USE OF ALDOSE REDUCTASE INHIBITORS TO ENHANCE INSULIN SENSITIVITY IN DIABETES MELLITUS

Abstract: A method of enhancing insulin sensitivity in mammals (e.g. humans) is described. The method is based on the use of aldose reductase inhibitors to restore and preserve intracellular reduced glutathione levels, thereby enhancing the formation of insulin receptor-mixed disulfide bonds.

Description: USE OF ALDOSE REDUCTASE INHIBITORS TO ENHANCE INSULIN SENSITIVITY IN DIABETES MELLITUS Background of the Invention The present invention relates to the field of diabetes mellitus therapy. More particularly, this invention relates to the use of com¬ pounds having aldose reductase inhibiting activity (hereinafter referred to as "aldose reductase inhibitors") to correct an abnormal metabolic pathway associated with diabetes mellitus, thereby enhancing and/or restoring insulin sensitivity. The term "diabetes mellitus" is used to describe chronic hyperglyce ia and the side effects of glucose toxicity. There are two general classifications of diabetes mellitus: (1) insulin-dependent (Type I), and (2) noninsul in-dependent (Type II). The present inven¬ tion is directed to the treatment of both Type I and Type II diabetes mellitus, particularly Type II. The above-cited classifications of diabetes mellitus are based on the role insulin plays in the disease state. Type I diabetes mellitu is generally attributable to an insulin deficiency. In contrast, it i clear that simple insulin deficiency cannot entirely account for the diabetic syndrome seen in Type II diabetes mellitus. This conclusion is supported by the following observations: (1) in many Type II dia- betics, insulin deficiency is not present; and (2) even in Type II diabetics who have impaired insulin secretion leading to an insulin deficiency, insulin resistance can be demonstrated to be responsible for their hyperglycemic state. Reference is made to the following articles for further background in this regard: Reaven et al., "Nonketotic diabetes mellitus: insulin deficiency or insulin resist¬ ance?", American Journal of Medicine, Vol. 60, page 80 (1976); Alford et al . , "The significance and interpretation of mildly abnormal oral glucose tolerance," Diabetoloqia, Vol. 7, page 173 (1971); and DeFron et al . , "Insulin sensitivity and insulin binding to onocytes in maturity-onset diabetes," Journal of Clinical Investigation, Vol. 63, page 939 (1979). It is known that the insulin resistance associated with Type II diabetes mellitus patients and consequent hyperglycemia can be par¬ tially reversed with frequent insulin injections. Moreover, it is known that insulin receptor function in Type II diabetes mellitus patients can be modified by sustained, rigorous caloric and/or carbohy¬ drate restriction, oral hypoglyce ic drug therapy, insulin injections, " ~ and/or physical exercise which results in weight Toss. With these therapeutic approaches, taken either alone or in combination (i.e., diet, exercise, insulin, and/or oral hypoglycemics) , the net overall effect is to lower blood glucose over a sustained time. This effect is called "induced hypoglycemia." The following articles may be referred to for further background in connection with known therapeutic methods of inducing hypoglycemia, and the resulting modification of insulin receptor function: Savag et al., "Diet induced improvement of abnor- alities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus," Diabetes Care, Vol. 5, pages 999-1007 (1979); Beck-Nielsen et al., "Normalization of the insulin sensitivity and the cellular insulin binding during treatment of obese patients following treatment with glibenclamide," Acta Endocrinology, Vol. 90, pages 103-112 (1979); Beck-Nielsen et al., "Increased insulin sensi¬ tivity and cellular insulin binding in obese diabetes following treat¬ ment with glibenclamide," Acta Endocrinology, Vol. 90, pages 451-462 (1979); Rizkalla et al . , "Insulin receptor changes in Type II diabetes after short-term insulin treatment," Horm. Metabol. Res., Vol. 17, pages 512-517 (1985); Scarlett et al . , "Insulin treatment reverses the insulin resistance of Type II diabetes mellitus," Diabetes Care, Vol. 5, pages 353-363 (1982); and Selig, "Hypoglycemi during prolonged exercise _i_n normal men," Endocrinology, Vol. 1983, pages 209-212 (1983). While applicant is not bound by any theory, it is believed that inducing hypoglycemia will, in time, increase insulin sensitivity in Type II diabetes mellitus. It follows that frequent episodes of hyper¬ glycemia in adults induced, for example, by a high calorie diet and lack of exercise, will eventually diminish insulin sensitivity and induce Type II diabetes mellitus. The aforementioned chronic process may be described as an insidious change in the glucose "set point" induced by improper life style and