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![Page 1: Glucose (mg/dl) 50 – 100 – 150 – 200 – 250 – 300 – 350 – 0 – 50 – 100 – 150 – 200 – 250 – -10-5051015202530 Years of diabetes Burger HG, et al. 2001. Diabetes.](https://reader035.fdocuments.net/reader035/viewer/2022062512/5542eb49497959361e8b4599/html5/thumbnails/1.jpg)
Glucose(mg/dl)
50 –
100 –
150 –
200 –
250 –
300 –
350 –
0 –
50 –
100 –
150 –
200 –
250 –
-10 -5 0 5 10 15 20 25 30Years of diabetes
Burger HG, et al. 2001. Diabetes Mellitus, Carbohydrate Metabolism, and Lipid Disorders. In Endocrinology. 4th ed. Edited by LJ DeGroot and JL Jameson. Philadelphia: W.B. Saunders Co., 2001.
Originally published in Type 2 Diabetes BASICS. (International Diabetes Center, Minneapolis, 2000).
Relativefunction
(%)
Fasting glucose
ObesityObesity IFGIFG DiabetesDiabetes UncontrolledUncontrolledhyperglycemiahyperglycemia
Insulin resistance
Insulin resistance and -cell dysfunction are fundamental to type 2 diabetes
Post-prandialglucose
Insulin secretionClinical diagnosis
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A Century of Diabetes Care
Sulfonylureas
Alpha-glucosidase InhibitorsBiguanide
GlitazonesMeglitinides
Insulin therapy
1920
Type 2
20001900 1950
Diet
Type 1
20001900 19501920
Insulin therapyPump th
erapy
Human insulin
Insulin analogs
First h
uman treated
NPH insulin
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*Lower extremity amputation or fatal peripheral vascular disease
Per
cen
tag
e re
du
ctio
n i
n r
elat
ive
risk
co
rres
po
nd
ing
to
a 1
% f
all
in H
bA
1c
–50
–45
–40
–35
–30
–25
–20
–15
–10
–5
0
21%
P < 0.0001
Any diabetes-related
endpoint
21%
P < 0.0001
Diabetes-related death
14%
P < 0.0001
All cause
mortality
14%
P < 0.0001
Myocardial infarction
12%
P = 0.035
Stroke
43%
P < 0.0001
Peripheral vascular disease*
37%
P < 0.0001
Microvascular disease
19%
P < 0.0001
Cataract extraction
Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.
UKPDS: reduced micro- and macrovascular complications for a 1% decrease in HbA1c
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EPIC-Norfolk study: Risk of CV events or Death Associated with HbA1c Level
Ag
e-ad
just
ed r
elat
ive
risk
Men
0
1
2
3
4
5
6
7
8
CHD events CVD events All-causemortality
CHD events CVD events All-causemortality
Women
5–5.4% 5.5–5.9% 7%6.5–6.9%6.0–6.4%HbA1c level:
P 0.001 for linear trend across HbA1c categories for all endpoints.
Khaw et al. Ann Intern Med 2004; 141: 413–20
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STENO-2 STUDY
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SECRETAGOGHI
•Sulfoniluree: Glibenclamide
Gliclazide
Glimepiride
•Glinidi: Repaglinide
Nateglinide
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K+
Ca++Ca++
K+
Precondizionamento ischemico
ATPADP
Cellula muscolarecardiaca o coronarica
Normale
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K+
Ca++Ca++
K+ ATP
ADP
Ischemia
Cellula muscolarecardiaca o coronarica
ContrattilitàConsumo energia
Rilascio muscoloVasodilatazione
Precondizionamento ischemico
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K+
Ca++Ca++
K+
SUR2
ATP
ADP
Cellula muscolarecardiaca o coronarica
Ischemia
FARMACO
ContrattilitàConsumo energia
Rilascio muscoloVasodilatazione
Precondizionamento ischemico
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Sulfaniluree e Preconditioning1: Lee TM, Chou TF. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab. 2003 Feb;88(2):531-7.
2: Riddle MC. Editorial: sulfonylureas differ in effects on ischemic preconditioning--is it time to retire glyburide? J Clin Endocrinol Metab. 2003 Feb;88(2):528-30.
3: Scognamiglio R, Avogaro A, Vigili de Kreutzenberg S, Negut C, Palisi M, Bagolin E, Tiengo A. Effects of treatment with sulfonylurea drugs or insulin on ischemia-induced myocardial dysfunction in type 2 diabetes. Diabetes. 2002 Mar;51(3):808-12.
