From ominous octet to dirty dozen sanjay kalra
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From ominous octet to dirty dozen Sanjay Kalra. Talk plan. The Stockholm 12 The pathophysiologic 12. Talk plan. The Stockholm 12. The dirty dozen. Stockholm Convention on Persistent Organic Pollutants (POPs) 1995/ 2001

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From ominous octet to dirty dozen Sanjay Kalra

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From ominous octet to dirty dozenSanjay Kalra


Talk plan

  • The Stockholm 12

  • The pathophysiologic 12


Talk plan

  • The Stockholm 12


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"


Characteristics

  • persistence,

  • bioaccumulation,

  • potential for long-range environmental transport (LRET), and

  • toxicity


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


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).


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.


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


Obesogens

  • pharmaceutical drugs: diethylstilbestrol, SSRI, TZD

  • environmental obesogens: bisphenol A, diethylhexylphthalate, perfluorooctanoate (PFOA), organotins (tributyltin)

  • High-fructose corn syrup (HFCS)


Precautionary principle

  • Plastics

  • Pesticides


Talk plan

  • The pathophysiologic 12


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


Therapeutic implications

  • Combination therapy

  • Secretagogues

  • Insulin sensitizers

  • Incretin based therapy

  • SGLT2 inhibitors


The more the merrier

  • Occam's razor

  • Anti-razor of diabetes:

  • Multiple pathophysiology

  • Multiple management

  • Away from algorithms

  • Preference for patient centeredness


Four more hormones

  • 9.Dopamine/catecholamines

  • 10.Vitamin D

  • 11.Testosterone

  • 12. Renin-angiotensin system


Stress

  • (Physiological/psychological response to) stressful external events/stimuli

  • Autonomic system

  • Neuroendocrine: stressor > CRF > ACTH > Cortisol

  • Immune system


Stress and diabetes

  • Diabetes distress

  • Stress linked with:

  • onset of T1,T2DM

  • Poor control in T1, T2DM

  • Pptn of DKA


Dopamine

  • The catecholamine with the highest concentration in brain

  • Sustained hyperadrenergism

  • country

  • individual


Therapeutic implication

  • Bromocriptine QR

  • Stress management

  • Coping skills

  • Anti anxiety drugs


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


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


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


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


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


Anahata chakra: 12 petals


RAS

  • Classical limited proteolysis linear cascade

  • To cascade with multiple mediators, enzymes, receptors, functions


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


RAS

  • Local

  • Circulating

  • Intracrine, paracrine, endocrine

  • RAS is present in beta cell

  • RAS-insulin signalling-Vit D cross talk


  • 1,25OHD is a negative endocrine regulator of renin gene expression.

  • cAMP stimulates renin expression: Vit D targets cAMP signaling pathway.


Therapeutic implication

  • vitamin D analogue + renin inhibitor combination: can block unwanted compensatory renin increase and thus increase therapeutic efficacy

  • paricalcitol or doxercalciferol


  • 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)


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


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


Mechanism: low T to DM

  • Hypogonadism [low T] is associated with more visceral fat

  • Androgens attenuate adipogenesis

  • Androgens decrease cytokine production from adipocytes


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


Therapeutic implication

  • Aim for high normal T levels

  • Screen for hypogonadism: beyond sexuality

  • Manage low T: do not over treat.

  • Oral; IM

  • Fenugreek extract


Pre-Conclusion

  • The final word is not yet written.

  • New hormonal players, in harmony, in the diabetes orchestra,

  • Catecholamines

  • Vit D

  • RAS

  • Testosterone


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


Hansen et al. Cell Metabolism, 20 September 2012


  • 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


Conclusion

  • From

  • Ominous octet

  • To

  • Dirty dozen

  • To

  • Treacherous thirteen

  • To -------------------------------------------------


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


  • A group of twelve things is called a ---

  • duodecad


  • 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".


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