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  • TRATAMENTUL DIABETULUI ZAHARAT

  • Diabetul-o problema mondialaDiabetul e cea mai importanta cauza in afectiunile renale,responsabil principal al costurilor mari implicate in dializa; Retinopatia diabetica e cauza principala de scadere a vederii a pacientilor(20-65ani) in tari industrializatePacientii cu diabet decedeaza cu 5-10 ani mai devreme decat cei care nu au diabet;

    Complicatiile cardiovasculare sunt cauza principala de deces in diabet;

    Riscul de accident vascular e dublu in cazul pacientului cu diabet zaharat.

    Diabetes Atlas,third edition, International Diabetes Federation, 2007

  • Criteriile unui bun control metabolicGlicemia preprandial: 80-110 mg/dlGlicemia postprandial: 100-145 mg/dlHbA1c: < 6,5 %Colesterol total: < 200 mg/dlTrigliceride a jeun: < 150 mg/dlTA < 130 / 80 mm Hg (120 / 70 mm Hg)IMC < 25 kg/m2 (B); < 24 kg/m2 (F)

  • Dieta:obiective Aport caloric nutritiv corespunzatorAsigura cresterea si dezvoltarea normala a organismuluiMentine greutatea optimaPrevine hipo, hiperglicemiileReduce factorii de risc cardio-vascular

  • Dieta: principii generaleNecesar caloric: estimat in functie de greutatea ideala si activitatea fizica prestataGi=50+0,75(T-150)+ (V-20)/4Sedentar = 25kcal/kgActivitate medie = 30-35 kcal/kgActivitate intensa = 35-40kcal/kg

  • Dieta

    Glucide=50-55%Excluderea dulciurilor rafinate si alimentelor gatite cu zaharPreferate glucidele complexe, cu continut crescut in fibre alimentare(legume,fructe, cereale si produse din cereale)Lipide=25-30%(

  • Dieta Diabetul tip 1:6 mese/zi:3 mese principale si 3 gustariCorelarea cantitatii de glucide cu activitatea fizica si doza de insulinaDiabetul tip 2:5 mese/zi, cu distribuirea uniforma a cantitatii de glucide pe mese

  • Tratamentul diabetului zaharat de tip 2DZ este o boal cronic

    Obiectivul principal: meninerea parametrilor clinici i biochimici specifici ct mai aproape de normal

    Tratamentul trebuie privit n perspectiva speranei de via

  • Insulinodeficientainsulinorezistenta

    Defecte fiziopatologice majoreDiabet =Hiperglicemieproductie hepatica de glucozapreluareglucozaAdaptat dupa American Diabetes Association Diabetes Care 2004;27(suppl 1):S5S10; Beers MH, Berkow R, eds. Merck Manual of Diagnosis and Therapy, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999. MusclePancreassecretieinsulinaLiverDisfunctie beta-celulara

  • Secreie de insulinDepolarizareCanale KATP nchiseAshcroft, Gribble, Diabetologia (1999) 42: 903-919SulfonilureeInflux de Ca2+ Ca2+glucoz Derivati de sulfoniluree: mecanism de actiune

  • Sulfoniluree: Caracteristici generale Mecanism de actiuneEficacitatea depinde deDozareEfecte secundareRiscul principal

    Adaptat dupa Siconolfi-Baez L et al Diabetes Care 1990;13(suppl 3):28; Riddle MC Am Fam Physician 1999;60(9):26132620; DeFronzo RA Ann Intern Med 1999;131:281303; Glynase prescribing information, Pharmacia Corporation, April 2002; Glucotrol prescribing information, Pfizer, 2000; Glucotrol XL prescribing information, Pfizer, 2003.cresc eliberarea de insulinafunctionalitatea celulelor o data sau de doua ori pe zicrestere in greutate hipoglicemie

  • Sulfonilureice

    NumeDurata de actiune(h)Doza/ziExcretiePrima generatieTolbutamidClorpropamid6-1024-72500-2000UrinaUrinaA doua generatieGliclazidGliclazid MRGlipizidGliquidonaGlibenclamid MR8242-41,3-1,515-201,5-3,380-32030-1202,5-40902,5-201,75-10,5Excretie biliara si urinaraRenala si biliara

    Biliara 95% Renala si biliara

    A treia generatie Glimepirid 712-24Renala 40%Biliara 60%

  • Adaptat dupa Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483. situl benzamidicVDCCProinsulinaCa2+celula beta pancreaticaGlucozaMetabolism ATP ADPInsulinaGenerareK+KATPTerapii curente in DZ de tip 2 Meglitinidele: Mecanism de actiune