4: Lee TM, Su SF, Chou TF, Lee YT, Tsai CH. Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation. 2002 Jan 22;105(3):334-40.
5: Ghosh S, Standen NB, Galinianes M. Failure to precondition pathological human myocardium. J Am Coll Cardiol. 2001 Mar 1;37(3):711-8.
6: Ovunc K. Effects of glibenclamide, a K(ATP) channel blocker, on warm-up phenomenon in type II diabetic patients with chronic stable angina pectoris.Clin Cardiol. 2000 Jul;23:535-9.
7: Tomai F, Danesi A, Ghini AS, Crea F, Perino M, Gaspardone A, Ruggeri G, Chiariello L, Gioffre PA. Effects of K(ATP) channel blockade by glibenclamide on the warm-up phenomenon. Eur Heart J. 1999 Feb;20(3):196-202.
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B D
437
Glibenclam.
p<0.05
3712
Insulin
p= NS
468 451
1
B DB D
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Impairment of Myocardial Protection in Type
2 Diabetic Patients: ST segment shift (mV)
0
0,2
0,4
0,6
0,8
1
1,2
Glibenclamide Glimepiride
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• Metformina
• (Fenformina)
BIGUANIDI
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a
c
b
Glucose 5 mM
Glucose 20 mM
Glucose 20 mM+Metformin
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UKPDS 34. Lancet 1998;352:854-865.
EFFECT OF METFORMIN IN OVERWEIGHT PATIENTS
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Is Metformin cardioprotective?
Diabetes Care 2002
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Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-
analysisSalpeter SR, Greyber E, Pasternak GA, Salpeter EE
There is no evidence to date that metformin therapy is associated with an increased risk of lactic acidosis or with increased levels of lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study conditions, taking into account contraindications.
Arch Intern Med 2003;163(21):2594-602
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CONTROINDICAZIONI E LINEE-GUIDA PER LA SOSPENSIONE DELLA METFORMINA
BMJ, 326, 2003
• Sospendere se la creatininemia è >150 mol/l*• Sospendere durante i periodi di sospetta ipossia tissutale (peres. durante infarto del miocardio, sepsi, etc.)• Sospendere per 3 giorni dopo somministrazione di mezzo dicontrasto contenente iodio e ripristinare solo dopo controllodei parametri di funzionalità renale• Sospendere 2 giorni prima di un’anestesia generale e ripristinare quando la funzionalità renale è stabile
*Qualsiasi concentrazione di creatinina venga scelta come livello cut-off perinsuficienza renale sarà arbitrario in considerazione della massa muscolaredell’individuo e del turnover proteico; precauzione nel paziente anziano.
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Condizioni associate Condizioni associate (% pazienti)(% pazienti)
Phillips, Phillips, BMJ BMJ 1:239, 19781:239, 1978
Metformina ed Acidosi LatticaMetformina ed Acidosi Lattica
0
20
40
60
80
100
I R Epat. CHF No
23 casi riportati in letteratura fino al 197823 casi riportati in letteratura fino al 1978
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Conclusions. Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associatedwith reduced all cause mortality in two of the three studies.
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Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm
for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of
Diabetes. Diabetologia 2006;49:1711-21.
