25-11-2013

!"#$%&"'(()(*"+&,&'-.+&/0#!

!"#$%&#'()*+,%-.#

!"#$%$&$'()*(+,-.,/'0'1%,

The Nobel Prize in Chemistry 1958

Frederick Sanger Amino acid sequence of insulin

The Nobel Prize in Chemistry 1964 (vit. B12)

Dorothy Hodgkin Insulins three-dimensional struture

The Nobel Prize in Physiology or Medicine 1977

Rosalyn Yalow For the development of radioimmunoassays of peptide hormones - insulin

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N Engl J Med 2012;367:1332-40

Insulin, glucagon, and glucose homeostasis

Goodman & Gilmans, 2011

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Synthesis and processing of insulin

Goodman & Gilmans, 2011

Regulao da Secreo da Insulina

Glicose Aminocidos cidos gordos Corpos cetnicos Hormonas Gastrointestinais

2

Adrenrgicos Vago

adrenrgicos

Hipoxia, Hipotermia, Cirurgia, Queimadura grave

Estimulantes

Inibidores

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Cintica da Insulina

Volume de Distribuio = Volume Extracelular

T!
Insulina = 5-6 min Pr-insulina = 17 min
(10 % da insulina imunoreactiva)

Potncia Metablica = 2 % Mitognese = 50 %

Pptido C = 30 min

Regulation of insulin secretion from a pancreatic cell

Goodman & Gilmans, 2011

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Pathways of insulin signaling

K+

K+

Goodman & Gilmans, 2011

Properties of Insulin Preparations

Short-acting

Long-acting

Insulin combinations

Goodman & Gilmans, 2011

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Insulin analogs

Goodman & Gilmans, 2011

Differences between Insulins

No clinically significantly lower HbA1c
Long Acting Insulins
Analogs vs NPH: incidence of nocturnal hypoglycemia Glargine vs Detemir: Once vs twice daily, higher daily dose Fewer injection site reactions vs less weight gain

Rapid Acting Insulins

Analogs vs Regular: postprandial glucose excursions Diabetes Care 2012;35:1364-79

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0.83-0.57=0.26 (45.6%)

Cochrane Database of Systematic Reviews 2011, Issue 7

Pharmacokinetic Profiles of Human Insulin and Insulin Analogues

N Engl J Med 2005;352:174-83

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24-h Plasma Glucose and Insulin Profiles in Healthy Individuals

Lancet 2001;358:739-46

Commonly used insulin regimens

Less intensive insulin regimen

Insulin pump

Goodman & Gilmans, 2011

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Factores que Afectam a

Absoro Subcutnea da Insulina

1. Local da injeco Abdomen (20-30 % mais rpida que o brao) Brao Glteo Coxa 2. Dbito sanguneo Massagem Banhos quentes Exerccio Ortostatismo (m.i.) 3. Profundidade da injeco (I.M. mais rpida)

Secreo Fisiolgica e Insulina Subcutnea

Diferenas

Nutrientes provocam aumento rpido e lento declnio

da secreo da insulina

No h libertao da insulina para a circulao portal

(sem efeito preferencial da insulina no fgado)

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Closed-loop system for type 1 diabetes therapy

(artificial pancreas)

Lancet 2013 Jul 25

Continuous Subcutaneous Insulin Infusion (CS II)

Reserved for those with special problems,

despite best attempts to improve control with optimized injection regimens:

Unpredictable hypoglycemia Hyperglycemia at dawn (between 4 and 8 am)

10

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N Engl J Med 2012;366:1616-24

INSULINOTERAPIA
Diabetes tipo 1

Hiperglicemia matinal

4,(53,(.!6&7(!
sem hipoglicemia nocturna

89,$/.!:.3.';$!
com hipoglicemia nocturna

! Mecanismo (?)
Libertao Nocturna:

!
!

No diabticos
Secreo insulina pr-dawn glicogenlise/neoglicognese heptica

"#$%&'$(&!! )*+,(&#$(&! !

-.+/$0.#1!2.+3.(&!*,!-+,0%$3,(/.!

11

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Continuous Subcutaneous Insulin Infusion (CS II) Unique Problems

Only short acting insulin Minimal amount of insulin in the subcutaneous pool Accidental interruption insulin ketoacidosis
Mechanical problems
Pump failure Dislodgement of the needle Aggregation of insulin in the infusion line Accidental kinking of the infusion catheter

Subcutaneous abcess

O fim da picada

N Engl J Med 2007;356:497-502

12

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INSULINOTERAPIA
Indicaes Teraputicas
Diabetes Tipo 1 Diabetes Tipo 2
no controlada pela dieta e/ou por frmacos hipoglicemiantes

Diabetes Ps-Pancreatectomia Diabetes Gestacional Ceto-Acidose Diabtica Coma No-Cetsico e Hiperosmolar Peri-Operatrio da Diabetes Tipo 1 e 2

