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Differential Response Between Type 1 and Type 2 Diabetes to Ischemia Reperfusion Injury

Fateh Entabi, Hassan Albadawi, David H Stone, Rameses L Sroufe, Mark F Conrad, Michael T Watkins
Massachusetts General Hospital, Boston, MA

Objective: Patients with type1 and type2diabetes have high incidence of peripheral vascular disease, complicated by acute limb ischemia, tissue and limb loss. Experiments were designed to compare the response to ischemia reperfusion between Streptozocin injected mice (SZ, Type1 diabetic model), and Leptin receptor mutant mice (DB, Type2 diabetic model).
Design: Prospective controlled animal study
Setting: Medical school affiliated university hospital.
Participants: BKS.Cg-m+/+ Lepr db/J
Interventions: DB, SZ, with similar blood glucose levels and their normoglycemic mutual wild type (WT) were subjected to 3 hrs of hind limb ischemia followed by 24 hrs of reperfusion (3I/24R). After reperfusion, mice were sacrificed, and limbs were harvested.
Main Outcome Measures: Tissue samples were assayed for mitochondrial activity (viability), local proinflammatory cytokine (KC), and angiogenic growth factor (VEGF) levels.
Results: DB mice had greater mitochondrial activity vs. both WT and SZ tissue after 3I/24R*p<0.01, while there was no significant difference between WT and SZ. Perfusion was similar in the three groups. KC was higher in SZ compared to DB**p<0.05. VEGF levels in SZ group were higher than both WT and DB †p<0.05, however there was no significant difference in KC, and VEGF expression between DB and WT.
Conclusions: DB and SZ mice respond differently to ischemia reperfusion injury. DB mice exhibit higher tissue viability and similar KC and VEGF levels as compared to WT. SZ mice express similar viability to WT, but express higher tissue VEGF levels. These data suggest that type of diabetes plays a role in predicting the outcome of limb salvage following acute ischemic insult.
Mitochondrial Activity
% Contralateral limbn=7-10 /group
KC protein
Fold base line
n=7/group
VEGF protein
Fold base line
n=7 /group
WT41±357±101.9±0.2
DB63±5*21±41.9±0.3
SZ45±3130±33**3.8±0.5†

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