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TIAZOLIDINEDIONI (GLITAZONI)
• Pioglitazone
• Rosiglitazone
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Adipocyte
Thiazolidinediones: mechanism of action
Thiazolidinedione (rosiglitazone, pioglitazone)
DNA
Nucleus
GLUT 4RNA
GLUT 4
Insulin
Glucose
Thiazolidinedione
Storage granule
Transcription
Translation
PPAR
Cytoplasm
GLUT 4+
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GLITAZONI - EFFETTI INDESIDERATI
Edema
Anemia (da diluizione)
Ipercolesterolemia
Incremento ponderale
Epatopatia
Insufficienza Cardiaca
ALTRI: trombocitopenia, ipoglicemia, sonnolenza, vertigini, cefalea, parestesie, dolori addome, flatulenza, nausea, alopecia, rash, astenia
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ADA-AHA 2006
Prima di iniziare la terapia verificare la presenza di cardiopatia, edema, dispnea
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STOP-NIDDM trial
Effect of acarbose and placebo on cumulative probability of remaning free of diabetes over
timeLancet, 2002
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Insulina
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Le insuline nella storia Insulina porcina: non piu’ in commercio differiva da quella umana per un aminoacido Insulina bovina: non piu’ in commercio differiva da quella umana per tre aminoacidi Insulina umana: disponibile, in produzione dagli anni ‘80 non differisce da quella umana e viene prodotta con la tecnica del DNA ricombinante: piu’ pura
Insulina analogo: disponibile, in produzione dal ‘96 differisce dall’umana: miglior farmacocinetica
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Comparison of Human Insulins / Analogues
Regular 30–60 min 2–4 h 6–10 h
Lispro/aspart 5–15 min 1–2 h 4–6 h
NPH/Lente 1–2 h 4–8 h 10–20 h
Ultralente 2–4 h Unpredictable 16–20 h
Glargine 1–2 h Flat ~24 h
Insulin Onset of action PeakDuration of action
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4:00 16:00 20:00 24:00 4:00
Breakfast Lunch Dinner
8:0012:008:00
Time
Glargineor
Detemir
Lispro Lispro Lispro
Aspart Aspart Aspartor oror
Pla
sma
insu
lin
Basal/Bolus Treatment Program withRapid-acting and Long-acting Analogs
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• Mantenere la normoglicemia
• Evitare le complicanze acute
• Evitare o arrestare la progressione delle complicanze croniche
• Migliorare la qualità di vita
Scopi del trattamento insulinico intensivo
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Dandona P et al, Am J Cardiol 2007;99[suppl]15B-26B.
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GLP-1
• “Incretin” hormone secreted by jejunal and ileal L cells in response to a meal
• Stimulates insulin secretion
• Decreases glucagon secretion
• Slows gastric emptying
• Reduces fuel intake (increases satiety)
• Improves insulin sensitivity
• Increases -cell mass and improves -cell function (animal studies)
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ProGIP GIP (1-42)
Cellule K – tratto GI prossimale(duodeno e digiuno prossimale)
Proglucagone GLP 1(7-37) GLP 1(7-36)NH2
Cellule L – tratto GI distale(ileo e colon)
GIP = polipeptide insulinotropico glucosio-dipendenteGLP 1 = peptide 1 glucagone-simile
Stimola la secrezione di insulina in
maniera glucosio-dipendente
Promuove la proliferazione e la
sopravvivenza delle cellule beta in
colture di isole pancreatiche
Adattato da Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.
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ProGIP GIP (1-42)
Cellule K – tratto GI prossimale(duodeno e digiuno prossimale)
Proglucagone GLP 1(7-37) GLP 1(7-36)NH2
Cellule L – tratto GI distale(ileo e colon)
GIP = polipeptide insulinotropico glucosio-dipendenteGLP 1 = peptide 1 glucagone-simile
Stimola la secrezione di insulina in
maniera glucosio-dipendente
Sopprime la produzione epatica di
glucosio attraverso l’inibizione glucosio-
dipendente della secrezione di glucagone
Promuove la proliferazione e la
sopravvivenza delle cellule beta in
modelli animali ed in colture di isole
pancreatiche umane
Adattato da Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.
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GLP-1 GIP
Secreto dalle cellule L dell’intestino distale (ileo e colon)
Secreto dalle cellule K dell’intestino prossimale (duodeno)
Stimola la secrezione insulinica in modo glucosio dipendente
Stimola la secrezione insulinica in modo glucosio dipendente
Sopprime la produzione epatica di glucosio inibendo la secrezione di glucagone in modo glucosio dipendente
Migliora la proliferazione e la sopravvivenza delle beta cellule (modelli animali e colture di cellule umane)
Migliora la proliferazione e la sopravvivenza delle beta cellule in linee di colture cellulari
GLP-1 e GIP
Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol 2002;174:233–246.
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Biosynthesis & Regulation of GLP-1
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Aumento del GLP-1
Adattato da: Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
Secrezione GLP-1 è ridotta in diabete di Tipo 2
GLP-1 naturale ha una emivita estremamente breve
Aggiungere GLP-1 analoghi con emivita più lunga:
• exenatide
• liraglutide
Iniettivi
Bloccare DPP-4, l’enzima che degrada GLP-1:• sitagliptin• vildagliptin
Orali
- Sitagliptin- FDA approvato- EMEA approvato
-Vildagliptin -FDA non approvato -EMEA approvato
- Exenatide - FDA approvata- EMEA approvata
- Liraglutide- Phase III
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Future Century of Diabetes Care: A new Paradigm
Sulfonylureas
Alpha-glucosidase Inhibitors
Metformin
Glitazones
Human insulin
Insulin analogs
First human treated
NPH insulin
Exendin
Cardiovascular protection
Metabolic control
?