  • Terapii curente in DZ de tip 2 Meglitinide: Caracteristici generaleMecanism de actiuneEficacitatea depinde deDozareEfecte secundareRiscul principal

    cresc eliberarea de insulinafunctionalitatea celulelor beta

    de doua, trei, ori pe zi

    crestere in greutateHipoglicemii

  • Terapii curente in DZ de tip 2 Biguanidele (Metforminul): Mecanism de ActiuneAdaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Kirpichnikov D et al Ann Intern Med 2002;137(1):2533; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Hundal RS et al Diabetes 2000;49(12):20632069.Metforminpreluare crescuta de glucoza in muschiReducerea insulino- rezistenteiproductie hepatica de glucoza redusa Reducerea glucozeiplasmatice

  • Biguanide (Metformin): Caracteristici generaleMecanism de actiune

    EficacitateaDozajEfecte secundareRiscul majorPrimar: reduc productia hepatica de glucozaSecundar: cresc aportul periferic de glucozaPrezenta insulineio data sau de doua ori pe zi greata, anorexie, diaree acidoza lactica

  • Inhibitorii de alfa-glicozidaza(acarboza, vogliboza)Adaptat dupa DeFronzo RA Ann Intern Med 1999;131:281303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483.intarzie absorbtia carbohidratilorintarzie eliberarea glucozei in circulatie, permitand celulelor beta sa elibereze insulina corespunzator eliberarii glucozeiinhibitor de alfa-glucozidazainhibitia fazei finale a digestiei CH la nivelul marginii in perie intestinale

  • PPAR Agonistii (pioglitazona)modifica factorii deinsulino-senzitivitate (ex., adiponectina)modifica expresia/actiuneafactorilor de insulino-rezistenta (ex., resistina/TNF)tesutadiposAgonistPPARmodifica preluarea AGsi lipolizamodifica AGliberiadipocite mici, insulino-senzitive modifica adipozitateavisceralamodifica expresia genica in adipociteModifica actiunea insulineiPPAR = Peroxisome Proliferator-Activated Receptor GammaAdaptat dupa Moller DE Nature 2001;414:821828.FicatMuschischeletic

  • Terapii curente in DZ de tip 2 Agonistii PPAR : Caracteristici generale cresc sensibilitatea tesuturilor la insulina prezenta insulinei cresteri in greutate, edeme, anemieICC; nevoia de monitorizare a enzimelor hepatice

    Mecanism

    EficacitateaEfecte secundareRisc major

  • Incretine Agonisti ai receptorilor de GLP-1(glucagon like-peptide)-EXENATIDE BYDUREON

    Inhibitori de DPP-4 (dipeptidil-peptidaza-4) SITAGLIPTINA

  • Efectele GLP-1 asupra esuturilor perifericeBaggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157 Reprodus cu permisiune Elsevier 2007.esut adiposSNC FicatPancreasMuchiStomacPreluarea i stocarea glucozeiSensibilitate la insulinSecreia de insulinSecreia de glucagonSinteza de insulinProliferarea beta-celularApoptoza celulelor beta

    Evacuarea coninutului gastricApetitulNeuroprotecieCardioprotecieFuncia cardiacProducia de glucozCord GLP-1Intestinul

  • PPAR=peroxisome proliferator-activated receptor agonistAdaptat dupa Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004; DeFronzo RA Ann Intern Med 1999;131:281303; Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483.Terapii curente in DZ de tip 2Cum actioneaza diferitele ADO in controlul glicemieicelule beta-pancreatice ameliorarea hiperglicemieiSulfonilureeMeglitinidestimuleaza eliberarea de insulinaGutinhibitori de alfa-glicozidazaintarzie eliberarea glucozei in sangemuschificatPPAR (tiazolidindione sau glitazone)BiguanideInsulinainhiba productia de glucozaPPAR (tiazolidindione sau glitazone)BiguanideInsulinastimuleaza preluarea de glucozaincretine

  • Inhibitorii de SGLT2(sodium-glucose co-transporter 2)SGLT2 este o protein care faciliteaz reabsorbia glucozei n rinichi.Inhibitorii de SGLT2 blocheaz reabsorbia glucozei n rinichi, cresc excreia ei renal scad glicemiaEx. empagliflozin, canagliflozin, dapagliflozin

