Islet neogenesis-associated protein pentadecapeptide (INGAP-PP): mechanisms involved in its effect upon beta-cell mass and function.
The effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) administration to normal male hamsters upon serum glucose and triglyceride levels, beta-cell mass and function was studied. INGAP-PP (500 mug) or saline was injected twice daily during 10 days. Both groups showed comparable body weight, serum glucose and triglyceride levels. INGAP-PP treated animals had significantly higher HOMA-IR and HOMA-beta and their islets released more insulin in response to glucose; they had lower islet DNA content, significantly increased number of islets/unit area, beta-cell replication rate and mass, cells co-expressing Pdx-1/INGAP and islets in contact with ducts, and decreased beta-cell apoptosis rate. The percentage of cells expressing Pdx-1 alone or together with INGAP or insulin increased significantly in ducts. These animals also showed a significantly higher concentration of Pdx-1 and Ngn-3 mRNA and a lower number of INGAP-positive cells. In conclusion, INGAP-PP promoted a controlled and functionally active increase of beta-cell mass; our data demonstrate for the first time the mechanism responsible for such changes; that Ngn-3 would be involved in INGAP-PP-induced neogenesis; and the existence of a negative feedback loop with endogenous INGAP-producing cells. Accordingly, INGAP-PP could be used to induce these effects in people with or at risk of developing diabetes.
Madrid
Viviana
V
CENEXA - Centro de Endocrinología Experimental y Aplicada (UNLP-CCT La Plata-CONICET, Centro Colaborador de la OPS/OMS), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Argentina.
Del Zotto
Héctor
H
Maiztegui
Bárbara
B
Raschia
María A
MA
Alzugaray
María E
ME
Boschero
Antonio C
AC
Barbosa
Helena C
HC
Flores
Luis E
LE
Borelli
María I
MI
Gagliardino
Juan J
JJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D014408:Biomarkers, Tumor / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D037181:Lectins, C-Type / Q000008:administration & dosage; D008297:Male; D008647:Mesocricetus; D009419:Nerve Tissue Proteins / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics; D014280:Triglycerides / Q000032:analysis
D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D001786:Blood Glucose; D018398:Homeodomain Proteins; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D000073718:Pancreatitis-Associated Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D015534:Trans-Activators; D014280:Triglycerides; C498696:Neurog3 protein, rat; C000612141:REG3A protein, human; C000612144:Reg3b protein, rat; C084010:pancreatic and duodenal homeobox 1 protein