The role of Islet Neogenesis-Associated Protein (INGAP) in islet neogenesis

Lipsett, Mark; Hanley, Stephen; Castellarin, Mauro; Austin, Emily; Suarez-Pinzon, Wilma L.; Rabinovitch, Alex; Rosenberg, Lawrence

doi:10.1007/s12013-007-0028-3

Cited by 29 publications

(18 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent information supports the effectiveness of islet neogenesis therapy to reduce HbA 1c values [46]. The finding that continual stimulation of islet cell neogenesis does not result in unbridled beta cell mass expansion, suggests that induction of islet neogenesis would be a safe therapy for individuals with diabetes.…”

Section: Discussionmentioning

confidence: 90%

“…Even though the induction of beta cell mass expansion does occur in a regulated manner, there still remains the question as to whether or not pharmaceutical expansion of the insulin-producing cell mass will prove effective in ameliorating both type 1 and type 2 diabetes. Results from clinical Phase IIa proof of principle trials suggest that new beta cells can be formed in the setting of both types [46]. It remains to be determined whether, and to what extent, these newly formed beta cells are protected from the autoimmune insulitis that characterises type 1 diabetes [50].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for the homeostatic regulation of induced beta cell mass expansion

et al. 2006

View full text Add to dashboard Cite

Aims/hypothesis Diabetes results from an insufficient insulin-secreting beta cell mass. Restoration of beta cell mass through pharmaceutically induced endogenous beta cell mass expansion may revolutionise diabetes therapy. However, it remains to be determined whether the induced beta cell mass expansion is under homeostatic regulation. Methods Beta cell mass expansion rates were derived from three separate studies of continuous stimulation of islet neogenesis, including the partial duct obstruction of euglycaemic Syrian hamsters, administration of a pentadecapeptide with the same amino acid sequence as residues 104-118 of islet neogenesis-associated protein ) to euglycaemic Syrian hamsters, as well as to euglycaemic CD-1 mice. The incidence of islet neogenesis, average beta cell size, and beta cell replication and apoptotic rates were determined. Results Partial duct obstruction led to a õ2.5-fold increase in endocrine tissue at day 56 (p<0.05). From day 0 to day 7 the average rate of change of islet area was 12.7% per day, and this rate decreased to 5.3% per day from day 7 to day 42, and to 2.8% per day from day 42 to day 56. Administration of INGAP [104][105][106][107][108][109][110][111][112][113][114][115][116][117][118] to adult hamsters led to a 31% increase in total beta cell mass at day 30 (p=0.031).From day 0 to day 10 the average rate of beta cell mass expansion was 148 μg/day, whereas from day 10 to day 30 it decreased to 45 μg/day. INGAP 104-118 administration to adult CD-1 mice resulted in an approximately twofold increase in beta cell mass after 31 days (p=0.021). However, at day 90, there was no significant difference vs age-matched control mice (p=0.30), even though the neogenic beta cell mass was approximately fourfold greater (p=0.026). Beta cell replication was decreased by 56% (p<0.048), whereas beta cell apoptosis was fourfold greater (p<0.003) in 90-day INGAP 104-118 -treated mice compared with age-matched control mice. Conclusions/interpretation These data indicate that in the presence of ongoing islet neogenesis, homeostatic regulatory mechanisms intervene to regulate beta cell mass according to the prevailing metabolic requirements.

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Evidence for the homeostatic regulation of induced beta cell mass expansion

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Specifically, two proteins of the Reg family, Reg3 (formerly named INGAP) and PSP/Reg, isolated from pancreatic extracts after cellophane wrapping or 90% partial PX, respectively, were shown to stimulate b-cell growth [93][94][95][96]. Recent clinical studies suggest that INGAP promotes insulin production in T1D patients and ameliorates glycemic control in T2D patients [97].…”

Section: Box 2 Biomolecules For B-cell Regenerationmentioning

confidence: 99%

β-Cell regeneration: the pancreatic intrinsic faculty

Desgraz¹,

Bonal²,

Herrera³

2011

Trends in Endocrinology & Metabolism

View full text Add to dashboard Cite

“…Staining within tubular complexes was particularly prominent. 123 These results from two different rat models support the role of a Reg protein closely related to INGAP in islet neogenesis. The temporal sequence of Reg3 expression and neogenesis is consistent with an inductive role of Reg proteins in the neogenesis process.…”

Section: Relevant Data From Other Rodentsmentioning

confidence: 56%

Prospects and Challenges for Islet Regeneration as a Treatment for Diabetes: A Review of Islet Neogenesis Associated Protein

Fleming

Rosenberg

2007

J Diabetes Sci Technol

Self Cite

View full text Add to dashboard Cite

Diabetes mellitus results from inadequate insulin action, which can be viewed as a consequence of the limited ability to restore b cells after they are lost as the result of metabolic exhaustion, autoimmune destruction, or surgical insult. Arguably, a uniformly effective therapeutic pathway to address all forms of diabetes would be to reverse the restrictions on b-cell and islet regeneration. The development from progenitor cells of islets with normal endocrine function does occur in adult humans; it is referred to as islet neogenesis. The induction of islet neogenesis is an important, if not essential, therapeutic approach for curing type 1 diabetes mellitus (T1DM) and could be valuable in the treatment of type 2 diabetes mellitus (T2DM) as well. Islet neogenesis associated protein (INGAP) is the first therapeutic candidate to be identified as the result of a purposeful search for an endogenous molecule with islet neogenic activity. It was found that partial obstruction of the pancreatic duct in hamsters induced islet neogenesis; under this condition, a neogenesis-promoting activity was identified and partially purified from a soluble tissue fraction. A 168-kDa protein product of the cloned gene was found to be responsible for the neogenesis activity. This molecule named INGAP contains an active core sequence of amino acids called INGAP peptide. Results from in vitro, animal, and human studies suggest that INGAP and INGAP peptide are neogenic in at least several vertebrate species, including humans. INGAP has since been found to be a member of the family of Reg proteins, which are found across and in multiple versions within species and are closely associated with embryonic and regenerative processes. Clinical results suggest that INGAP peptide can be a suitable neogenesis therapy, but optimization of the therapy and more data are required to fully access this potential. Understanding of the signaling pathways of INGAP and other related Reg proteins is a promising means of advancing therapeutic development for people with T1DM and T2DM. The quest for the fundamental restorative approach to lost insulin secretion is an enticing target for drug development. Abbreviations: (CK+) cytokeratin positive, (DLS) duct-like structures, (FANs) focal areas of neogenesis, (GLP-1) glucagon-like peptide-1, (IGF-1) insulinlike growth factor-1, (INGAP) islet neogenesis associated protein, (ILS) islet-like structures, (NOD) nonobese diabetic, (PDX-1) pancreatic and duodenal homeobox gene-1, (T1DM) type 1 diabetes mellitus, (T2DM) type 2 diabetes mellitus J Diabetes Sci Technol 2007; 2:231-244 Journal of Diabetes Science and Technology

show abstract

The role of Islet Neogenesis-Associated Protein (INGAP) in islet neogenesis

Cited by 29 publications

References 103 publications

Evidence for the homeostatic regulation of induced beta cell mass expansion

Evidence for the homeostatic regulation of induced beta cell mass expansion

β-Cell regeneration: the pancreatic intrinsic faculty

Prospects and Challenges for Islet Regeneration as a Treatment for Diabetes: A Review of Islet Neogenesis Associated Protein

Contact Info

Product

Resources

About