[Streptozotocin diabetes in the rat with special reference to glucose utilization by the musculature].
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Abstract:
The glucose utilization by different skeletal muscle tissues of short-term streptozotocin treated Wistar rats was studied both in vivo and in vitro. The findings permit the following statements: The reduced metabolic conversion of glucose is mainly the result of the diminished transport of glucose into the muscle cells. The utilization of the glucose taken up by the muscle cells for synthesis of glycogen is unchanged in the diabetic animals and can be stimulated by insulin correspondingly as in normal rats. The conversion of the glucose metabolized by the cells to lactate and the time course of the specific activity of glycogen and lactate lead to the conclusion that glycogenolysis in the muscles of streptozotocin diabetic rats during the incubation is enhanced.Keywords:
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Glycogenolysis
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Glycogenesis
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Previous studies have shown that Wistar rats injected at birth (n0) with STZ (n0-STZ) develop as adults a noninsulin-dependent diabetic state characterized by a lack of insulin response to glucose in vivo, a mild basal hyperglycemia, and an impaired glucose tolerance. Our former in vivo studies using the insulin-glucose clamp technique revealed an increased insulin action upon hepatic glucose production in these animals. We have now cultured hepatocytes from these mildly diabetic rats in parallel with hepatocytes from control rats, to examine more closely basal and insulin-regulated glucose production and glucose incorporation into glycogen. In addition, we extended our investigation to other hepatic functions such as lipid synthesis and amino acid transport, which could not be studied in vivo. Although glucose production from glycogenolysis or gluconeogenesis in absence or presence of glucagon was identical in the two cell populations, glucagon-stimulated glycogenolysis was more sensitive to insulin action in diabetic hepatocytes. Similarly, insulin action on glucose incorporation into glycogen, lipogenesis, and amino acid transport were enhanced in diabetic hepatocytes. The hormone effect was manifested by an increase in the sensitivity and/or in the responsiveness, reflecting the multiplicity of the pathways whereby the insulin signal is transduced through the insulin receptor to multiple postreceptor sites. To gain insight into the possible mechanism of these disturbances, we evaluated the initial insulin receptor interaction and the kinase activity of the receptor beta-subunit. In accordance with our previous study on intact livers, we found no alteration in either of these parameters in n0-STZ rat hepatocytes. Thus, the present study clearly demonstrates that these diabetic rats exhibit a postreceptor hyperresponsiveness to insulin at the cellular level. It strengthens the notion that a beta-cell deficiency with glucose intolerance does not necessarily lead to a hepatic insulin resistance.
Glycogenolysis
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Insulin oscillation
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Responses to insulin-induced hypoglycemia in fasted sham-operated (SHAM), adrenodemedullated (ADM), and epinephrine-infused ADM (ADM + E) rats were studied to ascertain the specific role of epinephrine in increasing resting skeletal muscle content of adenosine 3′,5′-cyclic monophosphate (cAMP) and fructose 2,6-bisphosphate (F-2,6-P2), which are involved in stimulation of muscle glycogenolysis and lactate production. Rats from each group were fasted for 24 h and then infused intravenously with insulin (30, 60, or 90 min) to produce plasma insulin values of approximately 92 microU/ml. One-half of the insulin-infused ADM rats were also infused with epinephrine (ADM + E). Muscle and blood lactate, muscle cAMP, and muscle F-2,6-P2 increased and muscle glycogen decreased in SHAM rats. Each of these changes was prevented or attenuated in ADM rats and restored in ADM + E rats. Liver cAMP, glycogen, and F-2,6-P2 responses to hypoglycemia were similar in SHAM, ADM, and ADM + E rats. Blood glucose decreased to 0.74 +/- 0.05 mM in ADM rats compared with 1.54 +/- 0.11 mM in SHAM and 1.34 +/- 0.15 mM in ADM + E rats after 90 min of insulin infusion. The increase in plasma epinephrine is therefore essential in the counterregulatory response to insulin-induced hypoglycemia in fasted rats. Resting skeletal muscle glycogenolysis and lactate production for hepatic gluconeogenic substrate appear to be important components of the counterregulatory response in fasted rats.