  • PRINCIPALELE PREPARATE COMERCIALE DE INSULIN

    Tipul de insulinAciunea ncepe la(h)Max.(h)Durataaciunii(h)Insuline cu aciune scurta(analogi rapizi)L-aspart(Novo-Rapid)Lispro(Humalog)Glulisina(Apidra)

  • SCHEME DE INSULINOTERAPIE

    1 INJECIE PE ZI: ANALOG RETARD-GLARGINE, DETEMIR2 INJECII PE ZI:- 2 INSULINE NPH ori- 2 INSULINE PREMIXATE TRATAMENT INTENSIV CU INSULIN:3 INJECII:- 2 INJECII CU INSULIN RAPID + 1 INSULIN PREMIXAT sau- 2 INJECII DE INSULIN PREMIXAT I O PRIZ DE INSULIN RAPID LA PRNZ 4 INJECII PE ZI:-3 INJECII DE INSULIN RAPID SAU DE ANALOG RAPID I O INJECIE DE INSULIN LONG ACTING LA CULCARE

  • Efectele insulinei in cadrul regimurilor de tratament conventionaleLebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004

  • Lebovitz HE, Therapy for Diabetes Mellitus and Related Disorders, 2004Efectele insulinei in cadrul regimurilor de tratament cu multi-injectii

  • INDICATIILE INSULINOTERAPIEI in DZ2Insulinoterapie definitivaDZ tip 1 (LADA)DZ tip 2 la care medicatia orala in asociere si la doze suficiente nu induce controlul glicemic propus Complicatii cronice evolutiveInsuficientele severe de organInsulinoterapie temporaraAfectiuni acute: IMA, infectii cu diferite localizariInterventii chirurgicale (pre-, intra- si postoperator)SarcinaComa hiperglicemica hiperosmolara

  • Hiperglicemiile matinaleSubinsulinizarea

    Fenomenul Somogyi

    Fenomenul de zori (Dawn phenomenon)

  • Efectele secundare ale insulinoterapieiHipoglicemia Creterea n greutateLipodistrofiaAbcesele la locul injecieiAlergia la insulinProducia de anticorpi la preparatele insuliniceNeuropatia dureroas (temporar)Scderea acuitii vizuale (temporar)

  • **********The progression to hyperglycemia in type 2 diabetes is characterized by a combination of relative insulin deficiency (inadequate insulin release relative to plasma glucose levels) due to pancreatic beta-cell dysfunction and insulin resistance (diminished ability of insulin to stimulate glucose uptake by skeletal muscle and unrestrained hepatic glucose output), leading to increased blood glucose levels and hyperglycemia.1,2 As beta-cell function progressively deteriorates, there is less ability to compensate for increasing insulin resistance.3Ref 1, p S5, C2, 1, L11-15

    Ref 2, p 166, Table 13-1, Entry 4,C1, 1, L1-2C2, L1-5

    Ref 3,p 63, 2, L1-3

    ReferencesAmerican Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004;27(suppl 1):S5S10.Beers MH, Berkow R, eds. Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories, 1999.Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Ref 1, p S7, C1, 1, L20-29Ref 2, p 166, C1, 1, L1-2C2, L1-5p 167, C1, 3, L4-11

    **Because sulfonylureas act by increasing insulin release from the pancreas by stimulating beta-cells, they depend on the presence of functioning beta-cells to exert their efficacy.1,2 Dosed once or twice daily,35 the sulfonylureas are associated commonly with undesirable effects such as weight gain, but their main risk is related to hypoglycemia.6

