Improving Glycaemic Control - A Mandatory Action Calling for Effective Therapeutic Management

Improving Glycaemic Control - A Mandatory Action Calling for Effective Therapeutic Management

Michele Aragona, Stefano Del Prato
European Endocrine Review 2006 - January 2006
Published: October 2008
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Diabetes mellitus is becoming one of the most common diseases in the world. The number of people with diabetes is estimated to double in the next 20 years, reaching 350 million affected people by 2025 (see Figure 1).1,2 This will be accompanied by an increased number of diabetic patients with long-term complications, causing a phenomenal increase in the health costs of several countries.1–3 At present there is no cure for diabetes, but many exciting steps have been taken in the past ten years, making the future of diabetic patients look cautiously optimistic.

Prevention of Diabetes
Along with advances in the treatment of hyperglycaemia and associated metabolic disturbances and diabetic complications, a future challenge will be to design preventative measures that may lower the incidence of diabetes in the world. Recent studies have highlighted the importance of lifestyle modification in preventing diabetes in high-risk individuals.4,5 Lifestyle modifications also provide beneficial effects on the entire cardiovascular risk profile.6–8 However, longterm adherence to such interventions and feasibility in a non-trial setting remain potentially limiting factors to widespread implementation.9

Pharmacological therapy may represent an interesting option. Positive results have been obtained with acarbose, metformin and glitazones, the latter suggesting that these compounds may actually modify the natural history of the disease.10–12 However, the data are not definitive and no single agent can currently be recommended for diabetes prevention. Effective treatment of obesity is also a valid opportunity, as suggested by early studies.13

The approach for effective prevention of type 1 diabetes is different. As the possibility of desensitising the immune system with small doses of insulin in the pre-hyperglycaemic phase has been dismissed, an innovative solution may arise from genetic and immunosuppressive advances.14–16

Transgenic expression of several proteins and transcription factors provides several theoretical opportunities. Expression of the pro-insulin gene in the thymus results in the disappearance of proinsulin reactive T-cells, preventing experimental type 1 diabetes.17 Similar results have been obtained with injection of islets or putative autoantigens, such as insulin B-chain or glutamate decarboxylase 65 (GAD65) proteins, in the thymus.18,19 Thus, injection of autoantigens in the thymus of high-risk individuals may represent an option, although more work is necessary to verify the efficiency of such a strategy.

Antigen-presenting cells (APC) are also the subject of much research as they are responsible for uptake and presentation of antigens to T-cells. APC residing in pancreas were then considered a target for gene therapy in type 1 diabetes. Genetic modification of APC in pancreas allows for local production of molecules that may interfere with activation and processing of antigens, limiting upregulation of adhesion molecules and interaction of APC-secreted factors with target cells.20–23 Gene transfer technology has been employed to ensure expression of interleukin (IL)-4 or modification of class I major histocompatibility complex (MHC) gene expression in pancreatic beta cells to prevent autoimmunity in non-obese diabetic mice.24–25 Optimisation of insulin secretion from residual beta cells was also achieved by gene transfer technology. Finally, transfer of the anti-apoptotic gene bcl-2 in beta cells may prevent apoptosis and autoimmune beta cell destruction or destruction of transplanted beta cells.26

Pancreatic beta cells are characterised by poor growth capacity. Although pancreatic stem cells are likely to be found in the pancreatic ductal epithelium, islet neogenesis in diabetic animals was not observed.27 However, stimulation of beta cell neogenesis and replication of residual beta cells might provide an effective strategy preventing type 1 diabetes. This goal is currently pursued via activation or insertion of pyruvate dehydrogenase complex protein X 1 (PDX1) into progenitor cells.28 Other genes include members of the regenerating gene (REG) family, also shown to be involved in beta cell regeneration in animal models.29

New Therapies for Type 2 Diabetes
For decades, treatment of type 2 diabetes has been limited to sulfonylureas and metformin. Recent years, however, have consigned new therapeutic options to the endocrinologist. These new therapeutic opportunities allow the endocrinologist to tackle, possibly in a more effective manner, the two main pathogenetic factors of type 2 diabetes: insulin resistance and defective insulin secretion. The new pharmacological options reflect significant advances in the understanding of the physiological regulation of insulin secretion and action. With respect to insulin secretion, major advances have been made thanks to the comprehension of the role of the incretins in determining the surge of insulin secretion after the ingestion of a meal. The crucial role of glucagon-like peptide 1 (GLP-1) has been recognised. Unfortunately, the native hormone has limited use in pharmacology due to its rapid degradation by dipeptidyl enzymes (DPP-IV).

