www.bhartihospital.org from ominous octet to dirty dozen sanjay kalra

www.bhartihospital.org

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

“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



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.



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)



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



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".

www.bhartihospital.org from ominous octet to dirty dozen sanjay kalra

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