Dúvidas
[email protected]
Arquivo
Medicamentos utilizados no tratamento do
diabetes mellitus
Site
www.gilbertodenucci.com
Diabetes Mellitus
Definição
Doença em que o organismo não produz ou utiliza
inadequadamente
a
insulina,
o
hormônio
hipoglicemiante, o que leva a estado de hiperglicemia
crônica
Glucose tolerance in normal person and in a person with diabetes
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 1 (juvenil)
O DM tipo 1 resulta primariamente da destruição das
células pancreáticas tipo beta. Inclui casos decorrentes de
doença auto-imune e aqueles nos quais a causa da
destruição das células beta não é conhecida
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 1 (juvenil)
•
Corresponde a 5-10% do total de casos. A
forma rapidamente progressiva é geralmente
observada em crianças e adolescentes. A forma
lentamente progressiva ocorre geralmente em
adultos sendo referida como diabetes latente autoimune do adulto (LADA)
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 2 (adulto)
O DM tipo 2 resulta de graus variáveis de resistência
à insulina e deficiência relativa de secreção de
insulina. A maioria dos pacientes tem excesso de peso
Principais tipos de Diabetes Mellitus
Diabetes Mellitus tipo 2 (adulto)
Corresponde a 90-95% do total de casos. O
diagnóstico é feito geralmente a partir dos 40 anos de
idade embora possa ocorrer mais cedo principalmente
em associação com a obesidade
Diabetes Mellitus tipo 1 x Diabetes Mellitus tipo 2
Tipo 1
Tipo 2
Início
< 30 anos
> 30 anos
História familiar de
Diabetes Mellitus
Raro
Comum
Peso corporal
Não obeso
Obeso
Cetoacidose
Comum
Raro
Tratamento com
insulina
Todos pacientes
Alguns pacientes
Auto-imunidade
Sim
Não
Prevalência na
população adulta
0.5%
5%
Associação com HLA
Sim
Não
Complicações comuns do diabetes tipo 2
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Intensive glycemic control and risk for microvascular complications
Overview of insulin replacement therapy — The Journal of Family Practice - August 2009 (Vol. 58, No. 8)
Intensive glycemic control and risk for MI and microvascular
complications
Overview of insulin replacement therapy — The Journal of Family Practice - August 2009 (Vol. 58, No. 8)
Maiores reduções da HbA conferem maior proteção contra as complicações
do diabetes
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Insulina
Proteína formada por 51 aminoácidos contidos no
interior de 2 cadeias peptídicas: uma cadeia A com 21
aminoácidos e uma cadeia B com 30 aminoácidos
As cadeias peptídicas são conectadas por duas pontes
dissulfeto e, além disso, há uma outra ponte dissulfeto
que liga as posições 6 e 11 da cadeia A
Insulina
Insulina
● = Carbono ● = Oxigênio ● = Nitrogênio, ● = Enxofre
Insulina
A insulina tende a formar dímeros em solução e
hexâmeros na presença do zinco
Dímero
Hexâmero
Hexâmero Insulina
Site: http://www.nature.com/nrd/journal/v4/n5/images/nrd1718-f2.jpg
Protein Crystal Recombinant Human Insulin
Site: http://mix.msfc.nasa.gov/IMAGES/HIGH/9802450.jpg
Insulina
A insulina endógena circulante tem meia-vida de 3-5
minutos
É catabolizada por insulinases no fígado, nos rins e na
placenta sendo que cerca de 50% da insulina são
removidos em uma única passagem pelo fígado
Insulina
A insulina é sintetizada nas células pancreáticas tipo beta
das ilhotas de Langerhans
Insulina
Forma-se inicialmente um pré-pró-hormônio insulínico
Este pré-pró-hormônio é clivado para formar uma próinsulina que, em sua maior parte, é clivada
adicionalmente liberando o peptídeo C para formar a
insulina
Insulina
Pró-insulina
Peptidases da célula
pancreática tipo beta
Insulina
Peptídeo C livre
Controle da liberação de insulina
Transportador de Glicose (1-5)
