Rate Of Hepatic Glucose Output Research Articles

Normal hepatic glucose production in the absence of GLUT2 reveals an alternative pathway for glucose release from hepatocytes.

Glucose production by liver is a major physiological function, which is required to prevent development of hypoglycemia in the postprandial and fasted states. The mechanism of glucose release from hepatocytes has not been studied in detail but was assumed instead to depend on facilitated diffusion through the glucose transporter GLUT2. Here, we demonstrate that in the absence of GLUT2 no other transporter isoforms were overexpressed in liver and only marginally significant facilitated diffusion across the hepatocyte plasma membrane was detectable. However, the rate of hepatic glucose output was normal. This was evidenced by (i) the hyperglycemic response to i.p. glucagon injection; (ii) the in vivo measurement of glucose turnover rate; and (iii) the rate of release of neosynthesized glucose from isolated hepatocytes. These observations therefore indicated the existence of an alternative pathway for hepatic glucose output. Using a [14C]-pyruvate pulse-labeling protocol to quantitate neosynthesis and release of [14C]glucose, we demonstrated that this pathway was sensitive to low temperature (12 degreesC). It was not inhibited by cytochalasin B nor by the intracellular traffic inhibitors brefeldin A and monensin but was blocked by progesterone, an inhibitor of cholesterol and caveolae traffic from the endoplasmic reticulum to the plasma membrane. Our observations thus demonstrate that hepatic glucose release does not require the presence of GLUT2 nor of any plasma membrane glucose facilitative diffusion mechanism. This implies the existence of an as yet unsuspected pathway for glucose release that may be based on a membrane traffic mechanism.

Hepatic Glycogen and Lactate Handling in Dietary Obese Rats

Hepatic balances for glucose and its precursor, lactate, were calculated by measuring hepatic blood flows and the arteriovenous differences of these metabolites in 2 groups of overweight rats: cafeteria diet-fed rats and post-cafeteria rats. Obese rats show abnormal hepatic glycogen handling, since they do not mobilize all hepatic glycogen stores after 24-hour starvation, in a situation in which a lower rate of hepatic glucose output and a higher capacity for lactate uptake are attained. The important decrease (about 50%) in the hepatic blood flows observed in post-cafeteria rats versus control rats was similar to that caused by 24-hour starvation in control animals, suggesting that after withdrawal of the cafeteria diet, the liver blood flow of the post-cafeteria rats was adapted to the low-food intake in order to make better use of the energy consumed. The results also suggest an increased efficiency of hepatic lactate uptake in post-cafeteria rats.

Chlorogenic acid and synthetic chlorogenic acid derivatives: novel inhibitors of hepatic glucose-6-phosphate translocase.

The enzyme system glucose-6-phosphatase (EC 3.1.3.9) plays a major role in the homeostatic regulation of blood glucose. It is responsible for the formation of endogenous glucose originating from gluconeogenesis and glycogenolysis. Recently, chlorogenic acid was identified as a specific inhibitor of the glucose-6-phosphate translocase component (Gl-6-P translocase) of this enzyme system in microsomes of rat liver. Glucose 6-phosphate hydrolysis was determined in the presence of chlorogenic acid or of new synthesized derivatives in intact rat liver microsomes in order to assess the inhibitory potency of the compounds on the translocase component. Variation in the 3-position of chlorogenic acid had only poor effects on inhibitory potency. Introduction of lipophilic side chain in the 1-position led to 100-fold more potent inhibitors. Functional assays on isolated perfused rat liver with compound 29i, a representative of the more potent derivatives, showed a dose-dependent inhibition of gluconeogenesis and glycogenolyosis, suggesting glucose-6-phosphatase as the locus of interference of the compound for inhibition of hepatic glucose production also in the isolated organ model. Gl-6-P translocase inhibitors may be useful for the reduction of inappropriately high rates of hepatic glucose output often found in non-insulin-dependent diabetes.

Effect of Amino Acid Infusion on Glucose Production in Trauma Patients

The relationship between precursor supply and hepatic glucose output (HGO) was examined in 8 control subjects and 12 trauma patients after a fasting period of approximately 60 hours. Glucose kinetics were measured with a primed-constant infusion of [U-14C]glucose and [6-3H]glucose. The basal rate of HGO was 5.45 +/- 0.22 micromol x kg-1 x min-1 in the controls and 13.16 +/- 0.76 micromol x kg-1 x min-1 following trauma (p < 0.001). Four hours after amino acid infusion of 1.3 g x kg-1 x 24 h-1, HGO in the controls was unchanged at 5.35 +/- 0.22 micromol x kg-1 x min-1 but it had decreased to 11.71 +/- 0.67 micromol x kg-1 after trauma (p < 0.001). We conclude that increasing the supply of gluconeogenic precursors does not stimulate HGO in normal subjects after fasting or after severe trauma and that factors other than to availability of amino acids are responsible for the enhanced rate of HGO in trauma patients.

