Liver Glycogen Synthase Activity Research Articles

Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis

The liver responds to an increase in blood glucose levels in the postprandial state by uptake of glucose and conversion to glycogen. Liver glycogen synthase (GYS2), a key enzyme in glycogen synthesis, is controlled by a complex interplay between the allosteric activator glucose-6-phosphate (G6P) and reversible phosphorylation through glycogen synthase kinase-3 and the glycogen-associated form of protein phosphatase 1. Here, we initially performed mutagenesis analysis and identified a key residue (Arg582) required for activation of GYS2 by G6P. We then used GYS2 Arg582Ala knockin (+/R582A) mice in which G6P-mediated GYS2 activation had been profoundly impaired (60–70%), while sparing regulation through reversible phosphorylation. R582A mutant–expressing hepatocytes showed significantly reduced glycogen synthesis with glucose and insulin or glucokinase activator, which resulted in channeling glucose/G6P toward glycolysis and lipid synthesis. GYS2+/R582A mice were modestly glucose intolerant and displayed significantly reduced glycogen accumulation with feeding or glucose load in vivo. These data show that G6P-mediated activation of GYS2 plays a key role in controlling glycogen synthesis and hepatic glucose-G6P flux control and thus whole-body glucose homeostasis.

Oral administration of melatonin counteracts several of the effects of chronic stress in rainbow trout

To assess a possible antistress role of melatonin in fish, we orally administered melatonin to rainbow trout for 10 d and then kept the fish under normal or high stocking density conditions during the last 4 d. Food intake; biochemical parameters in plasma (cortisol, glucose, and lactate concentrations); liver (glucose and glycogen concentrations, and glycogen synthase activity); enzyme activities of amylase, lipase, and protease in foregut and midgut; and content of the hypothalamic neurotransmitters dopamine and serotonin, as well as their oxidized metabolites, 3,4-dihydroxyphenylacetic acid and 5-hydroxy-3-indoleacetic acid, were evaluated under those conditions. High stocking density conditions alone induced changes indicative of stress conditions in plasma cortisol concentrations, liver glycogenolytic potential, the activities of some digestive enzymes, and the 3,4-dihydroxyphenylacetic acid-to-dopamine and 5-hydroxy-3-indoleacetic acid-to-serotonin ratios in the hypothalamus. Melatonin treatment in nonstressed fish induced an increase in liver glycogenolytic potential, increased the activity of some digestive enzymes, and enhanced serotoninergic and dopaminergic metabolism in hypothalamus. The presence of melatonin in stressed fish resulted in a significant interaction with cortisol concentrations in plasma, glycogen content, and glycogen synthase activity in liver and dopaminergic and serotoninergic metabolism in the hypothalamus. In general, the presence of melatonin mitigated several of the effects induced by stress, supporting an antistress role for melatonin in rainbow trout.

Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats

Glycogen deposition is impaired in diabetes, thus contributing to the development of hyperglycaemia. Several glucose-lowering strategies have attempted to increase liver glycogen deposition by modulating targets, which eventually trigger the activation of liver glycogen synthase (LGS). However, these targets also alter several other biological processes, and therefore their therapeutic use may be limited. Here we tested the approach of directly activating LGS and evaluated the potential of this strategy as a possible treatment for diabetes. In this study, we examined the efficacy of directly overproducing a constitutively active form of LGS in the liver to ameliorate streptozotocin-induced diabetes in rats. Activated mutant LGS overproduction in the liver of streptozotocin-induced diabetic rats normalised liver glycogen content, despite low levels of glucokinase and circulating insulin. Moreover, this overproduction led to a decrease in food intake and in the production of the main gluconeogenic enzymes, glucose-6-phosphatase, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase. The resulting combined effect was a reduction in hyperglycaemia. The restoration of liver glycogen ameliorated diabetes and therefore is considered a potential strategy for the treatment of this disease.

Hepatic Overexpression of a Constitutively Active Form of Liver Glycogen Synthase Improves Glucose Homeostasis

In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state.

