fatty acid oxidation are frequently observed in patients with non-insulin-dependent diabetes mellitus and may contribute to hyperglycaemia by both decreasing peripheral glucose disposal and, more importantly, by increasing the rate of gluconeogenesis and therefore hepatic glucose output. Despite this relationship between lipid and carbohydrate metabolism, fasting glucose concentrations do not fall acutely in patients with non-insulin-dependent diabetes mellitus when plasma non-esterified fatty acid concentrations and lipid oxidation rates are decreased, questioning the importance of this interaction to glycaemic control. We have therefore measured the acute changes that occur 120-150 min after administration of 500 mg of the antilipolytic agent acipimox in eight non-obese male patients with non-insulin-dependent diabetes mellitus. 2. After administration of acipimox, lipolysis was inhibited as reflected by lower plasma non-esterified fatty acid (0.05 +/- 0.02 versus 0.55 +/- 0.05 mmol/l, P less than 0.001) and blood glycerol (8 +/- 1 versus 56 +/- 8 mumol/l, P less than 0.001) concentrations. The lipid oxidation rate was decreased (0.63 +/- 0.05 versus 1.02 +/- 0.08 mg min-1 kg-1, P less than 0.001), whereas there was a significant increase in the carbohydrate oxidation rate (1.93 +/- 0.17 versus 1.22 +/- 0.18 mg min-1 kg-1, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dietary fat, carbohydrate, and protein on branched-chain amino acid catabolism during caloric restriction.

To assess the effect of each dietary caloric source on the catabolism of branched-chain amino acids, we investigated the rate of leucine oxidation before and after obese volunteers consumed one of the following diets for one week: (a) starvation, (b) 300 or 500 cal of fat/d, (c) 300 or 500 cal of carbohydrate/d, (d) 300 or 500 cal of protein/d, (e) a mixture of carbohydrate (300 cal/d) and fat (200 cal/d), or (f) a mixture of carbohydrate (300 cal/d) and protein (200 cal/d). Starvation significantly increased the rate of leucine oxidation (1.4 +/- 0.11 vs. 1.8 +/- 0.16 mmol/h, P less than 0.01). The same occurred with the fat and protein diets. In sharp contrast, the 500-cal carbohydrate diet significantly decreased the rate of leucine oxidation (1.3 +/- 0.13 vs. 0.6 +/- 0.09 mmol/h, P less than 0.01). The same occurred when a portion of the carbohydrate diet was isocalorically replaced with either fat or protein. The cumulative nitrogen excretion during the fat diet and starvation was not significantly different. As compared with the fat diets, the carbohydrate diets on the average reduced the urinary nitrogen excretion by 12 g/wk. Nitrogen balance was positive during the consumption of the 500-cal protein diet, but negative during the consumption of carbohydrate-protein diet. The fat diets, like the protein diets and starvation, greatly increased plasma leucine (119 +/- 13 vs. 222 +/- 15 microM, P less than 0.01) and beta-hydroxybutyrate (0.12 +/- 0.02 vs. 4.08 +/- 0.43 mM, P less than 0.01) concentrations, and significantly decreased plasma glucose (96 +/- 4 vs. 66 +/- 3 mg/dl, P less than 0.01) and insulin (18 +/- 4 vs. 9 +/- 1 microU/ml, P less than 0.05) concentrations. These changes did not occur, or were greatly attenuated, when subjects consumed carbohydrate alone or in combination with fat or protein. We conclude that during brief caloric restriction, dietary lipid and protein, unlike carbohydrate, do not diminish the catabolism of branched-chain amino acids and the decrease in branched-chain amino acid oxidation is associated with protein sparing.     

Loss of hepatic autoregulation after carbohydrate overfeeding in normal man.