Transportadores da glicose em humanos
GLUT-1
GLUT-2
GLUT-3
Todos os tecidos
Captação basal de glicose
Fígado e células pancreáticas tipo beta
Captação de glicose na hiperglicemia
Todos os tecidos
Captação basal de glicose
GLUT-4
Músculo esquelético e tecido adiposo
Captação de glicose dependente de insulina
GLUT-5
Intestino delgado e espermatozóides
Transportador de frutose
Ação da Insulina
Captação de
glicose
Insulina
Fosforilação
Fusão
GLUT-4
Translocação
Effect of insulin in enhancing the concentration of glucose inside muscle
cells
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Schematic of the insulin receptor
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
The actions of insulin and glucagon in liver, muscle and adipose tissue on the
overall flow of fuels
http://www.ncbi.nlm.nih.gov/books/bv
Insulin Secretion
Insulin Secretion
Insulin
Meal
Postpradial State
Postabsorbtive State
O
Glucose
oxidation
Glucose
Glycerol
Insulin permits rapid
entry of glucose into
muscle and fat cell
O
Glucose
Fatty acid
Triglycerides
O
CO2
+
H2 O
Glucose
Glucose
taken up
by muscle
Glucose
taken up
by fat
Glucose
Circulation
Circulation
Liver
O
O
Glucose
Glucose
Glycogen
Adipocyte
Efeitos da insulina no metabolismo
Carboidratos
Aumenta o transporte de glicose
Aumenta a síntese de glicogênio
Inibe a glicogenólise
Inibe a gliconeogênese
Lipídeos
Aumenta a atividade da lipoproteína lipase
Aumenta o armazenamento de gordura nos adipócitos
Aumenta a síntese de lipoproteínas no fígado
Inibe a lipólise
Inibe a oxidação de ácidos graxos
Proteínas
Aumenta o transporte de aminoácidos
Aumenta a síntese de proteínas
Insulinas de Mamíferos
Rapid-acting analogue (clear)
•
•
•
•
•
Onset: 10–15 min
Peak: 60–90 min
Duration: 4– 5 h
Humalog® (insulin lispro)
NovoRapid® (insulin aspart)
Insulin LisPro
Insulina Lispro e Aspart
Intermediate-acting (cloudy)
•
•
•
•
•
•
Onset: 1–3 h
Peak: 5–8 h
Duration: up to 18 h
Humulin®-N
Humulin®-L
Novolin®ge NPH
Long-acting (cloudy)
•
•
•
•
Onset: 3–4 h
Peak: 8–15 h
Duration: 22–26 h
Humulin®-U
Extended long-acting analogue
• Onset: 90 min
• Duration:24 h
• Lantus®* (insulin glargine)
Insulina Glarginina (Lantus)
Premixed (cloudy)
• A single vial contains a fixed ratio of insulin
(% rapid- or fast-acting to % intermediateacting insulin)
• Humalog® Mix25TM
• Humulin® (20/80, 30/70)
• Novolin®ge (10/90, 20/80, 30/70, 40/60, 50/50)
Terapia com insulina
Insulina plasmática em não
diabéticos µU/mL
40
30
20
10
0
Glicemia em não
diabéticos mg/dL
120
100
80
8am 10 12 2pm 4 6
Desjejum
Almoço
8 10 12 2am 4
Jantar
Lanche
6 8am
Terapia com insulina
Regime misto
NPH
Regular
NPH + Regular
NPH + Regular
Insulina
Ultralente
Regular
Ultralente
8am 10 12 2pm 4 6
Ultralente
+ Regular
Regular
8 10 12 2am 4
Regular
6 8am
Pacientes em uso de CSII nos EUA
100.000
100.000
90.000
80.000
70.000
60.000
50.000
40.000
30.000
20.000
10.000
81.000
60.000
42.000
35.000
26.500
15.000
11.400
6.600 8.700
90
91
92
93
20.000
94
Ano
95
96
97
98
99
00
Controle de glicemia em uso de CSII
n
Idade média
(anos ± DP)
HbA1c* préCSII (%)
HbA1c* pósCSII (%)
P
Folow-up
(meses)
143
34 ± 13
8.28
7.46
<0.001
42
Bode (adolescentes)
50
14.9 ± 2.6
9.64
8.24
<0.001
42
Rudolph and Hirsch
107
36 ± 10.4
7.6
7.1
<0.0001
36
Chanteleau
116
29 ± 1
7.7
6.7
<0.001
54
Roland
25
13.8 ± 2.1
8.4
7.5
0.02
12
Autores
Bode (adultos)
*
mg/dL
Controle de glicemia: adolescentes x adultos
10
9
HbA1c
(%)
9.64
*
8.24
8.28
*
7.46
8
7
6
Adolescentes
n = 50
Adultos
n=413
Pré-CSII
Pós-CSII
* P < 0.001
Hipoglicemia pré e pós CSII
n
Idade média
(anos ± DP)
Hipoglicemia
pré-CSII
(%)
Hipoglicemia
pós-CSII
(%)
P
55
39.2 ± 12.9
138
22
<0.0001
Rudolph and Hirsch
107
36 ± 10.4
73.2
19.2
<0.0001
Chanteleau
