Restoring HSP70 deficiencies improves glucose tolerance in diabetic monkeys

Abstract

We evaluated heat shock protein 70 (HSP70) changes in diabetes mellitus (DM) in a nonhuman primate model. To this end, two studies were conducted in DM vervet monkeys. 1) Normal control 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 wk after streptozotocin, exposed to ex vivo heat shock at 42°C, and immunoblotted for heat shock factor 1 (HSF1), HSP70, and phosphorylated HSF1. 2) Spontaneous DM monkeys that were not pharmacologically induced were included in a crossover study of the HSP70-inducing drug geranylgeranylacetone (GGA). GGA at 20 mg/kg was given for 14 days with a 6-wk washout period. Glucose tolerance testing and plasma and muscle HSP70 were the primary outcome measurements. 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 vs. normal monkeys. Activation of HSF1 appears to be important, because 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 (Ͼ12 wk). In naturally occurring DM, increased circulating HSP70 resulted in significantly improved glucose tolerance and significant, positive trends in other measurements 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.heat shock protein 70; chaperone proteins; geranylgeranylacetone; nonhuman primates; diabetes mellitus HEAT SHOCK PROTEINS (HSPs) are the largest family of transcriptionally regulated chaperone proteins that respond to cellular stress. HSPs aid in repair of protein damage and survival of normal cellular functions. Heat shock factor 1 (HSF1) mediates most transcriptional activation by binding to heat shock elements in the promoter region of the HSP genes, with resultant transcription of HSP70 mRNA being most abundant. HSF1 undergoes modifications such as trimerization, phosphorylation, and acetylation as well as product feedback inhibition to modulate the activation-attenuation cycle (1). Induction of HSPs not only protects de novo proteins being translated through the endoplasmic reticulum but also protects oxidized proteins and upregulates intracellular antioxidant mechanisms, which together minimize the chronic inflammatory state associated with insulin resistance (21, 37).Insulin-resistant and hyperglycemic people have reduced HSP70 protein and gene expression (7,9,29). Notably, new studies utilizing chemical chaperones show that insulin sensitivity may be restored in obese rodent models by limiting cellular stress in some tissues (39), and insulin signaling can be improved in obese people (24). Even more compelling...

Effects of heat stress on serum insulin, adipokines, AMP-activated protein kinase, and heat shock signal molecules in dairy cows

“…Heat stress response includes activation of the heat shock transcription factor (HSF) and increased expression of heat shock proteins (HSPs) (Collier et al, 2008). Intriguing work demonstrates that extracellular HSP70 concentrations also increase during heat stress (Kavanagh et al, 2011;Gaughan et al, 2013). Therefore, we need to further investigate serum HSF and HSPs.…”

Heat shock protein 70 and albuminuria in patients with type 2 diabetes: a matched case control study

“…Extensive literature relates abnormalities of HSP's and type 2 diabetes (Nakhjavani et al 2011;Nakhjavani et al 2010;Kavanagh et al 2011). Recent studies have shown the role of these molecules in the pathogenesis of diabetic nephropathy (Calabrese et al 2007;Buraczynska et al 2009).…”

Targeting Molecular Chaperones in Diabetic Peripheral Neuropathy

“…Clinically, poor HSP70 mRNA expression is found in diabetic humans and correlates with reduced mitochondrial enzyme activity (Bruce et al, 2003), increased JNK activity (Chung et al, 2008) and the degree of insulin resistance (Kurucz et al, 2002). Evidence from animal models of DM also supports this finding at the protein level (Atalay et al, 2004;Kavanagh et al, 2011). Given the profound impact of HSP on stress kinases and mitochondrial integrity, it is conceivable that reduced HSP expression might have unfettered the deleterious inflammatory signaling and redox homeostasis which accelerate the development of insulin resistance.…”

“…Nevertheless, there appear to be some compounds such as geranylgeranyl acetone (GGA) that directly modulate HSP70. GGA is currently the leading antiulcer drug in Japan (Ushijima et al, 2005) and has been shown to be neuroprotective against cerebral ischemia, polyQ toxicity (Sajjad et al, 2010) and recently in a diabetic monkey model to attenuate insulin resistance (Kavanagh et al, 2011) via the induction of HSP70. As many of the other HSR inducers or co-inducers, the HSP induction mechanism of GGA is not elucidated but has been suggested via dissociation of HSF-1 from HSP70 by competitively interacting with HSP70 C-terminal peptide-binding domain, which is the HSF-1 binding sites during HSP70-HSF-1 negative feedback (Otaka et al, 2007).…”

“…Chung et al further demonstrated that targeted overexpression of HSP70 in mouse skeletal muscles mimicked the effects of heat therapy in preventing fat-induced JNK phosphorylation, insulin resistance and fat deposition, suggesting that HSP70 might mediate the beneficial effects afforded by heat therapy (Chung et al, 2008). Indeed, pharmacological induction of HSP70 with the hydroxylamine derivative BGP-15, -lipoic acid or GGA improved glucose tolerance in insulin-resistant mice (Chung et al, 2008), rats (Gupte et al, 2009a) and monkeys (Kavanagh et al, 2011), respectively. Notably, administration of a HSP co-inducer BRX-220 to STZ-diabetic rats dose-dependently reduced insulin resistance and was associated with improved peripheral sensory and motor nerve deficits (Kurthy et al, 2002).…”