Further Studies on the Isolated Islets of Langerhans of Obese Hyperglycaemic Mice and their Normal Lean Littermates

Abstract

Investigation of mouse islet respiratory and secretory activity has shown microdissected islets to be more suitable for in Hits studies than collagenase isolated islets. The hypersecretory activity of obese islets was verified and estimations of LDH isoenzyme patterns have indicated substantial anaerobic metabolism despite an increased capacity for oxygen uptake. In vitro studies with normal and obese mouse islets or not demonstrated a ºAMP or dbc-AMP stimulation of glucose induced insulin secretion. A functional adenyl cyclase/ºAMP-phosphodiesterase system has been demonstrated; operating at a higher level in obese islets than in normal. The effects of pharmacological and _insulinogenic agents on membrane bound cyclase activity was investigated. Only limited correlation existed between the stimulation of islet cyclase or inhibition of islet phosphodiesterase and insulin secretion. The stimulation of islet adenyl cyclase was a ß-adrenergic receptor function and its reduction an ∝-adrenergic receptor function. Glucose does not initiate insulin secretion by the direct stimulation of ß-cell adenyl cyclase. An alternative path via glucagon has been suggested. The magnitude of cyclase and phosphodiesterase activity was similar in normal and in obese islets. The ionic requirements for insulin secretion were present in normal and obese islet tissue. Besides influencing directly the total biosynthesis and secretion of newly synthesized insulin and proinsulin in normal and obese islets, dbc-AMP may exert its effects on insulin secretion via islet glucose metabolism. Dbc-AMP increased the activity of islet G6PDH and islet glycogenolysis. Products of the latter may be utilised for the resynthesis of ATP from ADP. A correlation was made between the serum I.R.I. profile and the morphological/biochemical constitution of obese islets during the manifestation of the obese hyperglycaemic syndrome with age. The reis of the adenyl cyclase system in insulin biosynthesis/secretion; islet glucose metabolism and the aetiology of the obese hyperglycaemic syndrome in mice has been discussed.