Methods of treatment of type 2 diabetes

Inactive Publication Date: 2006-10-19
POLONSKY KENNETH +8
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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 regi

Method used

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  • Methods of treatment of type 2 diabetes
  • Methods of treatment of type 2 diabetes
  • Methods of treatment of type 2 diabetes

Examples

Experimental program
Comparison scheme
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Example

Example 1

Methods

Generation of a Physical Map and Sequence of the NIDDM1 Region

[0433] YAC clones containing sequences of interest were identified by screening the CEPH ‘A’ and ‘B’ Human YAC DNA pools (Research Genetics, Huntsville, Ala.) using PCR™ and standard methods. PAC (PAC-6539; Genome Systems, St. Louis, Mo.) and BAC clones (CITB Human BAC DNA Pools—Release IV, Research Genetics) were identified in a similar manner.

[0434] DNA was prepared from each clone and tested directly for the presence of each STS. STSs were selected from the Généthon human genetic linkage map and the human transcript map in the interval around D2S125-D2S140 (http: / / www.ncbi.nlm.nih.gov). Additional STSs were generated by sequencing ends of clones and by sequencing random PstI fragments from the PACs and BACs after cloning in pGEM-4Z. The sequences of these clones were compared to those in the nonredundant GenBank database to identify unmapped ESTs from this region.

[0435] The sequence of a 50 kb reg...

Example

Example 2

Physical Mapping of NIDDM1

[0448] Initial linkage studies localized NIDDM1 to the distal long arm of chromosome 2 near D2S125. Further genotyping and refinement of the genetic map placed NIDDM1 near D25140 at 263.56 cM in the genetic map (Broman et al., 1998) with a 1-lod confidence interval from 257-269 cM, a 12 cM interval which included D25125 (260.63 cM). Although the 1-lod confidence interval for NIDDM1 was quite large and thus made the identification of NIDDM1 a rather formidable task, subsequent genetic studies identified a region on chromosome 15 near CYP19 which interacts with NIDDM1 to affect susceptibility to type 2 diabetes.

[0449] Taking the evidence for linkage at chromosome 15 into account in linkage analyses on the NIDDM1 region of chromosome 2 increased the lod score from 4.0 to 7.3 and decreased the 1-lod confidence interval from 12 to 7 cM (i.e. from 259-266 cM). The inventors focused the inventors' search for NIDDM1 in the 7 cM interval from 259-266 cM,...

Example

Example 3

Identification of NIDDM1

[0453] Allele and haplotype frequencies were compared among controls (n=112), patients (patients all, n=110), the subgroup of patients from families most likely to have susceptibility at NIDDM1 (patients NIDDM1, n=37) and subsequently with a smaller subgroup from families most likely to have susceptibility at NIDDM1 and the interacting locus near CYP19 on chromosome 15 (patients NIDDM1 / CYP19, n=20), once this interaction became evident. The expectation was that the degree of association would increase as the inventors examined those patients with type 2 diabetes due to variation at NIDDM1 or to the interaction between NIDDM1 and the unknown diabetes susceptibility locus on chromosome 15. The inventors began the search for NIDDM1 by first typing SNPs that the inventors had identified in known genes and ESTs and comparing the frequencies of alleles and estimated haplotypes formed between adjacent markers (most haplotypes were between two adjacent mar...

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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...

Claims

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Application Information

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IPC IPC(8): C12Q1/68A61P3/10C12N9/64C12N15/12
CPCC12N9/6472C12Q1/6883C12Q2600/172C12Q2600/158C12Q2600/156A61P3/10
Inventor POLONSKY, KENNETHHORIKAWA, YUKIOODA, NAOHISACOX, NANCYSREENAN, SEAMUSZHOU, YUN-PINGOTANI, KENICHIHANIS, CRAIGBELL, GRAEME
Owner POLONSKY KENNETH
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