Yukio Shigeta

Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo

Abstract Shen et al.1 and Reaven et al.2 have recently reported increased insulin resistance in adult-onset type diabetes based on the steady state plasma glucose (SSPG) method. In this method, epinephrine and propranolol were used to suppress endogenous insulin secretion. Epinephrine and propranolol themselves elevate SSPG levels.3 Also, plasma levels of growth hormone (HGH) and glucagon may not be suppressed under these conditions, since paradoxical rises or less suppressibility of HGH4 and glucagon5 following glucose loads have been reported in diabetic subjects. We have therefore used somatostatin, which has been shown to have no direct effect on glucose and lipid metabolism,6 to suppress endogenous secretion of insulin, glucagon, and HGH. Using the newly revised method, we have assessed insulin sensitivity in diabetics treated with diet alone, sulfonylureas, or insulin, and in obese nondiabetic subjects with hyperinsulinism.

Enteral absorption of water-in-oil-in-water insulin emulsions in rabbits

SummaryWater-in-oil-in-water (W/O/W) insulin emulsions with a concentration of 100 U/ml of insulin were prepared, and the possible absorption of insulin in emulsion form was examined. The following results were obtained: W/O/W insulin emulsions were quite resistant to proteolytic enzymes in vitro. In the presence of pancreatic lipase, however, W/O/W insulin emulsion gradually lost its activity by the action of proteolytic enzymes. When administered to the jejunum at doses over 10 U/kg, a significant and consistent increase in plasma insulin was observed, followed by a fall in blood glucose. The infusion of W/O/W insulin emulsions into the jejunum was three to four times more effective than the administration of aqueous insulin. Insulin, when administered to the stomach, did not cause hypoglycemia at doses up to 150 U/kg. When W/O/W insulin emulsions were administered orally, on the other hand, definite responses were observed in 3 out of 7 rabbits with 100 U/kg and in 4 out of 7 rabbits with 150 U/kg. For developing an effective method for oral administration of insulin, the present results indicate a possible means of protecting insulin molecule from proteolytic destruction, and of facilitating intestinal absorption of insulin.

Increased intestinal absorption of insulin in a micellar solution: Water-in-oil-in-water insulin micelles

SummaryWater-in-oil-in-water (W/O/W) insulin micelles were prepared, and the possibility of insulin absorption in a micellar form was examined. In this preparation, insulin was trapped in oil droplets of oleic acid in glyceryl-α-monooleate. (1) W/O/W insulin micelles were absorbed from the ligated jejunal loop of rabbits to the order of 12.3 to 58.5% of the dose given (10 U/kg body weight) during the 3-h experimental period. (2) Alloxan diabetic rats were treated with intrajejunal administration of W/O/W insulin micelles at a dosage of either 25 or 50 U/100 g body weight, three times daily for as longs as 14 days. During treatment, a significant reduction in the daily excretion of urinary glucose was observed, concomitant with a decrease in fasting blood glucose. Quantitative estimates suggested that the effectiveness of 25 U/100 g of intrajejunal W/O/W insulin micelles was comparable to that of regular insulin at a dosage of 1 U/100 g i.m. These results would indicate that W/O/W insulin micelles, when given enterally, are more effective in lowering blood and urinary glucose levels than W/O/W insulin emulsions in which insulin was trapped in oil droplets of triglyceride.

Radioselenium pancreozymin-secretin test as a clinical test for pancreatic exocrine function

The appearance of radioselenium in the protein fraction of duodenal aspirates has been studied after an intravenous injection of75Se-selenomethionine. The continuous flow of pancreatic juice was stimulated by pancreozymin at 120 minutes and by secretin at 140 minutes. A good distinction between normal subjects and patients with pancreatic disease was obtained by measuring75Se-radioactivity in the protein fraction of duodenal aspirates; either cumulative radioactivity during the combined 80-minute post-pancreozymin-secretin period, or maximum75Se-specific activity during the postsecretin period was used as an index. The test presented here might be a useful and sufficiently reliable method for detecting abnormal pancreatic exocrine function. This test can be performed along with the conventional pancreozymin-secretin test, serum enzyme response to pancreozymin and secretin, and pancreatic scintiscanning.