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1. The metabolism of [U-(14)C]glucose by the isolated diaphragm muscle of normal rats, rats rendered diabetic with streptozotocin and rats with transitory insulin deficiency after an injection of anti-insulin serum was studied. 2. The incorporation of [(14)C]glucose into glycogen and oligosaccharides was significantly decreased in the diabetic diaphragm muscle and in the muscle from rats treated with anti-insulin serum. 3. Neither diabetes nor transitory insulin deficiency influenced the oxidation of glucose, or the formation of lactate and hexose phosphate esters from glucose. 4. Insulin fully restored the incorporation of glucose into glycogen and maltotetraose in the diabetic muscle, but the incorporation into oligosaccharides, although increased in the presence of insulin, was significantly lower than the values obtained with normal diaphragm in the presence of insulin.
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The effects of minimal increments in plasma insulin concentrations on hepatic glucose production and glucose uptake, skeletal muscle net glycogen synthesis and glycogenolysis, glycogen synthase and phosphorylase activity, glucose-6-phosphate and uridinediphosphoglucose (UDPG) concentrations were examined in 24-h and in 6-h fasted conscious rats. Insulin was infused for 120 min at rates of 1.5, 3, 6, 12, 24, and 108 pmol/kg per min in 24-h fasted rats and at rates of 3, 6, 9, 12, 36, and 108 pmol/kg per min in 6-h fasted rats while endogenous insulin release was inhibited by SRIF infusion and plasma glucose was maintained at the basal level. All rats received an infusion of [3-3H]glucose. The portion of the muscle glucose-6-phosphate (G6P) pool derived from net glycogenolysis was estimated from the ratio of specific activities of muscle UDPG and plasma glucose. Minimal increments in the circulating insulin levels, which did not stimulate glucose uptake, caused: (a) the increase in skeletal muscle glycogen synthase activity and the decrease in the rate of muscle glycogenolysis and in the G6P concentration; (b) the inhibition of hepatic glucose production. Net muscle glycogen synthesis was not stimulated despite submaximal activation of glycogen synthase, and its onset correlated with the rise in muscle G6P levels. Thus, insulin's inhibition of muscle glycogenolysis is the most sensitive insulin action on skeletal muscle and its dose-response characteristics resemble those for the inhibition of hepatic glucose production. These findings indicate that skeletal muscle glycogen synthase may play a major role in carbohydrate homeostasis even under postabsorptive (basal insulin) conditions and support the notion that insulin may exert some of its effects on the liver through an indirect or peripheral mechanism.
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Glucose 6-phosphate
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Muscle from rhesus fetuses, 125 days of gestational age, and from adult monkeys was incubated in the presence of glucose-6-14C with and without insulin. Insulin increased glucose uptake, lactate-14C production and 14CO2 production equally in both fetal and adult muscle. Glycogen concentrations did not change with insulin but 14C incorporation into glycogen increased markedly. Although a greater percentagepercentage of 14C from the glucose uptake appeared in glycogen in adult muscle, insulin stimulated the pathway glucose to glycogen to the same degree in fetal and adult muscle. We conclude that carbohydrate metabolism of muscle from the rhesus fetus at 125 days (75% of term) is responsive to insulin. (Endocrinology85: 615, 1969)
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Levels of the mRNA encoding the catalytic subunit of protein phosphatase type-1 (PP-1cat) were reduced in skeletal muscle but not liver in response to short-term (2h) chow refeeding after prolonged (40h) starvation in the rat. This reduction did not appear to be mediated by insulin per se since streptozotocin-induced diabetes was associated with a reduction in PP-1cat levels in skeletal muscle. It is suggested that glucose levels may be one factor that modulates skeletal muscle PP-1cat mRNA levels. Despite the changes in PP-1cat mRNA levels in skeletal muscle, total protein phosphatase-1 catalytic activity was not altered by either chow refeeding or streptozotocin-diabetes. By contrast, although total hepatic PP-1cat mRNA levels were not altered in response to chow refeeding, there was a marked reduction in glycogen phosphorylase phosphatase activity in the cytosol but not in the glycogen/microsomal fraction.
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Gluconeogenesis
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