Production of a rat pancreatic polypeptide-specific monoclonal antibody and its influence on glucose homeostasis by in vivo immunoneutralization.

To test the effect of endogenous pancreatic polypeptide (PP) on rat hepatic glucose homeostasis by immunoneutralization, a rat PP-specific monoclonal antibody (MAb) was produced. Binding of this IgG1 monoclonal antibody was inhibited 50% by 350 pM rat PP. Immunohistochemistry showed that the antibody produced the expected pattern of endocrine cell staining in rat pancreas. Groups of six adult male Sprague-Dawley rats were given 5 mg of Protein-A-purified anti-PP MAb or anti-KLH MAb (control) ip every 48 hr for 5 dosing intervals. The rate of hepatic glucose output during isolated liver perfusion was 0.25 +/- 0.03 mg/g/min for the PP MAb-treated rats and 0.17 +/- 0.02 mg/g/min for the control group (p < 0.05). Liver glycogen content was 21.8 +/- 2.9 mg/g for the PP MAb-treated rats and 14.7 +/- 2.4 mg/g for the control group (N = 5). Chronic in vivo immunoneutralization of PP with this new monoclonal antibody suggests that PP influences glucose homeostasis in the rat by affecting hepatic glucose output.

Insulin and glucose suppress hepatic glycogenolysis by distinct enzymatic mechanisms

Both insulin and hyperglycemia can effectively suppress hepatic glucose output (HGO). We examined whether insulin and hyperglycemia specifically suppress liver net glycogen breakdown in a rat model in which glycogen is the major source of HGO. We further examined whether insulin and hyperglycemia act by similar or distinct enzymatic mechanisms. HGO, the rate of net glycogen loss, and glycogen phosphorylase and synthase activities were measured in fed, anesthetized rats infused with saline or insulin (7 mU/min/kg) while either maintaining plasma glucose at basal (7.8 ± 0.2 mmol/L, euglycemic clamp [EC]) or at 10 mmol/L above basal (18 ± 0.4 mmol/L, hyperglycemic clamp [HC]). During the basal period, the rate of HGO in each group was comparable to the rate of net glycogen breakdown, averaging 76 ± 9 and 75 ± 5 μmol/min/kg, respectively. Thus glycogen breakdown appeared to be a major source of ongoing HGO. Over the last 60 minutes of the experimental period, the rate of glycogenolysis averaged 69 ± 8 μmol/min/kg in saline-treated rats; this could account for about 80% of the total HGO. During both EC and HC studies, HGO was suppressed (5.5 ± 3 and −3.6 ± 10 μmol/min/kg, respectively; P < .001 for each). Net glycogen breakdown decreased by 50% in EC rats ( P < .05) and ceased in HC rats ( P < .001). Glycogen synthase was predominantly in the active form in all three experimental groups (87% ± 2%, 89% ± 2%, and 95% ± 3% in saline, EC, and HC rats, respectively). The fraction of glycogen phosphorylase in the active form was similar in saline (41% ± 2%) and EC (40% ± 2%) rats, but lower (23% ± 5%, P < .03) in HC rats. In summary, insulin fully suppresses HGO and partially inhibits net glycogenolysis in vivo without affecting the phosphorylation state of glycogen phosphorylase. Addition of hyperglycemia enhances phosphorylase a to b conversion and fully suppresses net glycogenolysis. Glucose produced by residual glycogenolysis during EC does not reach the systemic circulation and must be disposed of glycolytically in liver.