116
29 ± 1
ND
10
25
13.8 ± 2.1
134
76
Autores
Bode
Roland
ND – Não disponível
0.01
Hipoglicemia pré e pós CSII
150
138
100
39
50
0
22
Pré CSII
1 ano
36
26
2 anos
3 anos
-------------------CSII----------------
4 anos
Redução no número de episódios de
cetoacidose após uso de CSII
0,5
0,4
Eventos por
ano
0,3
0,3
0,2
0,1
0,1
0,1
0
* P < 0.001
*
0,01
Adolescentes
n = 43
Pré-CSII
Adultos
n = 229
Pós-CSII
Endocr J. 2011 Aug 9.
Effects of a novel short-term continuous subcutaneous insulin infusion program evaluated by
continuous glucose monitoring on young adult type 1 diabetic patients in Taiwan.
Lin CH, Huang CH, Tsai JS, Hsieh SH, Sun JH, Huang BY, Huang MJ, Huang YY.
Source
Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital and Chang Gung University,
Taiwan.
Abstract
The aim of this study is to evaluate the effectiveness of blood sugar control by a short-course reinforcement program,
consisting of using continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) for young
adult type 1 diabetic patients. Twenty-six pump-naïve type 1 diabetic patients were successively enrolled in two years. The
mean disease duration was 13 years and the mean HbA1c was 8.8 %. Initially, a 3-day course of CGM was used to
evaluate the baseline glycemic status of the subjects, followed by 6-day intensive insulin adjustment by CSII therapy.
Thereafter, a second course of CGM was performed to evaluate the effectiveness of our outcomes in comparison to the
initial measurements. All participants received necessary education and instruction as required throughout the course of
the program. The glucose variability as measured by standard deviation of plasma glucose and mean amplitude of glucose
excursion decreased significantly (67.8 ± 2.7 to 52.0 ± 1.8 mg/dL and 140.4 ± 6.5 to 105.5 ± 5.3 mg/dL, p < 0.001). The
hypoglycemic events noted per patient were reduced by 46.4% (p = 0.003) and occurred significantly less often during
nocturnal periods (-63.2%, p = 0.002). Following the adjustment, the mean daily insulin requirement was reduced by
28.05% (from 0.82 to 0.59 IU/kg) and the new proportion of 40% as basal insulin was found. The short-term CSII
program provided significant improvement in blood sugar control for Type 1 diabetic patients, by reducing hypoglycemic
events, glucose excursion, and insulin dosage in our examined subjects.
Inhaled Insulin Device.
The Exubera inhaled insulin device is
closed for portability and opened before
use. It is activated after insertion of an
insulin blister. The release unit must be
changed every 2 weeks.
Exubera
Sulfoniluréias
Sulfoniluréias
(clorpropamida,
glipizida, gliclazida e glimepirida)
glibenclamida,
Estimulam a secreção de insulina ligando-se a um
receptor específico na célula beta o qual determina
o fechamento dos canais de potássio dependentes
de ATP resultando em despolarização da célula
Controle da liberação de insulina
Chlorpropamide (t ½ = 36 h)
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Chlorpropamide.svg
Gliclazide
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Gliclazide.svg
Tolbutamide
(1st generation)
Site: http://en.wikipedia.org/wiki/File:Tolbutamide.svg
Glibenclamide (t ½ = 10h)
(2st generation)
Site: http://en.wikipedia.org/wiki/File:Glibenclamide.svg
Glipizide ( t ½ = 2-4 hs)
(2st generation)
Site: http://en.wikipedia.org/wiki/File:Glipizide.svg
Glimepiride (t ½ = 5 h)
(3st generation)
Site: http://en.wikipedia.org/wiki/File:Glimepiride.svg
Meglitinidas
Derivados do ácido benzóico (repaglinida)
Derivados da d-fenilalanina (nateglinida)
Estimulam a secreção de insulina ligando-se a
receptores na célula beta em sítios distintos dos canais
de potássio dependentes de ATP.
