diabetes Johannes Ruige, UGent Overzicht Recente nieuwe ontwikkelingen tav type 2 diabetes mellitus Diabetes kan gezien worden als obesitas gerelateerde complicatie Hormonale veranderingen gastro-intestinale systeem? Hormonale veranderingen vetweefsel? Veranderingen myokine secretie vd spiercellen? Dieetfoutjes en sedentaire levensstijl… http://t2.gstatic.com/images?q= tbn:ANd9GcSI5rJe2-KunLh1CUCWKWGDa34XazfVuD_Z5hqyY_cfRkVNmQKI http://www.weightbalance.nl/artikelen/20060904telegraaf.jpg Resulteren in obesitas en gerelateerde complicaties zoals Non-alcoholic fatty liver disease Type 2 diabetes mellitus Atherosclerose Stages of type 2 diabetes -5 0 5 10 15 IGT DM Fasting Plasma Glucose > 100 - 126 mg/dl; A1c > 5.7 - 6.5% Prevention : identify and protect individuals at risk ….. Onduidelijkheid over de exacte pathogenese en daardoor over mogelijkheden tot (vroegtijdige) interventie http://i36.tinypic.com/29aqx4w.png Sommige bevindingen echter wèl klinische implicaties; bv Glucagon-like peptide 1 en Glucose-dependent insulinotropic polypeptide http://coe.jmu.edu/LearningTool box/images/algebra2.gif Gastro-intestinale systeem http://www.drsharma.ca/wp-content/uploads/sharma-obesity-guthor mones2.jpg Diminished incretin effect Normal incretin effect Oral glucose (50 g/400 ml) Isoglycemic intravenous glucose 0 –10 10 15 20 Venous plasma glucose (mmol/L) 5 60 120 180 Time (minutes) 0 40 60 80 insulin (mU/L) 20 Healthy controls (n=8) Type 2 diabetes (n=14) 0 10 15 20 5 Time (minutes) 0 40 60 80 insulin (mU/L) 20 –5 –10 60 120 180 –5 –10 60 120 180 –5 –10 60 120 180 –5 * * * * * * * * * * Venous plasma glucose (mmol/L) Nauck M et al (1986) Diabetologia. Incretine effect en diabetes Drucker DJ et al. (2006) Lancet; Drucker DJ (2007) J Clin Invest Pancreas-L Active GLP-1 and GIP Release of incretin gut hormones Pancreas Glycemic control GI tract intestine-L ↓ Glucagon (GLP-1) Glucose dependent α-cells LIVER-L hepatic glucose output ↓ ↑ Insulin (GLP-1 and GIP) Glucose dependent ß-cells Muscle-L peripheral glucose uptake ↑ Ingestion of food SPAGETTI Role of incretins - glucosehomeostasis body-smll Glucoregulatory actions α-cells: inhibitory effects on glucagon secretion Inhibitory effects on gastric emptying Reduce caloric intake and enhances satiety GLP-1 actions in various tissues Baggio LL & Drucker DJ (2007) Gastroenterology Nauck MA et al (1993) Diabetologia Glucose (mmol/L) Glucagon (pmol/L) Time (minutes) 250 200 150 100 50 15.0 12.5 10.0 7.5 5.0 20 15 10 5 0 60 120 180 240 Placebo GLP-1 infusion Insulin (pmol/L) * * * * * * * * * * * * * * * * * * * GLP-1 stimulates insulin and suppresses glucagon GLP-1 effect depends on glycemic level Therapeutic potential…. DPP4 – Dipeptidylpeptidase 4 GIP and GLP-1 actions GIP (1–42) GLP-1 (7–36) GIP (3–42) GLP-1 (9–36) Meal DPP-4 enzyme Rapid degradation (minutes) Incretin mimetics and DPP-4 inhibitors (in development) Exenatide (Byetta, Lilly) Incretin mimetics and DPP-4 inhibitors (in development) Exenatide (Byetta, Lilly) HbA1c > 1% gedaald is tov beginwaarde Sitagliptin (Januvia, MSD) Vildagliptin (Galvus, Novartis) Alogliptin (Takeda) Saxagliptin (BMS) BI 1356 (Boehringer) ABT 279 (Abbott) SK0403 (SKK) LY2463665 (Lilly) S40010 (Servier) PF 00734200 (Pfizer) PHX1149 (Phenomix) AR12243 (Arisaph) ........................ Terugbetaling indien metformin & sulfonylureum derivaat & HbA1c > 7.5% Terugbetaling indien metformin & HbA1c > 7% Adipose tissue is an endocrine organ adipokines adipose tissue pancreas Leptin DPP4 Activin A Chemerin Leptin Farooqi S et al (2006) Endo Rev DPP4 serum concentration and expression in adipose tissue from lean compared with obese patients (clinical study 1). Lamers D et al. Diabetes 2011;60:1917-1925 Copyright © 2011 American Diabetes Association, Inc. Risk for Diabetes Mellitus ↑ ↓ Android Obesity Gynoid Obesity Thakore4 Ruderman et al. (1998) Diabetes fat2 Android Obesity Gynoid Obesity Thakore4 Ruderman et al. (1998) Diabetes fat2 http://www.qualityoflife.org/memorialCMS/images/cancer/full/CDR 0000658698.jpg Locatie vetweefsel van belang voor nabij gelegen organen?? Verschillen adipokine secretie obesitas vs control Lehr S et al., Mol Cell Proteomics. 2012 Honderden adipokines…. Adipose tissue is an endocrine organ adipokines adipose tissue pancreas skeletal muscle liver vasculature heart http://t1.gstatic.com/images?q= tbn:ANd9GcRdwzqidbawTMEhi2ZDK0c0SNVPpI10v1-koRYXzNddzn2WiFEDUgJQ00I Enhanced secretion of activin A from epicardial adipose tissue of patients with type 2 http://img.medscape.com/pi/emed/ckb/radiology/336139-352591-7788tn.jpg http://www.ispub.com/journal/the-internet-journal-of-internal-medicine/volume-7-number-1/sarcoi dal-pericardial-effusion-masquerading-as-acute-myocardial-infarction.article-g02.fs.jpg Greulich S et al., Circulation, rev. Pearson correlations between the clamp-derived measure (MLBM) and surrogate Pearson correlations between the clamp-derived measure (MLBM) and surrogate Pearson correlations between the clamp-derived measure (MLBM) and surrogate in press Ruige JB et al. (1999) Diabetologia; Heine RJ et al (2008) JCEM Progression to diabetes; adaptive failure of ß-cells to compensate for insulin resistance? Effects of myokines on ß-cells adipokines adipose tissue pancreas skeletal muscle Bij evolutie van obesitas naar gerelateerde complicaties spelen veranderde hormonale en paracriene signalen een belangrijke rol Discussie De rol van die veranderde signalering (adipokines) vetweefsel, (hepatokines) lever, (myokines) spier, hersenen, huid, longen, vaten ed. is tot op heden volstrekt onvoldoende duidelijk. Desondanks zouden die nieuwe biomerkers (zoals bijv chemerin..) in de toekomst gebruikt kunnen worden voor klinische toepassingen http://bernheze.sp.nl/img/cartoons/cartoon060814.gif