To determine the effect of increased glycogen stores on hepatic carbohydrate metabolism, 15 nondiabetic volunteers were studied before and after 4 d of progressive overfeeding. Glucose production and gluconeogenesis were assessed with [2-3H] glucose and [6-14C] glucose (Study I, n = 6) or [3-3H] glucose and [U-14C]-alanine (Study II, n = 9) and substrate oxidation was determined by indirect calorimetry. Overfeeding was associated with significant (P < 0.01) increases in plasma glucose (4.97 +/- 0.10 to 5.09 +/- 0.11 mmol/liter), insulin (18.8 +/- 1.5 to 46.6 +/- 10.0 pmol/liter) and carbohydrate oxidation (4.7 +/- 1.4 to 18.0 +/- 1.5 mumol.kg-1.min-1) and a decrease in lipid oxidation (1.2 +/- 0.2 to 0.3 +/- 0.1 mumol.kg-1.min-1). Hepatic glucose output (HGO) increased in Study I (10.2 +/- 0.5 to 13.1 +/- 0.9 mumol.kg-1.min-1, P < 0.01) and Study II (11.17 +/- 0.67 to 13.33 +/- 0.83 mumol.kg-1.min-1, P < 0.01), and gluconeogenesis decreased (57.6 +/- 6.4 to 33.4 +/- 4.9 mumol/min, P < 0.01), indicating an increase in glycogenolysis. The increase in glycogenolysis was only partly compensated by an increase in glucose cycle activity (2.2 +/- 0.2 to 3.4 +/- 0.4 mumol.kg-1.min-1, P < 0.01) and the fall in gluconeogenesis, thus resulting in increased HGO. The suppression of gluconeogenesis despite increased lactate and alanine (glycerol was decreased) was associated with decreased free fatty acid (FFA) oxidation and negligible FFA enhanced gluconeogenesis. These studies suggest that increased liver glycogen stores alone can overwhelm normal intrahepatic mechanisms regulating carbohydrate metabolism resulting in increased HGO in nondiabetic man.     

Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss.

Insulin-stimulated kinase activity of adipocyte-derived insulin receptors is reduced in subjects with non-insulin-dependent diabetes mellitus (NIDDM) but normal in obese nondiabetics. To assess the reversibility of the kinase defect in NIDDM, insulin receptor kinase activity was measured before and after weight loss in 10 NIDDM and 5 obese nondiabetic subjects. Peripheral insulin action was also assessed in vivo by glucose disposal rates (GDR) measured during a hyperinsulinemic (300 mU/M2 per min) euglycemic clamp. In the NIDDMs, insulin receptor kinase activity was reduced by 50-80% and rose to approximately 65-90% (P less than 0.01) of normal after 13.2 +/- 2.0 kg (P less than 0.01) weight loss; comparable weight loss (18.2 +/- 1.5 kg, P less than 0.01) in the nondiabetics resulted in no significant change in insulin receptor kinase activity. Relative to GDR measured in lean nondiabetics, GDR in the NIDDMs was 35% of normal initially and 67% (P less than 0.01) of normal after diet therapy; weight loss in the nondiabetics resulted in an increase in GDR from 53 to 76% of normal (P less than 0.05). These results indicate that the insulin receptor kinase defect that is present in NIDDM is largely reversible after weight reduction. In contrast, the improvement in GDR, in the absence of any change in insulin receptor kinase activity in the nondiabetics, suggests that the main cause of insulin resistance in obesity lies distal to the kinase.     

The chemical compositions of the thoracic aorta in diabetics and nondiabetics

Chemical analysis of the composition of the thoracic aorta was performed in 19 age- and sex-matched pairs of diabetic and nondiabetic autopsy subjects. Contents of total lipid, cholesterol, triglyceride, phospholipid, free fatty acid and collagen in the aortic wall were greater in cases with advanced atherosclerosis than in those with less advanced atherosclerosis. According to severity of atherosclerosis, the ratio of cholesterol to total lipid in the aortic wall increased, while the ratios of triglyceride, phospholipid and free fatty acid to total lipid decreased. The cholesterol concentration in the aorta increased with dry weight of the aorta per area. The rate of increase was 2.6 times higher in diabetics than in nondiabetics. These results suggest that content of cholesterol in the aortic wall increases markedly according to the advance of atherosclerosis, especially in the diabetics.     