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References:
  1. Amos A F, McCarty D J, Zimmet P, “The rising global burden of diabetes and its complications: estimates and projectionsto the year 2010”, Diabet. Med. (1997);14(5): pp. S1–85.
  2. King H, Aubert R E, Herman W H, “Global burden of diabetes, 1995–2025: prevalence, numerical estimates, andprojections”, Diabetes Care (1998);21(9): pp. 1,414–1,431.
  3. Zimmet P, Alberti K G, Shaw J, “Global and societal implications of the diabetes epidemic”, Nature (2001);414(6,865):pp. 782–787.
  4. Diabetes Prevention Program Research Group, “Effects of withdrawal from metformin on the development of diabetes in theDiabetes Prevention Program”, Diabetes Care (2003);26: pp. 977–980.
  5. Lindstrom J, Louheranta A, Mannelin M et al. (Finnish Diabetes Prevention Study Group), “The Finnish DiabetesPrevention Study (DPS): lifestyle intervention and 3-year results on diet and physical activity”, Diabetes Care(2003);26(12): pp. 3,230–3,236.
  6. Laaksonen D E, Lakka H M, Niskanen L K et al., “Metabolic syndrome and development of diabetes mellitus: applicationand validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study”, Am. J. Epidemiol.(2002);156(11): pp. 1,070–1,077.
  7. DeFronzo R A, Bonadonna R C, Ferrannini E, “Pathogenesis of NIDDM. A balanced overview”, Diabetes Care(1992);15(3): pp. 318–368.
  8. DeFronzo R A, “Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemiaand atherosclerosis”, Neth. J. Med. (1997);50(5): pp. 191–197.
  9. Unwin N, Shaw J, Zimmet P, Alberti K G M M, “Impaired glucose tolerance and impaired fasting glycemia: the currentstatus on definition and intervention”, Diabet. Med. (2002);19: pp. 708–723.
  10. Chiasson J L, Josse R G, Gomis R et al., “Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDMrandomized trial”, Lancet (2002);359: pp. 2,072–2,077.
  11. The Diabetes Prevention Program Research Group, “Reduction in the incidence of type 2 diabetes with lifestyle interventionor metformin”, N. Engl. J. Med. (2002);346: pp. 393–403.
  12. Knowler W C, Hamman R F, Edelstein S L et al. (Diabetes Prevention Program Research Group), “Prevention of type2 diabetes with troglitazone in the Diabetes Prevention Program”, Diabetes (2005);54(4): pp. 1,150–1,156.
  13. Torgerson J S, Hauptman J, Boldrin M N, Sjostrom L, “XENical in the prevention of diabetes in obese subjects(XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes inobese patients”, Diabetes Care (2004);27(1): pp. 155–161.
  14. Diabetes Prevention Trial—Type 1 Diabetes Study Group, “Effects of insulin in relatives of patients with type 1 diabetesmellitus”, N. Engl. J. Med. (2002);346(22): pp. 1,685–1,691.
  15. Jun H S, Yoon J W, “Approaches for the cure of type 1 diabetes by cellular and gene therapy”, Curr. Gene Ther.(2005);5(2): pp. 249–262.
  16. Singh N, Palmer J P, “Therapeutic targets for the prevention of type 1 diabetes mellitus”, Curr. Drug Targets ImmuneEndocr. Metabol. Disord. (2005);5(2): pp. 227–236.
  17. French M B, Allison J, Cram D S et al., “Transgenic expression of mouse proinsulin II prevents diabetes in nonobesediabetic mice”, Diabetes (1997);46(1): pp. 34–39.
  18. Posselt A M, Naji A, Roark J H, Markmann J F, Barker C F, “Intrathymic islet transplantation in the spontaneouslydiabetic BB rat”, Ann. Surg. (1991);214(4): pp. 363–371.
  19. Cetkovic-Cvrlje M, Gerling I C, Muir A et al., “Retardation or acceleration of diabetes in NOD/Lt mice mediated byintrathymic administration of candidate beta-cell antigens”, Diabetes (1997);46(12): pp. 1,975–1,982.
