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The insulinotropic effects of alpha-ketoisocaproic acid and glucose reveal many common characteristics in vivo and in vitro. They qualify as initiators of insulin release, their action is amplified by potentiators of insulin release, and they have a similar potency at equimolar concentrations. The dynamics of insulin release evoked by alpha-ketoisocaproic acid and glucose are similar. Epinephrine completely inhibits the insulinotropic effect of glucose and alpha-ketoisocaproic acid. Mannoheptulose exhibits a complete, immediate and reversible blockade of glucose-induced insulin release. In contrast, inhibition of alpha-ketoisocaproic acid-induced insulin release occurs after a lag period and is not reversed by removal of the inhibitor. alpha-ketoisocaproic acid, at equimolar concentrations, is several-fold more effective than glucose in elevating cAMP content in islet. alpha ketoisocaproic acid and glucose are about equally effective in stimulating somatostatin release from isolated rat pancreatic islets. This stimulation is inhibited by epinephrine. Mannoheptulose inhibits only somatostatin release induced by glucose but not by alpha-ketoisocaproic acid. It suggested that the insulinotropic characteristics of glucose and alpha-ketoisocaproic acid reveal many common features, while their mode of action appears to be different.

Glucose stimulation increased the cAMP content of collagenase-isolated rat pancreatic islets fourfold above baseline values. The elevation was transient, lasting about 5 min, and was dose-dependent. Insulin release continued at a constant rate throughout the incubation. Glucagon, in the absence of glucose, increased cAMP for about 1 min but only slightly, and had no effect on insulin release. In the presence of glucose, however, glucagon enhanced islet cAMP content 15-fold and increased the release of insulin. Glucagon was most effective at high glucose concentrations (16.6 and 25 mM). This indicates that glucagon is critically dependent on the presence of glucose in order to increase the islet cAMP content and to stimulate insulin release. The inability of glucagon to generate sufficient cAMP in the absence of glucose might be one of the reasons why the hormone is a potentiator rather than an initiator of insulin release.

To investigate the role of endogenous insulin on the secretion of immunoreactive gastric inhibitory polypeptide (IR-GIP) the response of IR-GIP and immunoreactive insulin (IRI) to an oral fat load (100 g triglyceride) alone and during an intravenous glucose infusion (0.7 g/kg/h) was examined in normal weight and obese subjects. In normal weight subjects the fat induced integrated rise of IR-GIP was 112.7 +/- 9.4 ng/ml/120 min. When glucose and fat were given together this IR-GIP response was lowered to 46.2 +/- 2.9 ng/ml/120 min while the serum IRI response to i.v. glucose and the glucose tolerance were enhanced by fat ingestion. In obese subjects with normal glucose tolerance the GIP suppressing effect of i.v. glucose infusion was less marked than in controls. The integrated IR-GIP response to fat ingestion was 225.6 +/- 20.3 mg/ml/120 min and to fat plus glucose 152.6 +/- 14.8 ng/ml/120 min. In obese subjects with glucose intolerance i.v. glucose completely failed to lower the exaggerated secretion of IR-GIP following oral fat. Thus, a graded abnormality of the GIP response to glucose induced insulin release occurs in obesity with normal and pathological glucose tolerance. After reducing the ideal body weight of six obese subjects with glucose intolerance by hypocaloric diet for 3 weeks the exaggerated rise of IR-GIP after oral fat was reversed and the lowering effect of i.v. glucose on the IR-GIP response re-established.

Glucose stimulates somatostatin release from perifused pancreatic islets of diabetic rats 42-47 days after the induction of diabetes, and 48 h after withdrawal of insulin replacement therapy. The glucose effect is augmented by theophylline or glucagon. Basal somatostatin release and glucose-induced secretion are significantly higher in diabetic islets than in controls. It is suggested that glucose promotes somatostatin release by directly interacting with islet D cells but not via indirect pathways. Glucose-induced stimulation appears to be modulated by a D-cell adenylate cyclase/phosphodiesterase system. Reasons responsible for increased somatostatin secretion by diabetic islets include reduction in B-cell mass, suggesting that B cells may normally suppress the secretory activity of D cells.