Impaired Glucose Tolerance and Predisposition to the Fasted State in Liver Glycogen Synthase Knock-out Mice

Conversion to glycogen is a major fate of ingested glucose in the body. A rate-limiting enzyme in the synthesis of glycogen is glycogen synthase encoded by two genes, GYS1, expressed in muscle and other tissues, and GYS2, primarily expressed in liver (liver glycogen synthase). Defects in GYS2 cause the inherited monogenic disease glycogen storage disease 0. We have generated mice with a liver-specific disruption of the Gys2 gene (liver glycogen synthase knock-out (LGSKO) mice), using Lox-P/Cre technology. Conditional mice carrying floxed Gys2 were crossed with mice expressing Cre recombinase under the albumin promoter. The resulting LGSKO mice are viable, develop liver glycogen synthase deficiency, and have a 95% reduction in fed liver glycogen content. They have mild hypoglycemia but dispose glucose less well in a glucose tolerance test. Fed, LGSKO mice also have a reduced capacity for exhaustive exercise compared with mice carrying floxed alleles, but the difference disappears after an overnight fast. Upon fasting, LGSKO mice reach within 4 h decreased blood glucose levels attained by control floxed mice only after 24 h of food deprivation. The LGSKO mice maintain this low blood glucose for at least 24 h. Basal gluconeogenesis is increased in LGSKO mice, and insulin suppression of endogenous glucose production is impaired as assessed by euglycemic-hyperinsulinemic clamp. This observation correlates with an increase in the liver gluconeogenic enzyme phosphoenolpyruvate carboxykinase expression and activity. This mouse model mimics the pathophysiology of glycogen storage disease 0 patients and highlights the importance of liver glycogen stores in whole body glucose homeostasis.

Control of Liver Glycogen Synthase Activity and Intracellular Distribution by Phosphorylation

Eukaryotic glycogen synthase activity is regulated by reversible phosphorylation at multiple sites. Of the two GS isoforms found in mammals, the muscle enzyme (muscle glycogen synthase) has received more attention and the relative importance of every known phosphorylation site in the control of its activity and intracellular distribution has been previously addressed. We have analyzed the impact of the dephosphorylation at the homologous sites of the glycogen synthase liver (LGS) isoform. Serine residues at these sites were replaced by non-phosphorylatable alanine residues, singly or in pairs, and the resultant LGS variants were expressed in cultured cells using adenoviral vectors. The sole mutation at site 2 (Ser7) yielded an enzyme that was almost fully active and able to induce glycogen deposition in primary hepatocytes incubated in the absence of glucose and in FTO2B cells, a cell line that does not normally synthesize glycogen. Mutation at site 2 was also sufficient to trigger the aggregation and translocation of LGS from the cytoplasm to the hepatocyte cell cortex in the absence of glucose. However, this redistribution was not observed in hepatocytes incubated without glucose when an additional mutation (E509A), which renders the enzyme inactive, was introduced. This result suggests that LGS translocation is strictly dependent on glycogen synthesis.

Glycogen synthase kinase 3 inhibition improves insulin-stimulated glucose metabolism but not hypertension in high-fat-fed C57BL/6J mice

In the current study, the effect of a highly specific peptide inhibitor of glycogen synthase kinase 3 (GSK3) (L803-mts) on glucose metabolism and BP was examined in a high-fat (HF) fed mouse model of diabetes. C57/BL6J mice were placed on an HF diet for 3 months and treated with L803-mts for 20 days, following which glucose metabolism was examined by euglycaemic-hyperinsulinaemic clamp studies. BP and heart rate were measured by radio-telemetry. The HF mice were obese, with impaired glucose tolerance and high plasma insulin and leptin levels. L803-mts treatment significantly reduced the insulin levels and doubled the glucose infusion rate required to maintain a euglycaemic condition in the HF+L803-mts group compared with the HF group. Insulin failed to suppress the endogenous glucose production rate in the HF group while decreasing it by 75% in the HF+L803-mts group, accompanied by increased liver glycogen synthase activity and net hepatic glycogen synthesis. GSK3 inhibition also reduced peripheral insulin resistance. Plasma glucose disappearance rate increased by 60% in the HF+L803-mts group compared with the HF group. In addition, glucose uptake in heart and gastrocnemius muscle was markedly improved. Although mean arterial pressure increased following the HF diet, it did not change significantly during the 12 days of L803-mts treatment. These studies demonstrate that GSK3 inhibition improved hepatic and peripheral insulin resistance in a mouse model of HF-induced diabetes, but it failed to have an effect on BP. GSK3 may represent an important therapeutic target for insulin resistance.

