Glucagon and Insulin Relationships in Genetically Diabetic (db/db) and in Streptozotocin-Induced Diabetic Mice

Stearns, Susan B.; Benzo, Camillo A.

doi:10.1055/s-0028-1093473

Cited by 43 publications

(20 citation statements)

References 6 publications

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“…In this regard, the inhibitory function of leptin on alpha and beta cells would be similar to that of somatostatin, which is secreted from pancreatic delta cells [29]. This inhibitory role of leptin in the islet is consistent with the fact that mouse models lacking this hormone or deficient in leptin receptors develop hyperinsulinaemia and hyperglucagonaemia [13,14]. In addition to the effect of this hormone on the synthesis and secretion of insulin and glucagon, leptin can also regulate the action of these islet hormones [30].…”

Section: Discussionsupporting

confidence: 54%

“…Recently, it has been shown that leptin receptors are expressed in mouse and human alpha cells, and that leptin inhibits electrical activity, Ca 2+ signalling and exocytosis in these cells [10]. The possibility that leptin has a regulatory effect on glucagon release is further supported by mouse models with defects in leptin signalling, since these animals develop hyperglucagonaemia [13,14]. Thus leptin released from adipose tissue plays an important role in islet function and glucose homeostasis.…”

Section: Introductionmentioning

confidence: 79%

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Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets

et al. 2011

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Aims/hypothesis Leptin, released by adipocytes, can modulate glucose homeostasis through direct actions on pancreatic alpha and beta cells. Although this hormone rapidly regulates alpha cell exocytosis, its long-term effects on glucagon gene expression are currently unknown. Methods We analysed glucagon mRNA levels and protein content in alphaTC1-9 cells and isolated mouse islets cultured with leptin, as well as in islets from mice treated in vivo with leptin. We also studied the involvement of the signal transducers and activators of transcription (STAT) pathway by western blot, immunofluorescence and interference RNA. Results Leptin incubation (0.0625-18.75 nmol/l) for 24 h inhibited glucagon gene expression in alphaTC1-9 cells. This inhibitory effect was also observed in isolated mouse islets cultured with leptin, as well as in islets from mice treated with leptin for 5 days. In contrast, no changes were detected in islets from db/db mice, which lack leptin receptors. Leptin treatment also reduced the glucagon protein content in alphaTC1-9 cells and mouse islets. Moreover, leptin induced phosphorylation of STAT3 and its translocation to the nucleus, which was confirmed by western blot analysis in alphaTC1-9 cells and by immunofluorescence in isolated alpha cells. Interestingly, the effect of leptin on glucagon mRNA levels was significantly reduced by Stat3 knockdown. In contrast, pharmacological inhibition of the phosphoinositide 3-kinase pathway did not affect leptin actions. Conclusions/interpretation Our results demonstrate that leptin can regulate glucagon gene expression in alpha cells via a STAT3 pathway, and are important for understanding the role of leptin in glucose homeostasis.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 79%

Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets

et al. 2011

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“…The speculation was extended by Chan et al (7), who showed that hepatic glycogenolytic and gluconeo genic enzyme activities increased in db/db mice. While glucagon enhances hepatic glucose production by stimulating gluconeogenesis and glycogenolysis, db/db mice are hyperglucagonemic (4,8) presumably due to en hanced pancreatic glucagon release (9). These results sug gest that hyperglucagonemia which enhances hepatic glu cose production plays an important role in the develop ment of hyperglycemia in db/db mice.…”

supporting

confidence: 49%

The Possible Role of Age-Related Increase in the Plasma Glucagon/Insulin Ratio in the Enhanced Hepatic Gluconeogenesis and Hyperglycemia in Genetically Diabetic (C57BL/KsJ-db/db) Mice