Tratamento Intensivo e Convencional

de Doentes com DMID (DCCT) Hemoglobina Glicosilada / Glicemia
Hemoglobina Glicosilada (%)
11 10 9 8 7 6 5 300

Glicose Capilar (mg/dl)

250

Diabetes Control and Complications Trial 200

Resarch Group
150

0 1 2 3 4 5 6 7 8 1441 9 10

100 Doentes Peq. almoo

Almoo

Jantar Deitar

Anos de Estudo
N Engl J Med 1993;329:977-86

-.(=,(%$.(&#! <(/,(0$=&

13

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Tratamento Intensivo e Convencional

de Doentes com DMID (DCCT)
Relao com Hemoglobina Glicosilada 2<>?"@<-8A<)!"B)C8 !"#$!%&'&(

ndice Hipoglicemia Grave

120 (100 Doentes/Ano) 100 80 60 40 20 0 5.0 6.0 7.0 8.0

9.0

10.0

Hemoglobina glicosilada (%)

N Engl J Med 1993;329:977-86

Tratamento Intensivo e Convencional

de Doentes com DMID (DCCT)
INTERVENO SECUNDRIA

Percentagem de Doentes

50 40 30 20
Albuminuria 300 mg/dia -.(=,(%$.(&#! Albuminuria

40 mg/dia

P=0.001
<(/,(0$=&!

10 0

P=0.01
0 1 2 3 4 5 6 Anos de Estudo 7 8 9
PREVENO 1 risco em 34 % INTERVENO 2 risco 43 % - 56%

N Engl J Med 1993;329:977-86

14

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Tratamento Intensivo e Convencional

de Doentes com DMID (DCCT)
NEUROPATIA CLNICA

60 %

Percentagem de Doentes

40

P<0.001

30 20 10 0

P<0.001

P=0.04

Exame Autonomia Neurolgico Nervosa

N Engl J Med 1993;329:977-86 -.(=,(%$.(&#!

Conduo Nervosa
<(/,(0$=&!

Tratamento Intensivo de Doentes com DMID

Retinopatia PREVENO PRIMRIA Percentagem de Doentes
60 50 40 30 20 10 0

-.(=,(%$.(&#!
P<0.001

<(/,(0$=&!
0 1 2 3 4 5 6 7 8 9

risco 76 %

Anos de Estudo
N Engl J Med 1993;329:977-86

<(/,+=,(DE.!:,%F(*G+$&
)&*+,-.!*/!0).1)&((-.!&2!34!5

15

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Risco de Progresso da Retinopatia Associada

Hemoglobima Glicosilada na DMID 11% 9%

7%

JAMA 2002;287:2563-9

First of Any of the Predefined Cardiovascular Disease Outcomes

First Occurrence of Nonfatal Myocardial Infarction, Stroke, or Death from Cardiovascular Disease

57 %
42 %

N Engl J Med 2005;353:2643-53

16

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N Engl J Med 2011;365:2366-76

Factores risco para o desenvolvimento da DM2

Genticos Factores perinatais Obesidade
( gordura visceral)

Dieta Sedentarismo

Resistente

Resposta insulina

Sensvel

Captao glicose perifrica mediada pela insulina

(msculo esqueltico, tecido adiposo)

Supresso da neoglicognese heptica

Funo clula

Secreo normal

Hiperinsulinemia compensatria
( compensatrio secreo)

Deficit relativo insulina ( secreo)

Progressiva falncia celular

Tolerncia glicose

Glicmia em jejum

Normoglicemia

Tolerncia glicose

Diabetes Mellitus

Tempo, anos

JAMA 2007;297:196-204

17

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Progressive Decline in -Cell Function and Insulin Secretion in Type 2 Diabetes Mellitus

50 % of -cell insulin secretory capacity is lost every 6 years

IGT: impaired glucose tolerance PPH: postprandial hyperglycemia

JAMA 2003;289:2254-64

Major factors for progressive loss of -cell function and mass

Accelerated apoptosis
Glucotoxicity Lipotoxicity Proinflamatory cytokines Leptin Islet cell amyloid

Wajchenberg BL. Endocrine Reviews 2007;28:187-218

18

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Simplified scheme for the pathophysiology of type 2 DM

Antidiabticos
Reduzem a resistncia insulina

Biguanidas
Tiazolidionedionas ou glitazonas
Atrasam a absoro GI de hidratos de carbono

Inibidores das -glicosidases

Aumentam a excreo renal de glicose

Inibidores da SGLT2
Agonistas da amilina Estimulam a secreo de insulina

Sulfonilureias Glinidas Incretinas

GLP-1 anlogos Inibidores da DPP-4 ou Gliptinas

19

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BIGUANIDAS Metformina
Mecanismo de Aco