Glucose 6-Phosphate Produced by Gluconeogenesis and by Glucokinase Is Equally Effective in Activating Hepatic Glycogen Synthase

Glucose 6-phosphate (Glc-6-P) produced in cultured hepatocytes by direct phosphorylation of glucose or by gluconeogenesis from dihydroxyacetone (DHA) was equally effective in activating glycogen synthase (GS). However, glycogen accumulation was higher in hepatocytes incubated with glucose than in those treated with DHA. This difference was attributed to decreased futile cycling through GS and glycogen phosphorylase (GP) in the glucose-treated hepatocytes, owing to the partial inactivation of GP induced by glucose. Our results indicate that the gluconeogenic pathway and the glucokinase-mediated phosphorylation of glucose deliver their common product to the same Glc-6-P pool, which is accessible to liver GS. As observed in the treatment with glucose, incubation of cultured hepatocytes with DHA caused the translocation of GS from a uniform cytoplasmic distribution to the hepatocyte periphery and a similar pattern of glycogen deposition. We hypothesize that Glc-6-P has a major role in glycogen metabolism not only by determining the activation state of GS but also by controlling its subcellular distribution in the hepatocyte.

Regulation of Glycogen Synthase: IDENTIFICATION OF RESIDUES INVOLVED IN REGULATION BY THE ALLOSTERIC LIGAND GLUCOSE-6-P AND BY PHOSPHORYLATION

Regulation of Glycogen Synthase: IDENTIFICATION OF RESIDUES INVOLVED IN REGULATION BY THE ALLOSTERIC LIGAND GLUCOSE-6-P AND BY PHOSPHORYLATION

Time sequence of changes in the responsiveness of glycogen breakdown to adrenergic agonists in perfused liver of rats with insulin-induced hypoglycemia.

The time-course changes of the responsiveness of glycogen breakdown to alpha- and ss-adrenergic agonists during insulin-induced hypoglycemia (IIH) were investigated. Blood glucose levels were decreased prior to the alteration in the hepatic responsiveness to adrenergic agonists. The activation of hepatic glucose production and glycogenolysis by phenylephrine (2 microM) and isoproterenol (20 microM) was decreased in IIH. The changes in the responsiveness of glycogen catabolism were first observed for isoproterenol and later for phenylephrine. Hepatic ss-adrenergic receptors showed a higher degree of adrenergic desensitization than did alpha-receptors. Liver glycogen synthase activity, glycogen content and the catabolic effect of dibutyryl cyclic AMP (the ss-receptor second messenger) were not affected by IIH.

Insulin increases liver protein phosphatase-1 and protein phosphatase-2C activities in lean, young adult rhesus monkeys.

Liver glycogen synthase activity is increased, and glycogen phosphorylase activity and glucose 6-phosphate content reduced by in vivo insulin during a euglycemic hyperinsulinemic clamp in lean young adult rhesus monkeys. To examine the mechanism of dephosphorylation of liver glycogen synthase and glycogen phosphorylase, the enzyme activities of protein phosphatase-1, protein phosphatase-2C, cAMP-dependent protein kinase, glycogen synthase kinase-3, protein kinase C and protein tyrosine kinase were determined before and after three hours of in vivo insulin in these same monkeys. The bioactivity of an inositol phosphoglycan insulin mediator (pH 2.0) and cAMP concentrations were also measured in the liver before and after insulin administration. Insulin caused significant increases in protein phosphatase-1 (p = 0.005) and in protein phosphatase-2C activities (p = 0.001). Insulin-stimulated minus basal bioactivity of the pH 2.0 insulin mediator was strongly inversely related to the insulin-stimulated minus basal glucose 6-phosphate content (r = -0.93, p < 0.0001). These findings suggest that protein phosphatase-1 and protein phosphatase-2C may be involved in the mechanism of in vivo insulin activation of liver glycogen synthase and inactivation of liver glycogen phosphorylase.

