CA1310269C

CA1310269C - Use of aldose reductase inhibitors to enhance insulin sensitivity in diabetes mellitus

Info

Publication number: CA1310269C
Application number: CA000561908A
Authority: CA
Inventors: Billie M. York, Jr.
Original assignee: Alcan Laboratories Inc
Current assignee: Alcan Laboratories Inc
Priority date: 1987-03-20
Filing date: 1988-03-18
Publication date: 1992-11-17
Anticipated expiration: 2009-11-17
Also published as: AU1549088A; AU598366B2; EP0306525A4; EP0306525A1; WO1988006887A1; KR890700346A; JPH01503460A

Abstract

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

2 ~ 9 USE OF ALDOSE REDUCTASE INHIBITORS TO
ENHANCE INSULIN SENSITIVITY IN DIABETES MELLITUS
~_c~round of the Invention The present invention relates to the field of d~abetes mellitus therapy. More particularly, this invention relates to the use of com-pounds having aldose reductase inhibiting activity (herein~fter reterre~ to as "aldose reductase inhibitors") to correct an abnormal metabolic pathw~y associated with diabetes mellitus~ thereby enhancing - and/or restoring insulin sensitivity.
The term "diabetes mellitus" is used to describe chronlc hyperglycemia and the side effects of glucose toxiclty. There are two general classifications oF diabetes mellitus: (1) insulin-dependent (Type I), and (2) noninsulin-dependent (Type II). The present inven-tion is directed to the treatment of both Type I and Type II diabetes mellitus, partlcularly Type II.
The above-ci~ed classifications of diabetes mellitus are based on the role insulin plays in the disease state~ Type I diabetes mellitus is generally attributable to an insulin deficiency. In contrast, i~ is 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 IIdiabetics who have impaired insulin secretion leading to an insulin deficiency, ~nsulin resistance can be demonstrated to be responsible for their hyperglycemic state. Reference ~s made to the following articles fcr further background in this regard: Reaven et al., "Honketotic diabetes mellitus: insulin deficiency or insulin resist-ance?", American Jo_ nal of Medicine, Vol. 60, page 80 ~1976); Alford et al., "The significance and.interpretation of mildly abnormal oral glucose tolerance," Oiabetologia/ VolO 7, page 173 (1971); and DeFronzo et al., "Insulin sensitivity and insulin binding to monocytes in maturity-onset diabetes," Journal of Clinical Investigation, Vol. 63, page 939 (1979~.

~g ~ 3 ~

It ls known that the insulin resistance associated with Type II
diabetes mellitus patlents 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 modifled by sustained, rigorous caloric and/or carbohy-drate restriction, oral hypoglycemic drug therapy, insulin injections, and/or physical exercise which results in weight loss. 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 modiflcation of insulin receptor function: Savag et al., "Diet induced improvement of abnor-malities in insulin and glucagon secretion and in insulln 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 Endocrinolo~y1 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 Endocrinolo~y~ 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, "Hypoglycemia during prolonged exercise in nor~al men," Endocrinoloqy, Vol. 1g83, pages 209-212 (1~83).
While applicant is not bound by any theory, it is believed that inducing hypoglycemia will, in tlme, 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 Il diabetes mellitus. The aforementioned chronic process m~y be described as an insidious change in the glucose "set point"

~L 3 ~ 9 induced by improper life style and aging. The biochemical mechanism underlylng a loss of insulin sens~tivity and concomitant changes in glucose metabolism in connection w;th Type II d~abetes mellitus is believed to involve the energetically expensive enzymatic conversion of the aldose sugar, glucose, to sorbitol at the cost of NADPH. This loss of NADPH co-factor substantially suppresses the very dynamic reduction of oxid~zed glutathione into reduced glutathione. Reduced glutathione is believed to be involved in maintaining normal insulin receptor func-tion at the target cells.
~t 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 induce insulin release. See Hallman et al., "Stimul~tlon 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 in 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 reverslble thiol-disulfide regulated metabolic changes which result in a net increase in cellular gluconeogenesis. See Zlegler, "Role of reversible oxidatlon-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 reductase inhibitor regimen will prevent and/or reverse loss of insulin sensitivity. This treatment with aldose reductase inhibitors results in a gradual decrease ;n 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 ~ 3 ~ 9 conversion of intracellular ox~dized glutath~one to reduced glutathione); more specifically, the enhancement of insulin receptor sensit~vlty is believed to result directly from increased cellular levels of reduced glutathione.
s While applicant is not bound by any theory, it is believed that the~
above cited normallzation of glutathlone metabolism is the indirect result of interrupt~on of an abnormal metabolic pathway by aldose reductase inhibitors. More particularly, dlabel:es mellitus is believed to involve an abnormal metabolic pathway wherein the aldose sugar, glucose, is converted to sorbitol at the expense of NA~PH. 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 20 decrease in cellular reduced glutathione levels and thiol reduction potential by inhiblting glucose reducing enzymes, such as aldose reduc-tase and L-hexonate dehydrogenase, and thereby promote the binding of both endogenous and exogenous insulin to insul;n receptor sites.
The methods of the present invention are applicable to treatment of 25 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 administr tion 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 lnhibitor regimen to a patient afflicted with Type I diabetes mellitus, the amount of insulin required to maintain a normal blood -5~ 3~fi~
glucose level may be reduced. A similar result w~ll be expected in Type II diabetes mellitus patients who are receiving insul~n therapy.
In Type II patients receiving a combination of insulin and an aldose reductase inhibltor9 it may be possible to dlscontinue ;nsulin use after a relat~vely short course of therapy (e.~., several weeks) with thls comblnat~on, and to maintain a normal blood glucose level thereafter using only aldose reductase inhib~tor 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 ~ho are not yet diabetic in a clinical sense, but are predisposed to acqu;ring 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 ident;fied as latent or chem~cal diabetics, thereby preventing the progression of the disease state to a point at which the patients would ~e clinlcally 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 lnvention comprise any compound having aldose reductase inhib-iting activity which is therapeutically effective in enhancing insulin sensitivity 9 and is safe for use ;n humans and other mammals. Aldose reductase ;nh~bitors which are particularly suitable for use in the method of the present invention are disclosed in commonly assigned U.S.
Pdtent Nos. 4,537,892; 4,436,745; and 4,438,272~ The follow;ng patents disclose additional examples of aldose reductase inhibitors which may be used in the present invention: U.S. Patent Nos. 3,821,383;

