4 The dirty dozenStockholm 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 Characteristicspersistence, bioaccumulation, potential for long-range environmental transport (LRET), and toxicity
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 Obesogensforeign 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 diabetesexposure 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
22 Therapeutic implication Bromocriptine QR Stress management Coping skills Anti anxiety drugs
23 Vitamin D: T1DMImmunomodulatory 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: T2DMLow 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
29 RASClassical limited proteolysis linear cascade To cascade with multiple mediators, enzymes, receptors, functions
30 PointersFrequent association of DM and HT/nephro/CVD RAS(I) reduce incidence of vascular complications, by protective effects at + skeletal muscle + adipocytes + beta cells
31 RASLocal 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 TestosteroneLow 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 DMHypogonadism [low T] is associated with more visceral fat Androgens attenuate adipogenesis Androgens decrease cytokine production from adipocytes
38 Mechanism: DM to low TInsulin 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-ConclusionThe 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 Storypositive 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 ConclusionFrom 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".