  20. Giannoukakis N, Rudert W A, Ghivizzani S C et al., “Adenoviral gene transfer of the interleukin-1 receptor antagonistprotein to human islets prevents IL-1beta-induced beta-cell impairment and activation of islet cell apoptosis in vitro”,Diabetes (1999);48(9): pp. 1,730–1,736.li> Lenschow D J, Zeng Y, Thistlethwaite J R et al., “Long-term survival of xenogeneic pancreatic islet grafts induced byCTLA4lg”, Science (1992);257(5,071): pp. 789–792.
  21. Kenyon N S, Fernandez L A, Lehmann R, “Long-term survival and function of intrahepatic islet allografts in baboonstreated with humanized anti-CD154”, Diabetes (1999);48(7): pp. 1,473–1,481.
  22. Swenson K M, Ke B, Wang T et al., “Fas ligand gene transfer to renal allografts in rats: effects on allograft survival”,Transplantation (1998);65(2): pp. 155–160.
  23. Mueller R, Krahl T, Sarvetnick N, “Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes innonobese diabetic (NOD) mice”, J. Exp. Med. (1996);184(3): pp. 1,093–1,099.
  24. von Herrath M G, Efrat S, Oldstone M B, Horwitz M S, “Expression of adenoviral E3 transgenes in beta cells preventsautoimmune diabetes”, Proc. Natl. Acad. Sci. U. S. A., (1997);94(18): pp. 9,808–9,813.
  25. Liu Y, Rabinovitch A, Suarez-Pinzon W et al., “Expression of the bcl-2 gene from a defective HSV-1 amplicon vectorprotects pancreatic beta-cells from apoptosis”, Hum. Gene Ther. (1996);7(14): pp. 1,719–1,726.
  26. Bonner-Weir S, “Perspective: postnatal pancreatic beta cell growth”, Endocrinology (2000);141(6): pp. 1,926–1,929.
  27. Fernandes A, King L C, Guz Y et al., “Differentiation of new insulin-producing cells is induced by injury in adultpancreatic islets”, Endocrinology (1997);138(4): pp. 1,750–1,762.
  28. Bone A J, Banister S H, Zhang S, “The REG gene and islet cell repair and renewal in type 1 diabetes”, Adv. Exp.Med. Biol. (1997);426: pp. 321–327.
  29. Ratner R E, Want L L, Fineman M S et al., “Adjunctive therapy with the amylin analogue pramlintide leads to acombined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes”, Diabetes Technol.Ther. (2002);4(1): pp. 51–61.
  30. Bailey C J, “Potential new treatments for type 2 diabetes”, Trends Pharmacol. Sci. (2000);21: pp. 259–265.
  31. Bailey C J, “Drugs on the horizon for diabesity”, Curr. Diab. Rep. (2005);5(5): pp. 353–359.
  32. Owens D R, Zinman B, Bolli G, “Alternative routes of insulin delivery”, Diabet. Med. (2003);20(11): pp. 886–898.
  33. Patton J S, Bukar J G, Eldon M A, “Clinical pharmacokinetics and pharmacodynamics of inhaled insulin”, Clin.Pharmacokinet. (2004);43(12): pp. 781–801.
  34. Butler D, “Last chance to stop and think on risks of xenotransplants”, Nature (1998);391(6,665): pp. 320–324.
  35. Soria B, Roche E, Berna G et al., “Insulin-secreting cells derived from embryonic stem cells normalize glycemia instreptozotocin-induced diabetic mice”, Diabetes (2000);49(2): pp. 157–162.
  36. Blyszczuk P, Wobus A M, “Stem cells and pancreatic differentiation in vitro”, J. Biotechnol. (2004);113(1–3):pp. 3–13.
  37. Wobus A M, Holzhausen H, Jakel P, Schoneich J, “Characterization of a pluripotent stem cell line derived from a mouseembryo”, Exp. Cell Res. (1984);152(1): pp. 212–219.
  38. Klonoff D C, “European trends in diabetes technology—continuous glucose measurements and computerized informationprocessingtools”, Diabetes Technol. Ther. (2002);4(6): pp. 763–764.
  39. Del Prato S, Felton A M, Munro N et al. (on behalf of the Global Partnership for Effective Diabetes Management),“Improving Glucose Management: Ten steps to get more patients with type 2 diabetes to glycemic goal”, Int. J. Clin. Pract.(2005);59(11): pp. 1,345–1,355.

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