13~12~9 4,117,230- 4,130,714; and 4,181,728. The following compounds represent particularly preferred aldose reductase inhibitors:
d.

HN
0~

7,9-difluoro-2-methylspiro(5H-indeno [1,2-b]pyridin-5,3'-pYrolicline)-2',5'-dione;

O
~N~
00~ ~ NH

:: ~ N
F

.
7,9-difluoro-2-methylspjro(~H-indeno [l~2-blpyridin-5~4~im~dazolidine) : ~ 2',5'-dione;

:

~;

~3~2~

o HN ~
o ~ NH
F ~ F

a~
~.~

2,7-difluoro-4-methylspiro(9H-fluoren-g~4'-imidazolidine~-2',5'cl10ne:
d.
o I IN~
05=<~ NH
F~

~: 7-fluoro-2-methylspiro~5H-indeno[1,2-b]-pyridin-5,4'imidazolidine)-2',5'-dione :~ :

:: : :

-8- ~31~2~

HN ~
o ~ NH
F ~ F

:: .
2,7-difluoro-4-methylthiospiro(9H-fluoren-9,4'-imidazolidine)-2',5'-dione;
f.

HN~
0~ NH
F_~

7s9-difluoro-2-methylthiospiro(5H-ideno [1,2-b]pyridin-5,4'-imidazolidine)-2',5'-dione;

-9~

HNt ol NH
F; ~ F

CH~ F

2,5,7-trifluoro-4-methylspiro(9H-fluoren-9,4'-imidazolidine~-2',5'-dione;
h.

HN~
O~NH
F~F

~ .
2,5,7-trifluoro-4-methylthiospiro(9~-fluoren-9,4'-imidazolidine~-Z',5'-dione:

' -10- ~ 3~

HN~
0~ ~
H3C ~
\S~

7-methylthiospiro(5H-ideno[1,2-b]pyr~din-5~3'-pyrolidine)-2',5'-dione;
i- , : o HN~
o=51~X NH

F~ F

2,7-difluorospiro~9H-fluoren-9,4'1midazolidin)-2',5'-dione;
:

:
' 1 3 ~

k.

HN~
0~0 F_~. F

2,7-d~fluorospiro~9H-fluoren-9,5'-oxazolidine)-2'5'dione;

o~
F--~--F

~ 297-difluorospiro(9H-fluoren-g,3'-pyrolidine)-2'95'-dione;

.

-12- ~ 3~2~

m.

HN~
~ h~

(S)-6-fluorosplro[chro~an-4,4'-l~idazolidine]-2',5'dione (also called "SORBINIL~");
5 n. o ~ OH
S ~ N ~

~C~O~

Cf3 N-[~5-(trifluoromethyl~-6-methoxy-1-naphthalenyl]thioxomethyl]-n-methylglycine (~lso ca led "toLREsTAT~ tnd , ' o.f~ols ~N
l l I
N~

O ~ F

Br [3-(4-bromo-2-fluorobenzyl)-4-oxo-3H phthalazin-1-yl]acet~c acid (also called "STATIL0").
In accordance with the present invention, pat~ents affltcted with diabetes mellitus and patients predlsposed to acquiring d~abetes melli-tus are treated with one or more aldose reductase inhibltors in an amount effecti~e 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 admin1stration 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 pharmaceutlcal co~posltion employed.

'

Claims

1. A pharmaceutical composition for enhancing insulin sensitivity in a patient afflicted with diabetes mellitus, which comprises a therapeutically effective amount of an aldose reductase inhibitor.

2. A pharmaceutical composition according to claim 1, wherein the composition has the necessary concentration for preventing or retarding the onset of Type II diabetes mellitus in a patient predisposed to acquiring this condition.

3. A pharmaceutical composition according to claim 1, where the composition has the necessary concentration for adminstration to a hyperglycemic patient so as to increase the whole blood concentration of reduced glutathione in the patient.

4. A pharmaceutical composition according to claim 1, wherein the composition has the necessary concentration for adminstration to a patient diagnosed as a latent or chemical diabetic so as to increase the whole blood concentration of reduced glutathione in the patient.

5. A pharmaceutical composition according to claim 1, wherein the aldose reductase inhibitor is selected form the class consisting of spiro-indeno-pyridine, pyrrolidine diones, spiro-indeno-pyridine-imidazolidine diones, spiro-fluorene-imidazolidine-diones, spiro-pyridine-pyrrolidine diones, spiro-fluorene oxazolidine-diones, spiro-fluorene-pyrrolidine diones, spiro-chroman-imidazolidine-diones, naphthalenyl-thioxoglycines or benzyl-oxophthalazine acetic acids.