aging. The biochemical mechanism underlying a loss of insulin sensitivity and concomitant changes in glucose metabolism in connection with Type II diabetes mellitus is believed to involve the energetically expensive enzymatic conversion o the aldose sugar, glucose, to sorbitol at the cost of NADPH. This los of NADPH co-factor substantially suppresses the very dynamic reduction of oxidized glutathione into reduced glutathione. Reduced glutathione is believed to be involved in maintaining normal insulin receptor func¬ tion at the target cells. It has been previously demonstrated that insulin release in response to glucose is related to the redox state of islet cell thiols, and that reduced glutathione enhances the capacity of glucose to induc insulin release. See Hallman et al., "Stimulation of insulin release by thiols," Biochem. Biophys. Acta, Vol. 392, pages 101-109 (1975); and Ammon et al., "Cysteine analogues potentiate glucose-induced insulin release vn vitro," Diabetes, Vol. 35, pages 1390-1396 (1986), respec¬ tively. It has also been suggested that metabolic changes in cellular glutathione in diabetes mellitus cause other reversible thiol-disulfid regulated metabolic changes which result in a net increase in cellular gluconeogenesis. See Ziegler, "Role of reversible oxidation-reduction of enzyme thiol-disulfide in metabolic regulation," Annu. Rev. Biochem., Vol. 54, pages 305-329 (1984). Summary of the Invention The present invention is directed to enhancing insulin sensitivity at or within target tissues by administering one or more aldose reduc¬ tase inhibitors to patients who are either afflicted with diabetes mellitus or predisposed to acquiring this disease. An appropriate aldose rethictase inhibitor regimen will prevent and/or reverse loss of insulin sensitivity. This treatment with aldose reductase inhibitors results in a gradual decrease in insulin resistance by enhancing normal insulin receptor function at the target cells. This positive effect on insulin receptor function is believed to be the result of normalization of the redox state of the affected cells (i.e., normalization of the conversion of intracellular oxidized glutathione to reduced glutathione); more specifically, the enhancement of insulin receptor sensitivity is believed to result directly from increased cellular levels of reduced glutathione. While applicant is not bound by any theory, it is believed that the above-cited normalization of glutathione metabolism is the indirect result of interruption of an abnormal metabolic pathway by aldose reductase inhibitors. More particularly, diabetes mellitus is believed to involve an abnormal metabolic pathway wherein the aldose sugar, glucose, is converted to sorbitol at the expense of NADPH. This loss of NADPH affects the cellular redox state in a manner such that the conversion of oxidized glutathione to reduced glutathione is decreased, thereby decreasing the amount of reduced glutathione available at the insulin receptors. Reduced glutathione either directly or indirectly (e.g., via a transferase) maintains the insulin receptor in a reduced thiol state. An insulin receptor active site must be in a reduced thiol state in order for a mixed disulfide bond or an activated complex to form between insulin and the insulin receptor. Aldose reductase inhibitors prevent the above-described depletion of NADPH and resulting decrease in cellular reduced glutathione levels and thiol reduction potential by inhibiting glucose reducing enzymes, such as aldose reduc¬ tase and l-hexonate dehydrogenase, and thereby promote the binding of both endogenous and exogenous insulin to insulin receptor sites. The methods of the present invention are applicable to treatment of both Type I and Type II diabetes mellitus, and to reversal and preven¬ tion of Type II diabetes mellitus, and comprise administering a thera- peutically effective amount of an aldose reductase inhibitor. The administration of an appropriate aldose reductase inhibitor regimen effectively lowers blood glucose levels in Type I and Type II diabetes mellitus patients by enhancing the action of endogenous and exogenous insulin. As the result of the administration of an appropriate aldose reductase inhibitor regimen to a patient afflicted with Type I diabetes mellitus, the amount of insulin required to maintain a normal blood glucose level may be reduced. A similar result will be expected in Type II diabetes mellitus patients who are receiving insulin therapy. In Type II patients receiving a combination of insulin and an aldose reductase inhibitor, it may be possible to discontinue insulin use after a relatively short course of therapy (e.g., several weeks) with this combination, and to maintain a normal blood glucose level thereafter using only aldose reductase inhibitor therapy. The present invention also