Increase in Plasma Immunoreactive Insulin Following Administration of Insulin to the Gastrointestinal Tract of Rabbits

Changes in plasma insulin levels in response to enterai administration of insulin have been studied in rabbits. Insulin, when administered to the stomach, did not cause hypoglycemia at doses up to 150 U./kg. When insulin at doses over 40 U./kg. was infused to the upper jejunum via an indwelling catheter, there was a slight but significant increase in plasma insulin levels, followed by a significant fall in blood glucose. A considerable increase in plasma insulin was observed when insulin at doses over 20 U./kg. was infused to the Thiry-Velia loop of the jejunum in which no pancreatic secretion entered. With a dose of 100 U./kg., the mean plasma insulin rose promptly to the peak of 241 μU./ml., followed by a severe hypoglycemia. As judged by hypoglycemie and immunological responses, insulin can be absorbed from the intestine in a physiologically active form, but the fraction absorbed is relatively small.

Lack of Ketosis in Lipoatrophic Diabetes

Several metabolic studies wece performed on a thirty-year-old Japanese woman with lipoatrophic diabetes. The fasting serum levels of insulin were high, and the insulin response to glucose ingestion was subnormal. The serum growth hormone levels were normal. Lipolytic and ketonemic stimuli such as starvation and epinephrine injection failed to increase the serum concentrations of nonesterified fatty acids (NEFA) and ketone bodies. The absence of ketonemia was attributable to the lack of substrate delivered from adipose tissue.

A high incidence of positive provocation of plasma pancreatic enzymes in the poorly controlled diabetic subjects

SummaryAbnormal responses of plasma lipase, trypsin, and amylase to pancreozymin and secretin in poorly controlled diabetics were found in 42%, 41% and 30% while these responses in well controlled diabetics were 25%, 9% and 9% respectively. Positive provocation of at least one of these enzymes was observed in 67% of poorly controlled diabetics and was significantly more frequent than that (18%) in well controlled diabetics (p<0.01). An elevation of fasting lipase and amylase activities was also noted in 26% and 37% in the former in contrast to 0% and 18% in the latter. In the same 6 subjects the degree of abnormal plasma enzyme response was greater in the poorly controlled diabetic state than in the well controlled diabetic state. When insulin effect on plasma lipase response was tested in experimentally diabetic rats, insulin administration for 3 to 5 days normalized the abnormal provocation of lipase observed in chronically diabetic rats. These findings indicate that pancreatic enzymes tend to leak to the systemic circulation in insulin deficiency.

β-Naphthyl-azo-polystyrene-insulin as a means of protecting insulin molecule from digestive enzymes

Summary Insulin was bound to diazopolystyrene quenched with β-naphthol in the manner of physical adsorption. The β-naphthyl-azo-polystyrene-insulin was found to interfere with peptic and α-chymotryptic digestions in vitro and, when administered into the stomach, produced a hypoglycemic response in rabbits. The degree of hypoglycemic effect of β-naphthyl-azo-polystyrene-insulin was related to the dose of insulin between 20 and 150 units / kg.

The role of coenzyme Q on glucose oxidation and lipogenesis of rats in vivo and in vitro

Abstract Co Q7 promoted CO2 output and fatty acids synthesis from glucose taken up in epididymal adipose tissue of rats. In alloxan diabetic rats the decreased 14CO2 output from injected 14C-labeled glucose was recovered to normal level after the Co Q7 treatment.

Validation of I.V. small-dose insulin infusion therapy in diabetic ketoacidosis of depancreatized dogs.

SummaryA validation of small-dose insulin infusion therapy was studied by the constant i.v. infusion of various doses of insulin into ketoacidotic depancreatized dogs. Constant insulin infusion of 5 × B, 10 × B, 30 × B and 50 × B (B=225 µU/kg/min) was performed for 3 h by mechanical pump. The following results were obtained: (1) plasma concentrations of immunoreactive insulin (IRI) increased proportionally to the dose of infused insulin, but the higher IRI did not result in a greater fall in plasma glucose concentration, correspondingly; the mean rate of fall in plasma glucose concentration of 5 × B was not significantly lower than that of 50 × B; β-hydroxybutyrate and arterial pH improvements were observed in each group during the 3-h insulin infusion. These data suggested that for the improvement of diabetic ketoacidosis, the insulin infusion rate of more than 30 × B, which raised the plasma IRI levels above the physiological range, was not essential; (2) the necessity of potassium supplementation during the small-dose insulin infusion was suggested if the pre-treatment level of serum potassium was low. These results confirmed that in the absence of infection or severe acidosis small-dose insulin infusion therapy is as effective as the conventional large-dose insulin therapy.