Controle da liberação de insulina
Repaglinide
Nateglinide
Biguanides
Suggested mode action:
Reduces hepatic glucose production and glycogen metabolism
Improves insulin resistance via enhancing insulin-mediated
glucose uptake by skeletal muscle
Lowers triglycerides and total cholesterol levels
Raises high-density lipoprotein (HDL) levels and causes weight
loss
Metformin
Helpful in stabilizing blood sugar in brittle diabetics on insulin
therapy
Indicated alone in obese, mild diabetics because, unlike insulin, it
does not enhance lipogenesis
Glucose
Glucose-PO4
Lipogenesis
Krebs
cycle
Blood Glucose,
mg/100ml
Inhibition
of oxidative
metabolism
Lactic
acid
Blood glucose (diabetic)
100
Blood glucose (nondiabetic)
15
Blood insulin
Hours
0
1
2
3
Insulin
Microunits/ml
Pyruvic
acid
Administration
200
Metformin
Tiazolidinedionas
• Rosiglitazona
• Pioglitazona
Thiazolidinedione
Site: http://en.wikipedia.org/wiki/File:Thiazolidinedione.png
Rosiglitazone
Site: http://www.3dchem.com/imagesofmolecules/Rosiglitazone.gif
Pioglitazone
Site: http://www.dalton.com/images/pioglitazone.gif
Tiazolidinedionas
•
•
•
•
Reduz glicose plasmática
Aumenta uptake periférico de glicose
Reduz níveis de triglicerídeos
Aumenta a sensibilidade à insulina em tecidos
periféricos
Peroxisome proliferator-activated receptor (PPAR)
α (alpha) - liver, kidney, heart, muscle, adipose tissue and others
β/δ (beta/delta) - expressed in many tissues but markedly in brain,
adipose tissue and skin
γ (gamma) - although transcribed by the same gene, this PPAR
through alternative splicing is expressed in three forms:
• γ1 - expressed in virtually all tissues, including heart, muscle,
colon, kidney, pancreas, and spleen
• γ2 - expressed mainly in adipose tissue (30 amino acids longer)
• γ3 - expressed in macrophages, large intestine, white adipos tissue.
Alternative splicing resulting in protein isoforms
Site: http://en.wikipedia.org/wiki/File:Splicing_overview.jpg
Peroxisome proliferator - activated receptor pathway diagram
Site: http://en.wikipedia.org/wiki/File:PPAR-diagram.png
Thiazolidinediones
Effect of rosiglitazone and metformin on subcutaneous abdominal adipose
tissue (SCAAT) and visceral adipose tissue
Thiazolidinediones, insulin resistance and obesity: finding a balance - Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1272–1280
Bioactive GLP-1(7-36)amide and GIP (1-42) are released from the small intestine after meal
ingestion and enhance glucose stimulated insulin secretion (incretin action). DPP-4 rapidly
converts GLP-1 and GIP to their inactive metabolites GLP-1 (9-36) and GIP (3-42) in vivo.
Inhibition of DPP-4 activity prevents GLP-1 and GIP degradation, thereby enhancing incretin
action.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
GIP actions in peripheral tissues.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
Exenatide (Byetta)
•
•
•
•
•
•
53% idêntico ao GLP-1
Resistente a DPP-IV
Aumenta a secreção de insulina
Reduz a secreção de glucagon
Aumenta o tempo de esvaziamento gástrico
Sensação de saciedade – provoca queda de peso
GLP-1 actions in peripheral tissues. The majority of the effects of GLP-1 are mediated by direct
interaction with GLP-1Rs on specific tissues. However, the actions of GLP-1 in liver, fat, and
muscle most likely occur through indirect mechanisms.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
The inactivation process of GLP-1 by DPP-IV.
