Insulin resistance and -cell dysfunction are fundamental to type 2 diabetes Uncontrolled hyperglycemia Obesity IFG Diabetes 350 – Post-prandial glucose 300 – 250 – Glucose (mg/dl) Fasting glucose 200 – 150 – 100 – 50 – 250 – Relative function (%) 200 – Insulin resistance 150 – 3 There is a temporal relationship between insulin resistance, insulin secretion and the development of diabetes. In the early stages, as insulin resistance rises, there is a compensatory increase in insulin secretion and the individual remains normoglycemic. In the long term, as the -cells begin to fail, insulin secretion falls, hyperglycemia becomes apparent and frank type 2 diabetes develops. 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 (IDC), Minneapolis, Minnesota, 2000. 100 – Clinical diagnosis Insulin secretion 50 – 0 – -10 -5 5 10 15 20 25 30 Years 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).

A Century of Diabetes Care Pump therapy Human insulin Insulin analogs First human treated NPH insulin Type 1 2000 1900 1950 1920 Insulin therapy 1920 Type 2 2000 1900 1950 Diet Sulfonylureas Alpha-glucosidase Inhibitors Biguanide Glitazones Meglitinides Insulin therapy Type 1 Since the early 1920’s the only therapy available for type 1 diabetes has been insulin. (Banting and Best discovered insulin 1921) Improvements in insulin delivery have included pump therapy (mid-1970s), transition from animal to human insulin (1980s)1979 and the introduction of rapid acting insulin analogs (1990s) Type 2 Altlhough insulin has been available for type 2 diabetes patients since the 1920s, the major development has been the introduction of a number of oral agents: Sulfonylureas, the first available oral hypoglycemic agents (1956) Metformin (biguanides), although available in Europe for many years, recently available in this country since 1995 Alpha glucosidase inhibitors (starch blockers), thiazolidinediones (glitazones) and megltinides, agents introduced more recently A further landmark in our overall understanding of diabetes has been the completion of the two milestone intervention studies: DCCT – type 1 diabetes trial published in NEJM 1993 UKPDS –type 2 diabetes trial published in Lancet in 1998

Peripheral vascular disease* UKPDS: reduced micro- and macrovascular complications for a 1% decrease in HbA1c Any diabetes-related endpoint Diabetes- related death All cause mortality Peripheral vascular disease* Myocardial infarction Microvascular disease Cataract extraction Stroke –5 21% 21% 14% 14% 12% 43% 37% 19% –10 –15 P = 0.035 P < 0.0001 P < 0.0001 –20 P < 0.0001 Percentage reduction in relative risk corresponding to a 1% fall in HbA1c P < 0.0001 P < 0.0001 –25 –30 4 UK Prospective Diabetes Study (UKPDS) 35 was a prospective observational study to determine the relation between exposure to hyperglycemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes who were participants in the UKPDS. 3,642 white, Asian Indian and Afro-Caribbean UKPDS patients who had HbA1c measured three months after their diabetes diagnosis and with complete data for potential confounders were included in the sub-analysis of relative risk. Reductions in the risk of microvascular and macrovascular complications that might be achieved by lowering HbA1c by 1% were estimated. The incidence of clinical complications was found to be significantly associated with hyperglycemia. While any reduction in HbA1c is likely to reduce the risk of complications, the lowest risk was observed in those with HbA1c values in the normal range (< 6.0%). A 1% decrease in HbA1c was estimated to correspond with significant reductions in any diabetes-related endpoint, diabetes-related death, all cause mortality, myocardial infarction, stroke, peripheral vascular disease, microvascular disease and cataract extraction. The conversion factor for blood glucose mg/dl to mmol/l = x 0.0555. Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. –35 –40 P < 0.0001 –45 P < 0.0001 –50 *Lower extremity amputation or fatal peripheral vascular disease Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.

Age-adjusted relative risk EPIC-Norfolk study: Risk of CV events or Death Associated with HbA1c Level HbA1c level: 5–5.4% 5.5–5.9% 6.0–6.4% 6.5–6.9%  7% Men Women 8 7 6 5 Age-adjusted relative risk 4 3 2 1 CHD events CVD events All-cause mortality CHD events CVD events All-cause mortality P  0.001 for linear trend across HbA1c categories for all endpoints. Khaw et al. Ann Intern Med 2004; 141: 413–20

STENO-2 STUDY

SECRETAGOGHI Sulfoniluree: Glibenclamide Gliclazide Glimepiride Glinidi: Repaglinide Nateglinide

Precondizionamento ischemico Normale ATP ADP K+ K+ Cellula muscolare cardiaca o coronarica Ca++ Ca++

Precondizionamento ischemico Ischemia ATP ADP K+ K+ Cellula muscolare cardiaca o coronarica Ca++ Ca++ Contrattilità Consumo energia Rilascio muscolo Vasodilatazione

Precondizionamento ischemico FARMACO SUR2 Ischemia ATP ADP K+ K+ Cellula muscolare cardiaca o coronarica Ca++ Ca++ Contrattilità Consumo energia Rilascio muscolo Vasodilatazione

Sulfaniluree e Preconditioning 1: 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.

