• nonacetylated prodrug of salicylate• Obesity chronic inflammation role of anti-inflammatory agents• Therapeutic doses of upto 4 g/dayGoldfine AB, FonsecaV, Jablonski KA, Pyle L, Staten MA, Shoelson SE.The effects of salsalate on glycemiccontrol in patients with type 2 diabetes: a randomized trial. Annals of internal medicine. 2010;152(6):346–57.
•Inhibition of NF-k•Inhibition of cellular kinases•Upregulation of the heat shock response•Increases in circulating insulin concentrations
• Cost• Low incidence of hypoglycemia• low incidence of GI side effects (it is a prodrug and does not dissociate inacid pH of the stomach)
• Anakinra- improves cell function1• Etanercept – failed to improve insulin sensitivity in patients with metabolicsyndrome2• Inflammasome activation – field of active research31: Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, DonathMY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007 Apr12;356(15):1517-262. Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients withthe metabolic syndrome. Archives of internal medicine. 2006;166(8):902–8..3. Grant, Ryan W., and Vishwa D. Dixit. "Mechanisms of disease: inflammasome activation and thedevelopment of type 2 diabetes." Frontiers in Immunology 4 (2013).
• Used for metabolic syndrome/ type 2 DM11 HSD 1• Cortisone cortisol11 HSD 2
• Thiazolidinediones• Fibrates inhibit11 HSD1Adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones-compounds currently under investigation
• Acts as a glucose sensor• Rate-controlling enzyme for hepatic glucose clearance and glycogensynthesis• Present in pancreas and liver• Hepatic glucokinase entirely insulin dependent• Inactivating mutation results in MODY 2
• First published in nature in 2003• Over 100 patents filed and granted since then• Piragliatin- went to phase 2 trials – but discontinued• Primary impact is on hepatic glucokinase- hence mainly postprandial glucosereduction
•TAK-875•Stimulates glucose dependent insulin secretion•Type of improved sulfonylurea•Combination use of a DPP-4 inhibitor andTAK-875 -interestingAlquier,Thierry, andVincent Poitout. "GPR40: good cop, bad cop?." Diabetes58.5 (2009):1035-1036.
• Exubera-marketed in 2006 and discontinued in September 2007 due to poorsales by Pfizer• Afrezza*- ultrarapid acting meal time insulin (MannKind Corp)Rosenstock J, Lorger DL. Gnudi L, et. al. Prandial inhaled insulin plus basal insulinglargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomizedtrial Lancet 2010; 375: 2244-2253.
• Formulation of GLP-1 onTechnosphere® particles –inhaled• Escapes DPP4 degradation• Does not produce the nausea and vomiting characteristic of GLP-1analogues
• Consider in DM with BMI> 35• Can be considered for Asians at lower BMI cut offs(IDF positionstatement on bariatric surgery in DM- BMI 27.5 to 32.5)• An Australian report* recommends surgery be considered ifadolescents have BMI >40 , or >35 with severe co-morbidities,are 15 years or over & can provide informed consent*Baur LA & Fitzgerald DA. Recommendations for bariatric surgery in adolescents inAustralia and New Zealand. J Paediatr Child Health 46, 704-707 (2010).
RESTRICTIVE PROCEDURES• Creating a small gastric pouch & a degree of outlet obstructionleading to delayed gastric emptying• 1.VERTICAL BANDED GASTROPLASTY• 2.ADJUSTABLE GASTRIC BANDING (LAGB )• 3. SLEEVE GASTRECTOMY• 4.GASTRIC PLICATION• 5. INTRA GASTRIC BALLOON (GASTRIC BALLOON)
Malabsorption is achieved by creating a short gut syndrome and/or byaccomplishing distal mixing of bile and pancreatic juice with ingestednutrients thereby reducing absorption.NOT RECOMMENDED1. BILIOPANCREATIC DIVERSION2. THE JEJUNAL-ILEAL BYPASS3. ENDOLUMINAL SLEEVE
• Newly discovered hormone – Betatrophin• Can be injected yearly or monthly• Shown promising results in miceYi P, Park J-S, Melton DA. Betatrophin: A Hormone that Controls Pancreatic β CellProliferation. Cell. 2013;153(4):747–58.
• Using AAV (adeno associated virus vectors) transfection of skeletal musclewith insulin and glucokinase gene• Has been done successfully in dogsCallejas D, Mann CJ, Ayuso E, Lage R, Grifoll I, Roca C, Andaluz A, Ruiz-de Gopegui R, MontanéJ, Muñoz S, FerreT, HaurigotV, Zhou S, Ruberte J, Mingozzi F, High KA, Garcia F, Bosch F.Treatment of diabetes and long-term survival after insulin and glucokinase gene therapy.Diabetes. 2013;62(5):1718–29.O’BrienT. Gene therapy for type 1 diabetes moves a step closer to reality. Diabetes.2013;62(5):1396–7.
• DiaPep277• Synthetic peptide of 24 amino acids derived from the sequence of thehuman heat shock protein 60 (Hsp60)• Immunomodulator preventing cell destructionD.Tuccinardi, E. Fioriti, S. Manfrini, E. DAmico, and P. Pozzilli. "DiaPep277 peptide therapy in thecontext of other immune intervention trials in type 1 diabetes." Expert Opin BiolTher. 2011 JulyV. A. L. Huurman, P.E. van der Meide, G. Duinkerken, S. Willemen, I.R. Cohen, D. Elias, and B.O. Roep.“Immunological efficacy of heat shock protein 60 peptide DiaPep277TM therapy in clinical type 1diabetes.” Clin Exp Immunol. 2008 June;152(3):488-497
•Three approaches• Medical equipment•Bioengineering• Gene therapy
• Autologous bone marrow derived stem celltransplantation (ABMSCT)• Significant decrease in insulin requirement and glucagon stimulated Cpeptide levels shown*Bhansali A, A P, Walia R, Bhansali S, Gupta V, Jain A, Sachdeva N, Sharma RR, Marwaha N, Khandelwal N.Efficacy and Safety of Autologous Bone Marrow Derived Stem Cell Transplantation in patients with Type 2 Diabetes mellitus: A randomizedplacebo-controlled study.Cell Transplant. 2013 Apr 2