ADIPONECTIN  Organic product?  Goal/understand customers  What it is and What it does..  How and Where it acts..  When is it elevated and when decreased

  • View
    231

  • Download
    7

Embed Size (px)

Text of ADIPONECTIN  Organic product?  Goal/understand customers  What it is and What it does.. ...

  • Slide 1

ADIPONECTIN Organic product? Goal/understand customers What it is and What it does.. How and Where it acts.. When is it elevated and when decreased Who does and Why they would want to measure Adiponectin? Relevant data. Collin Shaw ALPCO Diagnostics Sales Manager (Diabetes & Obesity Product focus) [email protected] www.alpco.com Publications with Adiponectin in Abstract- 2008 to October, 2009= 2,344 Slide 2 Adiponectin- (also referred to as ADP, Ad, GBP-28, apM1, AdipoQ and Acrp30) acts in an endocrine manner and is exclusively secreted from adipocytes (fat cells) into the bloodstream- where it accounts for approximately 0.01% of all plasma protein at around 5-10 g/mL exists as multiple isoforms in circulation, self-associates into larger structures - What it is- Adiponectin, overview ADP The sum of which is referred to as TOTAL ADIPONECTIN TOTAL ADIPONECTIN (ADP or Ad) = S-S + Alb ( ) + + Globular ? ADIPONECTIN (gADP or gAd) * H. Ebinuma, O. Sato, et al. Sekisui Slide 3 TRIMERIC ADP (LMW)- The basic building block of circulating ADP, Trimeric ADP (aka-LMW) is formed through hydrophobic interactions of individual full length ADP monomers. Hexameric ADP (MMW)- Trimeric ADP is further assembled into Hexameric ADP. Trimer += )( Hexamer Hexameric ADP=6 Monomer ++ = )( Trimeric ADP=3 Alb Albumin Alb += )( Trimer Albumin Bound Trimer=3+Albumin HMW ADP- Hexameric ADP is further assembled into multiple HMW species (12, 18, 24, 30, 36..?) HMW ADP (12=DoDecamer) ( Hexamer += S-S ) + HMW-ADP (12) S-S = ) HMW ADP (18=HexaDoDecamer ( Hexamer TOTAL ADIPONECTIN (ADP or Ad) = S- S + Al b ( ) + + What it is - Adiponectin, isoforms & Nomenclature Slide 4 o ADP has extensive beneficial actions on multiple obesity, diabetic and cardiovascular dysfunctions, through its anti-inflammatory effects and actions on metabolic processing of glucose regulation and fatty acid catabolism. o Multiple ways ADP controls & regulate energy metabolism o Regulate glucose flux - o insulin sensitivity (Si)- AMPkinase o glucose uptake, gluconeogenesis o GSIS, C mass/function o adjust lipid catabolism- o -oxidation (FA), triglyceride clearance o anti-inflammatory activity- o TNF & other ProInflammatory cytokines o PAI-1 production & Activity o C apoptosis (in-vitro) o protection from endothelial dysfunction o NO production, o cell adhesion molecules, scavenger receptor expression Cholesterol uptake, o Endothelial cell necrosis- important facet of atherosclerotic formation o Control Satiety o Satiety, weight loss- weight reduction effects (some via the brain) o Most biological effects of adiponectin are mediated by the activation of the energy sensor AMPK (AMP activated protein kinase) as strong therapeutic target. o Thiazolidinediones (TZDs) are a class of peroxisome proliferator-activated receptor agonists (PPPAR) act primarily to increase the secretion of HMW Adiponectin o Rosiglitazone [HMW ADP] + [Glucose] What it does- Adiponectin is a Good Adipokine. What it does- Adiponectin is a Good Adipokine. Slide 5 o ADP has protective effects on multiple target tissues. o Sk. Muscle, Adipose Tissue, Brain, Heart/Vasculature, Beta Cell, ) Low adiponectin level yields insulin resistance and directly promotes atherosclerosis. Low Adiponectin level yields and deteriorates metabolic disease. [ADP] &/or [HMW ADP] Genetic factors ADP Gene polymorphisms Environmental Factors Environmental factors leading to obesity (High fat diet/ lack of exercise Inflammation, Insulin Resistance, type 2 diabetes atherosclerosis What it does- Adiponectin is a Good Adipokine. Islet/C- C functional Mass GSIS, Apoptosis CNS Food Intake Liver- Regul ate HGP NAFLD, Hep.Stotosis Sk. Muscle- Ins. Resistance Lipid accumulation Vasculature- HypTx (BV constriction) EndoDysf, Thrombosis, Arthrosclerosis, CHF/CHD, Fat- ProInflammatory Cytokines (IL-6, IL-1, TNF, MCP-1.) Resistin, Leptin, Visfatin, Hypertorphy, FFA production Slide 6 Adiponectin binds to multiple receptors, although their relative abundance varies in different target tissues Most biological effects of adiponectin are mediated by the activation of the energy sensor AMPK (AMP-activated protein kinase is a s strong therapeutic target) How & Where it acts- Adiponectin, Major receptors & function 1)AdipoR1 (adiponectin receptor 1) AMPkinase >sk. muscle, coronary arterioles, aorta.. 