Effect of feeding, fasting, and diabetes on liver glycogen synthase activity, protein, and mRNA in rats.

Hepatic glycogen synthase activity is increased in diabetic animals. However, the relationship between enzymic activity, enzyme protein mass, and mRNA abundance has not been well characterized. In the present study, these relationships were determined in 3- and 8-day diabetic, fed and fasted rats. The results were compared to data obtained in normal fed and fasted animals. In normal rats, total synthase specific activity and protein mass were similar in the fed and fasted state. However, in fed animals, the synthase mRNA abundance was increased 1.7-fold. In 3-day diabetic rats, total synthase specific activity was increased approximately 29% compared to normal controls. It was unaffected by feeding and fasting and was associated with an approximate 15% increase in enzyme mass. Synthase mRNA was increased 1.8 and 2.6-fold in fasted and fed animals, respectively. In 8-day diabetic rats, total synthase specific activity was increased more than 2-fold compared to controls. However, the enzyme protein mass was decreased by approximately 20%. The mRNA abundance in 8-day diabetic fasted rats was only 30% of controls, while in fed rats it was increased by 40%. These data indicate that feeding and fasting have a major effect on synthase mRNA abundance which is independent of synthase activity, or protein mass, or both, in normal and diabetic animals. Total synthase specific activity increased with duration of diabetes. This was associated with only a modest change in protein mass. Thus, diabetes induces an increase in synthase catalytic efficacy. The specific activity of phosphorylase is decreased in diabetic rats.

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, Liver Glycogen synthase activity, and β-oxidation in fructose-fed rats

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed-rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and gb-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid β-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Localization of glycogen synthase activity in liver of fasted normal and adrenalectomized rats after injection of dexamethasone

Hepatic glycogen synthase activity was localized in normal and adrenalectomized (ADX) rats after fasting overnight and in fasted ADX rats after injection of dexamethasone (DEX) 2-8 h prior to sacrifice to stimulate glycogen synthesis. Cryostat sections were incubated in medium containing substrate to demonstrate glycogen synthase activity as indicated by glycogen synthesized during incubation. Sections from fasted normal rats showed limited dispersed glycogen synthase activity in both periportal and centrilobular regions. In contrast, activity for glycogen synthase in hepatocytes from fasted ADX rats appeared as large aggregates in random hepatocytes throughout the lobule. Two hours after injection of DEX the reaction product appeared as aggregates in some hepatocytes, but other cells revealed dispersed enzyme activity. Glycogen synthase activity was evident in more hepatocytes after 4 h treatment with DEX and after 8 h virtually all hepatocytes contained abundant reaction product. The results suggest that synthase activity becomes concentrated in limited regions of selected hepatocytes in fasted ADX rats. DEX stimulation of glycogen synthesis for 4-8 h results in increased enzyme activity.

Accumulation of 1,2-sn-diradylglycerol with increased membrane-associated protein kinase C may be the mechanism for spontaneous hepatocarcinogenesis in choline-deficient rats.

