To investigate the role of glucagon in the development of diabetes mellitus, spontaneously diabetic non-obese mice were studied before (group 1) and after the onset of diabetes mellitus (group 2). In group 1, fasting blood glucose and insulin in plasma and pancreas did not differ significantly, while plasma glucagon was elevated (48.9 +/- 10.4 versus control 18.6 +/- 6.0 pmol/l). In group 2, the insulin content of plasma and the pancreas were markedly reduced, whereas plasma glucagon was elevated (180.9 +/- 59.1 pmol/l). When diabetic mice were treated with insulin for 4 weeks (group 3), plasma glucagon was markedly reduced compared with that of group 2 (30.3 +/- 9.0 pmol/l). In group 1, glucagon and glucagon-like immunoreactivity of the intestine were reduced. The glucagon content of the intestine was elevated in group 2. Group 3 elicited increased contents of gastric glucagon as well as intestinal glucagon-like immunoreactivity. We conclude that, in addition to insulin deficiency, hypersecretion of glucagon might contribute to the development and clinical course of diabetes mellitus in the non-obese diabetic mouse.

Recent studies have demonstrated that glicentin is released during nutrient ingestion. However, the biological function of glicentin remains unclear. In order to clarify the role of glicentin in the enteroinsular axis, the effect of glicentin-related peptides was investigated using in vivo local circulation of canine pancreas. Peaks I and II of gut glucagon-like immunoreactivity, partially purified from porcine intestinal extract by affinity chromatography and gel filtration, synthesized hexadecapeptide of N-terminal glicentin (1-16) and synthesized octapeptide of C-terminal glicentin (62-69) were administered for 10 min into the pancreaticoduodenal artery of canine pancreas. Blood samples were then drawn from the pancreaticoduodenal vein. The administration of peak I of glucagon-like immunoreactivity during arginine infusion in a dosage of 20 ng reduced the glucagon secretion by 42 pmol/l (p less than 0.05), whereas peak II of glucagon-like immunoreactivity (20 ng) slightly increased the plasma level of insulin, although not significantly. The administration of glicentin (1-16) in a dosage of 400 ng during saline infusion did not alter the plasma insulin level, but reduced the plasma glucagon level in the pancreaticoduodenal vein by 29 pmol/l (p less than 0.05). In addition, glicentin [62-69] in a dosage of 400 ng exerted a decrease in both the plasma insulin (40 mU/l, p less than 0.05) and glucagon level (27 pmol/l, p less than 0.05). The present study demonstrates the suppression of pancreatic glucagon release during the infusion of peak I glucagon-like immunoreactivity and N- or C-terminal glicentin-related peptide. Therefore, it is suggested that glicentin released during nutrient intake might inhibit the secretion of glucagon.

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To investigate the effect of long-term administration of oral hypoglycemic agents upon the development of vascular complications, a retrospective follow-up study was carried out on 214 diabetic patients for a period of 8 years. These patients were divided into three groups: 38 patients treated with diet alone (group I), 125 patients with sulfonylurea (group II) and 51 patients with insulin (group III). The mean fasting blood glucose levels were generally well controlled through the period of observation in each group. Blood pressure had been treated, but hypertension was observed in 2 to 10% of each diabetic group at the eighth year. Hypoglycemia, albuminuria and ketonuria occurred more frequently in group III than in the other groups. There had been no remarkable changes in serum lipids of these three diabetic groups through the observation period. The percentages of the patients with diabetic retinopathy increased during the follow-up period and significant differences were noted among the three groups at the eighth year (p<0.025). In contrast, no significant difference was demonstrated in the percentage of the ischemic heart disease among these groups. When correlation coefficients between variables in each group were calculated, it was difficult to find out any definite relationship between certain variables. The stepwise multiple-regression analyses suggested that the development of retino pathy or of abnormal ECG was affected by various factors. In addition, statisti cal analyses were performed on 152 deaths among 2100 diabetics who attended our Clinic between January 1, 1961 and August 31, 1976. The mortalities were 8.9% for the group with diet alone, 3.5% for the group with sulfonylureas and 11.9% for the group with insulin, and these values were different with a statistical significance (p<0.001). As a whole, 32 patients (21.7%) died of malignant neoplasma, 25 (16.4%) of renal diseases and 24 (15.8%) of cerebral vascular accidents. Fatal myocardial infarction and cardiac insufficiency were detected in 6 (3.9%) and 5 (3.3%) patients, respectively. The percentages of deaths from heart disease were low and no significant difference was observed in the mortality of cardiac events between the three groups. The results obtained in

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In order to investigate the relationship between the development of diabetes mellitus and glucagon, experimental studies were performed in genetically diabetic mice (KKA gamma and KK B1) and in C57 mice of various ages. In the KK mice, the fasting plasma glucose increased during the aging process and reached the maximum at 14 weeks. The fasting plasma insulin in the KK mice was significantly elevated during the aging process and continued to increase till 20 weeks of age. In contrast, an increase in the fasting plasma glucagon was observed only at the age of 4 weeks, although the plasma glucagon increased during the aging process. The content of the insulin in the pancreas of the KK mice was significantly higher than that of the C57 mice, continuing to increase during the aging process. the glucagon content of the pancreas increased during the aging process but no significant difference was observed between the KK mice and the control mice. The total immunoreactive glucagon in the jejunum measured by non-specific antiserum was slightly reduced in the KK mice at the age of 14 weeks, compared with the C57 mice. There was no difference in the glucagon content of the stomach between the KK mice and the C57 mice of various ages. The KK mice at 14 weeks showed an elevated plasma glucagon 30 min after glucose injection, compared with the C57 mice, which indicates a reduced suppression of glucagon in response to hyperglycemia in the KK mice. The plasma glucagon in the KK mice 30 min after arginine was slightly higher than in the control mice, although not significantly so. From these results it was concluded that the KK mice revealed an elevation of fasting plasma glucagon in the early stage of diabetes mellitus and a decrease in glucose-induced glucagon suppression at 14 weeks and that diabetes mellitus in the KK mice derived mainly from insulin resistance associated with hyperinsulinemia.