Methods of treatment of type 2 diabetes

Abstract

The present invention relates generally to the field of diabetes. More particularly, it concerns the identification of genes responsible for NIDDM1 for use in diagnostic and therapeutic applications. The present invention demonstrates that the NIDDM1 locus is, in fact, the calpain 10 gene. The invention further relates to the discovery that analysis of mutations in calpain genes and gene products can be diagnostic for type 2 diabetes. The invention also contemplates methods of treating diabetes in view of the fact that calpain mutations can cause diabetes. Further, the invention relates to novel polynucleotides of the NIDDM1 locus and polypeptides encoded by such polynucleotides.

Description

[0001] This application claims the benefit of U.S. Provisional Application, Ser. No. 60 / 105,052, filed Oct. 21, 1998 and U.S. Provisional Application, Ser. No. 60 / 134,175, filed May 13, 1999.[0002] The government may own rights in the present invention pursuant to grant numbers DK-20595, DK-47486, and DK-47487 from United States Public Health Service.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates generally to the field of treatment of diabetes mellitus. More particularly, it concerns methods of diagnosing a propensity for type 2 diabetes mellitus, methods of identifying compounds to treat type 2 diabetes mellitus, and new nucleic acid sequences encoding polypeptides related to type 2 diabetes mellitus. [0005] 2. Description of Related Art [0006] Diabetes mellitus is a phenotypically and genetically heterogeneous group of metabolic diseases all of which are characterized by high blood glucose levels resulting from an absolute or rela...

AI Technical Summary

Benefits of technology

[0026] The invention further concerns a method of modulating an insulin secretory response in an animal comprising the step of modulating calpain function in the animal. Modulating calpain function can be by providing a modulator of calpain function to the animal. The modulator can be an agonist or antagonist of a calpain polypeptide. In certain embodiments, the modulator may be an inhibitor of a calpain polypeptide. In preferred embodiments, the inhibitor inhibits calpain I and/or calpain II. The inhibitor may be calpeptin or calpain inhibitor 2 (N-Ac-Leu-Leu-methioninal, ALLM). Alternatively, the inhibitor may be a thiol protease inhibitor, such as E-64-d.

[0027] The invention also concerns a method of modulating insulin mediated glucose transport in an animal comprising the step of modulating calpain function in the animal. Modulating calpain function can be by providing a modulator of calpain function to the animal. The modulator can be an agonist or antagonist of a calpain polypeptide. In certain embodiments, the modulator may be an inhibitor of a calpain polypeptide. In preferred embodiments, the inhibitor inhibits calpain I and/or calpain II. The inhibitor may be calpeptin or calpain inhibitor 2 (N-Ac-Leu-Leu-methioninal, ALLM). Alternatively, the inhibitor may be a thiol protease inhibitor, such as E-64-d.

[0028] Other aspects of the invention concerns a method of increasing an insulin secretory response in an animal comprising the step of modulating calpain function in the animal. Modulating calpain function in the animal can be by providing a modulator of calpain function to the animal. The modulator of calpain function can be an agonist or antagonist of a calpain polypeptide

Problems solved by technology

Mutations in these genes lead to impaired pancreatic β-cell function or in the case of the insulin receptor to defects in insulin action in target tissues including the pancreatic β-cell.

It results from the autoimmunological destruction of the insulin-producing cells of the pancreas leading to an absolute deficiency of insulin and requirement of insulin therapy for survival.

It is characterized by defects in insulin action resulting in decreased glucose uptake by muscle and fat and increased hepatic glucose production, and by abnormalities in the normal pattern of glucose-stimulated insulin secretion.

Although disease genes for complex disorders can be localized through genetic studies, their identification still represents a major challenge if there are no candidates in the region of interest.

This is due in part to the fact that recombination events cannot be used to unambiguously define the boundaries of the region containing the susceptibility locus because of heterogeneity within and between families.

However, it is unclear how successful linkage disequilibrium mapping will be when only affected sibpairs are available for study as is the case for many common late-onset disorders such as type 2 diabetes.

Moreover, experience in identifying genes for complex disorders is so limited that it is not known whether the susceptibility is due to only one or a few variants or many.

The presence of a large number of disease-associated variants would confound linkage disequilibrium studies.

Despite the desirablity of these endeavors these needs remain unfulfilled.

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