Impaired free fatty acid utilization by skeletal muscle in non-insulin-dependent diabetes mellitus.

This study was undertaken to assess utilization of FFA by skeletal muscle in patients with non-insulin-dependent diabetes mellitus (NIDDM). 11 NIDDM and 9 nondiabetic subjects were studied using leg balance methods to measure the fractional extraction of [3H]oleate. Limb indirect calorimetry was used to estimate RQ. Percutaneous muscle biopsy samples of vastus lateralis were analyzed for muscle fiber type distribution, capillary density, and metabolic potential as reflected by measurements of the activity of seven muscle enzyme markers of glycolytic and aerobic-oxidative pathways. During postabsorptive conditions, fractional extraction of oleate across the leg was lower in NIDDM subjects (0.31 +/- 0.08 vs. 0.43 +/- 0.10, P < 0.01), and there was reduced oleate uptake across the leg (66 +/- 8 vs. 82 +/- 13 nmol/min, P < 0.01). Postabsorptive leg RQ was increased in NIDDM (0.85 +/- 0.03 vs. 0.77 +/- 0.02, P < 0.01), and rates of lipid oxidation by skeletal muscle were lower while glucose oxidation was increased (P < 0.05). In subjects with NIDDM, proportions of type I, IIa, and IIb fibers were 37 +/- 2, 37 +/- 6, and 26 +/- 5%, respectively, which did not differ from nondiabetics; and capillary density, glycolytic, and aerobic-oxidative potentials were similar. During 6 h after ingestion of a mixed meal, arterial FFA remained greater in NIDDM subjects. Therefore, despite persistent reduced fractional extraction of oleate across the leg in NIDDM (0.34 +/- 0.04 vs. 0.38 +/- 0.03, P < 0.05), rates of oleate uptake across the leg were greater in NIDDM (54 +/- 7 vs. 45 +/- 8 nmol/min, P < 0.01). In summary, during postabsorptive conditions there is reduced utilization of FFA by muscle, while during postprandial conditions there is impaired suppression of FFA uptake across the leg in NIDDM. During both fasting and postprandial conditions, NIDDM subjects have reduced rates of lipid oxidation by muscle.     

Mechanism of free fatty acid-induced insulin resistance in humans.

To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous 13C and 31P nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (approximately 5.2 mM) hyperinsulinemic (approximately 400 pM) clamp conditions for 6 h. During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be approximately 46% of control values after 6 h (P < 0.00001). Augmented lipid oxidation was accompanied by a approximately 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05). Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to approximately 50% of control values (4.0 +/- 1.0 vs. 9.3 +/- 1.6 mumol/[kg.min], P < 0.05). Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at approximately 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mM; P < 0.01). Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an approximately 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.     

Role of plasma non-esterified fatty acids during and after exercise.

1. The importance of circulating non-esterified fatty acids as a substrate during and after low-grade exercise has been examined by using a nicotinic acid analogue to inhibit lipolysis. Seven healthy men received acipimox or placebo on separate occasions. After 90 min, bicycle exercise was performed for 45 min (40% of pre-determined maximum oxygen uptake), followed by a 60 min recovery period. 2. The plasma concentration of non-esterified fatty acids increased during exercise after placebo (320 +/- 80 to 630 +/- 110 mumol/l) and remained elevated in the post-exercise period. Basal concentrations were lower after acipimox (100 +/- 10 mumol/l; P less than 0.05); they declined to 60 +/- 10 mumol/l during exercise and remained at this level for the rest of the study. 3. Lipid oxidation increased from 0.8 +/- 0.1 to 4.2 +/- 0.5 mg min-1 kg-1 during exercise after placebo (P less than 0.001) and remained elevated in the post-exercise period (1.2 +/- 0.1 mg min-1 kg-1). It was lower after acipimox, but still increased from 0.3 +/- 0.1 to 2.3 +/- 0.2 mg min-1 kg-1 with exercise. Carbohydrate oxidation was increased after acipimox compared with after placebo, but only reached significance during the post-exercise period (P less than 0.05). 4. Although acipimox abolished the rise in the plasma concentration of non-esterified fatty acids during exercise, there was only a 50% decrease in the rate of lipid oxidation. This suggests that an alternative source of non-esterified fatty acids makes an important contribution to the supply of lipid for oxidation during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus.

