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Specific antagonists for glucose-dependent insulinotropic polypeptide (gip)

Specific antagonists for glucose-dependent insulinotropic polypeptide (gip) description/claims

The work leading to this invention was supported in part by Grant Nos. DK08753 and RO1DK48042 from the National Institutes of Health. The U.S. Government may have certain rights to this invention.

This invention is directed to specific antagonists of glucose-dependent insulinotropic polypeptide (GIP). This invention is also directed to treatment of non-insulin dependent diabetes through increasing glucose tolerance without requirement for increased serum insulin, the treatment of obesity by the administration of a GIP antagonist, the development of nonpeptide GIP antagonist compounds, and compositions.

Insulin release induced by the ingestion of glucose and other nutrients is due part to both hormonal and neural factors (Creutzfeldt, et al., 1985, Diabetologia 28:565-573). Several gastrointestinal regulatory peptides have been proposed as incretins, the substance(s) believed to mediate the enteroinsular axis and that may play a physiological role in maintaining glucose homeostasis (Unger, et al., 1969, Arch. Intern. Med, 123:261-266; Ebert R., et al. 1987, Diab. Metab. Rev., 3:1-16; Dupré J., 1991, “The Endocrine Pancreas.” Raven Press, New York, p 253). Among these candidates, only glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (7-36)(GLP-1) appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (Dupré, et al. 1973, J. Clin. Endocrinol. Metab., 37:826-828; Nauck, et al., 1989; J. Clin. Endocrinol. Metab., 69:6540662; Kreymann, et al. 1987, Lancet, 2:1300-1304; Mojsov, et al., 1987, J. Clin. Invest., 79:616-619).

Following oral glucose administration, serum GIP levels increase several fold (see Cleator, et al., 1975, Am. J. Surg., 130:128-135; Nauck, et al. 1986, J. Clin. Endocrinol. Metab., 63:492-498; Nauck, et al., 1986, Diabetologia, 29:46-52; Salera, et al., 1983, Metabolism, 32:21-24; Kreymann, et al., 1987, Lancet, 2:1300-1304), and although the increment in plasma GLP-1 concentration in response to glucose is also significant, it is far smaller in magnitude (Kreymann, et al., 1987, Lancet, 2:1300-1304; Ørskov, et al., 1987, Scand. J. Clin. Lab. Invest., 47:165-174; Ørskov, et al., 1991, J. Clin. Invest., 87:415-423; Shuster, et al., 1988, Mayo Clin. Proc., 63:794-800). In human volunteers, Nauck et al. (1993, J. Clin. Endocrinol. Metab., 76:912-917) showed that GIP was a major contributor in the incretin effect after oral glucose, whereas GLP-1 appeared to play a major role. Shuster et al. (1988) also suggested that GIP was the most important, but not the sole, mediator of the incretin effect in humans.

Some studies have demonstrated that GIP and GLP-1 are equally potent in their capacity to stimulate insulin release (Schmid, et al., 1990, Z. Gastroenterol., 28:280-284; Suzuki, et al., 1990, Diabetes, 39:1320-1325), whereas others have suggested that GLP-1 possesses greater insulinotropic properties (Siegel, et al. 1992, Eur. J. Clin. Invest. 22:154-157; Shima, et al. 1988, Regul. Pept., 22:245-252). Recently, using a putative specific antagonist to the GLP-1 receptor, exendin (9-39), Wang et al. have demonstrated that exenden reduced postprandial insulin release by 48% and thus concluded that GLP-1 might contribute substantially to postprandial stimulation of insulin secretion (Wang, et al. 1995, J. Clin. Invest., 95:417-421). More recent studies, however, have shown that exendin might also displace GIP binding from its receptor and thereby reduce GIP-stimulated cyclic adenosine monophosphate (cAMP) generation (Wheeler, et al. 1995, Endocrinology, 136:4629-4639; Gremlich, et al. 1995, Diabetes, 44:1202-1208). Therefore, the antagonist properties of exendin (9-39) might not be limited to GLP-1.

The availability of a GIP-specific receptor antagonist would be invaluable for determining the precise roles of these peptides in mediating postprandial insulin secretion.

It is an object of this invention to provide specific antagonists of glucose-dependent insulinotropic polypeptide (GIP).

It is another object of this invention to provide alternative methods for treatment of non-insulin dependent diabetes which increase glucose tolerance without requirement for increased serum insulin, for treatment of obesity with a GIP antagonist which inhibits, blocks or reduces glucose absorption from the intestine of an animal, and for development of nonpeptide GIP antagonist compounds.

In one embodiment, this invention provides an antagonist of glucose-dependent insulinotropic polypeptide (GIP) consisting essentially of a 24-amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP.

In another embodiment, this invention provides a method of treating non-insulin dependent diabetes mellitus in a patient comprising administering to the patient an antagonist of glucose-dependent insulinotropic polypeptide (GIP).

In yet another embodiment, this invention provides a method of improving glucose tolerance in a mammal comprising administering to the mammal an antagonist of glucose-dependent insulinotropic polypeptide (GIP).

Using a reporter L-cell line stably transfected with rat GIP receptor cDNA (LGIPR2), the inventors have identified a fragment of GIP [GIP (7-30)-NH2] as a specific GIP receptor antagonist. This antagonist (referred to as ANTGIP) inhibited GIP-stimulated intracellular cAMP production in vitro, and ANTGIP competed with GIP for binding to cellular receptors, but did not complete with GLP-1. ANTGIP inhibited the GIP-dependent release of insulin in vivo, but ANTGIP had no effect on glucose-, GLP-1-, GIP-, and arginine-induced insulin release in anesthetized rats. In conscious rats, ANTGIP inhibited postprandial insulin release, without significantly affecting the serum glucose concentration. However, despite its inhibiting effect on insulin release, ANTGIP has been discovered to enhance glucose tolerance in an oral glucose tolerance test.

FIGS. 1A and 1B show cAMP-dependent β-galactosidase production by LGIPR2 cells in the presence of GIP or various GIP fragments.

FIG. 2 shows dose-dependent inhibition of ANTGIP on GIP-included cAMP-dependent β-galactosidase production in LGIPR2 cells.

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