    Ref 1, p 6, Fig 8 + legend,L1-9; p 7, C1, 1, L8-15Ref 2, p 2614, C1, 2, L3-6

    Ref 3,p 12, 4, L1-4Ref 4,p 8, 6, L1-2Ref 5,p 12, 2, L1-2

    Ref 6, p 290C2, 3, L5-7

    Ref 1, p 6, Fig 8 + legend,L1-9; p 7, C1, 1, L8-15

    Ref 2, p 2614, C1, 2, L3-6

    Ref 3,p 12, 4, L1-4Ref 4,p 8, 6, L1-2Ref 5,p 12, 2, L1-2

    Ref 6, p 290C2, 3, L5-7

    ReferencesSiconolfi-Baez L, Banerji MA, Lebovitz HE. Characterization and significance of sulfonylurea receptors. Diabetes Care 1990;13(suppl 3):28.Riddle MC. Oral pharmacologic management of type 2 diabetes. Am Fam Physician 1999;60(9):26132620.Glynase prescribing information, Pharmacia Corporation, April 2002.Glucotrol prescribing information, Pfizer, 2000.Glucotrol XL prescribing information, Pfizer, 2003.DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.**Like sulfonylureas, meglitinides are insulin secretagogues that bind to the sulfonylurea receptor, a subunit of the ATP-sensitive potassium channel (KATP) on the plasma membrane of pancreatic beta-cells. This subunit regulates the activity of the potassium channel and binds ATP and ADP, functioning as a glucose sensor and trigger for insulin release. In addition, binding at this site increases intracellular ATP and decreases ADP, closing the channel. The resulting membrane depolarization causes opening of the voltage-dependent calcium channels (VDCC), leading to calcium influx and subsequent increases in intracellular calcium and insulin release.1 Meglitinides bind to a site on the sulfonylurea receptor that accepts benzamido compounds, a site that is distinct from the site that binds classic sulfonylureas.2 Meglitinides have a short half-life and generally produce a faster and briefer stimulus to insulin secretion than sulfonlylureas because of their rapid absorption.1

    Ref 1,p 1463, C1, 1, L1-12, C1, 4, L1-3Ref 2,p 114, Fig 11.1legend, L11-16,2, L1-8

    Ref 1, p 1463,C1, 4, L1-3ReferencesBuse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483. Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004.

    Ref 1,p 1463,C1, 1, L1-12, 4, L1-3Ref 2,p 114, Fig 11.1legend, L11-16,2, L1-8

    *Like sulfonylureas, meglitinides such as repaglinide and nateglinide increase insulin release from the pancreas by stimulating beta-cells, and as such depend on the presence of functioning beta-cells to exert their efficacy.1,2 These drugs are used to control postprandial hyperglycemia and are thus taken with meals.1Dosed two, three, or four times daily,3,4 the meglitinides are associated commonly with undesirable effects, such as weight gain, but their main risk is related to hypoglycemia.5

    Ref 1, p 114, 2, L1-8Ref 2, p 2614, C1, 2, L3-6Ref 1, p 114, 2, L8-9

    Ref 3, p 2, C4, 7, L1-4 Ref 4, p 11, 4, L1-2

    Ref 5, p 298, C1, 1, L5-6Ref 1,p 114, 2, L1-8

    Ref 2, p 2614, C1, 2, L3-6

    Ref 3, p 2, C4, 7, L1-4 Ref 4, p 11, 4, L1-2

    Ref 5, p 298, C1, 1, L5-6

    ReferencesWilliams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Riddle MC. Oral pharmacologic management of type 2 diabetes. Am Fam Physician 1999;60(9):26132620.Prandin prescribing information, Novartis Pharmaceuticals, December 2000.Starlix prescribing information, Novartis Pharmaceuticals, December 2000.DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.*Metformin, the most widely used agent in the biguanide class,1 exerts its antihyperglycemic effects via two mechanisms that have not been fully elucidated at this time.2,3 The primary action is to reduce hepatic glucose production.2,4 Metformin also reduces fatty acidinduced insulin resistance by increasing insulin-stimulated glucose uptake in skeletal muscle and adipocytes.2

    Ref 1 p 291, C1, L2-4

    Ref 2, p E-31, C1, 2, L1-4Ref 3, p 112, 1, L3-5 Ref 2, p E-31, C1, 2, L1-4Ref 4, p 2065, C1, 1, L1-10;p 2068, C1, 2, L1-6, 11-13

    Ref 2, p E-26, C2, 3, L1-5;p E-28, Fig 2 legend, L1

    ReferencesDeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med 2002;137(1):2533.Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Hundal RS, Krssak M, Dufour S et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000;49(12):20632069. Ref 4, p 2065, C1, 1, L1-10;p 2068, C1, 2, L1-6, 11-13

    Ref 2, p E-26, C2, 3, L1-5;p E-28, Fig 2 legend, L1Ref 2, p E-31, C1, 2, L1-4

    *Metformin exerts its antihyperglycemic effects by decreasing hepatic glucose production and increasing peripheral glucose uptake; its efficacy in improving peripheral insulin sensitivity depends on the presence of insulin.1 In addition to decreasing HbA1c levels, metformin reduces plasma triglyceride and LDL-C levels.2 Metformin is administered once or twice daily with meals.3The most common side effects are gastrointestinal (GI) disturbances (nausea, anorexia, and diarrhea), which affect about one-third of patients.4 Lactic acidosis is a rare but potentially fatal side effect of metformin therapy.4 It may be avoided by not giving metformin to patients with renal, hepatic, cardiac, or respiratory failure and to those with a history of alcohol abuse.3