Role of IL-1α in central nervous system immunomodulation of glucoregulation

Hyperglycemia is a hallmark of the stress response, and has been largely attributed to elevated plasma levels of catabolic hormones. Recently, various cytokines have been shown to be endogenously produced within the brain and may represent an important component of the central regulation of this metabolic response. Therefore, the aim of the present study was to determine whether the intracerebroventricular (i.c.v.) injection of one such peptide, interleukin (IL)-1, can produce hormonal and metabolic alterations comparable to those observed under stress conditions. An i.c.v. cannula and vascular catheters were placed in rats prior to the experiment. Whole body glucose flux was assessed in overnight fasted conscious unrestrained rats using [3- 3H]glucose. A mild hyperglycemia was elicited 20 min after the i.c.v. injection of IL-1α (human recombinant, 100 ng) that was not detected in control rats. Glucose levels gradually increased and were 26% higher than control values during the last hour of the 3 h experimental period. The hyperglycemia resulted from a 44% increase in the rate of hepatic glucose output (HGO), which preceded a propertional rise in peripheral glucose utilization. No increase in metabolic clearance rate was observed, suggesting that the increased glucose uptake was the result of mass action. The increased glucose flux was associated with a transient hyperinsulinemia (+95%), and sustained elevations in the arterial concentrations of glucagon (56%) and corticosterone (175%). In contrast, glucose flux was not altered by intravenous administration of the same dose of IL-1α, or i.c.v. injection of IL-1β, or heat-inactivated IL-1α. Indomethacin (5 mg/kg, i.v.) blocked the hyperglycemia and increased HGO induced by i.c.v. injection of prostaglandin E 2 (100 ng) produced comparable increases in glucose flux. These results indicate that IL-1α can act centrally to enhance whole body glucose metabolism, and that this response is probably mediated by prostaglandins.

Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats.

To investigate whether thiazolidinediones (AD-4833 and CS-045), new oral antidiabetic agents, are effective in insulin-dependent diabetes mellitus, the effect of thiazolidinediones on streptozotocin-induced diabetic rats was studied by the glucose clamp technique. Diabetic rats were divided into five groups: (1) intensively insulin treated group given a daily injection of 4-6 units Ultralente insulin, (2) AD-4833 group treated with a daily injection of 2 units Ultralente insulin, the minimal dose to make urinary ketones negative, and ingestion of 10 mg/kg of AD-4833 suspended in 5% gum arabic, (3) gum arabic group treated in the same way as the AD-4833 group except for the active drug, (4) CS-045 group treated with the same insulin injection and ingestion of 200 mg/kg CS-045 suspended in 0.5% chlormethyl cellulose, (5) chlormethyl cellulose group treated as the control for the CS-045 group. Seven days after these treatments, all five groups of diabetic rats and normal control rats were subjected to the glucose clamp study in which 3 mU.kg-1.min-1 porcine insulin was continuously infused. Glucose infusion rates (GIR) for the gum arabic and chlormethyl cellulose groups were significantly lower than in control rats, and the rates of hepatic glucose output (HGO) of these two groups were not suppressed, indicating the presence of hepatic insulin resistance. Intensive insulin treatment as well as administration of AD-4833 and CS-045 with a minimal dose of insulin restored both GIR and HGO towards normal levels. It is concluded that thiazolidinediones improved hepatic insulin resistance in the presence of a minimal dose of insulin.

Evidence for increased liver glycogen in patients with noninsulin-dependent diabetes mellitus after a 3-day fast.

In order to assess hepatic glycogen stores in patients with noninsulin dependent diabetes mellitus (NIDDM) after a 3-day fast, the incremental glucose response to 1.0 mg iv glucagon (glucose area under the curve, glucoseAUC) was assessed in 19 obese diabetic subjects after an overnight (14 h) fast and again after a 3-day (64 h) fast. Results were compared to those of lean (n = 6) and obese (n = 15) nondiabetic subjects. During the fast, plasma glucose fell significantly in the lean (4.9 +/- 0.2 to 3.9 +/- 0.2 mmol/L), obese (5.1 +/- 0.1 to 4.2 +/- 0.2 mmol/L), and diabetic (14.7 +/- 0.7 to 10.3 +/- 1.0 mmol/L) subjects. However, in contrast to the fall in glucoseAUC observed in the lean (92.4 +/- 15.4 to 39.9 +/- 8.1 mmol min-1 L-1, P less than 0.02) and obese (64.4 +/- 11.1 to 48.4 +/- 9.4 mmol min-1 L-1) subjects, the glucoseAUC increased in diabetic subjects from 81.6 +/- 8.6 to 103.9 +/- 8.8 mmol min-1 L-1 during the fast, and was significantly greater than that of either the lean (P less than 0.001) or obese (P less than 0.001) nondiabetic subjects after the 64-h fast. Evidence that the glucose response to glucagon after a 64-h fast represents glycogenolysis and not gluconeogenesis was provided by studies in 10 additional subjects (5 obese nondiabetic subjects and 5 patients with NIDDM). Overall hepatic glucose output calculated from glucose kinetic data [( 3-3H]glucose) increased in diabetic and nondiabetic subjects during the first 30 min after glucagon administration and fell progressively thereafter. However, no increase in alanine gluconeogenesis (14C-alanine incorporation into glucose) was observed after glucagon administration in either subject group. The paradoxical accumulation of glycogen in the patients with NIDDM during the fast occurred despite basal rates of hepatic glucose output on the third day of the fast which were greater than those of obese nondiabetic subjects (9.0 +/- 1.2 vs. 5.6 +/- 0.5 mumol kg-1 min-1, P less than 0.05). A glycogen sparing action of increased gluconeogenesis is proposed as the explanation for the preservation of liver glycogen in patients with NIDDM.

