Differentiation of non-insulin producing cells into insulin producing cells by GLP-1 or exendin-4 and uses thereof

a technology of exendin-4 and non-insulin producing cells, which is applied in the direction of drug compositions, peptide/protein ingredients, metabolic disorders, etc., can solve the problems of beta cell absence, diabetes mellitus, and functional impairmen

Inactive Publication Date: 2007-02-22
THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DEPT OF HEALTH & HUMAN SERVICES NAT INST OF HEALTH OFFICE OF TECH TRANSFER +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Beta cell dysfunction and the concomitant decrease in insulin production can result in diabetes mellitus.
Thus, beta cells are absent in people with Type 1 diabetes and are functionally impaired in people with Type 2 diabetes.
Insulin therapy, although life-saving, does not restore normoglycemia, even when continuous infusions or multiple injections are used in complex regimes.
For example, postprandial levels of glucose continue to be excessively high in individuals on insulin replacement therapy.
Immunosuppressive drugs, such as cyclosporin A, however, have numerous side-effects, including the increase in potential for infection.
Transplantation, therefore, can result in numerous complications.
A major disadvantage of these drugs, however, is that insulin production and secretion is promoted regardless of the level of blood glucose.
However, the drop in hemoglobin A1c obtained by these newer agents is less than adequate (Ghazzi et al., 1997), suggesting that they will not improve the long-term control of diabetes mellitus.
In vivo studies using GLP-1 have been limited to the use of single or repeated bolus injections or short-term infusions of GLP-1 and subsequent evaluation of the insulin secreting effects.
Furthermore, GLP-1 has known limitations as a therapeutic agent in the treatment of diabetes because it has a short biological half-life (De Ore et al., 1997), even when given by a bolus subcutaneously (Ritzel et al., 1995).
Thus, studies to date have never suggested that either GLP-1 or Exendin-4 is therapeutically effective on pancreatic function in people with Type 1 diabetes or that there are GLP-1 or Exendin-4 target cells in the pancreas other than the beta cells.

Method used

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  • Differentiation of non-insulin producing cells into insulin producing cells by GLP-1 or exendin-4 and uses thereof
  • Differentiation of non-insulin producing cells into insulin producing cells by GLP-1 or exendin-4 and uses thereof
  • Differentiation of non-insulin producing cells into insulin producing cells by GLP-1 or exendin-4 and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0080] As GLP-1 in cultured insulinoma cells is known to impact positively on insulin secretion, insulin synthesis and insulin messenger RNA, GLP-1's effects on aging Wistar rats were evaluated.

[0081] Materials. GLP-1 and exendin [9-39] (Ex), a peptide receptor antagonist of GLP-1, were purchased from Bachem (King of Prussia, Pa.). Chemical reagents were from Sigma (St Louis, Mo.), unless otherwise stated.

[0082] Animals. Three month (young) and 22 month (old) old Wistar rats from the Wistar colony in the NIA (Baltimore, Md.) were used. They had been maintained on rat chow and fed ad libitum. All our aged rats are the offspring of ten founder families maintained at the NIA.

[0083] Protocols. To insure that old animals were capable of responding to GLP-1, we carried out an acute experiment with an intravenous bolus of GLP-1. Six old (22 months) and 6 young (3 months) Wistar rats were fasted overnight. Following anesthesia with 50 mg / kg pentobarbital, a catheter was placed in the fem...

example 2

[0105] Exendin-4 is a peptide produced in the salivary glands of the Gila Monster lizard. In the present example, we report that in Wistar rats, bred in the National Institute of Aging (NIA), it was a far more potent insulinotropic agent in several ways than is GLP-1. We further report that exendin-4 leads to sustained improvement of diabetic control in a rodent model of type 2 diabetes.

[0106] Materials. Exendin-4 and GLP-1 were purchased from Bachem (King of Prussia, Pa.). Chemical reagents were from Sigma (St Louis, Mo.), unless otherwise stated.

[0107] Animals. Four month old Wistar rats from the Wistar colony in the NIA (Baltimore, Md.) were used for the acute experiments of the effects of exendin-4 and GLP-1 (see Example 1). They had been maintained on standard lab chow and fed ad libitum. For the long-term experiments, diabetic mice (C57BLKS / J-Leprdb / Leprdb) lacking the leptin receptor, and their non-diabetic littermates were purchased at 4 weeks of age from Jackson Laborator...

example 3

[0126] Using the protocol of Example 1, GLP-1 was administered by continuous infusion for one to five days to young and old rats, whereas control rats received comparable saline infusions. Exendin-4, in contrast, was administered intraperitoneally one time daily for five days according to the protocol of Example 2.

[0127] Approximately 20% of the cells in the GLP-1 treated pancreata were positive for PCNA at five days. At the same time point, there were proliferating cells in the islet. In addition, there were proliferating cells lining the ducts and, more surprisingly, in the acinar tissue, an area generally considered to be devoid of stem cells. Also surprisingly, a number of insulin positive cells were found outside the islets among the acinar tissue, where insulin positive cells are not expected.

[0128] These results show that continuous infusion with GLP-1 or repeated intraperitoneal injection with Exendin-4 for at least two days results in an increase in total number of insuli...

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Abstract

The present invention relates to a population of insulin producing cells made by a process comprising contacting non-insulin producing cells with a growth factor selected from the group consisting of GLP-1 or Exendin-4, growth factors having amino acid sequences substantially homologous to GLP-1 or Exendin-4, and fragments thereof. The present invention also relates to methods of differentiating non-insulin producing cells into insulin producing cells and of enriching a population of cells for insulin-producing cells. The present invention also relates to methods of treating diabetes.

Description

[0001] This application is a continuation of U.S. patent application Ser. No. 09 / 762,538, filed on Jul. 19, 2001 (now allowed), which is a 35 U.S.C. § 371 application of PCT / US99 / 18099, filed Aug. 10, 1999, which claims priority to U.S. Application No. 60 / 095,917, filed Aug. 10, 1998. The aforementioned applications are hereby incorporated herein in their entirety by this reference.[0002] The government has certain rights to this invention. BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The present invention relates to a population of insulin producing cells differentiated from non-insulin producing cells by contacting the non-insulin producing cells with Glucagon-like peptide-1 (“GLP-1”), exendin-4, or related peptides. The present invention also relates to the methods for obtaining the insulin producing cells and therapeutic uses in the treatment of diabetes mellitus. [0005] 2. Background Art [0006] The mammalian pancreas is composed of two distinct types of g...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/39C12N5/08A61K35/12C12N15/09A61K38/04A61K38/22A61K38/26A61P3/10C07K14/575C12N5/071C12Q1/68C12R1/91
CPCA61K38/26C07K14/57563C12N5/0676C12N2501/335A61K38/00A61K35/39A61P5/48A61P5/50A61P3/10
Inventor EGAN, JOSEPHINEPERFETTI, RICCARDOPASSANITI, ANTONINOGREIG, NIGELHOLLOWAY, HAROLDHABENER, JOELSTOFFERS, DORIS
Owner THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SEC DEPT OF HEALTH & HUMAN SERVICES NAT INST OF HEALTH OFFICE OF TECH TRANSFER
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