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Saxagliptin
Site: http://en.wikipedia.org/wiki/File:Saxagliptin.svg
Sitagliptin
Site: http://en.wikipedia.org/wiki/File:Sitagliptin.svg
Vildagliptin
Site: http://en.wikipedia.org/wiki/File:Vildagliptin_Structural_Formulae.png
Mechanism of action of vildagliptin.
In response to a meal, active glucagonlike peptide-1 (GLP-1) is secreted by the L cells of the intestines. Without the
presence of vildagliptin, GLP-1 is rapidly inactivated and degraded by the enzyme dipeptidyl peptidase IV (DPP4); when
vildagliptin is present, vildagliptin binds to DPP4, allowing GLP-1 to remain active. Active GLP-1 causes the pancreas to
increase insulin release and decrease glucagon release.
Vildagliptin: A novel oral therapy for type 2 diabetes mellitus - Am J Health-Syst Pharm—Vol 64 Jun 15, 2007
Target 2 physiologic glucose-lowering actions with a single
oral agent
Glucose-dependent mechanism target 2 key defects: insulin release and hepatic glucose
production
Site: www.januvia.com
In a single-dose pharmacokinetic study of patients with
type 2 diabetes
Rapidly increased active incretins (GLP-1 and GIP) through a full 24 hours
Site: www.januvia.com
A single oral dose sustains powerful DPP-4 inhibition for a
full 24 hours
Site: www.januvia.com
Significantly improved key meassures of beta-cell and
alpha-cell responsiveness to glucose
Site: www.januvia.com
Amylin
37 amino acid compound
Co-secreted with insulin from beta cells
Deficient in type 1 and type 2 DM
Renal clearance
Amylin - Physiological effects
1. Suppression of endogenous glucagon production
(especially in the postprandial state)
2. Reduction in postprandial hepatic glucose production
3. Reduction in gastric emptying time
4. Centrally mediated induction of satiety
5. Reduction in postprandial glucose levels
Pramlintide
Synthetic analogue of Amylin (3 amino acid substitutions with
proline for native amino acids)
Subcutaneous administration
Pramlintide
The most commonly reported adverse
effects associated with pramlintide use in type 1
DM were nausea, anorexia, and hypoglycemia in
these studies.
Mean percent changes in lipid values in 203 type 2 diabetic patients on
placebo and 3 different doses of pramlintide for 4 weeks.
Byron J Hoogwerf, Krupa B Doshi, Dima Diab Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk.
Vascular Health and Risk Management 2008:4(2) 355–362
Diabetic Neuropathy
1 - accumulation of advanced glycation end products
2 - formation of reactive oxygen species
3 - activation of protein kinase C, development of diabetic
microangiopathy (disease of the small blood vessels)
4 - increased aldose reductase activity
The Polyol Pathway
Site: http://www.medbio.info/images/Time%203-4/new_se11.gif
Epalrestat
SGLT2 mediates glucose reabsorption in the kidney. SGLT2 catalyzes the active transport of
glucose (against a concentration gradient) across the luminal membrane by coupling it with
the downhill transport of Na+. The inward Na+ gradient across the luminal epithelium is
maintained by active extrusion of Na+ (driven by ATP) across the basolateral surface into the
intercellular fluid, which is in equilibrium with the blood. Glucose passively diffuses of the
cell down a concentration gradient via basolateral facilitative transporters, GLUT2 (and
GLUT1).
A Paradigm Shift in Diabetes Therapy — Dapagliflozin and Other SGLT2 Inhibitors - Figure 1.
Comparison of sodium-Glucose Contransporters
A Paradigm Shift in Diabetes Therapy — Dapagliflozin and Other SGLT2 Inhibitors - tab 01
Normal glucose homeostasis. Diagram outlining the hormonal interactions that are important in regulating normal glucose
homeostasis. Normal fasting glucose homeostasis involves the hormonal regulation of glucose utilization and production, as
well as the filtration and reabsorption of glucose by the kidney. Under basal conditions, glucose uptake by the tissues is
matched by glucose production from the liver; this enables fine regulation of glucose at a very fixed level. Gluconeogenesis
in the liver helps prevent hypoglycemia. Adapted from DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus.