Increased nonesterified fatty acid (NEFA) levels may be important in causing insulin resistance in skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM). The acute effect of the antilipolytic nicotinic acid analogue Acipimox (2 X 250 mg) on basal and insulin-stimulated (3 h, 40 mU/m2 per min) glucose metabolism was therefore studied in 12 patients with NIDDM. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated steady-state periods. Acipimox reduced NEFA in the basal state and during insulin stimulation. Lipid oxidation was inhibited by Acipimox in all patients in the basal state (20 +/- 2 vs. 33 +/- 3 mg/m2 per min, P less than 0.01) and during insulin infusion (8 +/- 2 vs. 17 +/- 2 mg/m2 per min, P less than 0.01). Acipimox increased the insulin-stimulated glucose disposal rate (369 +/- 49 vs. 262 +/- 31 mg/m2 per min, P less than 0.01), whereas the glucose disposal rate was unaffected by Acipimox in the basal state. Acipimox increased glucose oxidation in the basal state (76 +/- 4 vs. 50 +/- 4 mg/m2 per min, P less than 0.01). During insulin infusion Acipimox increased both glucose oxidation (121 +/- 7 vs. 95 +/- 4 mg/m2 per min, P less than 0.01) and nonoxidative glucose disposal (248 +/- 47 vs. 167 +/- 29 mg/m2 per min, P less than 0.01). Acipimox enhanced basal and insulin-stimulated muscle fractional glycogen synthase activities (32 +/- 2 vs. 25 +/- 3%, P less than 0.05, and 50 +/- 5 vs. 41 +/- 4%, P less than 0.05). Activities of muscle pyruvate dehydrogenase and phosphofructokinase were unaffected by Acipimox. In conclusion, Acipimox acutely improved insulin action in patients with NIDDM by increasing both glucose oxidation and nonoxidative glucose disposal. This supports the hypothesis that elevated NEFA concentrations may be important for the insulin resistance in NIDDM. The mechanism responsible for the increased insulin-stimulated nonoxidative glucose disposal may be a stimulatory effect of Acipimox on glycogen synthase activity in skeletal muscles.     

Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus.

Insulin resistance in non-insulin-dependent diabetes is associated with a defective insulin activation of the enzyme glycogen synthase in skeletal muscles. To investigate whether this may be a primary defect, we studied 20 young (25 +/- 1 yr) Caucasian first-degree relatives (children) of patients with non-insulin-dependent diabetes, and 20 matched controls without a family history of diabetes. Relatives and controls had a normal oral glucose tolerance, and were studied by means of the euglycemic hyperinsulinemic clamp technique, which included performance of indirect calorimetry and muscle biopsies. Insulin-stimulated glucose disposal was decreased in the relatives (9.2 +/- 0.6 vs 11.5 +/- 0.5 mg/kg fat-free mass per (FFM) min, P less than 0.02), and was due to a decreased rate of insulin-stimulated nonoxidative glucose metabolism (5.0 +/- 0.5 vs 7.5 +/- 0.4 mg/kg fat-free mass per min, P less than 0.001). The insulin-stimulated, fractional glycogen synthase activity (0.1/10 mmol liter glucose-6-phosphate) was decreased in the relatives (46.9 +/- 2.3 vs 56.4 +/- 3.2%, P less than 0.01), and there was a significant correlation between insulin-stimulated, fractional glycogen synthase activity and nonoxidative glucose metabolism in relatives (r = 0.76, P less than 0.001) and controls (r = 0.63, P less than 0.01). Furthermore, the insulin-stimulated increase in muscle glycogen content over basal values was lower in the relatives (13 +/- 25 vs 46 +/- 9 mmol/kg dry wt, P = 0.05). We conclude that the defect in insulin activation of muscle glycogen synthase may be a primary, possibly genetically determined, defect that contributes to the development of non-insulin-dependent diabetes.     