Insulin p= NS 468 4511 437 Glibenclam. p<0.05 3712 B D B D B D

Impairment of Myocardial Protection in Type 2 Diabetic Patients: ST segment shift (mV)

BIGUANIDI Metformina (Fenformina)

Glucose 5 mM a Glucose 20 mM b Glucose 20 mM+ Metformin c

EFFECT OF METFORMIN IN OVERWEIGHT PATIENTS UKPDS 34. Lancet 1998;352:854-865.

Is Metformin cardioprotective? Diabetes Care 2002

Salpeter SR, Greyber E, Pasternak GA, Salpeter EE Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis Salpeter 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

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 (per es. durante infarto del miocardio, sepsi, etc.) • Sospendere per 3 giorni dopo somministrazione di mezzo di contrasto contenente iodio e ripristinare solo dopo controllo dei 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 per insuficienza renale sarà arbitrario in considerazione della massa muscolare dell’individuo e del turnover proteico; precauzione nel paziente anziano.

Metformina ed Acidosi Lattica Condizioni associate (% pazienti) 23 casi riportati in letteratura fino al 1978 Phillips, BMJ 1:239, 1978

Conclusions. Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies.

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.

TIAZOLIDINEDIONI (GLITAZONI) Pioglitazone Rosiglitazone

Thiazolidinediones: mechanism of action Thiazolidinedione (rosiglitazone, pioglitazone) DNA Nucleus GLUT 4 RNA Insulin Glucose Thiazolidinedione Storage granule Transcription Translation PPAR Cytoplasm Adipocyte +

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

Prima di iniziare la terapia verificare la presenza di cardiopatia, edema, dispnea ADA-AHA 2006

STOP-NIDDM trial Effect of acarbose and placebo on cumulative probability of remaning free of diabetes over time Lancet, 2002

Insulina

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

Comparison of Human Insulins / Analogues Duration of action Insulin Onset of action Peak Regular 30–60 min 2–4 h 6–10 h NPH/Lente 1–2 h 4–8 h 10–20 h Ultralente 2–4 h Unpredictable 16–20 h Lispro/aspart 5–15 min 1–2 h 4–6 h Glargine 1–2 h Flat ~24 h

Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro Plasma insulin Glargine or Detemir 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time

Scopi del trattamento insulinico intensivo Mantenere la normoglicemia Evitare le complicanze acute Evitare o arrestare la progressione delle complicanze croniche Migliorare la qualità di vita 2

Dandona P et al, Am J Cardiol 2007;99[suppl]15B-26B.

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 b-cell mass and improves b-cell function (animal studies)

Proglucagone  GLP 1(7-37)  GLP 1(7-36)NH2 Stimola la secrezione di insulina in maniera glucosio-dipendente Promuove la proliferazione e la sopravvivenza delle cellule beta in colture di isole pancreatiche 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-dipendente GLP 1 = peptide 1 glucagone-simile 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.

Proglucagone  GLP 1(7-37)  GLP 1(7-36)NH2 ProGIP  GIP (1-42) Cellule K – tratto GI prossimale (duodeno e digiuno prossimale) 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 Proglucagone  GLP 1(7-37)  GLP 1(7-36)NH2 Cellule L – tratto GI distale (ileo e colon) GIP = polipeptide insulinotropico glucosio-dipendente GLP 1 = peptide 1 glucagone-simile 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.

