1989 Fiscal Year Final Research Report Summary
Ketosis Proneness and Insulin Dependency in Diabetes Mellitus
| Project/Area Number |
62480250
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
内分泌・代謝学
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| Research Institution | Shiga University of Medical Science |
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Principal Investigator |
HIDAKA Hideki Shiga Univ. Med. Sci., Dep. of Med., Instructor, 医学部, 助手 (80156603)
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| Co-Investigator(Kenkyū-buntansha) |
KOSUGI Keisuke Shiga Univ. Med. Sci., Dep of Med., Instructor, 医学部, 助手 (00153544)
HARANO Yutaka Nat, Cardiovas. Center, Dep of Med Chief, Div. of Metab., 動脈硬化・代謝部門, 部長 (10028615)
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| Project Period (FY) |
1987 – 1989
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| Keywords | Blood Ketone body / Diabetes mellitus / Hormonal action / Isolated hepatocytes / FFA oxidation / Self-monitoring of ketone body |
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| Research Abstract |
Fasting serum levels of ketone bodies were determind using a method reported by us(Harano et al, Clin. Chim. Acta 22:327, 1983) in more than 300 subjects with insulin-dependent diabetes mellitus(IDDM) as well as non-insulin-dependent diabetes mellitus(NIDDM). The levels were higher in subjects with IDDM than in those with NIDDM, and the discriminant equation between IDDM and NIDDM has been developed. The concentrations were also higher in NIDDM patients who required insulin therapy than in the patients who did not require the insulin therapy even though markers for the control of blood glucose levels were similar in both groups, indicating that the serum ketone levels may be used as a marker for the indication of insulin therapy(insulin dependency) in NIDDM patients. The mechanisms of the elevated blood ketone body levels were studied in hepatocytes isolated from NIDDM model rats which were made diabetic by inpraperitoneal injection of streptozotocin at neonatal periods. Ketone body pr
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oduction rates in the hepatocytes from NIDI)M rats were regulated by hormones, and were significantly increased than in those from normal rats, but lower than in those from ketotic rats. These data indicate that the kotogenesis of the liver in non-obese NIDDM is elevated due to insulin deficiency, and that the elevation of plasma levels of insulin antagonists and substrate(free fatty acids) also contributes to the increased concentrations of ketone bodies.
Diabetic coma is classified into two types; diabetic ketoacidosis and non-ketotic hyperosmolar coma. However, the pathophysiological mechanisms of these two states have not been clearly known. We have observed that intravenous infusion of anti-ditiretic hormone(ADH) decreased the plasma ketone body levels without changing the plasma concentrations of free fatty acids. Since plasma ADH levels are elevated in non-ketotic hyperosmolar coma, the hormone may play a role in the disease states through depressing the ketogenesis of the liver. A study of the ADH actions in isolated rat hepatocytes revealed that protein kinase C plays a role in ketogenesis. We have also found that the phosphorylation of carnitine-palmitoyl transferase; the rate limiting enzyme of fatty acid oxidation has taken place when the enzyme is activated by hormones. A new carnitine analogue; emeriamine was shown to reverse diabetic ketoacidosis and to have organ specificty; less effective in heart and other organs than in the liver.
A new system for the rapid determination of a major plasma ketone body; 3-hydroxybutyrate(3-OHBA) has been developed and applied to a clinical use. The system consists with a film, containing 3-OHBA dehydrogenase and dye, and a reflectance meter. The blood ketone body levels can be measured within 3 minutes accurately even by children with IDDM. Monitoring of the levels at home revealed that the con centrations were increased on sick days as well as during exercise even though the blood glucose levels were not changed in a considerable magnitude. We believe that the self-monitoring of blood glucose and ketone body levels will decrease the incidence of ketoacidosis and will improve the diabetic control not only over glucose but also fatty acid metabolism. Less
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