A summary of recent advances and a look into the possible future directions in research and patient care in diabetes

1. Appraisal and Reappraisal
of Diabetes in 2013
Karthik Balachandran
Department of Endocrinology

3. Appraisal
Reappraisa
l

5. • nonacetylated prodrug of salicylate
• Obesity chronic inflammation role of anti-inflammatory agents
• Therapeutic doses of upto 4 g/day
Goldfine AB, FonsecaV, Jablonski KA, Pyle L, Staten MA, Shoelson SE.The effects of salsalate on glycemic
control in patients with type 2 diabetes: a randomized trial. Annals of internal medicine. 2010;152(6):346–57.

6. •Inhibition of NF-k
•Inhibition of cellular kinases
•Upregulation of the heat shock response
•Increases in circulating insulin concentrations

7. • Cost
• Low incidence of hypoglycemia
• low incidence of GI side effects (it is a prodrug and does not dissociate in
acid pH of the stomach)

8. • Anakinra- improves cell function1
• Etanercept – failed to improve insulin sensitivity in patients with metabolic
syndrome2
• Inflammasome activation – field of active research3
1: Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath
MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007 Apr
12;356(15):1517-26
2. Bernstein LE, Berry J, Kim S, Canavan B, Grinspoon SK. Effects of etanercept in patients with
the 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 the
development of type 2 diabetes." Frontiers in Immunology 4 (2013).

9. • Used for metabolic syndrome/ type 2 DM
11 HSD 1
• Cortisone cortisol
11 HSD 2

11. • Thiazolidinediones
• Fibrates inhibit11 HSD1
Adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones-
compounds currently under investigation

12. • Acts as a glucose sensor
• Rate-controlling enzyme for hepatic glucose clearance and glycogen
synthesis
• Present in pancreas and liver
• Hepatic glucokinase entirely insulin dependent
• Inactivating mutation results in MODY 2

14. • 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 glucose
reduction

15. •TAK-875
•Stimulates glucose dependent insulin secretion
•Type of improved sulfonylurea
•Combination use of a DPP-4 inhibitor andTAK-875 -
interesting
Alquier,Thierry, andVincent Poitout. "GPR40: good cop, bad cop?." Diabetes58.5 (2009):
1035-1036.

16. Two alternative hypotheses on the mechanisms behind lipid-induced insulin resistance and β-
cell compensation.
Alquier T , and Poitout V Diabetes 2009;58:1035-1036
Copyright © 2011 American Diabetes Asociation, Inc.

17. • Exubera-marketed in 2006 and discontinued in September 2007 due to poor
sales by Pfizer
• Afrezza*- ultrarapid acting meal time insulin (MannKind Corp)
Rosenstock J, Lorger DL. Gnudi L, et. al. Prandial inhaled insulin plus basal insulin
glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomized
trial Lancet 2010; 375: 2244-2253.

19. • Formulation of GLP-1 onTechnosphere® particles –inhaled
• Escapes DPP4 degradation
• Does not produce the nausea and vomiting characteristic of GLP-1
analogues

20. NewerTechnology

21. •Devices used for glucose monitoring
•Insulin delivery devices

26. Surgical options

27. • Consider in DM with BMI> 35
• Can be considered for Asians at lower BMI cut offs(IDF position
statement on bariatric surgery in DM- BMI 27.5 to 32.5)
• An Australian report* recommends surgery be considered if
adolescents 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 in
Australia and New Zealand. J Paediatr Child Health 46, 704-707 (2010).

28. • 1. PREDOMINANTLY RESTRICTIVE PROCEDURES
• 2. PREDOMINANTLY MALABSORBTIVE PROCEDURES
• 3. MIXED OR COMBINATION PROCEDURES

29. RESTRICTIVE PROCEDURES
• Creating a small gastric pouch & a degree of outlet obstruction
leading 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)

30. Malabsorption is achieved by creating a short gut syndrome and/or by
accomplishing distal mixing of bile and pancreatic juice with ingested
nutrients thereby reducing absorption.NOT RECOMMENDED
1. BILIOPANCREATIC DIVERSION
2. THE JEJUNAL-ILEAL BYPASS
3. ENDOLUMINAL SLEEVE

31. 1.GASTRIC BYPASS ROUX-EN-Y ( RYGBP)
2.SLEEVE GASTRECTOMY WITH DUODENAL SWITCH
3.IMPLANTABLE GASTRIC STIMULATION

34. • Poorly controlled type 1 DM with diabetic nephropathy may be an indication
• Not standardized
• Experience poor in many centers

35. Newer Approaches

36. • Newly discovered hormone – Betatrophin
• Can be injected yearly or monthly
• Shown promising results in mice
Yi P, Park J-S, Melton DA. Betatrophin: A Hormone that Controls Pancreatic β Cell
Proliferation. Cell. 2013;153(4):747–58.

38. • Using AAV (adeno associated virus vectors) transfection of skeletal muscle
with insulin and glucokinase gene
• Has been done successfully in dogs
Callejas D, Mann CJ, Ayuso E, Lage R, Grifoll I, Roca C, Andaluz A, Ruiz-de Gopegui R, Montané
J, 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.

40. • DiaPep277
• Synthetic peptide of 24 amino acids derived from the sequence of the
human heat shock protein 60 (Hsp60)
• Immunomodulator preventing cell destruction
D.Tuccinardi, E. Fioriti, S. Manfrini, E. D'Amico, and P. Pozzilli. "DiaPep277 peptide therapy in the
context of other immune intervention trials in type 1 diabetes." Expert Opin BiolTher. 2011 July
V. 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 1
diabetes.” Clin Exp Immunol. 2008 June;152(3):488-497

41. •Three approaches
• Medical equipment
•Bioengineering
• Gene therapy

42. Bioengineering approach
Principle
Implant implant bioengineeried
tissue containing islet cells

43. • Autologous bone marrow derived stem celltransplantation (ABMSCT)
• Significant decrease in insulin requirement and glucagon stimulated C
peptide 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 randomized
placebo-controlled study.
Cell Transplant. 2013 Apr 2

44. Strategies to obtain β cells from organ-specific stem or progenitor cells
Aguayo-Mazzucato, C. & Bonner-Weir, S. (2010) Stem cell therapy for type 1 diabetes mellitus
Nat. Rev. Endocrinol. doi:10.1038/nrendo.2009.274
Permission obtained from Macmillan Publishers Ltd © Bonner-Weir S. &Weir G. C.
Nature Biotechnology 23, 857–861 (2005)

45. Mouse embryonic stem cells