Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Euglycaemic clamp experiments with single or combined infusions of human biosynthetic proinsulin and insulin were performed in 6 healthy, normal weight subjects in order to assess the possibility of antagonistic, additive, or synergistic effects on whole body glucose metabolism. Insulin (i: 2.02 pmol x kg-1 x min-1) or proinsulin (p: 9.26 pmol x kg-1 x min-1) were infused under euglycaemic clamp conditions over 240 min. After 120 min, the infusion rates were doubled (protocols ii and pp), or proinsulin (protocol ip) or insulin (protocol pi) infusions were added. After 240 min of infusing insulin or proinsulin alone, euglycaemia was maintained for an additional 60 min period without hormone infusions to measure the decay of hormone concentrations and of effects on glucose metabolism. Effects on glucose uptake were measured as the glucose infusion rate necessary to maintain euglycaemia. IR-insulin, IR-proinsulin, IR-C-peptide and IR-glucagon were determined by specific radioimmunoassays. After 240 min, similar steady state glucose infusion rates were reached for all protocols (mean +/- SEM, mg x kg-1 x min-1: ii: 10.6 +/- 1.0; ip: 9.1 +/- 0.4; pi: 10.0 +/- 0.9; pp: 8.4 +/- 0.7). The infusion rate with proinsulin alone (pp), however, was significantly smaller than with insulin alone (ii), indicating a somewhat lower effectiveness of the proinsulin dose employed. With all protocols, nonesterified fatty acid and IR-glucagon concentrations were decreased to a similar extent. Steady state hormone concentrations were reached within 30 min of each infusion period.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of single and combined infusions of human biosynthetic proinsulin and insulin on glucose metabolism and on plasma hormone concentrations in euglycaemic clamp experiments. 305 14

In the present study, we describe the specificity and the autoradiographic distribution of insulin binding sites in the rat central nervous system (CNS) after in vitro incubation of brain sections with [125I]-14A insulin. Increasing concentrations of unlabeled insulin produced a dose-dependent inhibition of [125I]-insulin binding which represented 92 +/- 2% displacement with 3 X 10(-5) M, whatever the brain sections tested. Half-maximum inhibition with native insulin was obtained with 2.2 X 10(-9) M, with 10(-7) M proinsulin whereas glucagon had no effect. Under our experimental conditions, no degradation of [125I]-insulin was observed. Autoradiograms obtained by apposition of LKB 3H-Ultrofilm showed a widespread distribution of [125I]-insulin in rat CNS. However, quantitative analysis of the autoradiograms with 10(-10) M of labeled insulin, showed a high number of [125I]-insulin binding sites in the choroid plexus, olfactory areas, in both cerebral and cerebellar cortices, the amygdaloid complex and in the septum. In the hippocampal formation, the dorsal dentate gyrus and various subfields of CA1, CA2 and CA3 were labeled. Moreover, arcuate, dorso- and ventromedial nuclei of the hypothalamus contained high concentrations of [125I]-insulin whereas a low density was observed in the mesencephalon. The metabolic role of insulin in the CNS is supported by the large distribution of insulin binding sites in the rat brain. However, the presence of high affinity binding sites in selective areas involved in perception and integrative processes as well as in the regulation of both feeding behavior and neuroendocrine functions, suggests a neuromodulatory role of insulin in the brain.
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PMID:[Radioautographic and quantitative study of insulin binding sites in the rat brain]. 309 89

The SHR/N-cp rat is a new genetically obese model for non-insulin-dependent diabetes mellitus. Expression of the diabetes is enhanced by a high-sucrose (54%) diet. After 4 wk on the diet, the cp/cp rats weigh significantly more than their +/? controls, have postprandial hyperglycemia (greater than 400 mg/dl), and are hyperinsulinemic, with immunoreactive insulin (IRI) levels 10- to 20-fold greater than controls. Total pancreatic IRI tends to be increased 1.6-fold in the cp/cp rats (although not significantly). There is no increase in pancreatic proinsulin content as a percent of total IRI. Studies of in vitro pancreatic function were carried out with the isolated nonrecirculating perfused pancreas method. The cp/cp rats (n = 10) showed impaired or absent IRI responses to 16.5 mM glucose, whereas +/? rats (n = 9) responded with classic biphasic curves. Comparison of insulin secreted in 20 min revealed a greater than 53% decrease in IRI secretion in cp/cp rats (P less than .05). A paradoxical hypersecretion of IRI at glucose concentrations of 0-2.7 mM was noted in cp/cp but not lean rats, i.e., 1.8 +/- 0.2 mU/min IRI in cp/cp rats vs. 0.04 +/- 0.007 mU/min in +/? rats. Perfusion of pancreases for 45 min with buffers containing no glucose resulted in restoration of a normal biphasic IRI response to 16.5 mM glucose in the cp/cp rats, whereas response in the lean rats was markedly reduced. Brisk IRI responses to 10 mM arginine in buffers with no glucose also occurred in cp/cp but not +/? rats. Glucagon secretion was relatively suppressed in the cp/cp rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reversible impairment of glucose-induced insulin secretion in SHR/N-cp rats. Genetic model of type II diabetes. 328 29

