KU-32, a Novel Drug for Diabetic Neuropathy, Is Safe for Human Islets and ImprovesIn VitroInsulin Secretion and Viability

Abstract

KU-32 is a novel, novobiocin-based Hsp90 inhibitor that protects against neuronal glucotoxicity and reverses multiple clinical indices of diabetic peripheral neuropathy in a rodent model. However, any drug with potential for treating diabetic complications must also have no adverse effects on the function of pancreatic islets. Thus, the goal of the current study was to assess the effect of KU-32 on the in vitro viability and function of human islets. Treating human islets with KU-32 for 24 hours showed no toxicity as assessed using the alamarBlue assay. Confocal microscopy confirmed that with a minimum of 2-day exposure, KU-32 improved cellular viability by blocking apoptosis. Functionally, isolated human islets released more glucose-stimulated insulin when preincubated in KU-32. However, diabetic BKS-db/db mice, a model for type 2 diabetes, administered KU-32 for 10 weeks did not show any significant changes in blood glucose and insulin levels, despite having greater insulin staining/beta cell in the pancreas compared to untreated BKS db/db mice. In summary, KU-32 did not harm isolated human islets and may even be protective. However, the effect does not appear significant enough to alter the in vivo metabolic parameters of diabetic mice.

Variations in Rodent Models of Type 1 Diabetes: Islet Morphology

“…The intensity of the insulin immunolabeling (Figure 6(a), red), an indication the insulin content/ β -cell [14, 15], was not different during the early stages of diabetes (less than 10 days duration). Average insulin intensity staining was as follows: controls 126 ± 10, 7 days diabetes 141 ± 4, and 9 days 150 ± 11.…”

Stimulation of heat shock protein 90 chaperone function through binding of a novobiocin analog KU-32

“…The "KU" series of compounds are synthetic NB derivatives that exhibit improved binding affinity for the Hsp90 CTD and manifest increased anti-proliferative activity relative to NB (21)(22)(23)(24). KU-32, however, was observed to behave as a neuroprotective agent in the treatment of diabetic peripheral neuropathy and did not exert any adverse effect on pancreatic islets (25,26). The present study was designed to utilize biochemical and cell-based assays to determine how KU-32 modulates the function of Hsp90 differently than its parent compound NB.…”

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

“…This class of drugs raises Hsp 70 and improves insulin signaling, preserves diabetic islet cells, and reduces diabetic neuropathy. ) Improves glycemia, insulin signaling, anti-inflammatory, mitochondria generation renal, and nerve protection; blocks weight gain to antipsychotic medications; ischemia protection; improves diabetic wound healing; reduces liver fat; improves dyslipidemia Geranylgeranylacetone (Kavanagh et al 2011) Improves glycemia, insulin signaling, anti-inflammatory Alpha-lipoic acid (Gupte et al 2009b) Improves glycemia, insulin signaling, anti-inflammatory Xenohormetic plant compounds (Hooper et al 2010)-curcumin (Sahin et al 2012;Maradana et al 2013), carvacrol (Cho et al 2012;Wieten et al 2010), resveratrol (Han et al 2012;Ito-Nagahata et al 2013), metformin (Tsuei and Martinus 2012), astaxanthine (Lee et al 2010;Yuan et al 2011), naringin (Sharma et al 2011), rhodiola (Wang et al 2012;Panossian et al 2009), capsaicin (Luo et al 2012;Joo et al 2010) Improves glycemia, insulin signaling, and anti-inflammatory; reduce fatty liver; improves exercise performance; reduces fatigue; preserves kidney function; reduces diabetes-related cancer risk; improves endothelial function; extends life span of nematode Hemeoxygenase inducers (Li et al 2008) Improves glycemia, insulin signaling, anti-inflammatory Hsp90 inhibitors (Lee et al 2013;Farmer et al 2012) Improves glycemia, insulin signaling, anti-inflammatory Chemical chaperones (Kars et al 2010;Raciti et al 2010) Improves glycemia, insulin signaling, anti-inflammatory GLP agonist (Cunha et al 2009) Protects islets cells Hsp27 (Dai et al 2009) and Hsp72 (Chung et al 2008) gene overexpression Improves glycemia, improves insulin signaling, reduces inflammatory cytokines, reduces body fat, preserves beta cells…”

“…Unfortunately, the inhibition of Hsp 90 increases the toxicity of this class of compounds (Lee et al 2013;Farmer et al 2012).…”