Methods for preventing beta cell degeneration, such as necrosis or apoptosis of beta cells in a subject, comprising administering a DPP-IV inhibitor to a subject in need thereof. The invention furthermore relates to a method for increasing the number and/or the size of beta cells. The invention also relates to a method for delaying the progression of Impaired Glucose Tolerance (IGT) to type 2 diabetes, as well as a method for delaying the progression of non-insulin demanding type 2 diabetes to insulin-demanding type 2 diabetes.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to a method of treating beta cell degeneration comprising administering a DPP-IV inhibitor. "Beta cell degeneration" includes necrosis or apoptosis of .beta.-cells. "Treatment" or "treating" beta cell degeneration includes preventing, modulating, inhibiting, and/or decreasing beta cell degeneration. The term "inhibition," and "decreasing" are meant to include reduction and arresting beta cell degeneration.

The invention also relates to use of a DPP-IV inhibitor for the preparation of a medicament for increasing the number of beta cells.

In another aspect, the invention is a method of increasing the size of beta cells by administering to a subject a DPP-IV inhibitor.

In yet another aspect, the invention is a method of increasing the number of beta cells by administering to a subject a DPP-IV inhibitor.

The invention furthermore relates to a method of delaying the progression of Impaired Glucose Tolerance (IGT) to type 2 diabetes by administering to a subject a DPP-IV inhibitor.

The invention furthermore relates to a method of delaying the progression of Impaired Impaired Fasting Glucose (IFG) to type 2 diabetes by administering to a subject a DPP-IV inhibitor.

The invention furthermore relates to a method of delaying the progression of non-insulin demanding type 2 diabetes to insulin demanding type 2 diabetes.

The subject is preferably a mammal, more preferably a human patient in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

The insulinotropic hormone Glucagon like peptide-1 (GLP-1) has been shown to stimulate glucose-induced insulin release and insulin biosynthesis and to restore glucose competence. In our efforts to identify beta cell growth factors we discovered that GLP-1 indeed could stimulate beta cell proliferation in vitro. The proliferation was measured as incorporation of the thymidine analogue 5-bromo-2-deoxyuridine (BrdU) into DNA in insulin-positive cells in pancreatic islet cells from newborn rats. GLP-1 was found to increase the number of labelled beta cells.

Dipeptidyl peptidase-IV (DPP-IV), a serine protease belonging to the group of post-proline/alanine cleaving amino-dipeptidases, specifically removes the two N-terminal amino acids from proteins having proline or alanine in position 2.

DPP-IV has been implicated in the control of glucose metabolism because its substrates include the insulinotropic hormones Glucagon like peptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIP are active only in their intact forms; removal of their two N-terminal amino acids inactivates them.

In vivo administration of synthetic inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and GIP, resulting in higher plasma concentrations of these hormones, increased insulin secretion and, therefore, improved glucose tolerance. It has now been found that inhibition of DPP-IV could stimulate beta cell proliferation in vivo.

The invention also relates to the use according to any of the above uses in a regimen which additionally comprises treatment with human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen; the use of human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen for the preparation of a medicament for inhibiting the beta cell degeneration, such as necrosis or apoptosis of .beta.-cells in a subject; the use of human growth hormone, a growth hormone releasing agent or a growth factor such as prolactin or placental lactogen for the preparation of a medicament for treatment of beta cell degeneration, such as necrosis or apoptosis of .beta.-cells in a subject.

In embodiments of the invention the DPP-IV inhibitor is selected from peptides, polypeptides, proteins, enzymes, antibodies as well as non-peptides, e.g. a small organic molecule; each of which constitutes individual embodiments.

In a still further embodiment of the invention the DPP-IV inhibitor is a non-peptide.

In a preferred embodiment, the DPP-IV inhibitor is a N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidine or a N-(substituted glycyl)-4-cyano pyrrolidine.

In another embodiment of the invention the DPP-IV inhibitor exhibits inhibition of DPP-IV from 1 to 100%. Further embodiments are individually at least 10% inhibition, from 10 to 100% inhibition, or from 10 to 90% inhibition.

Any possible combination of two or more of the embodiments described herein is comprised within the scope of the present invention.

The route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, in particular oral.

Pharmaceutical compositions (or medicaments) containing a DPP-IV inhibitor may be administered parenterally to patients in need of such a treatment. Parenteral administration may be performed by subcutaneous, intramuscular or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump. A further option is a composition that may be a powder or a liquid for the administration of the DPP-IV inhibitor in the form of a nasal or pulmonal spray. As a still further option, the DPP-IV inhibitor can also be administered transdermally, e.g. from a patch, optionally a iontophoretic patch, or transmucosally, e.g. bucally. As a still further option, the DPP-IV inhibitor can also be administered by gene therapy, such as by implanting a cell line transformed with a vector such that it secretes the DPP-IV inhibitor. The implanted cells may be encapsulated in semi permeable membranes, e.g. macro- or microencapsulated. The above-mentioned possible ways to administer a DPP-IV inhibitor are not considered as limiting the scope of the invention.

Pharmaceutical compositions containing a DPP-IV inhibitor may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences, 1985 or in Remington: The Science and Practice of Pharmacy, 19.sup.th edition, 1995.

Thus, the injectable compositions of the DPP-IV inhibitor can be prepared using the conventional techniques of the pharmaceutical industry which involves dissolving and mixing the ingredients as appropriate to give the desired end product.

Further to the above-mentioned components, solutions containing a DPP-IV inhibitor may also contain a surfactant in order to improve the solubility and/or the stability of the DPP-IV inhibitor.

A composition for nasal administration of certain peptides may, for example, be prepared as described in European Patent No. 272097 (to Novo Nordisk A/S) or in WO 93/18785.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The DPP-IV inhibitor can be used in the treatment of various diseases. The particular DPP-IV inhibitor to be used and the optimal dose level for any patient will depend on the disease to be treated and on a variety of factors including the efficacy of the specific peptide derivative employed, the age, body weight, physical activity, and diet of the patient, on a possible combination with other drugs, and on the severity of the case. It is recommended that the dosage of the DPP-IV inhibitor be determined for each individual patient by those skilled in the art.
 

Claim 1 of 23 Claims

1. A method of inhibiting beta cell degeneration in a subject suffering from loss of beta cell function, beta cell dysfunction, necrosis or apoptosis of beta cells, said method comprising administering a DPP-IV inhibitor to said subject, wherein the DPP-IV inhibitor is selected from N-substituted adamantyl-amino-acetyl-2-cyano pyrrolidine or N-(substituted glycyl)-4-cyano pyrrolidine.

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