Regulation of plasma immunoreactive glucagon in obese hyperglycaemic (ob/ob) mice

Abstract

This study examines the role of glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) syndrome in mice. Plasma C-terminal immunoreactive glucagon concentrations were measured in fed and fasted ob/ob mice at different ages between 5-40 weeks, and in 20-week-old mice after the administration of established stimulators and inhibitors of glucagon secretion. Plasma glucagon concentrations were inappropriately raised irrespective of age, nutritional status and the accompanying prominent changes in plasma glucose and insulin concentrations. Glucose suppressed plasma glucagon in the fed but not the fasted state, suggesting a dependence on the marked hyperinsulinaemia associated with feeding. Administration of 0.25 units insulin/kg to fasted mice failed to affect plasma glucagon and glucose concentrations. Increasing the dose to 100 units/kg restored the normal suppressive actions of insulin. Fasted mice showed an exaggerated glucagon response to arginine but not to the parasympathomimetic agent pilocarpine. Fed mice displayed normal plasma glucagon responses to the sympathomimetic agents noradrenaline and adrenaline. Administration of insulin antiserum or 2-deoxy-D-glucose raised plasma glucagon concentrations of fed mice. Contrary to the lack of suppression by glucose in the fasted state, heparin-induced increase in free fatty acids reduced plasma glucagon concentrations. This study demonstrates inappropriate hyperglucagonaemia and defective A-cell function in ob/ob mice. The extent of the abnormality is exacerbated by fasting and appears to result from insensitivity of the A-cell to the normal suppressive action of insulin.

Increased responsiveness to glucoregulatory effect of opiates in obese-diabetic ob/ob mice

“…However, differences in the biological stability and reactivity of these agents could be contributory factors. The responses cannot be attributed to a stress reaction, since saline did not significantly affect glucose and insulin concentrations in this test system, as noted previously [26].…”

“…This role of opiates may reflect increased Bcell sensitivity to these insulinotropic peptides, or increased opiate biosynthesis and release by the pituitary and gastro-intestinal tract of ob/ob mice [36][37][38][39][40][41][42]46]. Since ob/ob mice show a reduced insulin-releasing effect of hyperglycaemia per se [25,26,47], the greater insulin response to opiate agonists in the ob/ob mice is not attributable to the greater rise in glycaemia. The very short half life of endogenous opiates in the peripheral circulation [48] draws attention to the possible significance of recent studies demonstrating that opiate peptides are synthesised and released within the islet [12-151. Thus, opiates appear to participate in the control of glucose homeostasis through a transient insulinotropic effect involving IX-and 8-opiate receptors.…”

“…Food, but not water, was withheld during all tests. The mice were adapted to the manipulative procedures for 2-3 weeks before study to obviate any stress response [26]. The doses of opiates used must be regarded as pharmacological.…”

“…bridge, UK. Other chemicals and reagents were obtained as previously [26]. Whereas naloxone is an antagonist of all known subtypes of opiate receptors, with an especially potent effect at ~t-opiate receptors, the enkephalin analogues Tyr-D-Ala-Gly-MePhe-NH(CH2)zOH and Tyr-D-Ala-Phe-Gly-D-Leu are predominantly agonists at Ix-and fi-opiate receptors, respectively, and show a high degree of stability when administered in vivo [27,28].…”

Effect of a hypoglycaemic agent M&B 39890A on glucagon secretion in isolated rat islets of Langerhans

“…M&B 39890A (5 p~mol/1) also inhibited glucagon secretion in vitro in the presence of 2 mmol/1, 6 mmol/1 and 20 retool/1 glucose, while exerting no effect on insulin secretion. These results suggest that the hypoglycaemic action of M&B 39890A may be due to its direct and selective effect on glucagon secretion; this appears to operate by a mechanism different to that of glucose.Key words: Islets of Langerhans, hypoglycaemia, glucagon release, insulin release, ob/ob mice.A role for glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) condition has been suggested [1][2][3]. One of the agents discovered to reduce hyperglycaemia in the obese mouse was the compound M&B 39890A, N-(3-imidazol-l-ylpropyl)-2-(3-trifluoromethylbenzenesulphonamido) benzamide hydrochloride.…”