Actividade AMPK
Oxidao cidos gordos Uptake glicose
Glicognio msculo Sensibilidade insulina

Neoglicognese heptica
Lipognese
Absoro intestinal da glicose
Converso de glicose em lactato pelos entercitos

AMPK, 5' adenosine monophosphate-activated protein kinase

Metformin Pharmacology Pharmacokinetic

Not metabolized Protein binding of metformin is negligible Cleared by glomerular and tubular secretion (interaction cimetidine,
furosemide, nifedipine)

Elimination half-life Plasma: 6.2 hours Red blood cells: 17.6 hours

20

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Metformin-associated Lactic acidosis

Mechanisms
Metformin lactate uptake by the liver

Lactate is a substrate for hepatic gluconeogenesis Metformin production of lactate in the small intestine

Renal function clearance of metformin and lactate

BIGUANIDAS
Efeitos Secundrios

)-<6?:8!@H-I<-)!
Metformina
Risco Acumulao do frmaco (insuf. renal) Concomitante lactato (hipxia tecidual na
insuf. respiratria ou circulatria)

Remoo lactato (insuf. heptica)

Fenformina 10 vezes mais frequente que Metformina

21

25-11-2013

BIGUANIDAS
Efeitos Secundrios

)(.+,J$&!
6$&++,$&! KGF0,&0! :&L.+!A,/G#$%. )L0.+DE.!<(/,0/$(&#!*,! C$/&3$(&!MNO!,!4.#&/. Sem Hipoglicemia
(Biguanidas so Anti-hiperglicemiantes)

20 %

Sem

Peso

BIGUANIDAS
Contra-Indicaes

Insuficincia Renal (Clcr< 30 ml/min) Doena Heptica Histria de Acidose Lctica Insuficincia Cardaca Doena Pulmonar Obstrutiva Crnica
Clcr < 60 ml/min 2 3 g/dia Clcr 60-30 ml/min < 1.5 g/dia Clcr < 30 ml/min suspender

Suspenso imediata
Enfarte do miocrdio Sepsis

22

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Tiazolidionedionas
Troglitazona Pioglitazona Rosiglitazona
Hepatotxica
(Actos ) (Avandia )

Ligao aos receptores nucleares PPAR-

(peroxisoma proliferator-activated receptor-

)%DE.!*&!$(0F#$(&!(.0!/,%$*.0!P,+$9Q+$%.0
K,.'#$%.'Q(,0,!R,PG/$%&!

Tiazolidionedionas

Mecanismo de Aco
Sntese e translocao dos transportadores da glicose

!I+&(0P.+/,!*,!'#$%.0,!P&+&!*,(/+.!*.!3S0%F#.!,!/,%$*.!&*$P.0. Sem PPAR-

TZDs

AG livres
1 Ef. Hipolipidmico

Adiponectina
Oxidao AG

Entrada AG no msculo

2 Ef. Hipoglicmico
Ef. 1 3 meses

Sensibilidade Insulina Insulin sensitizers

23

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Tiazolidinedionas

Mecanismo de Aco in vivo em Humanos

Peso Tecido adiposo subcutneo Sensibilidade insulina Lpidos intramiocitos

Adiponectina c. gordos livres

MMP-9 IL-6 PCR Excreo Uendotelina PAI-1

Gordura heptica Sensibilidade heptica insulina

Insulina

N Engl J Med 2004;351:1106-18

Comparative Effects of Maximal Doses of Rosiglitazone and Pioglitazone

on Serum Lipids and Lipoproteins

in Randomized, Controlled Trials

+ sulfonylurea

+ metformin

Pioglitazone (30 to 45 mg)

Rosiglitazone (8 mg)

N Engl J Med 2004;351:1106-18

+ insulin

24

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Meta-analysis
Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes
N Engl J Med 2007;356:2457-71

25

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Long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes

CMAJ 2009;180(1):32-9

Tiazolidinedionas Aco na Diferenciao das Clulas Mesenquimatosas

TZDs

Adipcito progenitor

Clulas mesenquimatosas

Osteoprogenitor

Pr-osteoblasto

Medula ssea Adiposidade Osteoblastognese Aromatase Estrognios Reabsoro ssea

Condrcito progenitor

Formao ssea Actividade osteoblstica

Osteoblasto

Revista Portuguesa de Diabetes 2008;3(3):157-63

26

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Tiazolidinedionas

Efeitos Adversos
Peso ( Gordura visceral) Reteno hdrica Edema perifrico Insuficincia cardaca ( 2x)

Contra-indicado IC classe 3 ou 4
Enfarte do miocrdio (30-40 %) LDL

Rosiglitazona
Fracturas sseas

Comparison of Metformin and Thiazolidinediones

Goodman & Gilmans, 2011

27