From ominous octet to dirty dozen Sanjay Kalra

1. From ominous octet to dirty dozenSanjay Kalra

2. Talk plan • The Stockholm 12 • The pathophysiologic 12

3. Talk plan • The Stockholm 12

4. The dirty dozen • Stockholm Convention on Persistent Organic Pollutants (POPs) 1995/2001 • “chemical substances that persist in the environment, bio-accumulate through the food web, and pose a risk of causing adverse effects to human health and the environment"

5. Characteristics • persistence, • bioaccumulation, • potential for long-range environmental transport (LRET), and • toxicity

6. The dirty dozen • Aldrin, Chlordane • Dieldrin, Endrin • Heptachlor, Hexachlorobenzene • Mirex, Toxaphene, DDT • Polychlorinated biphenyls (PCBs) • Polychlorinated dibenzo-p-dioxins ("dioxins") and polychlorinated dibenzofurans • Polychlorinated biphenyls (PCBs) • Hexachlorobenzene

7. Endocrine disruptor chemicals • chemicals that interfere with endocrine (or hormone system) in animals, including humans. • "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis (normal cell metabolism).

8. Obesogens • foreign chemical compounds that disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. • chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.

9. EDCs and diabetes • exposure to DDT in utero can increase a child's risk of childhood obesity • PCB congeners: childhood obesity in children exposed prenatally, may increase the risk of diabetes • Bisphenol A: elevated rates of diabetes, early puberty, obesity

10. Obesogens • pharmaceutical drugs: diethylstilbestrol, SSRI, TZD • environmental obesogens: bisphenol A, diethylhexylphthalate, perfluorooctanoate (PFOA), organotins (tributyltin) • High-fructose corn syrup (HFCS)

11. Precautionary principle • Plastics • Pesticides

12. Talk plan • The pathophysiologic 12

14. Ominous octet • 1.Beta cell • 2-4. IR: liver, skeletal muscle, adipose tissue • 5. Alpha cell • 6. GIT • 7. Kidney • 8. Brain: cerebral insulin resistance

15. Therapeutic implications • Combination therapy • Secretagogues • Insulin sensitizers • Incretin based therapy • SGLT2 inhibitors

16. The more the merrier • Occam's razor • Anti-razor of diabetes: • Multiple pathophysiology • Multiple management • Away from algorithms • Preference for patient centeredness

17. Four more hormones • 9.Dopamine/catecholamines • 10.Vitamin D • 11.Testosterone • 12. Renin-angiotensin system

18. Stress • (Physiological/psychological response to) stressful external events/stimuli • Autonomic system • Neuroendocrine: stressor > CRF > ACTH > Cortisol • Immune system

19. Stress and diabetes • Diabetes distress • Stress linked with: • onset of T1,T2DM • Poor control in T1, T2DM • Pptn of DKA

20. Dopamine • The catecholamine with the highest concentration in brain • Sustained hyperadrenergism • country • individual

22. Therapeutic implication • Bromocriptine QR • Stress management • Coping skills • Anti anxiety drugs

23. Vitamin D: T1DM • Immunomodulatory • Decreases proinflam Th1 cytokines: IL2, IFN • Increases antiinflam Th2 cytokines IL4, IL10 • Reduces autoimmune insulitis • Maternal/infant Vit D intake protects against T1DM

24. Vitamin D: T2DM • Low Vit D associated with high MetS, DM, obesity, HT, CAD, stroke • Confounders: • Lack of physical activity • Obesity –sequestration of vit D • Less bioactive d in nephropathy • Genetic variations; VDBP polymorphism

25. Mechanism: insulin secretion • Vit D receptors; 1hydroxylase are present in beta cell • Insulin gene promoter has a VD response element • Insulin gene is activated by 1,25 OHD • VD ensures normal Ca pool for normal insulin release

26. Mechanism: insulin sensitivity • VD receptors present in muscle cells • VD increases expression and sensitivity of insulin receptors • VD ensures normal Ca pool for normal insulin action

27. Therapeutic implication • Be aware of skeletal and extra-skeletal effects of vit D def • Maintain optimal Vit D levels in all • Vit D is not an anti diabetic drug

28. Anahata chakra: 12 petals

29. RAS • Classical limited proteolysis linear cascade • To cascade with multiple mediators, enzymes, receptors, functions

30. Pointers • Frequent association of DM and HT/nephro/CVD • RAS(I) reduce incidence of vascular complications, by protective effects at • + skeletal muscle • + adipocytes • + beta cells

31. RAS • Local • Circulating • Intracrine, paracrine, endocrine • RAS is present in beta cell • RAS-insulin signalling-Vit D cross talk

32. 1,25OHD is a negative endocrine regulator of renin gene expression. • cAMP stimulates renin expression: Vit D targets cAMP signaling pathway.

33. Therapeutic implication • vitamin D analogue + renin inhibitor combination: can block unwanted compensatory renin increase and thus increase therapeutic efficacy • paricalcitol or doxercalciferol

34. Interaction b/w RAS and insulin signaling pathways, thru’ AT1 receptors • Inhibition of cross talk b/w Ang II signaling and insulin signaling • (Ang II receptors stimulate ROS, ICAM-1, ET-1; lead to IR)

35. Therapeutic implication • ACE(I), ARBs are drug of choice in diabetes associated hypertension • These drugs are ass with a lower incidence of new onset diabetes (HOPE, NAVIGATOR) • Not proven for primary prevention

36. Testosterone • Low T precedes onset of DM • ADT [androgen deprivation therapy] exacerbates IR, worsens glycemia [RR of DM 1.36] • Androgen Rx of hypogonadal men improves IS, glycemia, atherosclerosis; reduces insulin req • Free T is inversely proportional to IR

37. Mechanism: low T to DM • Hypogonadism [low T] is associated with more visceral fat • Androgens attenuate adipogenesis • Androgens decrease cytokine production from adipocytes

38. Mechanism: DM to low T • Insulin stimulates Leydig cell steroidogenesis thru’ local cytokines • Low FSH in diabetic men • Adipose tissue factors, eg, leptin, modulate T production • TNF inhibits T biosynthesis

39. Therapeutic implication • Aim for high normal T levels • Screen for hypogonadism: beyond sexuality • Manage low T: do not over treat. • Oral; IM • Fenugreek extract

41. Pre-Conclusion • The final word is not yet written. • New hormonal players, in harmony, in the diabetes orchestra, • Catecholamines • Vit D • RAS • Testosterone

42. P.S.:The Iron Story • positive association between high body iron stores (ferritin) and T2DM/IR • increased activity of divalent metal transporter 1 (DMT1) damages beta cell. • Removal of this iron transporter in beta cells in genetically engineered mice, protects against diabetes

43. Hansen et al. Cell Metabolism, 20 September 2012

44. Evolutionary biology: short-term increase in the amount of oxygen radicals is critical to the fine-tuning of insulin production during bouts of fever and stress. • However, nature had not foreseen the long-term local production of signal substances around the beta cells, which we see in diabetes

45. Conclusion • From • Ominous octet • To • Dirty dozen • To • Treacherous thirteen • To -------------------------------------------------

46. Acknowledgement, with pride • This presentation has been made predominantly from two Indian sources: • Manual of Clinical Endocrinology: ESI, 2012 • IJEM 2011, 2012 • Except for slide 38,39: from Cell Metabolism, 20 Sept 2012

47. A group of twelve things is called a --- • duodecad

48. The duodenum (from Latin duodecim, "twelve") • Twelve inches long. • In German the duodenum is Zwölffingerdarm, and in Dutch, twaalfvingerige darm, both meaning "twelve-finger bowel".