1. Incretinele :
mai mult decit hipoglicemiante
Ofelia Spinu

4. disfunctia celulelor α

5. in diabet efectul de amplificare ↓↓ sau absent

6. incretine/efectul de potentare
definitie – diferenta dintre rata de secretie a insulinei ca
raspuns la ingestia orala vs administrarea sistemica a glucozei
definitie – diferenta dintre rata de secretie a insulinei ca
raspuns la ingestia orala vs administrarea sistemica a glucozei

7. GLP-1
GRPP GLUCAGON GLP-1 GLP-2
GRPP GLUCAGON GLP-1 GLP-2
GRPP GLUCAGON GLP-1 GLP-2
proglucagon
Celule α pancreatice
Celule L intestinale

8. GLP-1

9. GIP

11. GLP-1

12. GLP-1-stimularea secretiei de insulina
indusa de glucoza

13. THE GLUCAGONOSTATIC AND INSULINOTROPIC EFFECTS OF GLUCAGON-LIKEPEPTIDE-1 CONTRIBUTE EQUALLY TO ITS GLUCOSE-LOWERING ACTION, Kristine J. Hare, Diabetes, feb 2010
↓ secretia de glucagon

14. Efecte digestive

15. scaderea ponderala

16. GIP

17. Efect hipolipemiant

18. Diabetologia 1993,M. A. Nauk Normalization of fasting hyperglycaemia by
exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent)
diabetic patients
Administrarea continua de GLP-1 amide iv 4h la pacienti in tratament cu SU,
HbA1c 11.7%+/- 1.7%→↑ insulina serica si peptidul C ,↓ glucagonului seric,
normalizarea glicemiei.
Lancet, martie 2002 , M. Zander , Effect of 6-week course of glucagon-like peptide
1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a
parallel-group study
Administrarea de GLP-1 nativ 6 saptamini → ↓ HbA1c 1.3%, glicemia fasting ↓
4.3 mmol/L, ↓ 30% conc AG , ↓ G 1.9 kg
GLP-1 nativ la pacientii cu diabet zaharat tip 2

21. eficienta terapeutica
Clinical Therapeutics Volume 34, Number 6, 2012 Vanita R. Aroda, Efficacy of GLP-1 Receptor
Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic Review
80 studii eligibile/362 publicate dupa 2005, durata 24-30 sapt (65%), faza III, HbA1c
medie initiala 8-8.6%
↓HbA1c max 1.54% exenatide actiune prelungita, 1.08% exenatid bd, 1.22% liraglutide
DPP-4 I 0.6% linagliptina, 0.98% vildagliptina
↓ glicemia fasting – scadere semnificativa ambele clase, maxim exenatide actiune
prelungita si vildagliptina

22. Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic Review
Vanita R. Aroda, MD, Robert R. Henry, MD, Jenny Han, MS, Wenying Huang, PhD
Clinical Therapeutics Volume 34, Issue 6 2012 1247 - 1258.e22

23. efecte cardiovasculare
↑ FE post IM, CMD
 Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left
ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006
miocard ischemic post revascularizatie percutana
 Nikolaidis LA Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left
ventricular dysfunction after successful reperfusion. Circulation. 2004
scad TA, sistolica si diastolica; vasodilatatie, ↑natriureza
 A, Hoogwerf et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes
mellitus: A double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol. 2010
 Tanaka T The role of incretins in salt-sensitive hypertension: The potential use of dipeptidyl peptidase-IV
inhibitors. Curr Opin Nephrol Hypertens. 2011
disfunctia endoteliala si placa de aterom
 M, Mita T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic
lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010
 Nyström T, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients
with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004

24. efecte cardiovasculare
hipolipemiante : ↓ TG, ↓ apo B48, ↑HDL, ↓ lipemia postprandiala
 Bunck M et al. One-year treatment with exenatide vs.insulin glargine: Effects on postprandial
glycemia, lipid profiles, and oxidative stress. Atherosclerosis. 2010
 Horton ES Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with
type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care. 2010
↓ riscul cardiovascular mediat prin ↓ ponderala
 Williamson Intentional weight loss and mortality among overweight individuals with diabetes.
Diabetes Care. 2000
 DeFronzo RA Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in
metformin-treated patients with type 2 diabetes. Diabetes Care. 2005

25. scaderea ponderala
↓ Ponderala – semnificativa la analogii de GLP-1, maxim exenatide cu actiune
prelungita -2.4 kg, gliptine 0.2- 0.6 kg
Vanita R. Aroda Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and
Systematic Review Clinical Therapeutics Volume 34, Issue 6 2012

26. Clasa Compusi Mecanisme celulare Actiune fiziologica Avantaje Dezavantaje cost
DPP-4i Sitagliptin
Vildagliptina
Saxagliptin
Linagliptin
Alogliptin
Inhiba activitatea DPP-
4, creste concentratiile
plasmatice ale
incretinelor active
(GLP-1, GIP)
↑Secretia de insulina
dependenta de glucoza
↓ Secretia de glucagon
dependenta de glucoza
Toleranta buna
Nu dau
hipoglicemie
Eficacitate
modesta
(HbA1c)
Urticarie/edem
? Pancreatita
mare
Agonisti
rec.
GLP-1
Exenatide
Exenatide
extended
release
Liraglutide
Activeaza receptorii
GLP-1
↑Secretia de insulina
dependenta de glucoza
↓Secretia de glucagon
dependenta de glucoza
↓ evacuarea gastrica
↑ satietatea
Nu produc
hipoglicemie
Scadere
ponderala
? Posibil efect
trofic celule β
? Posibil efect ↑
functional
? Posibil efecte
protectoare
cardiovasculare
Efecte digestive
( greata,
varsaturi)
? Pancreatita
acuta
Mod de
administrare
injectabil
Necesita
instruirea
pacientilor
mare
Management of Hyperglycemia in Type2 Diabetes: A Patient-Centered Approach
Position Statement of the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD)
DIABETES CARE, VOLUME 35, JUNE 2012

27. Management of Hyperglycemia in Type2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes
Association (ADA) and the European Association for the Study of Diabetes (EASD) DIABETES CARE, VOLUME 35, JUNE 2012

28. amplificarea axei incretinelor – nou concept terapeutic
interfera un mecanism patogenic important in
patogenia diabetului zaharat tip 2
scadere ponderala
beneficii cardiovasculare
efecte trofice celule celule β
↑ sintezei de insulina
efecte anti inflamatorii→insulinorezistenta
studii suplimentare pentru precizarea impactului clinic
concluzii