Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

Laube, H.; Fußgänger, R.; Maier, V.; Pfeiffer, Ernst-Friedrich

doi:10.1007/bf01239436

Cited by 43 publications

(17 citation statements)

References 19 publications

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“…1). We also found an absent A-cell response to glucose, in accordance with previous reports [17][18][19]. Thus there are similarities in the abnormalities of somatostatin and glucagon secretion in experimental diabetes which could both be due to insulin deficiency, as suggested previously for glucagon [20].…”

Section: Discussionsupporting

confidence: 81%

“…There are similarities here to the abnormal A-cell function found in experimental diabetes. Continuous IV insulin administration can reduce hyperglucagonaemia and restore abnormal glucagon responses to various stimuli in man [20] and animals [23,24] in vivo, while in vitro insulin administration has minor or no effect on basal and glucose stimulated glucagon secretion [17,19,25,26], as indeed we have found (Fig. 2).…”

Section: Discussionsupporting

confidence: 73%

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Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

1979

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Summary. Somatostatin release from the isolated pancreas of 3 normal and 6 streptozotocin diabetic dogs has been measured in response to various stimuli to determine whether abnormalities in somatostatin release are present in the diabetic pancreas. Simultaneous measurement of glucagon secretion was also made. In the pancreas from normal dogs increases in perfusate glucose from 25 to 200mg/100ml induced a 2-3 fold increase in somatostatin release and a two thirds decrease in glucagon secretion. In contrast, in the diabetic pancreas glucose caused no change in the secretion of the two hormones. In the diabetic pancreas addition of insulin to the perfusate (25,000 ~U/ml) for periods from 10 to 75 minutes aimed at restoring normal extracellular insulin levels in the islets failed to restore either somatostatin or glucagon secretion to normal. In contradistinction to the lack of effect of glucose, the somatostatin and glucagon responses to arginine (5 mmol/1), isoproterenol (2 ng/ml) and calcium (5 mmol/1) were normal in the diabetic pancreas. The data suggests the presence of a selective glucoreceptor abnormality of the D as well as of B and A cells in the streptozotocin diabetic dog.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 73%

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

1979

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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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“…Glucose or arginine stimulates hypersecretion of both glucagon and insulin in islets that are isolated from 2-to 3-month-old db/db mice (Laube et al, 1973). Here, we showed that glucagon and insulin hypersecretion appeared even earlier in 6-week-old db/db mouse islets (Fig.…”

Section: Discussionmentioning

confidence: 49%

An optical method to evaluate both mass and functional competence of pancreatic α- and β-cells

Wang

Han

Zhu

et al. 2016

Journal of Cell Science

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Imbalanced glucagon and insulin release leads to the onset of type 2 diabetes. To pinpoint the underlying primary driving force, here we have developed a fast, non-biased optical method to measure ratios of pancreatic α-and β-cell mass and function simultaneously. We firstly label both primary α-and β-cells with the red fluorescent probe ZinRhodaLactam-1 (ZRL1), and then highlight α-cells by selectively quenching the ZRL1 signal from β-cells. Based on the signals before and after quenching, we calculate the ratio of the α-cell to β-cell mass within live islets, which we found matched the results from immunohistochemistry. From the same islets, glucagon and insulin release capability can be concomitantly measured. Thus, we were able to measure the ratio of α-cell to β-cell mass and their function in wild-type and diabetic Lepr db /Lepr db (denoted db/db) mice at different ages. We find that the initial glucose intolerance that appears in 10-week-old db/db mice is associated with further expansion of α-cell mass prior to deterioration in functional β-cell mass. Our method is extendable to studies of islet mass and function in other type 2 diabetes animal models, which shall benefit mechanistic studies of imbalanced hormone secretion during type 2 diabetes progression.

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Hyperglucagonemia of the isolated perfused pancreas of diabetic mice (db/db)

Cited by 43 publications

References 19 publications

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

Streptozotocin diabetes: A glucoreceptor dysfunction affecting D cells as well as B and A cells

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

An optical method to evaluate both mass and functional competence of pancreatic α- and β-cells

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