GLP-1 e GIP 2/Ahren 2003, p 367, C1, ¶2, L1-14 3/Drucker 2002, p 535, C1, ¶1, L1-9 1/Drucker 2003B, p 2931, C3, ¶1, L1-33; p 2932, C1, L1-3, ¶1, L1-23 5/Farilla 2003, p 5150, C1, ¶1, L4-6; p 5157, C1, ¶1, L1-3 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 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 2/Ahren 2003, p 370, C1, ¶2, L8-9 9/Trümper 2001, p 1567, C1, ¶2, L14-16 10/Trümper 2002, p 244, C2, ¶2, L1-3 1/Drucker 2003B, p 2934, Table 1; p 2929, C1, ¶1, L1-8, ¶1, L23-26; p 2930, C1, L4-5,24-26 2/Ahren 2003, p 366, Table 1 p 2929,C3, L6-9 3/Drucker 2002, p 535, C1, ¶1, L1-9 p 535, C1, ¶1, L6-9 4/Nauck 1997, p E985, C1, ¶5, L1-6 p 2931, C3, ¶1, L1-33; p 2932, C1, L1-3, ¶1, L1-23 5/Farilla 2003, p 5150, C1, ¶1, L4-6; p 5157, C2, ¶1, L1-3 6/Farilla 2002, p 4397, C2, ¶2, L1-3 p 370, C1, ¶2, L8-9 7/Meier, p E624, C2, L4-5 8/Nauck 1993A, p 302, C1, ¶2, L9-12; p 306, C2, ¶1, L4-7 p 2934, Table 1 9/Trümper 2001, p 1567, C1, ¶2, L14-16 10/Trümper 2002, p 244, C2, ¶2, L1-3 Incretins are gut hormones released in response to ingestion of a meal, the most important of which are glucagon-like peptide 1 (GLP-1), which is synthesized by L cells in the distal gut (ileum and colon), and glucose-dependent insulinotropic polypeptide (GIP), which is secreted by K cells in the proximal gut (duodenum).1,2 GLP-1 and GIP are the major incretins that play a role in the insulin response as nutrients are absorbed by the body.1 In addition to stimulating insulin release when glucose is elevated, GLP-1 inhibits glucagon secretion.3 These actions are highly glucose dependent.3 In healthy volunteers, administration of GLP-1, at levels surpassing physiologic production, has been shown to exert profound, dose-dependent inhibition of gastric emptying.4 In in vitro and in vivo rodent studies and isolated human islets, GLP-1 has been shown to promote the expansion of beta-cell mass through proliferative and anti-apoptotic pathways.1,5,6 Whereas GIP also stimulates a glucose-dependent insulin response,2 this hormone does not appear to affect gastric emptying.7 When given at supraphysiologic doses to patients with type 2 diabetes, the insulinotropic activity of GIP was less than that observed in normal subjects.8 GIP does not appear to affect satiety or body weight.1 In islet cell lines, GIP has been shown to enhance beta-cell proliferation and survival.9,10 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. References Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929–2940. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Nauck MA, Niedereichholz U, Ettler R et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol 1997;273(5 pt 1):E981–E988. Farilla L, Bulotta A, Hirshberg B et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149–5158. Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes islet growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002;143:4397–4408. Meier JJ, Goetze O, Anstipp J et al. Gastric inhibitory polypeptide does not inhibit gastric emptying in humans. Am J Physiol Endocrinol Metab 2004;286:E621–E625. Nauck MA, Heimesaat MM, Ørskov C et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301–307. Trümper A, Trümper K, Trusheim H et al. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001;15:1559–1570. Trümper A, Trümper K, Hörsch D. Mechanisms of mitogenic and anti-apoptotic signaling by glucose-dependent insulinotropic polypeptide in β(INS-1)-cells. J Endocrinol 2002;174:233–246.

Biosynthesis & Regulation of GLP-1

Aumento del GLP-1 Iniettivi Orali Secrezione GLP-1 è ridotta in diabete di Tipo 2 GLP-1 naturale ha una emivita estremamente breve - Sitagliptin - FDA approvato - EMEA approvato -Vildagliptin -FDA non approvato -EMEA approvato Aggiungere GLP-1 analoghi con emivita più lunga: exenatide liraglutide Iniettivi Bloccare DPP-4, l’enzima che degrada GLP-1: sitagliptin vildagliptin Orali - Exenatide - FDA approvata - EMEA approvata - Liraglutide - Phase III GLP-1 enhancement Postprandial plasma levels of GLP-1 are depressed in Type 2 diabetes, indicating an impaired GLP-1 response to nutrient ingestion. For this reason, continuous GLP-1 infusion therapy has proven useful in short-term studies but is not a practical long-term therapy. The effort to identify effective forms of GLP-1 administration is challenged by its extremely short half-life (the enzyme DPP-4 degrades GLP-1 rapidly following its release from gut cells) [Drucker 2006; Drucker 2001]. Much research has focused on compounds with molecular structures and incretin activity that are similar to GLP-1, but which have longer half-lives because they are not degraded by DPP-4 or are resistant to DPP-4. These compounds include exenatide and liraglutide, which are injectable treatments. Another approach is to identify compounds that inhibit the activity of DPP-4, thus prolonging the half-life of naturally occurring GLP-1. Two oral agents that act as DPP-4 inhibitors are sitagliptin and vildagliptin [Gallwitz, 2006]. REFERENCES Drucker DJ. Cell Metab. 2006;3:153-165. Drucker DJ. Curr Pharm Des. 2001;7:1399-1412. Gallwitz B. Eur Endocr Dis. June 2006:43-46. Adattato da: Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

Cardiovascular protection Future Century of Diabetes Care: A new Paradigm Cardiovascular protection ? Insulin analogs Exendin Glitazones Alpha-glucosidase Inhibitors Human insulin Metformin NPH insulin Sulfonylureas First human treated Metabolic control