Glucose transport and NIDDM.

Three major metabolic abnormalities contribute to hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) including defective glucose-induced insulin secretion, elevated rates of hepatic glucose output, and insulin's impaired ability to stimulate glucose uptake in peripheral target tissues (insulin resistance). These functions involve cellular glucose transport in beta-cells, liver, adipose tissue, and skeletal muscle; and, in some instances, abnormalities in glucose transporter isoforms (GLUT) specifically expressed in these tissues may constitute key biochemical lesions underlying defective glucose homeostasis. In animal models of NIDDM, suppression of GLUT2 in beta-cells is correlated with loss of high-Km glucose transport and glucose-sensitive insulin secretion. Although there are no data on humans with NIDDM, GLUT2 loss would constitute an attractive mechanism for defective glucose sensing in beta-cells if it can be shown that transport then becomes rate limiting for glucose metabolism. In the liver, however, hepatocyte glucose transport via GLUT2 probably plays only a permissive role in sustaining increased glucose efflux. Peripheral insulin resistance is associated with decreased glucose transport activity, the likely rate-limiting step for glucose uptake in fat and muscle. Accordingly, the insulin-responsive GLUT4 isoform expressed exclusively in insulin target tissues has been studied intensively in NIDDM. In these studies, pretranslational suppression of GLUT4 appears to be the key mechanism of insulin resistance in adipocytes. However, levels of GLUT4 protein and mRNA are normal in vastus lateralis and rectus abdominis, inferring that defects in GLUT4 functional activity or insulin-mediated translocation cause insulin resistance in muscle. Thus, the intensified study of glucose transport has provided important new insights into NIDDM pathogenesis over the past 5 yr and has presented investigators with additional intriguing hypotheses.

Pathogenesis of NIDDM. A balanced overview.

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.

Effects of free fatty acids and ketone bodies on in vivo non-insulin-mediated glucose utilization and production in humans

The current study was undertaken to examine the effect of an acute elevation of serum levels of free fatty acids (FFA) and ketone bodies (KB) on non-insulin-mediated glucose uptake (NIMGU) in humans. The study group consisted of 11 healthy men, mean age (± SD) 30 (± 7) years and mean weight (±SD) 72 (± 7) kg. To examine the effects of FFA levels on NIMGU and insulin-mediated glucose uptake (IMGU), glucose uptake was measured isotopically ( 3H-3-glucose) in six subjects on four separate days during saline infusion or lipid + heparin infusion with concomitant infusions of somatostatin (SRIF, 0.16 μg/kg/min) with or without insulin infusion (40 mU/m 2/min) while the serum glucose level was clamped at ∼11 mmol/L. To examine the effect of KB on NIMGU, saline or sodium acetoacetate (20 μmol/kg/min) was infused in five subjects on separate days during SRIF-induced insulinopenia while the serum glucose level was clamped sequentially at euglycemia and at ∼11 mmol/L. During insulinopenia basal FFA levels rose twofold during saline infusion and sixfold during infusion of lipid + heparin. Rates of NIMGU were 2.49 ± 0.27 v 2.41 ± 0.14 mg/kg/min during saline and lipid infusion, respectively ( P = NS). Rates of IMGU were decreased by 55% during lipid + heparin infusion. During insulinopenia basal β-hydroxybutyrate (BOB) levels rose twofold during saline and ∼11-fold during sodium acetoacetate infusion. Rates of NIMGU were unchanged by the sodium acetoacetate infusion at euglycemia and hyperglycemia. Rates of hepatic glucose output (HGO) during insulinopenia were markedly stimulated by lipid + heparin infusion and suppressed by the infusion of sodium acetoacetate. In summary and conclusion, (1) the metabolic substrate FFA and acetoacetate have no effect to modulate NIMGU, (2) FFAs have a marked effect to decrease rates of IMGU and thus regulate IMGU and NIMGU separately, and (3) during insulin deficiency FFAs stimulate, whereas ketone bodies suppress HGO.

Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics.

Elevated rates of basal hepatic glucose output (bHGO) are significantly correlated with the fasting serum glucose (FSG) level in subjects with non-insulin-dependent diabetes mellitus (NIDDM). This observation suggests that bHGO is a major determinant of the severity of the diabetic state in these subjects. In addition, basal glucagon levels (bGL) are higher in these diabetics than in control subjects, despite the concurrent basal hyperglycemia and hyperinsulinemia, two factors known to suppress glucagon secretion. Although bGL is responsible for sustaining two-thirds of bHGO in normal humans, its role in sustaining elevated rates of bHGO in NIDDM has not been previously defined. To this end, we have studied 13 normal and 10 NIDDM subjects; mean FSG levels were 90 +/- 2 and 262 +/- 21 mg/dl, respectively (P less than .001). The mean fasting serum insulin and glucagon levels were higher in the diabetics than in the controls: 17 +/- 2 vs. 9 +/- 1 microU/ml (P less than .01) and 208 +/- 37 vs. 104 +/- 15 pg/ml (P less than .01), respectively. On separate days, HGO was assessed isotopically (with 3-[3H]glucose) in the basal state and during infusion of somatostatin (SRIF) (600 micrograms/h) alone and in conjunction with replacement infusions of glucose and insulin. The results demonstrate that bHGO is higher in diabetics than in controls (145 +/- 12 vs. 89 +/- 3 mg X m-2 X min-1, P less than .01); during infusion of SRIF alone, HGO was suppressed by 25% (P less than .05) and 34% (P less than .05) of the basal value in controls and diabetics, respectively; when the studies were repeated with glucose levels held constant at or near the FSG level by the glucose-clamp technique, the pattern and degree of HGO suppression was similar to that obtained by infusion of SRIF alone; during isolated glucagon deficiency (SRIF + insulin, 5 mU X m-2 min-1, with serum glucose maintained at basal level), HGO was suppressed by 71 +/- 8% of the basal value in controls (P less than .001) and by 58 +/- 7% in diabetics (P less than .001); and when isolated glucagon deficiency with similar hyperglycemia was created in control subjects, HGO was suppressed by 87% of the basal value.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics

Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics

The Effects of Biosynthetic Human Proinsulin on Carbohydrate Metabolism in Non-Insulin-Dependent Diabetes Mellitus

We compared the glucose-lowering effect of proinsulin, the precursor molecule of insulin, with that of insulin itself. In patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom proinsulin (0.2 U per kilogram of body weight) was subcutaneously injected at 9 a.m., fasting glucose levels (247 +/- 22 mg per deciliter [+/- SEM]) became normal within six hours and elevated rates of hepatic glucose output were lowered. The response to regular insulin (0.2 U per kilogram) was of similar magnitude but faster. Glucose clearance was stimulated less by proinsulin, reflecting its preferential action in suppressing glucose output. Hypoglycemia occurred in five of nine insulin-treated patients, but in only one of nine proinsulin-treated patients. After proinsulin injection at bedtime (30.5 +/- 4 U), serum proinsulin concentrations reached a peak by five hours and declined gradually thereafter. Fasting hepatic glucose output became normal, and euglycemia was sustained without overnight hypoglycemia. Proinsulin reduced plasma glucose more effectively than an equal unit dosage of NPH insulin, but since higher doses of NPH insulin were not used, no conclusions could be drawn about the relative desirability of these preparations for clinical use. We conclude that subcutaneously injected proinsulin has prolonged pharmacokinetics in plasma and can normalize plasma glucose in NIDDM characterized by severe hyperglycemia; as compared with the hypoglycemic effects of regular insulin, those of proinsulin are mostly due to suppression of hepatic glucose output, with little stimulation of glucose disposal and less hypoglycemia; and proinsulin may have a role in the treatment of NIDDM.

Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes mellitus.

