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Review

Investigational agents that protect pancreatic islet β-cells from failure

, &
Pages 1241-1250 | Published online: 27 Sep 2005

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  • ••Findings from the Diabetic PreventionProgram suggesting that TZDs can prevent the progression to Type 2 diabetes.
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  • ••An excellent and concise review of GLP-1analogues and DPP-IV inhibitors, and their clinical trial status.
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  • •A useful review of OLP-1 and its potential therapeutic benefits.
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  • ••Outcomes of the LIFE study showingpositive effects of losartan.
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  • •The first study to show that the inhibition of RAS is beneficial to islet function and pathology in an animal model of Type 2 diabetes.
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  • KAJIMOTO Y, MATSUOKA T, KANETO H et al: Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells. Diabetologia (1999) 42:1417–1424.
  • KANETO H, KAJIMOTO Y, J et al.: Beneficial effects of antioxidants in diabetes. Possible protection of pancreatic 0-cells against glucose toxicity. Diabetes (1999) 48:2398–2406.
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  • MARSHAK S, LEIBOWITZ G, BERTUZZI F et al.: Impaired 0-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose. Diabetes (1999) 48:1230–1236.
  • PIERCY V, TOSELAND CD, TURNER NC: Potential benefit of inhibitors of advanced glycation end products in the progression of Type II diabetes: a study with aminoguanidine in C57/13LKsJ diabetic mice. Metabolism (1998) 47:1477–1480.
  • KOOPTIWUT S, KEBEDE M, ZRAIKA S et al.: High glucose-induced impairment in insulin secretion is associated with reduction in islet glucokinase in a mouse model of susceptibility to islet dysfunction.. Endocrinol. (2005) 35:39–48.
  • EVANS JL, GOLDFINE ID, BA, GRODSKY GM: Are oxidative stress-activated signaling pathways mediators of insulin resistance and 0-cell dysfunction? Diabetes (2003) 52:1–8.
  • ROBERTSON RP, HARMON J, TRAN PO, TANAKA Y, TAKAHASHI H: Glucose toxicity in 0-cells: Type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes (2003) 52:581–587.
  • ••Excellent review of the mechanisms ofoxidative stress in islet 13-cell dysfunction.
  • GRANKVIST K, MARKLUND SL, TALJEDAL TB: Cu Zn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochein. J. (1981) 199:393–398.
  • LENZEN S, DRINKGERN J, M: Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic. Biol. Med. (1996) 20:463–466.
  • ROBERTSON RP, HARMON J, TRAN PO, POITOUT V: 0-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in Type 2 diabetes. Diabetes (2004) 53\(Suppl. 1):S119–S124.
  • BAYNES JW: Role of oxidative stress in development of complications in diabetes. Diabetes (1991) 40:405–412.
  • HUNT JV, DEAN RT, WOLFF SP: Hydroxyl radical production and autoxidative glycosylation. Glucose autoxidation as the cause of protein damage in the experimental glycation model of diabetes mellitus and ageing. Biochem. ./. (1988) 256:205–212.
  • WOLFF SP, DEAN RT: Glucose autoxidation and protein modification. The potential role of `autoxidative glycosylatioff in diabetes. Biochein. J. (1987) 245:243–250.
  • TANAKA Y, TRAN PO, HARMON J, ROBERTSON RP: A role for glutathione peroxidase in protecting pancreatic 0-cells against oxidative stress in a model of glucose toxicity. Proc. Natl. Acad. Sci. USA (2002) 99:12363–12368.
  • FRIDLYAND LE, PHILIPSON LH: Does the glucose-dependent insulin secretion itself cause oxidative stress in pancreatic 0-cells? Diabetes (2004) 53: 1942-1948.
  • ••Very important review presenting evidencethat the pathway involved in glucose-mediated insulin secretion may also be responsible for generating harmful oxidative stress in the 13-cell.
  • WU L, NICHOLSON W, KNOBEL SM et al.: Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines. J. Biol. Chem. (2004) 279:12126–12134.
  • KANETO H, XU G, SONG KH et al.: Activation of the hexosamine pathway leads to deterioration of pancreatic 0-cell function through the induction of oxidative. J.Chem. (2001) 276:31099–31104.
  • TAKAHASHI H, TRAN PO, LEROY E et al.: D-Glyceraldehyde causes production of intracellular peroxide in pancreatic islets, oxidative stress, and defective 0-cell function via non-mitochondrial pathways. ./. Biol. Chem. (2004) 279:37316–37323.
  • TIEDGE M, LORTZ S, MUNDAY R, LENZEN S: Protection against the co-operative toxicity of nitric oxide and oxygen free radicals by overexpression of antioxidant enzymes in bioengineered insulin-producing RINm5F cells. Diabetologia (1999) 42:849–855.
  • IHARA Y, YAMADA Y, TOYOKUNI S et al.: Antioxidant a-tocopherol ameliorates glycemic control of GK rats, a model of Type 2 diabetes. FEBS Lett. (2000) 473:24–26.
  • TAJIRI Y, GRILL VE: Interactions between vitamin E and glucose on B-cell functions in the rat: an in vivo and in vitro study. Pancreas (1999) 18:274–281.
  • KANETO H, KAJIMOTO Y, J et al: Beneficial effects of antioxidants in diabetes: possible protection of pancreatic 0-cells against glucose toxicity. Diabetes (1999) 48:2398–2406.
  • TANAKA Y, GLEASON CE, TRAN PO, HARMON JS, ROBERTSON RP: Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc. Natl. Acad. Sci. USA (1999) 96:10857–10862.
  • MAXWELL S, GREIG L: Anti-oxidants - a protective role in cardiovascular disease? Expert Opin. Phannacother. (2001) 2:1737–1750.
  • LONN E, YUSUF S, HOOGWERF B et al: Effects of vitamin Eon cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. Diabetes Care (2002) 25:1919–1927.
  • ECONOMIDES PA, KHAODHIAR L, CASELLI A et al.: The effect of vitamin E on endothelial function of micro- and macrocirculation and left ventricular function in Type 1 and Type 2 diabetic patients. Diabetes (2005) 54:204–211.
  • HARDING HP, RON D: Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes (2002) 51\(Suppl. 3):5455–5461.
  • •A helpful review describing ER stress and how it may be acting in the diabetic situation.
  • DELEPINE M, NICOLINO M, BARRETT T et al: EIF2AK3, encoding translation initiation factor 2-a kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat. Genet. (2000) 25:406–409.
  • HARDING HP, ZENG H, ZHANG Y et al: Diabetes mellitus and exocrine pancreatic dysfunction in perk mice reveals a role for translational control in secretory cell survival. Mol. Cell (2001) 7:1153–1163.
  • ••The first study to describe 13-celldysfunction and diabetes in a genetically manipulated mouse model of the ER stress response.
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