In Type II, non-insulin-dependent diabetes, insulin secretion is often reduced to the point where oral hypoglycaemic agents fail to control the plasma glucose level. We studied 12 patients (age 41-66 years; 4 lean, 8 obese) with Type II diabetes mellitus for 1-25 years who were uncontrolled despite maximal dose glibenclamide and metformin. After withdrawal of medication, blood glucose control was determined by measuring glucose before and 2 h after each meal for 48 h, and beta-cell function by insulin or C-peptide response to glucagon and to iv glucose. Following these tests, intensive insulin treatment (CSII) was initiated, and near-euglycaemia (mean of 7 daily glucose determinations less than 7.7 mmol/l) was maintained for 16.6 +/- 1.5 days, at which time the tests were repeated. Mean daily insulin requirement was 61 +/- 9 IU (0.81 +/- 0.09 IU/kg). Glucose control was improved after cessation of CSII (mean glucose 12.7 +/- 0.6 mmol/l after vs 20 +/- 1.5 mmol/l before, P less than 0.005). Maximum incremental C-peptide response improved both to glucagon (214 +/- 32 after vs 134 +/- 48 pmol/l before, P = 0.05) and to glucose iv bolus injection (284 +/- 53 vs 113 +/- 32 pmol/l, P less than 0.05). Peak insulin response, measured after iv glucose infusion, also tended to be higher in the post-CSII test (42 +/- 18 vs 22 +/- 5.6 mU/l). Basal and stimulated proinsulin concentrations were high relative to C-peptide levels during the pre-treatment period, but returned to normal after CSII.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Improved beta-cell function after intensive insulin treatment in severe non-insulin-dependent diabetes. 329 39

The function of the pancreatic B- and A- cell during a carbohydrate-rich meal was investigated in hyperthyroid patients, since these patients frequently present an altered handling of glucose. In basal conditions the plasma levels of glucose, immunoreactive insulin (IRI), C-peptide (CPR), proinsulin were higher in hyperthyroid patients than in normal subjects, whereas plasma glucagon was similar in the two groups. Hyperthyroid patients had high post-breakfast incremental areas of glucose and IRI and those of CPR and glucagon were normal. In post-breakfast plasma, the hyperthyroid patients had high proinsulin and normal insulin levels. The molar ratio between CPR and IRI was low throughout the test in the hyperthyroid group. In conclusion, in the hyperthyroid group the plasma levels of proinsulin were high and those of glucagon were normal; in response to the standard breakfast the levels of insulin and C-peptide were normal. These findings do not explain the altered glucose handling present in these patients.
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PMID:Plasma glucose, insulin, proinsulin, C-peptide and glucagon before and after a carbohydrate-rich meal in hyperthyroid patients. 331 63

Hemolysates of human erythrocytes contain a highly specific insulin- and glucagon-degrading activity which is comparable to the so-called insulin- and glucagon-degrading proteinase (IGP, EC 3.4.23.5) found in other tissues. Glucagon degradation is inhibited by its cleavage products. Insulin, proinsulin and also cleavage products of insulin are effective inhibitors of glucagon degradation. The isolated insulin A- and B-chains are also capable of inhibiting the splitting of glucagon, but a higher concentrations. On the other hand, glucagon influences insulin degradation. Naturally occurring substances within commercially available human serum albumin have remarkable inhibitory effects on the glucagon degradation.
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PMID:Glucagon- and insulin degradation by hemolysate of human erythrocytes. 332 71