A Paradigm Shift in Diabetes Therapy — Dapagliflozin and Other SGLT2 Inhibitors - Ann Intern Med 131(4):281-303, 1999 – fig 02
Renal glucose handling before and following inhibition of SGLT2. With gradual infusion of glucose, as the plasma glucose
concentration increases, the reabsorption progressively increases following the line marked reabsorption curve (in red). At
plasma glucose concentrations <200 mg/dL, all the filtered glucose is reabsorbed and there is no excretion. When glucose
reaches a threshold, around 200-250 mg/dL, the maximum capacity of the renal tubule to reabsorb glucose -- or the Tmax - is
exceeded and once it passes this, glucose begins to be excreted into the urine (green line, labeled “excretion”). The breaking
point, however, is not abrupt -- splay, which represents glucose excretion in the urine before saturation (Tmax) is fully attained;
and is explained by some nephrons releasing glucose at a slightly lower threshold, some a bit higher; and the relatively low
affinity of the Na-glucose carriers. The dotted yellow lines depict renal glucose handling after SGLT2 inhibition. The SGLT2
inhibitors lower the Tmax of glucose, which in turn increases the excretion of glucose via the kidneys
A Paradigm Shift in Diabetes Therapy — Dapagliflozin and Other SGLT2 Inhibitors - Figure 4.
Acarbose
É um inibidor competitivo de α-glicosidases
intestinais tais como maltase, isomaltase, sacarase e
glicoamilase, retardando a absorção de carboidratos
Activation and inactivation of poly(ADP-ribose) polymerase (PARP):
interactions with specific signal-transduction pathways
Site: http://www.nature.com/nrd/journal/v4/n5/images/nrd1718-f2.jpg
Insulina
Liberação de
insulina
Canal de potássio
dependente de ATP,
sensível à gliburida
Exocitose
Ca2+
Ca2+
K+
Ca2+
Insulina
ATP
Célula pancreática
tipo beta estimulada
por glicose
Ca2+
Ca2+
Retículo
endoplasmático
Significantly improved measures of insulin synthesis and
release from the beta cell
Site: www.januvia.com
Structures of (A) the proglucagon gene, (B) mRNA, and (C) protein. (D) Tissue-specific
posttranslational processing of proglucagon in the pancreas leads to the generation of Glicentinrelated polypeptide (GRPP), glucagon (GLUC), intervening peptide-1 (IP-1), and major
proglucagon fragment (MPGF), whereas glicentin, oxyntomodulin (OXM), intervening peptide-2
(IP-2), and GLP-1 and GLP-2 are liberated after proglucagon processing in the intestine and brain.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
(A) ProGIP gene, (B) mRNA, and (C) protein. Bioactive GIP is
generated from its proGIP protein precursor by posttranslational
cleavage at single arginine residues that flank GIP.
Biology of Incretins: GLP-1 and GIP - GASTROENTEROLOGY 2007;132:2131–2157
Structure, synthesis and
metabolism of insulin and glucagon
01 - Structure of the primary transcript of RNA
02 -Mature messenger (m) RNA after exicision of
the introns
03 - Structure of proinsulin after cleavage of the
signal sequence from pre-proinsulin
04 - Cleavage of the C peptide leaving biologically
active insulin
05 - Packaging of insulin and C-peptide in
secretory granules for storage and release
http://www.ncbi.nlm.nih.gov/books/bv
Synthesis of glucagon and post-translational processing of the
proglucagon gene
Schematic representation of the major products of proglucagon in the human pancreas and intestine. The
processing of glucagon in the gut produces two important peptides - glucagon-like peptide 1 (GLP-1) and
oxyntomodulin - which are known as incretins as they increase the insulin response to glucose. GRPP, glucagon
related pancreatic peptide; IP, intervening peptide
http://www.ncbi.nlm.nih.gov/books/bv
Ação da insulina
Domínio de
ligação da
insulina
Domínio intracitoplasmático
NH2
NH2
β
Insulina
Receptor de insulina
ativado (ação tirosinaquinase intrínseca)
β
COOH
COOH
COOH
Estrutura do
receptor de
insulina
Receptor de
insulina
Cascata de
fosforilações
(GLUT- 4,
transferrina, LDL-R
e IGF 2-R)
Tratamento do Diabetes Mellitus
Nova modalidade de tratamento
CSII (Continuous subcutaneous insulin infusion)
Terapia que utiliza bomba de infusão subcutânea
contínua de insulina indicada quando 3 ou 4 aplicações