Choline deficiency, via deprivation of labile methyl groups, is associated with a greatly increased incidence of hepatocarcinoma in experimental animals. This dietary deficiency also causes fatty liver, because choline is needed for hepatic secretion of lipoproteins. We hypothesized that fatty liver might be associated with the accumulation of 1,2-sn-diradylglycerol and subsequent activation of protein kinase C. Several lines of evidence indicate that cancers might develop secondary to abnormalities in protein kinase C-mediated signal transduction. We observed that rats fed a choline-deficient diet for 1, 6, or 27 weeks had increased hepatic concentrations of 1,2-diradylglycerol. At 1 and 6 weeks, hepatic plasma membrane from choline-deficient rats had increased concentrations of 1,2-sn-diacylglycerol and 1-alkyl, 2-acylglycerol, with the latter accounting for 20-26% of membrane 1,2-sn-diradylglycerol (as compared with only 2-5% in controls). Protein kinase C activity was increased in hepatic plasma membrane at 1 week of choline deficiency. By Western blotting there was an increase in the amount of protein kinase C zeta and a decrease in the amount of protein kinase C delta in liver at 1 week. By 6 weeks of choline deficiency, hepatic plasma membrane and cytosolic protein kinase C (PKC) activities were increased significantly, with increased amounts of hepatic plasma membrane protein kinase C alpha, and delta detected by Western blotting. Glycogen synthase activity in liver was diminished after 1 week of choline deficiency; this enzyme is inhibited by PKC-mediated phosphorylation. We suggest that choline deficiency perturbed PKC-mediated transmembrane signaling within liver and that this contributed to the development of hepatic cancer in these animals.

Mechanism of activation of liver glycogen synthase by swelling.

The mechanism linking the stimulation of liver glycogen synthesis to swelling induced either by amino acids or hypotonicity was studied in hepatocytes, in gel-filtered liver extracts, and in purified preparations of particulate glycogen to which glycogen-metabolizing enzymes are bound. High concentrations of KCl, but not of potassium glutamate, were found to inhibit glycogen synthesis in permeabilized hepatocytes. Similarly, physiological concentrations (30-50 mM) of Cl- ions were also found to inhibit synthase phosphatase in vitro, whereas 10-20 mM Cl- ions, a concentration found in swollen hepatocytes, did not inhibit synthase phosphatase. Synthase phosphatase activity was more sensitive to inhibition by Cl- ions at low (0.1%) than at high (1%) concentrations of glycogen. By contrast, 10 mM glutamate and aspartate, a concentration observed in hepatocytes incubated with glutamine or proline, stimulated synthase phosphatase in vitro. Therefore, it is proposed that the fall in intracellular Cl- concentration as well as the increase in intracellular glutamate and aspartate concentrations, that are observed in swollen hepatocytes in the presence of amino acids, are responsible, at least in part, for the stimulation of synthase phosphatase and, hence, of glycogen synthesis.

Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase

Isolated hepatocytes from streptozotocin-diabetic rats failed to respond to a glucose load with an activation of glycogen synthase. This lesion was associated with severely decreased activities of glycogen-synthase phosphatase and of glucokinase. All these defects were abolished after consumption for 13-18 days of drinking water containing Na3VO4 (0.7 mg/ml), and they were partially restored after 3.5 days, when the blood glucose concentration was already normalized. In all conditions the maximal extent of activation of glycogen synthase in cells closely parallelled the activity of glycogen-synthase phosphatase.

Short-term hormonal control of protein phosphatases involved in hepatic glycogen metabolism