provides a method of preventing, or at least retarding, the onset of Type II diabetes mellitus in patients who are predisposed to acquiring this disease. A fasting blood glucose level of greater than 140 mg of glucose per deciliter of blood is gen ¬ erally associated with a clinical diagnosis of Type II diabetes melli¬ tus. In contrast, a patient having a fasting blood glucose level of greater than 100 mg per deciliter of blood but less than 140 mg per deciliter is considered to be "hyperglycemic." There is a further class of patients who are not yet diabetic in a clinical sense, but are predisposed to acquiring diabetes. These patients are referred to as "latent" or "chemical" diabetics. In accordance with the present invention, it is possible to retard the progression of the underlying disease state in both patients who are hyperglycemic and patients who may be identified as latent or chemical diabetics, thereby preventing the progression of the disease state to a point at which the patients would be clinically diagnosed as having Type II diabetes mellitus. This prevention or prophylaxis is achieved by enhancing the action of endogenous insulin, as explained above. Detailed Description of the Invention The aldose dose reductase inhibitors which may be employed in the present iTvention comprise any compound having aldose reductase inhib¬ iting activity which is therapeutically effective in enhancing insulin sensitivity, and is safe for use in humans and other mammals. Aldose reductase inhibitors which are particularly suitable for use in the ir.ethod of the present invention are disclosed in commonly assigned U.S. Patent Nos. 4,537,892; 4,436,745; and 4,438,272. The following patents disclose additional examples of aldose reductase inhibitors which may be used in the present invention: U.S. Patent Nos. 3,821,383; 4,117,230; 4,130,714; and 4,181,728. The entire contents of the above- cited patents are hereby incorporated by reference in the present specification. The following compounds represent particularly preferred aldose reductase inhibitors: a. 7,9-difluoro-2-methylspiro(5H-iπdeno [l,2-b]pyridin-5,3'-pyrolidine)- 2 [ ,5'-dione; b. 7,9-difluoro-2-methylspiro(5H-indeno Cl,2-b]pyridin-5,4' imidazolidine)- 2' ,5'-dione; 2,7-dif luoro-4-methylspi o(9H-fluoren-9,4' -imidazol idine) -2' ,5'dione; d. 7-fluoro-2-methylspiro(5H-indeno[l,2-b]-pyridin-5,4' imidazol idine)' ' ,5'-dione; e. 2,7-difluoro-4-methylthiospiro(9H-fluoren-9,4' -imidazol idine)-2' ,5' dione; f. 7,9-difluoro-2-methylthιospiro(5H-ideno [l,2-b]pyridin-5,4' - imidazolidine)-2" ,5' -dione; 2,5,7-trifluoro-4-methylspiro(9H-fluoren-9,4'-imidazolidine)-2' ,5' dione; h. 2,5,7-trifluoro-4-methylthiospiro(9H-f1uoren-9,4'-imidazolidine)-2' ,5 dione; 1. 7-methylthiospiro(5H-idenoCl,2-b]pyridin-5,3'-pyrolidine)-2 , ,5 , -dιone; 2,7-difluorospiro(9H-fluoren-9,4' imidazolidin)-2' ,5'-dione; , 7-d i f 1 uorosp i ro (9H-f 1 uoren-9 , 5 ' -oxazo 1 idine) -2 ' 5 ' di one ; ,7-difluorospiro(9H-fluoren-9,3'-pyrolidine)-2' ,5' -dione; m. (S)-6-fluorospiro[chroman-4,4'-imidazolidiπe]-2' ,5'dione (also called "SORBINIt®"); n. N-C[5-(tr fluoromethyl)-6-methoxy-l-naphthalenyl]thioxomethyl ]-n- methylglyciπe (also called "TOLRESTAT®"); and [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-l-yl ]acetic acid (also called "STATIL®"). In accordance with the present invention, patients afflicted with diabetes mellitus and patients predisposed to acquiring diabetes melli¬ tus are treated with one or- more aldose reductase inhibitors in an amount effective to enhance insulin sensitivity (i.e., a "therapeu- tically effective" amount). The aldose reductase inhibitor(s) may be administered to the patient by means- of a variety of dosage forms and routes of administration, as will be readily appreciated by those skilled in the art. Oral administration is generally preferred, but topical administration and administration by injection may be found preferable in some instances. Dosage regimens (i.e., amount and frequency) will be determined by the clinician based on factors such as the patient's physical condition and the duration of action of the pharmaceutical composition employed.

Claims: What is claimed is: 1. A method of enhancing insulin sensitivity in a patient afflicted with diabetes mellitus, which comprises administering a therapeutically effective amount of an aldose reductase inhibitor to the patient. 2. A method of preventing or retarding the onset of Type II diabetes mellitus in a patient predisposed to acquiring this condition, which comprises administering a therapeutically effective amount of an aldose reductase inhibitor to the patient.

Inventors: YORK BILLIE M JR, YORK, BILLIE, M., JR.
Applicants: ALCON LAB INC, ALCON LABORATORIES, INC.
Application year: 1988
Main classification: A61K31
IPC codes: A61K31, A61P3