    Ref 1, p E-26, C2, 3, L1-5; p E-27, C1, 2, L1-2

    Ref 2, p 293, C2, 2, L1-4

    Ref 3, p 5,C1, 7, L1-2

    Ref 4, p 112, 1, L9-11

    Ref 4, p 112, 1, L9-11

    Ref 3, p 3,Warnings box

    ReferencesKirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med 2002;137(1):2533.DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.Glucophage/Glucophage XR prescribing information, Bristol-Myers Squibb, April 2003.Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004.Ref 1, p E-26, C2, 3, L1-5

    Ref 1, p E-27, C1, 2, L1-2

    Ref 3,p 5, C1, 7, L1-2

    Ref 4, p 112, 1, L9-11

    Ref 4, p 112, 1, L9-11

    *Unlike other oral agents used in the treatment of type 2 diabetes, alpha-glucosidase inhibitors do not act by reversing any of the pathophysiologic abnormalities of the diseaseincreased hepatic glucose production, decreased muscle glucose uptake, or impaired insulin release. Rather, alpha-glucosidase inhibitors inhibit the terminal step of carbohydrate digestion at the brush border of the intestinal epithelium. Carbohydrate absorption is thus shifted to more distal parts of the intestine and colon and thereby delayed. Alpha-glucosidase inhibitors do not cause malabsorption, however. By slowing digestion/absorption, glucose entry into the circulation is delayed. This allows the beta-cell time to augment insulin release in response to an increase in plasma glucose.1,2

    Ref 1,p 282, Fig 1;p 294, C1, 2, L7-16Ref 2,p 1463, C2, 3, L1-6ReferencesDeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483.Ref 1,p 282, Fig 1;p 294, C1, 2, L7-16

    Ref 2,p 1463, C2, 3, L1-6

    *Insulin sensitization achieved with PPAR-gamma agonists occurs through several potential mechanisms. In adipose tissue, binding to the PPAR-gamma receptor results in specific changes in adipose gene expression. Altered expression of fatty acid transport genes may contribute to reduced production of free fatty acids, which improves insulin sensitization in muscle and in the liver.1By modifying the expression of genes such as 11 beta-hydroxysteroid dehydrogenase type 1, which converts cortisone to cortisol, PPAR-gamma agonists may increase insulin action in adipocytes. PPAR-gamma agonists may also have a role in reducing expression or activity of insulin resistance factors such as TNF-alpha, resistin, and adiponectin, thereby potentially increasing glucose utilization and insulin action in liver and muscle.1

    Ref 1, p 825, Fig 4 legend, L1-12

    Ref 1, p 825, C2, 2,L14-16,Fig 4 legend, L12-16

    Ref 1, p 825, Fig 4 legend,L16-21,C1, 1, L1

    ReferenceMoller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001;414:821828.Ref 1, p 825, Fig 4& legend

    *PPAR-gamma agonists act by enhancing insulin sensitivity in liver and muscle tissues,1 and as such depend on the presence of insulin in order to exert their therapeutic effects.2 Rosiglitazone can be dosed once or twice daily; pioglitazone is dosed once daily.3,4Side effects of PPARs include weight gain, edema, and anemia;3,4 the main risk associated with these agents is that of heart failure due to fluid retention.3,4Because of the potential for weight gain and fluid retention, caution is recommended when administering these agents with insulin or to patients with a history of cardiac failure or renal insufficiency. The first PPAR, troglitazone, was withdrawn from the market because of hepatotoxicity; regular liver function tests are recommended for patients taking rosiglitazone and pioglitazone.5

    ReferencesMoller DE. New drug targets for type 2 diabetes and the metabolic syndrome. Nature 2001;414:821828.Riddle MC. Oral pharmacologic management of type 2 diabetes. Am Fam Physician 1999;60(9):26132620.Actos prescribing information, Takeda Pharmaceuticals, December 2003.Avandia prescribing information, GlaxoSmithKline, May 2004.Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Ref 1, p 825, Fig 4 legend, L1-12

