Improvement of Insulin Sensitivity by a Novel Drug, BGP-15, in Insulin-resistant Patients: A Proof of Concept Randomized Double-blind Clinical Trial

Abstract

The efficacy and safety of the new drug, BGP-15, were compared with placebo in insulin-resistant patients in a 28-day dose-ranging study. Forty-seven nondiabetic patients with impaired glucose tolerance were randomly assigned to 4 weeks of treatment with 200 or 400 mg of BGP-15 or placebo. Insulin resistance was determined by hyperinsulinemic euglycemic clamp technique and homeostasis model assessment method, and β-cell function was measured by intravenous glucose tolerance test. Each BGP-15 dose significantly increased whole body insulin sensitivity (M-1, p=0.032), total body glucose utilization (M-2, p=0.035), muscle tissue glucose utilization (M-3, p=0.040), and fat-free body mass glucose utilization (M-4, p=0.038) compared to baseline and placebo. No adverse drug effects were observed during treatment. BGP-15 at 200 or 400 mg significantly improved insulin sensitivity in insulin-resistant, nondiabetic patients during treatment compared to placebo and was safe and well-tolerated. This was the first clinical study demonstrating the insulin-sensitizing effect of a molecule, which is considered as a co-inducer of heat shock proteins.

Key words

BGP-15 - insulin resistance - heat shock protein inducer - hyperinsulinemic euglycemic clamp - glucose utilization

