The mean fasting plasma immunoreactive glucagon (IRG) concentration in 25 non-insulin-dependent, maturity-onset diabetics (MODs) was 15.4 ± 3.1 pmol/L, which was not significantly different from the 16.8 ± 2.4 pmol/L in 17 normal controls of similar age. However, in seven MODs with autonomic neuropathy (AN) the mean fasting IRG concentration of 44.7 ± 4.4 was significantly greater than the 17.4 ±1.3 pmol/L in 18 MODs without neuropathy and compared with controls. We, therefore, investigated IRG concentrations in five age-matched, non-insulin-dependent MODs with AN and five without it. Plasma IRG concentrations were measured in the basal state on three separate occasions and in response to insulin and to a mixed meal. Fasting or basal IRG concentrations were measured in the morning with and without a preceding 12-h insulin infusion to determine the effects of reduction in fasting plasma glucose concentrations and after 12 h of nasogastric aspiration to exclude continued stimulation caused by delayed gastric emptying. In the select group of Subjects the mean basal plasma IRG concentration was raised above the normal in diabetics with AN (49.4 ± 5.1) and was 16.2 ± 2.1 in diabetics without AN, which was within normal limits. Neither 12 h of insulin infusion (0.5–0.8 U/h) nor 12 h of nasogastric aspiration altered basal IRG concentrations in either group. The maximum incremental IRG response to acute insulin administration (0.2 U/kg) in diabetics with AN was 6.8 ± 3.9, which was significantly impaired compared with 24.9 ± 4.8 in nine MODs without AN and with 26.3 ± 6.7 in five normal controls. The maximum increment in IRG response to acute insulin administration in diabetics with AN rose significantly to 32.8 ± 12.9 after 12 h of insulin infusion. Although the maximum IRG responses to a mixed meal were higher in both diabetic groups than in the normal controls, there was a delayed initial rise and persistent elevation in diabetics with AN. We suggest that (1) basal IRG concentrations may be dependent on the integrity of the autonomic nervous system in MODs; (2) MODs without AN seem to have a normal response to insulin-induced hypoglycemia, whereas in MODs with AN the response is impaired and can be corrected by an adequate degree of both insulinization and reduction in fasting blood glucose concentration; and (3) the maximum IRG response to a mixed meal is exaggerated in all MODs and is not dependent on the integrity of the autonomic nervous system, although the pattern of response may be altered in the presence Of AN.

Oral glucose tolerance tests were done in eight insulin-requiring pancreatic diabetic patients to study the effect of withdrawal of insulin treatment on gut hormone release. Basal levels of gastric inhibitory polypeptide (GIP), glucagon-like immunoreactivity, and immunoreactive glucagon levels rose on insulin withdrawal, more so in patients on short-acting insulin, and were lowered by insulin treatment. Insulin treatment did not affect the GIP, glucagon-like immunoreactivity, or IRG responses to oral glucose. Improved glucose tolerance was greater in patients receiving soluble insulin than in those receiving lente insulin, and there was a significant positive linear correlation between basal plasma GIP and blood glucose levels in these patients. Therefore, it is suggested that insulin treatment lowers basal hormones levels, possibly via a metabolic effect, whereas the hormone responses to oral glucose may be controlled by several factors unrelated to insulin administration or changes in glucose homeostasis.

Glucose-dependent insulin-releasing peptide or gastric inhibitory polypeptide (GIP) is released into the circulation after ingestion of a mixed meal and is thought to enhance glucose-induced insulin release. We investigated basal and meal-stimulated GIP secretion in noninsulin-dependent maturity-onset diabetics (MODs). Twelve MODs and 12 healthy normal subjects were studied. Mean (+/- SE) basal plasma GIP concentrations were similar in MODs (297 +/- 34.5 pg/ml) and healthy subjects (305 +/- 29.7 pg/ml). Overnight insulin infusion normalized basal glucose levels in the MODs and induced a slight but insignificant rise in plasma GIP levels in MODs to 362 +/- 40.9 pg/ml; overnight gastric aspiration caused a further slight rise in basal GIP concentration to 392 +/- 56.6 pg/ml. The GIP responses to a mixed meal were significantly impaired at 90-240 min in MODs. The MODs were divided into 2 groups, each with 6 subjects: 1 group with autonomic neuropathy (AN) and the other without. The GIP responses in MODs without AN were similar to those in healthy subjects, but were significantly reduced in MODs with AN at all times after the meal. We suggest that the release of GIP after a meal is dependent upon the integrity of the autonomic nervous system; the mechanism may be related to the loss of autonomic control of gastric emptying or dependence of GIP secretion on autonomic modulation.

True or 'pancreatic' glucagon-like immunoreactivity (GLI) was found in the plasma of a pancreatectomized patient. In contrast with the regulation of pancreatic GLI in normal controls, there was paradoxical release after oral glucose, no response to arginine or insulin-hypoglycaemia and somatostatin did not suppress its release, but tolbutamide did. Similar to controls, this pancreatic GLI appeared to be under adrenergic beta-receptor control. There was no apparent effect on blood glucose regulation despite marked changes in pancreatic GLI levels during the various manipulations. On polyacrylamide gel electrophoresis, pancreatic GLI from our patient's plasma eluted as two equivalent peaks: one with the glucagon marker and the other in a more cathodal position. We therefore suggest that, although the extra-pancreatic 'pancreatic' GLI in our patient's plasma has immunologic similarities with pancreatic glucagon, the responses to stimulation and suppression are quite different from those in controls and the biologic activity does not appear to be that of pancreatic glucagon.

Oral glucose administration caused an exaggerated release of cross-reacting gastrointestinal glucagon-like immunoreactivity (GLI) and a slight early rise in immunoreactive glucagon (IRG) concentration in patients with chronic pancreatitis, who have impaired insulin release. Intravenous administration of 200 microgram of somatostatin, followed by infusion of 200 microgram over 2 1/2 h, abolished the GLI and insulin responses, but did not change glucose tolerance. This contrasts with the relatively minor effects of somatostatin on GLI responses in control subjects where the clear deterioration in glucose tolerance may relate to inhibition of insulin release.