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Diabetes, Nitric Oxide, and Heat Shock Proteins

From the Department of Endocrinology, University of Colorado Health Sciences Center, Glen Haven, Colorado

Heat shock proteins (Hsps) or stress proteins are a highly evolutionary conserved family of polypeptides that are cytoprotective, protecting proteins, lipids, and nucleic acids from damage by reducing oxidation, preventing apoptosis, suppressing proinflammatory cytokines, repairing ion channels, and aiding in protein folding (1). Hsps have recently been found to be low in individuals with type 2 diabetes, moderately low in the nondiabetic identical twin with a diabetic co-twin, and low in individuals with type 1 diabetes (2). Furthermore, in a study comparing 5,600 genes of nondiabetic subjects with those of insulin-resistant diabetic subjects, Hsp 70 was 1 of only 17 genes that were markedly lower in individuals with diabetes (3). The data suggest that low Hsps in diabetes may be an acquired as well as an inherited genetic defect. Interestingly, a study of individuals with type 1 diabetes with neuropathy observed that -lipoic acid administration was associated with restoration of nitric oxide (NO) production, restoration of Hsp levels, and improvement in neuropathic symptoms (4). NO synthesis increases Hsp expression, whereas blocking NO synthesis lowers Hsp expression (5). Relevantly, medications that have been associated with improved outcome in diabetes—ß-adrenergic blockers (6), HMG CoA reductase inhibitors (7), ACE inhibitors (8), and thiazolidinediones (9)—have all demonstrated restoration of endothelial NO synthase, which may result in Hsp expression and cytoprotection from the metabolic stresses of diabetes. Exercise increases NO production (10) and increases Hsp expression (11), perhaps contributing to the improved outcomes associated with exercise and diabetes. Importantly, a drug designed to increase Hsp expression, bimoclomol, improves diabetic retinopathy, neuropathy, nephropathy, wound healing, cardiac ischemia, and insulin resistance in laboratory diabetic animal models (12,13). Finally, heat therapy, via hot tub immersion, improves diabetic glycemic control and symptomatic diabetic neuropathy in patients with type 2 diabetes (14).

Decreased Hsps in type 1 and type 2 diabetes may be a primary factor leading to the development of diabetes and its diverse, widespread organ damage. Therapy directed at raising Hsps may limit the development of diabetes, but may also reduce the morbidity and mortality in those with diabetes.

Footnotes

Address correspondence to Philip L. Hooper, PO Box 245, Glen Haven, CO 80532. E-mail: phoopermd{at}msn.com.

References

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2. Kurucz I, Morva A, Vaag A, Eriksson KF, Huang X, Groop L, Koranyi L: Decreased expression of heat shock protein 72 in skeletal muscle of patients with type 2 diabetes correlates with insulin resistance. Diabetes 51:1102–1109, 2002[Abstract/Free Full Text]
   
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5. Malyshev IY, Manukhina EB, Mikoyan VD, Kubrina LN, Vanin AF: Nitric oxide is involved in heat-induced HSP70 accumulation. FEBS Lett 370:159–62, 1995[Medline]
   
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7. Hattori Y, Nakanishi N, Kasai K: Statin enhances cytokine-mediated induction of nitric oxide synthesis in vascular smooth muscle cells. Cardiovasc Res 54:649–658, 2002[Abstract/Free Full Text]
   
8. Angiotensin-converting: enzyme inhibitors improve coronary flow reserve in dilated cardiomyopathy by a bradykinin-mediated, nitric oxide-dependent mechanism. Circulation 105:2785–2790, 2002[Abstract/Free Full Text]
   
9. Fujishima S, Ohya Y, Nakamura Y, Onaka U, Abe I, Fujishima M: Troglitazone, an insulin sensitizer, increases forearm blood flow in humans. Am J Hypertens 11:1134–1137, 1998[Medline]
   
10. Roberts CK, Barnard RJ, Jasman A, Balon TW: Acute exercise increases nitric oxide synthase activity in skeletal muscle. Am J Physiol 277 (2 Pt 1):E390–E394, 1999
    
11. Walsh RC, Koukoulas I, Garnham A, Moseley PL, Hargreaves M, Febbraio MA: Exercise increases serum Hsp72 in humans. Cell Stress Chaperones 6:386–393, 2001[Medline]
    
12. Vigh L, Literati PN, Horvath I, Torok Z, Balogh G, Glatz A, Kovacs E, Boros I, Ferdinandy P, Farkas B, Jaszlits L, Jednakovits A, Koranyi L, Maresca B: Bimoclomol: a nontoxic, hydroxylamine derivative with stress protein-inducing activity and cytoprotective effects. Nat Med 3:1150–1154, 1997[Medline]
    
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14. Hooper PL: Hot-tub therapy for type 2 diabetes mellitus. N Engl J Med 341:924–925, 1999[Free Full Text]
    

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