Action of Streptozotocin on Insulin and Glucagon Responses of Rat Islets

Katsilambros, Nicholas; Ya, Rahman; Hinz, Michael; Fußgänger, R.; Ke, Schröder; Straub, K. D.; Ef, Pfeiffer

doi:10.1055/s-0028-1095056

Cited by 41 publications

(16 citation statements)

References 5 publications

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“…First, the finding of glucagon immunoreactivity in plasma after pancreatectomy, using antiserum 30K, need no longer be regarded as evidence of assay nonspecificity but may indicate the presence of polypeptide identical to pancreatic glucagon. The fact that levels of extrapancreatic glucagon (1-3) increase in untreated dogs after pancreatectomy means that pancreatic diabetes, like every other form of acute and chronic experimental diabetes (33)(34)(35), and spontaneous diabetes in man (36)(37)(38) and Chinese hamsters (39) is accompanied by relative or absolute hyperglucagonemia. The only known situation in which glucagon lack and insulin lack coexist is during somatostatin administration and, in this circumstance, glucose tends to decrease rather than rise (40).…”

Section: Discussionmentioning

confidence: 99%

Identification of glucagon in the gastrointestinal tract.

Sasaki¹,

Rubalcava²,

Baetens³

et al. 1975

J. Clin. Invest.

166

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A B S T R A C T Gel filtration studies on Bio-Gel P-10 columns of a 50-fold purified porcine duodenal extract revealed a main peak of glucagon-like immunoreactivity (GLI) in the 2,900 mol wt zone and a smaller peak in the 3,500 mol wt zone, the same zone as the pancreatic glucagon marker. Like pancreatic glucagon, samples of 3,500 mol wt material gave essentially identical measurements in radioimmunoassays employing the pancreatic glucagon-specific antiserum 30K and the GLI crossreacting antiserum 78J, whereas the 2,900 mol wt peptide gave 60-fold higher readings in the 78J assay. On disk gel electrophoresis, the 3,500 mol wt fraction, like pancreatic glucagon, migrated at pH 8.3, whereas the 2,900 mol wt peptide remained at the origin; at pH 4.7, the 2,900 mol wt peptide migrated while the 3,500 mol wt immunoreactive peptide and glucagon remained at the origin. Isoelectric focusing revealed the 3,500 mol wt moiety to have an isoelectric point (pI) of 6.2, the same as pancreatic glucagon, whereas the 2,900 mol wt peptide had an pI > 10. The glycogenolytic activity of the 3,500 mol wt peptide in the perfused rat liver did not differ significantly from glucagon, and its adenylate cyclase stimulating activity in partially purified liver cell membranes was comparable to that of glucagon; the 2,900 mol wt peptide had less than 20% of these activities. In samples of 3,500 mol wt material subjected to isoelectric focusing, adenylate cyclase-stimulating activity was confined to fractions containing 30K immunoreactivity with a pI of 6.2. In samples of 2,900 mol wt material subjected to isoelectric focusing, Dr. Sasaki's present address is The

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Section: Discussionmentioning

confidence: 99%

Identification of glucagon in the gastrointestinal tract.

Sasaki¹,

Rubalcava²,

Baetens³

et al. 1975

J. Clin. Invest.

166

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“…Animals were randomly divided into diabetic and control groups. Diabetes was induced by an intraperitoneal injection of 80 mg/kg STZ (Sigma, St. Louis, MO) (15,16). After STZ injection, blood glucose was measured every other day.…”

Section: Methodsmentioning

confidence: 99%

Regulation of α-Cell Function by the β-Cell During Hypoglycemia in Wistar Rats: the “Switch-off” Hypothesis

