Persistent correction of hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice by a non-conventional radical scavenger.
We previously reported that in a diabetes mouse model, characterised by moderate hyperglycaemia and reduced beta-cell mass, the radical scavenger bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate di-hydrochloride (IAC), a non-conventional cyclic hydroxylamine derivative, improves metabolic alterations by counteracting beta-cell dysfunction associated with oxidative stress. The aims of this study were to ascertain whether the beneficial effects of IAC treatment could be maintained after its discontinuation and further elucidate the underlying mechanisms. Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Diabetic mice were treated for 7 weeks with various doses of IAC (7.5, 15, or 30 mg/kg b.w./die i.p.) and monitored for additional 8 weeks after suspension of IAC. Then, pancreatic tissue was used for determination of beta-cell mass by immunohistochemistry and beta-cell ultrastructural analysis. STZ-NA mice showed moderate hyperglycaemia, glucose intolerance and reduced beta-cell mass (25% of controls). IAC-treated STZ-NA mice (at both doses of 15 and 30 mg/kg b.w.) showed long-term reduction of hyperglycaemia even after discontinuation of treatment, attenuation of glucose intolerance and partial preservation of beta-cell mass. The lowest IAC dose was much less effective. Plasma nitrotyrosine levels (an oxidative stress index) significantly increased in untreated diabetic mice and were lowered upon IAC treatment. At ultrastructural level, beta cells of IAC-treated diabetic mice were protected against degranulation and mitochondrial alterations. In the STZ-NA diabetic mouse model, the radical scavenger IAC induces a prolonged reduction of hyperglycaemia associated with partial restoration of beta-cell mass and function, likely dependent on blockade of oxidative stress-induced damaging mechanisms.
Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Università degli Studi di Pisa, Via Roma, 55-Scuola Medica, 56126, Pisa, Italy.
M
M
Novelli
B
B
Bonamassa
M
M
Masini
N
N
Funel
D
D
Canistro
V
V
De Tata
M
M
Martano
A
A
Soleti
D
D
Campani
M
M
Paolini
P
P
Masiello
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D015394:Molecular Structure; D009536:Niacinamide; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D013311:Streptozocin; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D001786:Blood Glucose; D016166:Free Radical Scavengers; D007328:Insulin; D010880:Piperidines; C526136:bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate; D009536:Niacinamide; C002744:3-nitrotyrosine; D014443:Tyrosine; D013311:Streptozocin