diárias ainda são insuficientes para o controle da
glicemia
Também indicada para pacientes motivados com
cotidiano que não permite a terapia convencional com
auto-aplicações de insulina
Tratamento do Diabetes Mellitus
Objetivo
Glicemia de jejum em torno de 110 mg/dL
Glicemia após 2 h de refeição em torno de 140 mg/dL
Thiazolidinediones: Clinical Rationale and Adverse Effects
Rosiglitazone
Thiazolidinediones increase
sensitivity of cells to existing insulin
Adipocyte
Muscle
O
Glucose
oxidation
Glucose
Glycerol
O
Glucose
O
CO2
+
H2 O
Glucose
Glucose
taken up
by muscle
Reduced triglycerides
increased HDL and LDL
Hepatic glucose
production reduced
Liver
Fatty acid
Triglycerides
O
O
Glucose
Glucose
Glycogenolysis
Glycogen
Adverse reactions reported in ≥5.0% of patients and more commonly than in
patients given placebo, regardless of investigator assessment of causality, number
of patients(%)
Site: www.januvia.com
Proven 24-hours glycemic control
Dosage for patients with renal insufficency
Site: www.januvia.com
Fatores de risco para o desenvolvimento de doença coronariana nos pacientes com
diabetes tipo 2
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Relação contínua entre os níveis de HbA após o tratamento do diabetes e a incidência de
complicações do diabetes
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Taxas constantemente baixas de controle glicêmico em pacientes
tratados na comunidade
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
O desenvolvimento de resistência à insulina e o comprometimento relativo da
secreção de insulina fazem parte da progressão do diabetes tipo 2
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Estratégia para o controle mais intensivo do diabetes, como uso mais
precoce do tratamento combinado
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Propriedades farmacocinéticas de Glucovance e da associação livre de metformina e
glibenclamida
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Esquema terapêutico diário de um paciente que apresenta diabetes tipo 2 e doenças
concomitantes típicas. Este paciente precisa tomar um total de 19 comprimidos por dia, em
quatro horários diferentes.
Monografia de Glucovance – Site: http://www.merck.com.br/pdf/glucovance_monografia.pdf
Selective insulin resistance in T2DM.
In skeletal muscle, insulin action on glucose transport and utilisation is impaired due to decreased IRS tyrosine phosphorylation and activity of the kinases PI 3kinase and Akt. In endothelial cells (EC), the defect in insulin-stimulated PI 3-kinase/Akt activity is also responsible for reduced eNOS synthesis and nitric oxide (NO)
generation, which contributes to endothelial dysfunction. The defective glucose metabolism leads to increased insulin concentrations (hyperinsulinaemia), which
stimulate the Shc/MAP kinase pathway normally or more effectively than normal in vascular smooth muscle cells (VSMC), leading to increased secretion of
plasminogen activator inhibitor-1 (PAI-1) and endothelin-1 (ET-1), which further exacerbate endothelial dysfunction. PY, tyrosine phosphorylation; eNOS, endothelial
nitric oxide synthase.
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Mechanisms of action of thiazolidinediones (TZDs).
The TZDs act by binding to the nuclear receptor peroxisome proliferator activated receptors-γ (PPARγ), thereby inducing expression of genes involved in glucose and
lipid metabolism in adipocytes, as well as secretion of the adipokines adiponectin and tumor necrosis factor (TNF)-α. In addition, the TZDs inhibit hepatic
gluconeogenesis, stimulate lipid uptake and oxidation by the liver, and promote glucose oxidation by the skeletal muscle. The ultimate effects are to lower circulating
FFA and enhance whole-body insulin sensitivity. GLUT4, insulin-stimulated glucose transporter; CAP, cbl-associated protein involved in insulin signaling; LPL,
lipoprotein lipase; FATP, fatty acid transport protein; ACS, acetyl CoA synthase; UCP, uncoupling protein; FFA, free fatty acid; PEPCK, phosphoenolpyruvate
carboxykinase.
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Potential mechanisms leading to β-cell dysfunction in T2DM.