Kodama¹,

Fujita²,

Yamazaki³

et al. 1994

Japanese Journal of Pharmacology

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ABSTRACT-Genetically diabetic db/db mice and their normoglycemic littermates (+/+ mice) were studied to determine plasma levels of glucose, glucagon and insulin and hepatic gluconeogenic enzyme ac tivities. Plasma glucose levels did not differ significantly between the 5-week-old db/db and + / + mice, but increased with age in the former until the animals were 16-week-old. Similar age-associated changes were observed in the activities of the gluconeogenic enzymes, glucose-6-phosphatase (G-6-Pase) and fructose-l,6 diphosphatase (F-1,6-DPase). While the plasma levels of insulin and glucagon that peaked at 7 weeks of age did not parallel the hyperglycemia, the plasma glucagon/insulin (G/I) ratio roughly paralleled the hyperglycemia. Analysis of individual values for the db/db mice revealed statistically significant (P<0.001) correlations between plasma glucose levels and hepatic G-6-Pace (r=0.78) or F-1, 6-DPase (r=0.74) activ ity. There were also significant correlations between the G/I ratio and plasma glucose levels (P<0.001, r=0.66), hepatic G-6-Pase (P<0.01, r=0.48) or F-1,6-DPase (P<0.01, r=0.57) activity. It is thus conclud ed that the relative predominance of glucagon over insulin action plays an important role in the age associated development of hyperglycemia in db/db mice. Glucagon presumably activates the hepatic gluconeogenic enzymes to enhance hepatic glucose output.Keywords: Diabetic (db/db) mouse, Glucagon/insulin ratio, Gluconeogenesis, Hyperglycemia Genetically diabetic (db/db) mouse was first described by Hummel et al. (1) as an animal model of NIDDM (non-insulin-dependent diabetes mellitus). Detailed stud ies from the same laboratory have later showed that hyperinsulinemia was the first detectable abnormality in the mice (2-4). Interestingly, the blood insulin levels which decrease with age appear to be inversely correlated with the blood glucose levels. On the other hand, we have recently demonstrated that insulin resistance occurred in db/db mice before the manifestation of hyperglycemia and remained constant during the course of developing hyperglycemia (5). We thus speculate that insulin resistance causes compensatory insulin release that causes age-associated insulin depletion and leads to development of hyperglycemia. Decreased glucose utilization due to in sufficient insulin release was considered to be an explana tion for the hyperglycemia in db/db mice.It has also been postulated that accelerated glucose production contributes to the hyperglycemia of db/db mice (6). The speculation was extended by Chan et al. (7), who showed that hepatic glycogenolytic and gluconeo genic enzyme activities increased in db/db mice. While glucagon enhances hepatic glucose production by stimulating gluconeogenesis and glycogenolysis, db/db mice are hyperglucagonemic (4, 8) presumably due to en hanced pancreatic glucagon release (9). These results sug gest that hyperglucagonemia which enhances hepatic glu cose production plays an important role in the develop ment of hyperglycemia in db/db mice.As described ...

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“…1 and 2). Levels of immunoreactive glucagon are increased in the genetically diabetic mouse (3). This hormonal imbalance agrees with present (but controversial) views that, in addition to a lack of effective insulin, absolute or relative glucagon excess is one of the major causes of hyperglycemia in the diabetic state (4).…”

supporting

confidence: 75%

Increased ATP inhibition of liver phosphofructokinase from genetically diabetic mice.

Hosey¹,

Chatterjee²,

Cohen³

et al. 1980

Proc. Natl. Acad. Sci. U.S.A.

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Phosphofructokinase (ATP:D-fructose-6phos-phate 1-phosphotransferase, EC 2.7.1.11) was partially purified the livers of genetically diabetic mice (C57BL/Ksj-db) and their lean littermates (C57BL/KsJ). These genetically diabetic mice have been shown to be hyperglucagonemic and to exhibit symptoms resembling those of maturity-onset diabetes in humans. Two isozymes of phosphofructokinase were obtained after DEAE-Sephadex chromatography of extracts of livers from either normal or diabetic animals. One of these isozymes, peak II, from the genetically diabetic mice was shown to be more sensitive to ATP inhibition at physiological pH than the peak II isozyme from the normal animals. In addition, the peak II isozyme from the diabetic mice exhibited decreased affinity for fructose 6-phosphate. The (4). Enhanced gluconeogenesis appears to be a major factor in the hyperglycemia of diabetic mice. Studies of gluconeogenic fluxes and metabolite levels in diabetic mice indicate that the increased liver gluconeogenesis is likely to be due to a facilitation of the fructose 1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) reaction or a restraint of the phosphofructokinase (ATP:D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) reaction or both (5). Studies on gluconeogenic rates in isolated rat liver cells also led to the proposal that glucagon enhances gluconeogenesis and inhibits glycolysis at the site of fructose 1,6-bisphosphatase and phosphofructokinase (6).With this background it appeared to us that a comparative study of both phosphofructokinase and fructose 1,6-bisphosphatase from the livers of C57BL/KsJ normal and diabetic hyperglucagonemic mice could provide an insight into the mode of action of glucagon at the metabolic steps catalyzed by the above enzymes.The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. 2497A previous study of fructose 1,6-bisphosphatase isolated from the livers of diabetic mice and from the normal controls showed no difference in either molecular or enzymatic properties between the two purified enzymes (7). In this communication we show that phosphofructokinase isolated from the livers of diabetic mice is more sensitive to ATP inhibition than is the enzyme isolated from the livers of normal controls and therefore may represent a physiologically less active form of phosphofructokinase. These results are entirely in accord with three recent independent reports which have indicated decreased liver phosphofructokinase activity after either administration of glucagon to rats (8) or addition of glucagon to isolated rat hepatocytes (9, 10). MATERIALS AND METHODSFructose 6-phosphate, fructose 1,6-bisphosphate, ATP, NADH, DEAE-Sephadex A-25, and aldolase were purchased from Sigma. Triose-phosphate isomerase and a-glycerophosphate dehydrogenase were from Boehringer Mannheim. Ammonium sulfate was from ...

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Glucagon and Insulin Relationships in Genetically Diabetic (db/db) and in Streptozotocin-Induced Diabetic Mice

Cited by 43 publications

References 6 publications

Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets

Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets

The Possible Role of Age-Related Increase in the Plasma Glucagon/Insulin Ratio in the Enhanced Hepatic Gluconeogenesis and Hyperglycemia in Genetically Diabetic (C57BL/KsJ-db/db) Mice

Increased ATP inhibition of liver phosphofructokinase from genetically diabetic mice.

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