The prominent protein phosphatases involved in liver glycogen metabolism are the AMD (ATP, Mg-dependent, type-1) and PCS (polycation-stimulated, type-2A) phosphatases. The glycogen synthase phosphatase activity, measured from the rate of activation of liver glycogen synthase, is virtually accounted for by AMD phosphatases; the bulk of the activity belongs to the glycogen-bound protein phosphatase G and a small part is present in the cytosol. The major part of the phosphorylase phosphatase activity present in the post-mitochondrial supernatant is shared by protein phosphatase G and cytosolic enzymes, and a minor part belongs to a microsomal AMD phosphatase. In the liver cytosol, the phosphorylase phosphatase activity is about equally distributed between AMD and PCS phosphatases. Studies in vivo as well as on isolated, perfused livers have shown that glucagon (which raises the level of cyclic AMP) as well as vasopressin (which increases the cytosolic Ca 2+ concentration) decrease the phosphorylase phosphatase activity in liver extract or cytosol (filtered through Sephadex G-25) by about 25% within a few minutes. These effects were not additive, and the activity of glycogen synthase phosphatase was not affected. Conversely, insulin as well as glucose increased both phosphatase activities by about 25%, and these effects were additive. Vanadate mimicked the effect of insulin on the perfused liver. All the activity changes were only observed when the assays were performed at high tissue concentration. Upon subcellular fractionation all the effects were well expressed in the cytosol, but not in the particulate fraction (glycogen and microsomes). However, quantitatively the hormonal responses were largely lost during the fractionation procedure; they could be restored by recombination of the liver cytosol from a hormone-treated rat with the particulate fraction from either a treated or an untreated animal. It appears that the effects of glucagon, insulin and glucose are mediated by cytosolic, transferable effectors of the V max of protein phosphatases. These effectors are eluted in the void volume of a Sephadex G-25 column. Rats of the gsd/gsd strain, which have a genetic deficiency of hepatic phosphorylase kinase, responded to an injection of insulin plus glucose with a normal increase in the cytosolic phosphorylase phosphatase activity. In contrast, they failed to respond to glucagon as well as vasopressin. A transient 80% inhibition of the phosphorylase phosphatase activity could be induced in vitro in a concentrate liver cytosol from Wistar rats upon addition of MgATP. No change in the phosphorylase phosphatase activity occurred when the same experiment was performed with cytosol from gsd/gsd rats, except after addition of phosphorylase kinase (either partially purified from rat liver, or pure enzyme from rabbit skeletal muscle). Additional data indicate that phosphorylase kinase, when covalently activated by glucagon treatment or stimulated by vasopressin-released Ca 2+, triggers the inhibition of phosphorylase phosphatase by direct phosphorylation of a hitherto unidentified protein substrate, which is distinct from inhibitor-1.

In vivo regulation of liver and skeletal muscle glycogen synthase activity by glucose and insulin.

The regulation of liver and skeletal muscle glycogen synthase by plasma insulin and glucose has not been investigated in vivo at physiological blood glucose concentrations. We have, therefore, used the glucose clamp technique to investigate the effects of these variables independently in rats. Short-term streptozocin-(0.15 g/kg) diabetic animals were used in addition to normal rats to avoid endogenous insulin secretion during hyperglycemic clamps. In normal and diabetic animals, 3 h of hyperinsulinemia without change in blood glucose concentrations caused only a small increase in liver glycogen synthase activity (+34%), whereas hyperglycemic clamps at 6.0 and 10.0 mmol/L resulted in marked increases (+268 and +394% of basal, P less than 0.001). Liver glycogen concentrations at the end of the clamps reflected these changes. In skeletal muscle, glycogen synthase was increased by +58% by the euglycemic hyperinsulinemic clamp and was not increased significantly further by hyperglycemia. Similarly, muscle glycogen concentration increased with the 4.0-mmol/L clamp but during the hyperglycemic clamps was only raised more in direct proportion to blood glucose concentrations. The results confirm that blood glucose concentration is the major short-term regulator of glycogen synthase activity in the liver but that insulin is of prime importance in skeletal muscle.

Hepatic glycogen metabolism and insulin receptor status after long-term peripheral insulin delivery in the islet-transplanted diabetic rat.

Severely diabetic (0.15 g/kg streptozocin) rats were transplanted with fetal pancreatic islets under the renal capsule to model peripheral insulin delivery, or into the splenic pulp to model portal delivery. In both groups of transplanted rats, weight gain and blood glucose concentrations were normal. Peripheral insulin delivery abolished the physiologic portal-peripheral insulin concentration gradient but was not associated with peripheral hyperinsulinemia. Incorporation of 3H2O into liver glycogen and the increase in hepatic glycogen concentration after a meal were normal in animals receiving insulin peripherally for 10 wk. Activation of liver glycogen synthase in response to the meal was also normal. Hepatic insulin receptor status in animals with peripheral insulin delivery was identical to that of normal control and splenic pulp islet-transplanted rats. The findings indicate that portal insulin delivery is not a prerequisite for normal hepatic glycogen metabolism in the rat, and that receptor upregulation and increased hepatic extraction of insulin are unlikely to explain the normal hepatic metabolism with peripheral insulin delivery.