2)AdipoR2 (adiponectin receptor 2) AMPkinase >mostly Liver, some in sk. muscle, arterioles, ca. muscle 3) T-cadherin (T-Cad) Adiponectin enhances the binding of APPL1 (key signaling molecule) which couples ADP receptor signaling to AMPK activation Different adiponectin forms have different affinities to T-Cad, ADPR1 and ADPR2 *T. Kadowaki, et al, JCI. 2006. Slide 7 Who and Why measure ADP - Adiponectin Physiology- Who does and Why they would want to measure ADP? Biotech/Pharma- How does our drug candidate work? Drug Discovery, Target/Lead Validation, Safety/Toxicity Departments, Clinical Studies. Does a drug increase ADP (&/or HMW)? If so, good. If not, what else does it do. Therapeutically Measure ADP to evaluate efficacy & Safety of treatments (drug candidates) for treating DM, CVD &/or Metabolic Syndrome Academic/B.S.R.- understand etiology of Metabolic Syndrome Use Multiple models (transgenic animal/cell line), KI/KO modelsto study (patho)biology Since ADP is beneficial, how does their model change ADP levels. Study various known therapies to study and identify (if) a pathway involves s in ADP. Slide 8 Who and Why measure ADP - Adiponectin Physiology- Many studies have reported HMW ADP, ratio of multimers (e.g. HMW/Total) vs. total ADP, to be more relevant to the pathogenesis of type 2 diabetes, obesity, metabolic syndrome, and vascular disease. HMW ADP, has a longer t1/2, is the most Active & may have most effects The HMW form of adiponectin exhibits the highest AMP kinase phosphorylation Evidence that HMW ADP has the major insulin-sensitizing effects of the multiple bioactive forms- HMW levels, or its ratio index (HMWR), are more useful than the total adiponectin level for predicting insulin resistance and the development of metabolic syndrome Elevated total [Adiponectin] is good. Higher [HMW Adiponectin] is even better. Predictive of TIIDM. Levels of [Adiponectin] are Inversely correlated to the increase in pathology (a.k.a. [ADP]=metabolic disease) [Adiponectin] = TIIDM, Metabolic Syndrome and Obesity [Adiponectin] = Coronary Artery Disease, Coronary Heart Disease Slide 9 Thiazolidinediones (TZDs) (eg. Rosiglitizone) act primarily to increase the secretion of HMW Adiponectin. TZDs are a class of peroxisome proliferator-activated receptor agonists (PPPAR). JA Wagner, et al. Clinical Pharmacology and Therapeutics. 2009 M&M: TIIDM patients treated 26 wks of +/- PPAR . PPAR Rx [ADP] (total ADP) [Glucose], HbA1c, hematocrit, and triglycerides, TC & LDL, HDL-C, in levels of blood urea nitrogen, creatinine Who and Why measure ADP- Adiponectin Physiology- Who and Why measure ADP- Adiponectin Physiology- Results: Changes in [ADP] at 6-8 wks of therapy, predict changes in HbA1c at 24-52 wks. Early (68 weeks) increases in levels of adiponectin after treatment with PPAR agonists showed a negative correlation (r = 0.21, P < 0.0001) with subsequent changes in levels of HbA1 These analyses confirm previously demonstrated relationships between adiponectin levels and metabolic parameters and support the robust predictive utility of adiponectin across the spectrum of glucose tolerance. Main Point: clinical trials utilize changes in HbA1c as the therapeutic endpoint, ADP predicts this outcome in 6 wks. Slide 10 HMW ADP, ratio of multimers (e.g. HMW/Total) vs. total ADP, more relevant to the pathogenesis of insulin resistance, type 2 diabetes, obesity, metabolic syndrome, and vascular disease. *von Eynatten, M., et al. Atherosclerosis 2007. *Ebinuma, H., Kadowaki, T., et al. Diabetes Care 2006. Figure 1ROC curves of plasma total adiponectin levels and HMWR values for the prediction of insulin resistance, defined as a HOMA-IR index 2.5 (n 171). The AUC for the HMWR values was significantly larger than that for plasma total adiponectin levels (0.713 [95% CI 0.6200.805] vs. 0.615 [0.522 0.708], P 0.0160). Fig. 2. ROC curves of ADP (total, HMW & HMWR)& predictive values for the extent of coronary atherosclerosis. Prediction of CAD extent was based on discrimination between subjects with moderate (Extent Score 75 percentile) coronary wall irregularities. HMW adiponectin: 0.673 [95%CI 0.6000.746] vs. total adiponectin: 0.568 [95%CI 0.4910.646], P < 0.001). HMW/total-adiponectin ratio: 0.718 [95%CI 0.6440.792] vs. total ADP 0.568 [95%CI 0.4910.646], P = 0.010). No statistically significant difference between the AUC for HMW adiponectin and the HMW/total-adiponectin ratio (P = 0.265). Relevant clinical Data HMW or HMW/Total > than Total ADP- Slide 11 Eg. Of measuring Adiponectin for Academic/Clinical/BSR- HMW levels, or its ratio index (HMWR), are more useful than the total adiponectin level for predicting insulin resistance and the development of metabolic syndrome MM. Swarbrick, PJ. Havel, et al. Diabetologia 2006. M&M- Obese patients treated with Roux-en-Y Gastric Bypass Surgery Measure [ADP] (and many others) before and after (t= 1mo & 12 mo) GBP. RESULTS- Insulin sensitivity (HOMA-IR), @1 month, if measured total, would see no change in [ADP] @12 mo Total [ADP], [HMW ADP], even though in over all fat mass The increase of HMW, but not that of total adiponectin, predicted the relative decrease of insulin resistance (HMW: p=0.0044; total: p=0.0775, after adjustment for covariates, 12mo post GBP). Relevant clinical Data -HMW or HMW/Total > than Total ADP- Slide 12 Mice are Good Model for Diabetes Research. In mouse elevated total [Adiponectin] is good. Higher [HMW Adipo

Search related