References

• 1 DeFronzo RA. The triumvirate: β-cell, muscle, liver.  A collusion responsible for NIDDM. Diabetes. 1988;  37 667-687
• 2 Hollenberg NK. Considerations for management of fluid dynamic issues associated with thiazolidinediones.  Am J Med. 2003;  8 ((Suppl 8A)) 111S-115S
• 3 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  N Engl J Med. 2007;  356 2457-2471
• 4 Racz I, Tory K, Gallyas Jr F, Berente Z, Osz E, Jaszlits L, Bernath S, Sumegi B, Rabloczky G, Literati-Nagy P. BGP-15 – a novel poly(ADP-ribose) polymerase inhibitor – protects against nephrotoxicity of cisplatin without compromising its antitumor activity.  Biochem Pharmacol. 2002;  63 1099-1111
• 5 Chen JD, Evans RM. A transcriptional co-repressor that interacts with nuclear hormone receptors.  Nature. 1995;  377 454-457
• 6 Nagy L, Kao HY, Love JD, Li C, Banayo E, Gooch JT, Krishna V, Chatterjee K, Evans RM, Schwabe JW. Mechanism of corepressor binding and release from nuclear hormone receptors.  Genes Dev. 1999;  13 3209-3216
• 7 Chung J, Nguyen AK, Henstridge DC, Holmes AG, Chan MH, Mesa JL, Lancaster GI, Southgate RJ, Bruce CR, Duffy SJ, Horvath I, Mestril R, Watt MJ, Hooper PL, Kingwell BA, Vigh L, Hevener A, Febbraio MA. HSP72 protects against obesity-induced insulin resistance.  Proc Natl Acad Sci USA. 2008;  105 1739-1744
• 8 Kolonics A, Literati-Nagy P, Peitl B, Bajza A, Jaszlits L, Laszlo L, Horvath T, Kulcsar E, Porszasz R, Paragh G, Bernath S, Literati B, Koranyi L, Szilvassy Z, Tory K, Roth J. BGP-15, a new type of insulin sensitizer.  Diabetes. 2006;  55 ((Suppl 1)) 2091-PO
• 9 Expert Commitee on the Diagnosis and Classification of Diabetes Mellitus . Position Statment.  Diabetes Care. 2003;  26 3160-3167
• 10 Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study.  Diabetes Care. 1997;  20 1087-1092
• 11 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance.  Am J Physiol. 1979;  237 E214-E223
• 12 Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, Khunti K. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis.  BMJ. 2007;  10 299
• 13 The Diabetes Prevention Program Research Group . Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the Diabetes Prevention Program.  Diabetes Care. 2005;  28 888-894
• 14 American Diabetes Association . Standards of Medical Care in Diabetes.  Diabetes Care. 2005;  28 ((Suppl 1)) S4-S36
• 15 Ou H-Y, Cheng J-T, Yu E-H, Wu T-H. Metformin on insulin sensitivity and plasma β-endorphin in human subjects.  Horm Metab Res. 2006;  38 106-111
• 16 Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.  JAMA. 2005;  294 2581-2586
• 17 Watkins PB. Insight into hepatotoxicity: the troglitazone experience.  Hepatology. 2005;  41 229-230
• 18 Hampton T. Diabetes drugs tied to fractures in women.  JAMA. 2007;  297 1645
• 19 Jessen N, Selmer E, Buhl R, Pold O, Schmitz S, Lund. A novel insulin sensitizer (S15511) enhances insulinstimulated glucose uptake in rat skeletal muscles.  Horm Metab Res. 2008;  40 269-275
• 20 Hargitai J, Lewis H, Boros I, Rácz T, Fiser A, Kurucz I, Benjamin I, Vígh L, Pénzes Z, Csermely P, Latchman DS. Bimoclomol, a heat shock protein co-inducer, acts by the prolonged activation of heat shock factor-1.  Biochem Biophys Res Commun. 2003;  307 689-695
• 21 Vígh L, Literáti PN, Horváth I, Török Z, Balogh G, Glatz A, Kovács E, Boros I, Ferdinándy P, Farkas B, Jaszlits L, Jednákovits A, Korányi L, Maresca B. Bimoclomol: a nontoxic, hydroxylamine derivative with stress proteininducing activity and cytoprotective effects.  Nat Med. 1997;  3 1150-1154
• 22 Kieran D, Kalmar B, Dick JR, Riddoch-Contreras J, Burnstock G, Greensmith L. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice.  Nat Med. 2004;  10 402-405
• 23 MacCarty MF. Induction of heat shock proteins may combat insulin resistance.  Med. Hypotheses. 2006;  66 527-534
• 24 Kolonics A, László L, Ábrahám CsS, Literáti PN, Tory K. BGP-15, a hydroximic acid derivative induces HSP72, activates neuronal NOS and preserves mitochondria number in hyperglycemic rat brain endothelial cell models.  Fundam Clin Pharmacol. 2004;  18 ((Suppl 1)) 23-126 , P11.34
• 25 Patti ME, Butte A, Cusi K, Kohane I, Landaker EJ, Defronzo R, Mandarino LJ, Kahn CR. Analysis of differential gene expression in skeletal muscle from subjects with insulin resistance and type 2 diabetes.  Diabetes. 2001;  50 ((Suppl 2)) A247