Tolbutamide (1 g/kg body wt) was administered to male rats for 3 days to determine the effects of this pretreatment on subsequent insulin biosynthesis and compartmental storage characteristics of freshly isolated islets. Islets were isolated 16 h after the last tolbutamide administration, at a time when fed plasma glucose concentrations were normal. Islet glucagon was unchanged but insulin content was significantly reduced (38 +/- 1.2 ng IRI/islet from seven untreated rats versus 7.9 +/- 1.2 ng IRI/islet from eight treated rats). After tolbutamide pretreatment, the rate of incorporation of 3H-leucine into islet proinsulin was unchanged, but the t1/2 of labeled proinsulin-to-insulin conversion was significantly (P less than 0.001) decreased from 36 to 20 min. After treatment, actual rates of glucose-stimulated insulin secretion were 50% lower, however, because due to the proportionately greater depletion of islet insulin content, the fractional rate of secretion was increased two-fold. After treatment, there was evidence of compartmental, heterogeneous insulin storage, and glucose still marked newly synthesized insulin for preferential release; however, the differential release of new and old insulin converged rapidly with time. Mathematical integration of the data suggested dilution of the newly synthesized insulin compartment with unlabeled insulin during the chase period, but additionally indicated more rapid mixing of newly synthesized with previously stored, unlabeled insulin. Thus, tolbutamide-treated rats partially compensated for acute insulin depletion by increasing the rate of proinsulin-to-insulin conversion, but not increasing the rate of proinsulin biosynthesis; doubling the glucose-stimulated fractional secretory rate of the depleted cellular insulin storage compartment; and retaining compartmental storage characteristics but mixing newly synthesized insulin more rapidly with the compartment of previously stored, unlabeled insulin.
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PMID:Effects of tolbutamide pretreatment on the rate of conversion of newly synthesized proinsulin to insulin and the compartmental characteristics of insulin storage in isolated rat islets. 351 Jan 40

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 microgram/m2/min) or proinsulin (2.75 micrograms/m2/min), achieving steady-state serum levels of 32 +/- 3 microU/ml (equivalent to 0.23 +/- 0.02 pmol/ml) and 3.7 +/- 0.2 pmol/ml, respectively. Suppression of HGO was similar (83-84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 +/- 0.43 versus 1.98 +/- 0.28 mg/kg/min, P less than 0.001). Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions. In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.
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PMID:In vivo deactivation of proinsulin action on glucose disposal and hepatic glucose production in normal man. 351 41

Glucose tolerance deteriorates in normal human pregnancy but 99% of all pregnant women retain normal glucose tolerance whereas the remaining 1% develop abnormal glucose tolerance and are designated gestational diabetics. The possibility that glucose tolerance deteriorates in pregnancy because of diabetes-like changes in the secretory function of the endocrine pancreas has been investigated in gestational diabetics and healthy controls. Even though the insulin responses to oral glucose and mixed meals are equally large in gestational diabetics and normal pregnant women, the insulin responses of the gestational diabetics differ in two pertinent ways from those of the normals. First, a delayed insulin response is frequently seen, and second, the insulin response per unit of glycaemic stimulus (the 'insulinogenic index') is normally significantly lower than that of the normal pregnant women. Diabetes-like changes in the secretion of glucagon are not seen in neither group. Insulin degradation is unaffected by pregnancy and the proinsulin share of the total plasma insulin immunoreactivity does not increase in pregnancy. It is therefore likely that the main reason for the diabetogenicity of pregnancy is insulin resistance. Most pregnant women are able to increase their insulin secretion and thus overcome the resistance. Some pregnant women do, however, seem to have a more limited insulin secretory capacity which eventually may lead to the development of gestational diabetes.
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PMID:Endocrine pancreatic function in women with gestational diabetes. 353 65

Insulin binding was studied in rabbit semimembranosus proprius and psoas major muscles composed of slow-twitch oxidative (SO) and fast-twitch glycolytic (FG) fibers, respectively. For this purpose, we developed a technique using cryostat microtome muscle slices. Degradation of 125(I)-insulin during the incubation period was prevented by the addition of 1 mM bacitracin in the buffer. Specific binding to muscle slices plateaued by the 24 hrs. of incubation at 4 degrees C. It increased as a function of the amount of muscle, with a maximum binding occurring at about 5 mg of muscle slices. Triton X-100 has been shown to increase specific binding from a critical concentration of 10(-4) M with a maximum effect occurring at 3.3 10(-4) M. Under this condition, the binding was specific since displacement studies showed no inhibition of 125(I)-insulin binding by GH, HCG, ACTH and glucagon, whereas half maximal inhibition was achieved using 5 10(-10) M insulin, 3 10(-9) M IGF1 and 2 10(-8) M proinsulin. The analysis of the binding data yielded curvilinear Scatchard plots. The number of high affinity insulin receptors was higher in the SO muscle than in the FG muscle (4.3 +/- 0.7 vs 0.7 +/- 0.2 fmol/mg fresh muscle; P less than 0.001) with similar high affinity dissociation constants (Kd = 1.5 10(-10) M). Analogous results were obtained using muscle microsomal fractions. The differences in insulin binding might be related to the more intense metabolism of SO fibres which contract more often than FG fibres in vivo.
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PMID:Characterization of insulin binding to slices of slow and fast twitch skeletal muscles in the rabbit. 353 33


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