We evaluated heat shock protein (HSP)70 changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, 2 studies were conducted in DM vervet monkeys. 1) Normal control monkeys, and streptozotocin induced DM monkeys (Stz-DM) that were differentiated into moderately or poorly controlled DM by judicious insulin administration, were evaluated. Liver was collected at 4, 8, 12, 16 and 20 weeks after streptozotocin, exposed to ex vivo heat shock at 42°C, and immunoblotted for heat shock factor (HSF)1, HSP70 and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced (Spont-DM) were included in a cross-over study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-week washout period. Glucose tolerance testing, and plasma and muscle HSP70 were the primary outcome measures. In Stz-DM, hyperglycemia reduced hepatic HSP70 in a dose-dependent fashion. HSF1 was increased in livers of monkeys with Stz-DM, but responses to ex vivo heat shock were impaired versus normal monkeys. Activation of HSF1 appears to be important, as the phosphorylation change with heat stress was nearly perfectly correlated with HSP70 increases. Impaired HSF1 activation was also seen in Stz-DM after chronic hyperglycemia (>12 weeks). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant positive trends in other measures of insulin resistance. No change in muscle HSP70 content was observed. We conclude that increasing HSP70, potentially through targeting hyperglycemia-related deficits in HSF1 induction and activation in the liver, is a potent and viable strategy to improve glucose tolerance.
- chaperone proteins
- nonhuman primates
- diabetes mellitus
- Copyright © 2010, American Journal of Physiology - Endocrinology and Metabolism