Increased clearance of propranolol and theophylline by high-protein compared with high-carbohydrate diet

The objective of this study was to determine whether changes in dietary protein and carbohydrate influence the oral clearance of propranolol, a high-clearance drug, and theophylline, a low-clearance drug. Six normal subjects studied in a clinical research center each received a single oral dose of propranolol, 80 mg, and theophylline, 5 mg/kg, after having been on each of two well-defined diets for a period of 10 days. When the diet was altered from high carbohydrate/low protein to low carbohydrate/high protein, the oral clearance of propranolol increased by 74% +/- 20% (mean +/- SE; range 9% to 156%; P less than 0.01) with no change in plasma half-life or plasma binding. This dietary change resulted in an increase in theophylline clearance of 32% +/- 6% (range 18% to 50%; P less than 0.02) and a corresponding decrease in plasma half-life of 26% +/- 6% (range 6% to 42%; P less than 0.05) with no alteration in the apparent volume of distribution. These observations reemphasize the importance of diet in drug disposition and suggest that the clearance of high-clearance drugs like propranolol is more susceptible than the clearance of low-clearance drugs to dietary manipulations, effects that may have to be considered in drug therapy.     

Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance

Renal tubular sodium handling was evaluated in 27 non-azotemic cirrhotic patients with ascites and positive sodium balance and in 17 controls after at least 5 days of a constant sodium intake using the lithium clearance as an index of fluid delivery to the distal tubule. Plasma renin activity and plasma aldosterone were also evaluated. Sodium fractional excretion, filtered sodium load, absolute sodium distal delivery, lithium fractional excretion and absolute distal sodium reabsorption were significantly lower in cirrhotics than in controls (0.58 +/- 0.11 vs. 1.29 +/- 0.12%, P less than 0.001; 12529 +/- 677 vs. 15707 +/- 796 microEq min-1 1.73 m-2 BSA, P less than 0.005; 2384 +/- 135.2 vs. 3685 +/- 219.3 microEq min-1 1.73 m-2 BSA, P less than 0.001; 19.5 +/- 1.0 vs. 24.2 +/- 1.3%, P less than 0.01; 2299 +/- 127 vs. 3485 +/- 214 microEq min-1 1.73 m-2 BSA, P less than 0.001, respectively). A correlation was found between lithium clearance and sodium clearance only in cirrhotic patients (r = 0.62; P less than 0.01). Distal sodium reabsorption evaluated as a per cent of filtered sodium load was lower in cirrhotics than in controls (19.1 +/- 1.0 vs. 22.4 +/- 1.2%, P less than 0.05) while distal sodium reabsorption evaluated as a per cent of sodium distal delivery was higher in cirrhotics than in controls (96.7 +/- 0.4 vs. 94.4 +/- 0.5%, P less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Composition of very-low-density lipoproteins in non-insulin-dependent diabetes mellitus

