High beta-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice.
Thioredoxin-interacting protein (TxNIP) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets, and recent studies suggest that TxNIP is a proapoptotic factor in beta-cells that may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic beta-cell mass and/or insulin secretion. TxNIP-deficient (Hcb-19/TxNIP(-/-)) mice had lower baseline glycemia, higher circulating insulin concentrations, and higher total pancreatic insulin content and beta-cell mass than control mice (C3H). Hcb-19/TxNIP(-/-) did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although beta-cell mass remained higher in Hcb-19/TxNIP(-/-) mice compared with C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1beta, interferon-gamma, and tumor necrosis factor-alpha. Furthermore, when corrected for insulin content, isolated pancreatic islets from TxNIP(-/-) mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of beta-cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be because of an increase in beta-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced beta-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.
Masson
Elodie
E
Dept. of Medicine, Mount Sinai Hospital, 60 Murray St., Lebovic Bldg, Rm. 5028, Toronto, ON, Canada M5T 3L9.
Koren
Shlomit
S
Razik
Fathima
F
Goldberg
Howard
H
Kwan
Edwin P
EP
Sheu
Laura
L
Gaisano
Herbert Y
HY
Fantus
I George
IG
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000473:pathology* / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000502:physiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D051381:Rats; D013311:Streptozocin / Q000494:pharmacology; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D007328:Insulin; C493796:TXNIP protein, rat; C445672:Txnip protein, mouse; D013879:Thioredoxins; D013311:Streptozocin; D005947:Glucose