1. From ominous octet to dirty dozen Sanjay 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 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
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 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
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".