基于β细胞为靶标的2型糖尿病药物治疗研究进展

摘要/Abstract

摘要： 2型糖尿病是以进行性β细胞功能损害和β细胞数量和质量减少为特征的。当β细胞数量和质量减少到一定程度,剩余的β细胞不能维持正常血糖需要的数量时,增加β细胞数量和质量而不需要使用额外的降糖药将是唯一的选择。因此治疗糖尿病的最终目的是保护、修复、再生或替代β细胞的数量和功能,从而最有效地缓解或修复此疾病发展进程。本文将以β细胞为靶标对2型糖尿病药物治疗研究进展进行综述。

关键词: 2型糖尿病, β细胞质量, β细胞保护

Abstract: Type 2 diabetes is characterized by progressive β-cell dysfunction and a reduction in β-cell mass. If the β-cell mass is already below the threshold for maintaining normoglycemia, the expansion of β-cell mass is the only option for achieving normoglycemia without the use of additional glucose lowering agents. Therefore, the ultimate goal of therapies on type 2 diabetes is preserving, regenerating or replacing the β-cell mass. In this review, we address the mechanisms involved in β-cell dysfunction and β-cell loss, and provide a rationale for pharmacological intervention for the preservation and/or expansion of β-cell mass in type 2 diabetes.

Key words: Type 2 diabetes, β-cell mass, Preservation of β-cell mass

中图分类号:

R966

柳军, 张陆勇. 基于β细胞为靶标的2型糖尿病药物治疗研究进展[J]. 中国临床药理学与治疗学, 2010, 15(5): 588-595.

LIU Jun, ZHANG Lu-yong. Advancement on the therapy of type 2 diabetes by targeting β-cell mass[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2010, 15(5): 588-595.