• 26 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. 2002;  51 1102-1109
• 27 Soti C, Nagy E, Giricz Z, Vigh L, Csermely P, Ferdinandy P. Heat shock proteins as emerging therapeutic targets.  Br J Pharmacol. 2005;  146 769
• 28 Bruce CR, Carey AL, Hawley JA, Febbraio MA. Intramuscular heat shock protein 72 and heme oxygenase-1 mRNA are reduced in patients with type 2 diabetes.  Diabetes. 2003;  52 2338-2345
• 29 Sadri P, Lautt WW. Blockade of hepatic nitric oxide synthase causes insulin resistance.  Am J Physiol. 1999;  277 G101-G108
• 30 Shankar RR, Wu Y, Shen HQ, Zhu JS, Baron AD. Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance.  Diabetes. 2000;  49 684-687
• 31 Kashyap SR, Roman LJ, Lamont J, Masters BS, Bajaj M, Suraamornkul S, Belfort R, Berria R, Kellogg Jr DL, Liu Y, DeFronzo RA. Insulin resistance is associated with impaired nitric oxide synthase (NOS) activity in skeletal muscle of type 2 diabetic subjects.  J Clin Endocrinol Metab. 2005;  90 1100-1105
• 32 Park HS, Lee JS, Huh SH, Seo JS, Choi EJ. Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase.  EMBO J. 2001;  20 446-456
• 33 Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance.  Nature. 2002;  420 333-336
• 34 Kolonics A, Horváth T, Kiss E, Matkó J, Kulcsár E, Literáti NP, Literáti NB, Barta K, Korányi LI, Tory K. Mitochondrial status of lymphocytes shows correlation with metabolic state.  Diabetes. 2006;  55 ((Suppl 1)) 602-60P
• 35 Nedvetsky PI. There's NO binding like NOS binding: protein-protein interactions in NO/cGMP signaling.  Proc Natl Acad Sci USA. 2002;  99 16510-16512
• 36 Venema VJ, Marrero MB, Venema RC. Bradykinin-stimulated protein tyrosine phosphorylation promotes endothelial nitric oxide synthase translocation to the cytoskeleton.  Biochem Biophys Res Commun. 1996;  226 703-710
• 37 García-Cardeña G, Fan R, Shah V, Sorrentino R, Cirino G, Papapetropoulos A, Sessa WC. Dynamic activation of endothelial nitric oxide synthase by Hsp90.  Nature. 1998;  392 821-824
• 38 Bender AT, Silverstein AM, Demady DR, Kanelakis KC, Noguchi S, Pratt WB, Osawa Y. Neuronal nitric oxide synthase is regulated by the hsp90-based chaperone system in vivo.  J Biol Chem. 1999;  274 1472-1478
• 39 Gratton JP, Fontana J, O’Connor DS, Garcia-Cardena G, MacCabe TJ, Sessa WC. Reconstitution of an endothelial nitric-oxide synthase (eNOS), hsp90, and caveolin-1 complex in vitro. Evidence that hsp90 facilitates calmodulin stimulated displacement of eNOS from caveolin-1.  J Biol Chem. 2000;  275 22268-22272
• 40 Fontana J, Fulton D, Chen Y, Fairchild TA, MacCabe TJ, Fujita N, Tsuruo T, Sessa WC. Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release.  Circ Res. 2002;  90 866-873
• 41 Brouet A, Sonveaux P, Dessy C, Balligand JL, Feron O. Hsp90 ensures the transition from the early Ca2-dependent to the late phosphorylation-dependent activation of the endothelial nitric-oxide synthase in vascular endothelial growth factor-exposed endothelial cells.  J Biol Chem. 2001;  276 32663-32669
• 42 Gabai VL, Meriin AB, Mosser DD, Caron AW, Rits S, Shifrin VI, Sherman MY. Hsp70 prevents activation of stress kinases. A novel pathway of cellular thermotolerance.  J Biol Chem. 1997;  272 18033-18037
• 43 Hooper PL, Hooper PL. Inflammation, heat shock proteins and type 2 diabetes.  Cell Stress Chaperones. 2008;  , Aug 22 [Epub ahead of print]
• 44 Juhl CB, Hollingdal M, Porksen N, Prange A, Lonnqvist F, Schmitz O. Influence of rosiglitazone treatment on beta-cell function in type 2 diabetes: evidence of an increased ability of glucose to entrain high-frequency insulin pulsatility.  J Clin Endocrinol Metab. 2003;  88 3794-3800
• 45 Pacinic G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function.  Best Pract Res Clin Endocrinol Metab. 2003;  17 305-322 , (Review)
• 46 Fulghesu AM, Angioni S, Portoghese E, Milano F, Paletta B, Paoletti AM, Melis GB. Failure of the homeostasis model assessment calculation score for detecting metabolic deterioration in young patients with polycystic ovarium syndrome.  Fertil Steril. 2006;  86 398-404
• 47 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modelling.  Diabetes Care. 2004;  27 1487-1495

Correspondence