To quantitate the effects of weight loss on the mechanisms responsible for hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), eight obese subjects with NIDDM were studied before and after weight reduction with posttreatment assessment after 3 wks of isocaloric (weight maintenance) refeeding. After weight loss of 16.8 +/- 2.7 kg (mean +/- SE), the fasting plasma glucose level decreased 55% from 277 +/- 21 to 123 +/- 8 mg/dl. The individual fasting glucose levels were highly correlated with the elevated basal rates of hepatic glucose output (HGO) (r = 0.91, P less than .001), which fell from 138 +/- 11 to 87 +/- 5 mg X m-2 X min-1 after weight loss. The change in fasting plasma glucose also correlated significantly with the change in the basal rates of HGO (r = 0.74, P less than .05). This was associated with reduced fasting serum levels of glucagon (from 229 +/- 15 to 141 +/- 12 pg/ml), reduced free fatty acids (from 791 +/- 87 to 379 +/- 35 mu eq/L), and unchanged basal insulin levels (17 +/- 4 to 15 +/- 2 microU/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin and non-esterified fatty acids. Acute regulators of lipogenesis in perfused rat liver.

Livers from fed rats were perfused with whole rat blood and infused with oleate to maintain constant concentrations of serum non-esterified fatty acids over a wide physiological range. Infusion of insulin opposed the antilipogenic effects of increasing concentrations of serum non-esterified fatty acids. Secretion of very-low-density-lipoprotein triacylglycerols was directly proportional to the concentration of serum non-esterified fatty acids and was increased by insulin. The secretion of newly-synthesized fatty acids in very-low-density-lipoprotein triacylglycerols decreased with increasing concentrations of serum non-esterified fatty acid. Insulin opposed this change. Cholesterol biosynthesis was unaffected by alterations in concentration of serum non-esterified fatty acid but was increased by insulin. Equilibrium concentrations of perfusate lactate and glucose were increased by serum non-esterified fatty acids but steady-state rates of hepatic glucose output and lactate uptake were unchanged. Insulin decreased perfusate glucose concentrations and abolished the increase in its concentration that resulted from increases in non-esterified fatty acid concentrations.

Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

On the mechanism of hyperglycemia and stimulation of growth hormone secretion by L-dopa.

The mechanism of hyperglycemia produced by L-dopa was studied in normal trained dogs with 3-3H-glucose infusion to measure rates of hepatic glucose output (production) and overall glucose uptake (utilization). Infusion of L-dopa (20 mg/kg/h) increased glucose production causing hyperglycemia. Despite the hyperglycemia plasma insulin did not increase nor did glucose uptake, indicating a relative inhibition of glucose utilization. These effects resemble those produced by epinephrine infusion. Pretreatment with a decarboxylase inhibitor, carbidopa, prevented the L-dopa effect to increase glucose production and no hyperglycemia occurred. Hyperglycemia was not prevented by pimozide, a dopamine receptor blocker, nor by propranolol but was prevented by phentolamine. L-Dopa also increased plasma growth hormone levels without affecting plasma cortisol. The effect on growth hormone was prevented by carbidopa and by phentolamine but not by pimozide; propranolol potentiated the rise in growth hormone. The data suggest that the L-dopa-induced hyperglycemia is due to a peripheral action, whereas stimulation of growth hormone secretion may be due to a central action of a L-dopa metabolite.

Glucose turnover in the exercising dog with chemically induced diabetes and the effect of methylprednisolone.

Dogs with indwelling polyethylene arterial and venous catheters ran on a treadmill (slope 15 per cent, speed 100 m./min.). Diabetes was produced by alloxan or by a combination of alloxan and streptozotocin. Glucose turnover was measured according to the primed constant-rate infusion technics with 2-3H-glucose as tracer. In resting diabetic dogs plasma glucose varied between 200 and 650 mg./100 ml. There was a direct linear correlation between the hepatic glucose output (Ra) and the plasma glucose level. Exercise increased both Ra and the clearance rate (CR) of glucose; however, Ra could not match the rate of disappearance (=renal loss plus glucose uptake of the muscle), causing the plasma glucose to decline more rapidly than in the running control dogs. Two to three days' treatment with methylprednisolone (MP, 3-3.2 mg./kg./day) caused a higher resting glucose level and a higher Ra. Exercise greatly increased the plasma glucose concentration, partly because MP enhanced the hepatic response but mainly because it essentially prevented the rise of CR. It is concluded that (a) in chemically induced diabetes, the variable glucose level is the result of a variable rate of hepatic glucose output; (b) the increase of Ra by MP treatment does not increase the plasma glucose in the normal dog but significantly aggravates the alloxan diabetes, (c) diabetes reduces the effect of exercise on the glucose uptake of the muscle, and this effect is potentiated by the inhibitory action of the glucocorticoid. This latter becomes unmasked only when the insulin secretion is impaired.