参考文献

[1] Pick A, Clark J, Kubstrup C, et al. Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetic fatty rat[J]. Diabetes, 1998, 47(3):358-364.
[2] Danial NN, Walensky LD, Zhang CY, et al. Dual role of proapoptotic BAD in insulin secretion and β-cell survival[J]. Nat Med,2008, 14(2):144-153.
[3] Butler AE, Janson J, Bonner-Weir S, et al. β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes[J]. Diabetes, 2003, 52(1):102-110.
[4] Kendall DM, Sutherland DE, Najarian JS. et al. Effects of hemipancreatectomy on insulin secretion and glucose tolerance in healthy humans[J]. N Engl J Med,1990, 322(13):898-903.
[5] Leahy JL, Bonner-Weir S, Weir GC, et al. Minimal chronic hyperglycemia is a critical determinant of impaired insulin secretion after an incomplete pancreatectomy[J]. J Clin Invest, 1988,81(5):1407-1414.
[6] Finegood DT, Scaglia L, Bonner-Weir S. Dynamics of β-cell mass in the growing rat pancreas. Estimation with a simple mathematical model[J]. Diabetes, 1995, 44(3):249-256.
[7] Matveyenko AV, Veldhuis JD, Butler PC, et al. Mechanisms of impaired fasting glucose and glucose intolerance induced by an approximate 50% pancreatectomy[J]. Diabetes, 2006, 55(8):2347-2356.
[8] Kjems LL, Kirby BM, Welsh EM, et al. Decrease in β-cell mass leads to impaired pulsatile insulin secretion, reduced postprandial hepatic insulin clearance, and relative hyperglucagonemia in the minipig[J]. Diabetes, 2001, 50(9):2001-2012.
[9] Goodner CJ, Koerker DJ, Weigle DS, et al. Decreased insulin- and glucagon-pulse amplitude accompanying β-cell deficiency induced by streptozocin in baboons[J]. Diabetes, 1989, 38(7):925-931.
[10] Laybutt DR, Glandt M, Xu G, et al. Critical reduction in β-cell mass results in two distinct outcomes over time. Adaptation with impaired glucose tolerance or decompensated diabetes[J]. J Biol Chem, 2003,278(5):2997-3005.
[11] Unger RH ,Zhou YT. Lipotoxicity of beta cells in obesity and other causes of fatty acid spillover[J]. Diabetes, 2001, 50 ( Suppl 1): S118-S121.
[12] Pickup JC, Mattock MB, Chusney GD, et al. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X[J]. Diabetologia, 1997, 40(11):1286-1292.
[13] Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance[J]. J Clin Invest, 2006,116(8):1793-1801.
[14] Donath MY, Størling J, Maedler K, et al. Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes[J]. J Mol Med, 2003,81(8):455-470.
[15] Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus[J]. N Engl J Med, 2007,356(15):1517-1526.
[16] Haffner SM, Greenberg AS, Weston WM, et al. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus[J]. Circulation, 2002,106(6):679-684.
[17] Haffner S. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance[J]. Diabetes, 2005,54(5):1566-1572.
[18] Jandeleit-Dahm KA, Tikellis C, Reid CM, et al. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes[J]. J Hypertens, 2005,23(3):463-473.
[19] Schupp M. Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-g activity[J]. Circulation, 2004,109(17):2054-2057.
[20] Tikellis C, Wookey PJ, Candido R, et al. Improved islet morphology after blockade of the renin-angiotensin system in the ZDF rat[J]. Diabetes, 2004,53(4):989-997.
[21] Lammert E, Cleaver O, Melton D. Induction of pancreatic differentiation by signals from blood vessels[J]. Science, 2001,294(19):564-567.
[22] Lammert E, Gu G, McLaughlin M, et al. Role of VEGF-A in vascularization of pancreatic islets[J]. Curr Biol, 2003,13(12):1070-1074.
[23] Johansson M, Mattsson G, Andersson A, et al. Islet endothelial cells and pancreatic β-cell proliferation: studies in vitro and during pregnancy in adult rats[J]. Endocrinology, 2006,147(5):2315-2324.
[24] Homo-Delarche F, Calderari S, Irminger JC, et al. Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat[J]. Diabetes, 2006,55(6),1625-1633.
[25] Li X, Zhang L, Meshinchi S, et al. Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes[J]. Diabetes, 2006,55(11):2965-2973.
[26] Mizuno A, Noma Y, Kuwajima M, et al. Changes in islet capillary angioarchitecture coincide with impaired β-cell function but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats: dimorphism of the diabetic phenotype at an advanced age[J]. Metabolism, 1999,48(4):477-483.
[27] Rask-Madsen C, King GL. Mechanisms of disease: endothelial dysfunction in insulin resistance and diabetes[J]. Nat Clin Pract Endocrinol Metab, 2007,3(1):46-56.
[28] Olsson R,Carlsson PO. The pancreatic islet endothelial cell: emerging roles in islet function and disease[J]. Int J Biochem Cell Biol, 2006,38(5/6):710-714.
[29] Rabelink TJ, Wijewickrama DC, de Koning EJ. Peritubular endothelium: the Achilles heel of the kidney[J] ? Kidney Int, 2007,72:926-930.
[30] Drucker DJ,Nauck MA. The incretin system: glucagonlike peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes[J]. Lancet, 2006,368(11):1696-1705.
[31] Holst JJ. The physiology of glucagon-like peptide 1[J]. Physiol Rev, 2007,87(4):1409-1439.
[32] Susini S, Roche E, Prentki M, et al.Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic ((INS-1) cells[J]. FASEB J, 1998,12(12):1173-1182.
[33] Nauck M, Stöckmann F, Ebert R, et al. Reduced incretin effect in type 2 (non-insulindependent) diabetes[J]. Diabetologia, 1986,29(1):46-52.
[34] Rachman J, Barrow BA, Levy JC, et al. Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM[J]. Diabetologia, 1997,40(2):205-211.
[35] Rachman J, Gribble FM, Barrow BA,et al. Normalization of insulin responses to glucose by overnight infusion of glucagon-like peptide 1 (7-36) amide in patients with NIDDM[J]. Diabetes, 1996,45(11):1524-1530.
[36] Toft-Nielsen MB, Madsbad S, Holst JJ.Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients[J]. Diabetes Care, 1999, 22(7):1137-1143.
[37] Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study[J]. Lancet, 2002,359(9309):824-830.