    Ref 2, p 2615, C1, 4, L1-3, C2, 3, L1-2

    Ref 3, p 2, C3, 9, L1Ref 4, p 21, 2, L1-3

    Ref 3, p 2, C1, 17,18,20Ref 4, p 14, 2, L1-2;p 19, 5, L1-4

    Ref 3, p 2, C1, 9, L1-3 Ref 4, p 12, 6, L1-3Ref 5, p 115, 2, L1-10

    Ref 1, p 825, Fig 4 legend, L1-12

    Ref 2, p 2615, C1, 4, L1-3, C2, 3, L1-2

    Ref 3, p 2, C3, 9, L1 Ref 4, p 21, 2, L1-3

    Ref 3, p 2, C1, 17,18,20Ref 4, p 14, 2, L1-2;p 19, 5, L1-4

    Ref 3, p 2, C1, 9, L1-3 Ref 4, p 12, 6, L1-3

    Ref 5, p 115, 2, L1-10

    ***DISCUSSIONIn the peripheral tissues, the majority of the effects of glucagon-like peptide 1 (GLP-1) are mediated by direct interaction with the specific tissue GLP-1 receptorsIndirect mechanisms of action of GLP-1 occur in liver, adipose, and muscle tissues

    BACKGROUNDGLP-1 is synthesised and released from the L-cells located predominantly in the ileum and colon, and to a lesser extent, in the duodenum and jejunumThere are multiple sites of GLP-1 action, including pancreatic beta and alpha cells, and the gastrointestinal, cardiovascular, and central nervous (CNS) systemsActions are receptor mediatedThrough indirect actions, such as inhibiting hepatic glucose production and stimulating glucose uptake in fat and muscle, GLP-1 can influence glucoregulatory physiological responses

    *The various therapeutic agents available for the treatment of type 2 diabetes act on different pathways to hyperglycemia. Sulfonylureas act in the pancreas, stimulating insulin release by binding to the sulfonylurea receptor of beta-cell membranes.1,2 Meglitinides, derived from the nonsulfonylurea benzamide portion of glibenclamide, also act in the pancreas, stimulating insulin release by binding to the benzamide site on beta-cells.1 They are used to control postprandial hyperglycemia.PPARs (peroxisome proliferator-activated receptor agonists, also known as glitazones or thiazolidinediones) act primarily in muscle, but also exert effects in the liver and adipose tissue. These agents reduce insulin resistance by entering cells and bind to the nuclear peroxisome proliferator-activated receptor-gamma (PPARg), leading to enhanced expression of certain proteins involved in glucose and lipid metabolism. This action increases glucose uptake, decreases circulating fatty acids, and may also decrease the production of mediators involved in the pathogenesis of insulin resistance.1,2Alpha-glucosidase inhibitors lower postprandial blood glucose concentrations by inhibiting disaccharidase enzymes in the gut, thereby delaying carbohydrate absorption.1 This action retards glucose entry into the systemic circulation, allowing beta-cells ample time to increase insulin release.2 These agents require adequate beta-cell function to be effective and may therefore be more suitable for use early in the course of type 2 diabetes.Biguanides, of which metformin is the most widely used, act primarily in the liver by decreasing hepatic glucose output through a mechanism that has not been fully elucidated.1,2Subcutaneous injection of insulin supplements endogenous insulin production; in the basal state, insulin acts in the liver to decrease glucose production, whereas in the postprandial state, insulin facilitates glucose uptake into muscle as well as fat.3

    Ref 1, p 112, 2, L1-2Ref 2, p 288, C1, 2, L1-3

    Ref 1, p 114, 2, L1-8Fig. 11.11 legend, L11-16

    Ref 1, p 115, 1, L1-13Ref 2, p 282, Fig 1

    Ref 1, p 116, 1, L1-5Ref 2, p 294, C1, 1, L1-3,C1, 2, L7-14

    Ref 1, p 112, 1, L3-5 Ref 2, p 282, Fig 1;p 291, C1, L2

    Ref 3,p 1463, C2, 4, L3; p 1464,C1, L1-6

    Ref 1, p 112, 2, L1-2Ref 2, p 288, C1, 2, L1-3

    Ref 1, p 114, 2, L1-8Fig. 11.11 legend, L11-16

    Ref 1, p 115, 1, L1-13Ref 2, p 282, Fig 1

    Ref 1, p 116, 1, L1-5Ref 2, p 294, C1, 1, L1-3, C1, 2, L7-14

    Ref 1, p 112, 1, L3-5 Ref 2, p 282, Fig 1; p 291, C1, L2

    Ref 3, p 1463, C2, 4, L3;p 1464, C1, L1-6References1.Williams G, Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell Publishing, 2004.2.DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med 1999;131:281303.3.Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:14271483.*********