et al. 2004

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The glucagon response is the first line of defense against hypoglycemia and is lost in insulin-dependent diabetes. The ␤-cell "switch-off" hypothesis proposes that a sudden cessation of insulin secretion from ␤-cells into the portal circulation of the islet during hypoglycemia is a necessary signal for the glucagon response from downstream ␣-cells. Although indirect evidence exists to support this hypothesis, it has not been directly tested in vivo by provision and then discontinuation of regional reinsulinization of ␣-cells at the time of a hypoglycemic challenge. We studied streptozotocin (STZ)-induced diabetic Wistar rats that had no glucagon response to a hypoglycemic challenge. We reestablished insulin regulation of the ␣-cell by regionally infusing insulin (0.025 U/min) directly into the superior pancreaticoduodenal artery (SPDa) of STZ-administered rats at an infusion rate that did not alter systemic venous glucose levels. SPDa insulin infusion was switched off simultaneously when blood glucose fell to <60 mg/dl after a jugular venous insulin injection. This maneuver restored the glucagon response to hypoglycemia (peak change within 5-10 min ‫؍‬ 326 ؎ 98 pg/ml, P < 0.05; and peak change within 15-20 min ‫؍‬ 564 ؎ 148 pg/ml, P < 0.01). No response was observed when the SPDa insulin infusion was not turned off (peak change within 5-10 min ‫؍‬ 44 ؎ 85 pg/ml, P ‫؍‬ NS; and peak change within 15-20 min ‫؍‬ 67 ؎ 97 pg/ml, P ‫؍‬ NS) or when saline instead of insulin was infused and then switched off (peak change within 5-10 min ‫؍‬ ؊44 ؎ 108 pg/ml, P ‫؍‬ NS; and peak change within 15-20 min ‫؍‬ ؊13 ؎ 43 pg/ml, P ‫؍‬ NS). No responses were observed during euglycemia (peak change within 5-10 min ‫؍‬ 48 ؎ 35 pg/ml, P ‫؍‬ NS; and peak change within 15-20 min ‫؍‬ 259 ؎ 129 pg/ml, P ‫؍‬ NS) or hyperglycemia (peak change within 5-10 min ‫؍‬ 49 ؎ 62 pg/ml, P ‫؍‬ NS; and peak change within 15-20 min ‫؍‬ 138 ؎ 87 pg/ml, P ‫؍‬ NS). Thus, the glucagon response to hypoglycemia that was absent in rats made diabetic by STZ was restored by regional infusion and then discontinuation of insulin. These data provide direct in vivo support for the ␤-cell "switch-off" hypothesis and indicate that the ␣-cell is not intrinsically abnormal in insulin-dependent diabetes because of STZ-induced destruction of ␤-cells.

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“…This is true for human diabetes (2)(3)(4)(5), as well as in many forms of spontaneous and experimental diabetes in animals (6)(7)(8)(9)(10), particularly in pancreatectomized dogs (11)(12)(13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Glucagon Immunoreactivities and Amino Acid Profile in Plasma of Duodenopancreatectomized Patients

Müller¹,

Berger²,

Suter³

et al. 1979

J. Clin. Invest.

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A B S T R A C T Glucogon immunoreactivity (IRG) was measured in plasma of duodenopancreatectomized subjects with a nonspecific (K-4023) and a specific (30-K) glucagon antiserum. After an overnight fast, plasma IRG (K-4023) was significantly (P < 0.05) higher in the subjects without pancreas, averaging 782±79 (SEM) pgeq/ml, than in the controls (482±80 pgeq/ml). IRG (30-K) of 162±68 pglml did not change during an infusion ofarginine (450 mg/kg per 40 min). Insulin deprivation during 3 d in one patient did not restore the IRG response to arginine as reported in depancreatized dogs.Bio-Gel P-30 column chromatography revealed that virtually all IRG (30-K) measured in whole plasma was of different molecular weight than glucagon, and primarily of a mol wt 2 40,000. Intravenous arginine did not significantly alter the chromatographic pattern of these plasmas. Thus, as postulated by others, duodenopancreatectomized humans have virtually no circulating 3,500-dalton glucagon. Hence, the presence of 3,500-dalton glucagon in plasma is not a condition for the diabetic state. It might, nevertheless, when present in normal or excessive amounts, worsen the metabolic state of diabetic patients.Among 14 amino acids measured in plasma of these patients, the concentrations of alanine, serine, ornithine, and arginine were significantly (P < 0.05) elevated to approximately twice that of normal: alanine and serine are both substrates for gluconeogenesis, whereas ornithine and arginine are involved in the formation of urea, the second product of hepatic gluco-

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Action of Streptozotocin on Insulin and Glucagon Responses of Rat Islets

Cited by 41 publications

References 5 publications

Identification of glucagon in the gastrointestinal tract.

Identification of glucagon in the gastrointestinal tract.

Regulation of α-Cell Function by the β-Cell During Hypoglycemia in Wistar Rats: the “Switch-off” Hypothesis

Glucagon Immunoreactivities and Amino Acid Profile in Plasma of Duodenopancreatectomized Patients

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