We studied the characteristics of very-low-density lipoproteins (VLDLs) composition in patients with non-insulin-dependent diabetes mellitus. VLDLs were isolated from 28 diabetics and 33 nondiabetics with a wide range of plasma lipid concentrations, so we could compare VLDL composition between the two groups at similar lipid concentrations. The mean cholesterol and triglyceride concentrations in plasma of diabetic subjects were 2170 (SD 570) and 2510 (SD 2230) mg/L, respectively, and 2230 (SD 560) and 2210 (SD 1830) mg/L in nondiabetics. Diabetic subjects showed positive correlations between plasma triglyceride concentrations and either preprandial blood glucose or glycated hemoglobin values (P less than 0.02 and less than 0.01, respectively). Concentrations of triglycerides, cholesterol, and apolipoproteins (apo) B, CII, CIII, and E in VLDL were not significantly different between diabetics and nondiabetics. At comparable triglyceride concentrations, the chemical compositions of the VLDL in the two groups were still very similar. Dividing the concentration of each component by the VLDL-apo B concentrations yielded similar contents of each component per unit of VLDL for the two groups. We conclude that the composition of VLDLs in diabetics is much the same as that in nondiabetics at comparable concentrations of triglycerides in plasma.     

Plasma acetate levels in response to intravenous fat or glucose/insulin infusions in diabetic and non-diabetic subjects

We measured plasma levels of acetate, glucose, insulin, fatty acids and 'ketone bodies' (KB), during fat infusion and continuous simultaneous infusion of insulin and glucose according to a computerized algorithm to maintain fasting euglycaemia and derive indices of tissue insulin sensitivity (hyperinsulinaemic euglycaemic clamping HEC). (i) Plasma acetate levels (mmol/l) approximately doubled (0.14 +/- (SEM) 0.02 to 0.25 +/- 0.02, p less than 0.01) during INTRALIPID infusion in 7 non-diabetic individuals while total 'ketone bodies' and non-esterified fatty acids (NEFAs) increased 10-fold. (ii) Early in the HEC, plasma acetate levels decreased as did NEFAs in 13 non-diabetic (0.17 +/- 0.01 to 0.12 +/- 0.01, p less than 0.001) and 9 diabetic (0.22 +/- 0.02 to 0.15 +/- 0.01, p less than 0.005) individuals. However while acetate levels later rose to fasting values in the non-diabetics, they remained low in the diabetics. NEFA levels were low throughout the clamp but glucose flux was increased as judged from the glucose infusion even with maintained euglycaemia. The change in acetate values during the second hour of the clamp correlated with neither BMI nor two indices of insulin sensitivity (glucose metabolic clearance rate and steady state glucose infusion rate). These results accord with acetate production from glucose and fat oxidation, via acetyl CoA. The differing metabolism of acetate in the second hour of clamping between diabetics and non-diabetics may reflect altered post-receptor glucose metabolism with the onset of diabetes.     

Fatty acid kinetic responses to exercise. Effects of obesity, body fat distribution, and energy-restricted diet.

Upper body obesity (UB Ob) is associated with a reduced net free fatty acid (FFA) response to epinephrine compared with nonobese (Non Ob) and lower-body obese (LB Ob) women. Because catecholamines regulate some of the metabolic responses to exercise, we hypothesized that UB Ob would have a reduced net FFA response to exercise. Plasma FFA rate of appearance (Ra) ([1-14C]palmitate) and fatty acid oxidation (indirect calorimetry) were therefore measured during 2.5 h of stationary bicycle exercise (45% VO2 peak) in 13 UB Ob, 11 LB Ob, and 8 Non Ob premenopausal women. 10 UB Ob and 8 LB Ob women were retested after an approximately 8-kg weight loss. Results: During exercise Non Ob and LB Ob women had greater increments in FFA availability (51 +/- 7 and 53 +/- 8 mmol, respectively) than UB Ob women (27 +/- 4 mmol, P < 0.05). Total exercise FFA availability and fatty acid oxidation were not different between Non Ob, LB Ob, and UB Ob women, however. Following weight loss (approximately 8 kg), the FFA response to exercise increased (P < 0.01) and remained greater (P < 0.05) in LB Ob than in UB Ob women. In conclusion, the FFA response to exercise was reduced in UB Ob women before and after weight loss, but no effects on fatty acid oxidation were apparent.