www.bhartihospital.org from ominous octet to dirty dozen sanjay kalra
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www.bhartihospital.org
From ominous octet to dirty dozen
Sanjay Kalra
www.bhartihospital.org
Talk plan
The Stockholm 12
The pathophysiologic 12
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Talk plan
The Stockholm 12
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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"
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Characteristics
persistence,
bioaccumulation,
potential for long-range environmental transport (LRET), and
toxicity
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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
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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).
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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.
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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
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Obesogens
pharmaceutical drugs: diethylstilbestrol, SSRI, TZD
environmental obesogens: bisphenol A, diethylhexylphthalate, perfluorooctanoate (PFOA), organotins (tributyltin)
High-fructose corn syrup (HFCS)
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Precautionary principle
Plastics
Pesticides
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Talk plan
The pathophysiologic 12
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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
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Therapeutic implications
Combination therapy
Secretagogues
Insulin sensitizers
Incretin based therapy
SGLT2 inhibitors
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The more the merrier
Occam's razor
Anti-razor of diabetes:
Multiple pathophysiology
Multiple management
Away from algorithms
Preference for patient centeredness
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Four more hormones
9.Dopamine/catecholamines
10.Vitamin D
11.Testosterone
12. Renin-angiotensin system
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Stress
(Physiological/psychological response to) stressful external events/stimuli
Autonomic system
Neuroendocrine: stressor > CRF > ACTH > Cortisol
Immune system
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Stress and diabetes
Diabetes distress
Stress linked with:
onset of T1,T2DM
Poor control in T1, T2DM
Pptn of DKA
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Dopamine
The catecholamine with the highest concentration in brain
Sustained hyperadrenergism
country
individual
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Therapeutic implication
Bromocriptine QR
Stress management
Coping skills
Anti anxiety drugs
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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
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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
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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
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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
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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
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Anahata chakra: 12 petals
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RAS
Classical limited proteolysis linear cascade
To cascade with multiple mediators, enzymes, receptors, functions
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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
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RAS
Local
Circulating
Intracrine, paracrine, endocrine
RAS is present in beta cell
RAS-insulin signalling-Vit D cross talk
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1,25OHD is a negative endocrine regulator of renin gene expression.
cAMP stimulates renin expression: Vit D targets cAMP signaling pathway.
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Therapeutic implication
vitamin D analogue + renin inhibitor combination: can block unwanted compensatory renin increase and thus increase therapeutic efficacy
paricalcitol or doxercalciferol
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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)
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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
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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
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Mechanism: low T to DM
Hypogonadism [low T] is associated with more visceral fat
Androgens attenuate adipogenesis
Androgens decrease cytokine production from adipocytes
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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
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Therapeutic implication
Aim for high normal T levels
Screen for hypogonadism: beyond sexuality
Manage low T: do not over treat.
Oral; IM
Fenugreek extract
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Pre-Conclusion
The final word is not yet written.
New hormonal players, in harmony, in the diabetes orchestra,
Catecholamines
Vit D
RAS
Testosterone
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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
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Hansen et al. Cell Metabolism, 20 September 2012
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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
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Conclusion
From
Ominous octet
To
Dirty dozen
To
Treacherous thirteen
To -------------------------------------------------
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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
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A group of twelve things is called a ---
duodecad
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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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