Reduction of oxidative stress by a new low-molecular-weight antioxidant improves metabolic alterations in a nonobese mouse diabetes model.
OBJECTIVE
We have previously established a nonobese diabetes mouse model characterized by moderate hyperglycemic levels, like those usually occurring in human type 2 diabetes. As oxidative stress is considered a major mechanism of progressive beta-cell damage in diabetes, we tested in this model the protective effects of a new low-molecular-weight antioxidant, namely, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate dihydrochloride (IAC).


METHODS
Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Two weeks later, STZ-NA mice were treated for 5 weeks with different doses of IAC (15 or 30 mg/kg per day intraperitoneally) and monitored for glycemia, insulinemia, glucose tolerance, and pancreatic insulin content.


RESULTS
Streptozotocin-NA mice showed moderate hyperglycemia, hypoinsulinemia, glucose intolerance, growth impairment, and markedly reduced pancreatic insulin content (22% of controls). IAC-treated STZ-NA mice showed clear-cut reduction of hyperglycemia and attenuation of glucose intolerance, associated to higher residual pancreatic insulin content with respect to untreated diabetic animals. Plasma nitrotyrosine levels (an index of oxidative stress), enhanced 3-fold in diabetic mice, were significantly reduced by IAC treatment. Significant correlations were found between plasma nitrotyrosine values and either blood glucose levels or pancreatic insulin content.


CONCLUSIONS
In the STZ-NA diabetic mouse model, the new antioxidant, IAC, improves diabetic metabolic alterations, likely by counteracting beta-cell dysfunction and loss associated with oxidative stress.
Novelli
Michela
M
Dipartimento di Patologia Sperimentale, University of Pisa, Pisa, Italy.
D'Aleo
Valentina
V
Lupi
Roberto
R
Paolini
Moreno
M
Soleti
Antonio
A
Marchetti
Piero
P
Masiello
Pellegrino
P
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005230:Fatty Acids, Nonesterified / Q000097:blood; D018149:Glucose Intolerance / Q000188:drug therapy / Q000378:metabolism; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009536:Niacinamide; D018384:Oxidative Stress / Q000187:drug effects*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013311:Streptozocin; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives / Q000097:blood
D000975:Antioxidants; D001786:Blood Glucose; D004952:Esters; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; 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