[38] Kjems LL, Holst JJ, Vølund A, et al. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects[J]. Diabetes, 2003, 52(2):380-386.
[39] Xu G, Kaneto H, Laybutt DR, et al. Downregulation of GLP-1 and GIP receptor expression by hyperglycemia: possible contribution to impaired incretin effects in diabetes[J]. Diabetes, 2007, 56(6):1551-1558.
[40] Bregenholt S, Møldrup A, Blume N, et al. The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits β-cell apoptosis in vitro[J]. Biochem Biophys Res Commun,2005, 330(2): 577-584.
[41] Buteau J, El-Assaad W, Rhodes CJ, et al. Glucagon-like peptide-1 prevents β-cell glucolipotoxicity[J]. Diabetologia, 2004, 47(5):806-815.
[42] Li L, El-Kholy W, Rhodes CJ, et al. Glucagon-like peptide-1 protects β-cells from cytokine-induced apoptosis and necrosis: role of protein kinase B[J]. Diabetologia, 2005, 48(7):1339-1349.
[43] Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates β-cell apoptosis[J]. J Biol Chem, 2003,278(1):471-478.
[44] Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets[J]. Endocrinology, 2003, 144(12):5149-5158.
[45] Farilla L, Hui H, Bertolotto C, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats[J]. Endocrinology, 2002, 143(11):4397-4408.
[46] Wang Q,Brubaker PL. Glucagon-like peptide-1 treatment delays the onset of diabetes in 8 week-old db/db mice[J]. Diabetologia, 2002, 45(9) :1263-1273.
[47] Hui H, Nourparvar A, Zhao X, et al. Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 50-adenosine monophosphatedependent protein kinase A- and a phosphatidylinositol -kinasedependent pathway[J]. Endocrinology, 2003, 144(4):1444-1455.
[48] Kwon G, Pappan KL, Marshall CA, et al. cAMP dose-dependently prevents palmitateinduced apoptosis by both protein kinase A- and cAMP-guanine nucleotide exchange factor-dependent pathways in β-cells[J]. J Biol Chem, 2004,279(10):8938-8945.
[49] Sarkar SA, Gunter J, Bouchard R, et al. Dominant negative mutant forms of the cAMP response element binding protein induce apoptosis and decrease the anti-apoptotic action of growth factors in human islets[J]. Diabetologia, 2007,50(8):1649-1659.
[50] Jhala US, Canettieri G, Screaton RA, et al. cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2[J]. Genes Dev, 2003,17(13):1575-1580.
[51] Goldstein BJ, Feinglos MN, Lunceford JK,et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes[J]. Diabetes Care, 2007,30(8):1979-1987.
[52] Pospisilik JA, Martin J, Doty T, et al. Dipeptidyl peptidase IV inhibitor treatment stimulates β-cell survival and islet neogenesis in streptozotocin-induced diabetic rats[J]. Diabetes, 2003, 52(3):741-750.
[53] Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic β-cell mass and function in a rodent model of type 2 diabetes[J]. Diabetes, 2006,55(6):1695-1704.
[54] Yasuda N, Inoue T, Nagakura T, et al. Enhanced secretion of glucagon-like peptide 1 by biguanide compounds[J]. Biochem Biophys Res Commun, 2002,298(5):779-784.
[55] Marchetti P, Del Guerra S, Marselli L, et al. Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin[J]. J Clin Endocrinol Metab, 2004,89(11):5535- 5541.
[56] Lupi R, Del Guerra S, Marselli L,et al. Rosiglitazone prevents the impairment of human islet function induced by fatty acids: evidence for a role of PPAR-g2 in the modulation of insulin secretion[J]. Am J Physiol Endocrinol Metab, 2004, 286(4): E560-E567.
[57] Lin CY, Gurlo T, Haataja L, et al. Activation of peroxisome proliferator-activated receptor-g by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 30-kinasedependent pathway[J]. J Clin Endocrinol Metab, 2005,90(12):6678-6686.
[58] Higa M, Zhou YT, Ravazzola M, et al. Troglitazone prevents mitochondrial alterations, β-cell destruction, and diabetes in obese prediabetic rats[J]. Proc Natl Acad Sci USA, 1999,96(20): 11513-11518.
[59] Finegood DT, McArthur MD, Kojwang D, et al. (-Cell mass dynamics in Zucker diabetic fatty rats. Rosiglitazone prevents the rise in net cell death[J]. Diabetes, 2001,50(5):1021-1029.
[60] Kawasaki F, Matsuda M, Kanda Y, et al. Structural and functional analysis of pancreatic islets preserved by pioglitazone in db/db mice[J]. Am J Physiol Endocrinol Metab, 2005, 288(3): E510-E518.
[61] Ishida H, Takizawa M, Ozawa S,et al. Pioglitazone improves insulin secretory capacity and prevents the loss of β-cell mass in obese diabetic db/db mice: possible protection of β-cells from oxidative stress[J]. Metabolism, 2004, 53(4):488-494.
[62] Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic b-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women[J]. Diabetes, 2002, 51(9):2796-2803.
[63] Wang CY, Mayo MW, Baldwin AS Jr.TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-κB[J]. Science, 1996, 274(5288):784-787.
[64] Beg AA,Baltimore D. An essential role for NF-(B in preventing TNF-β-induced cell death[J]. Science, 1996, 274(5288):782-784.
[65] Heimberg H, Heremans Y, Jobin C, et al. Inhibition of cytokine-induced NF-κB activation by adenovirus-mediated expression of a NF-κB superrepressor prevents β-cell apoptosis[J]. Diabetes, 2001, 50(10):2219-2224.
[66] Giannoukakis N. Protection of human islets from the effects of interleukin-1 beta by adenoviral gene transfer of an I(B repressor[J]. J Biol Chem, 2000, 275:36509-36513.
[67] Kopp E,Ghosh S. Inhibition of NF-κB by sodium salicylate and aspirin[J]. Science, 1994, 265(5174):956-959.
[68] Kim S, Millet I, Kim HS, et al. NF-κB prevents β-cell death and autoimmune diabetes in NOD mice[J]. Proc Natl Acad Sci USA,2007, 104(6):1913-1918.
[69] Fleischman A, Shoelson SE, Bernier R, et al. Salsalate improves glycemia and inflammatory parameters in obese young adults[J]. Diabetes Care, 2008, 31(2):289-294.
[70] Ding P,Zhu JP. Study on the clinical therapeutic effect of Heshouwu granula on type 2 diabetic hyperlipemia[J]. Chin J Clin Pharmacol Ther, 2009,14(4):443-446.