Potential Causes of β-Cell Dysfunction in Type 2 Diabetes
Reversible metabolic abnormalities
Glucotoxicity
Lipotoxicity
Hormonal changes
Inadequate incretin action
Increased glucagon secretion
Genetic abnormalities of β-cell proteins
Glucokinase, SUR1/Kir6, IPF-1, HNF-4α, HNF-2α, Insulin receptor, IRS-1
Reduction of β-cell mass
Increase in amyloid
Apoptosis
SUR1/Kir6, complex formed by the sulphonylureas receptor (SUR) and the K+ channel; IPF-1, insulin promoter
factor-1; HNF, hepatocyte nuclear factor; IRS-1, insulin receptor substrate-1.
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Schematic flow-chart of the use of hypoglycaemic drugs in the therapy of
T2DM.
Use of Hypoglycaemic drugs in the therapy of T2DM
Diet + Physical activity
HbA1c>7%
Insulin-sensitizing agent and/or insulin secretagogue
HbA1c>7%
Basal insulin (NPH/Glargine)
Prandial insulin (Lispro/Aspart)
FPG target: <100 mg/dl
PPG target: <140 mg/dl
When diet and physical activity fail to achieve an HbA1c value of <7%, insulin-sensitizing agents and insulin secretagogues are used alone or in various combinations. If
the HbA1c target of <7% is still not met, insulin therapy should be considered. A ‘basal’ insulin, such as NPH insulin or glargine, is used to lower fasting plasma glucose
(FPG) below 100 mg/dl; a ‘prandial’ insulin, preferably a short-acting analogue such as lispro or aspart, is used to control post-prandial glucose (PPG) excursions below
140 mg/dl.
Pathophysiology of type 2 diabetes: Rationale for different oral antidiabetic treatment strategies - Diabetes Res Clin Pract. 2005 Jun;68 Suppl1:S22-9.
Change in weight (%) by category in patients with type 2 diabetes treated
with rosiglitazone plus metformin (n ¼ 10,321).
Thiazolidinediones, insulin resistance and obesity: finding a balance - Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1272–1280
Mean change in weight in the United Kingdom Prospective Diabetes
Study (overweight cohort).
Thiazolidinediones, insulin resistance and obesity: finding a balance - Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1272–1280
Effect of rosiglitazone 8 mg/day vs. placebo on intra-abdominal,
subcutaneous and intrahepatic fat
Thiazolidinediones, insulin resistance and obesity: finding a balance - Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1272–1280
The time course of changes in serum alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) during treatment with rosiglitazone
Thiazolidinediones, insulin resistance and obesity: finding a balance - Journal compilation ª 2006 Blackwell Publishing Ltd Int J Clin Pract, October 2006, 60, 10, 1272–1280
The pathway of muscle glycogen synthesis.
GLUT 4 glucose transporter 4; UDP uridine 5’-diphosphate.
Etiology of Insulin Resistance - The American Journal of Medicine (2006) Vol 119 (5A), 10S-16S
GLUT 4 = glucose transporter 4;
IRS = insulin-receptor substrate;
PI 3-kinase = phosphatidylinositol 3-kinase;
nPKC = novel protein kinase C.
Etiology of Insulin Resistance - The American Journal of Medicine (2006) Vol 119 (5A), 10S-16S
The mechanism of fatty acid-induced
insulin resistance in muscle (A) and
liver (B).
Alternative causes of insulin resistance (IR) mediated via fat
accumulation in skeletal muscle and liver.
Etiology of Insulin Resistance - The American Journal of Medicine (2006) Vol 119 (5A), 10S-16S
Antidiabetogenic effects of GLP-1
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
GLP-1 mimetics under development
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Potency and selectivity of some DPP-IV inhibitors
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Structures of DPP-IV inhibitors.
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
DPP-IV inhibitors in various clinical phases
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Physiological processes modulated by DPP-IV activity
GLP-1 based therapy for type 2 diabetes - european journal of pharmaceutical sciences 2 8 ( 2 0 0 6 ) 96–1081
Biochemical reactions for the storage of triglycerides in adipose
tissue.
http://www.ncbi.nlm.nih.gov/books/bv
Major aspects of lipid turnover in man
http://www.ncbi.nlm.nih.gov/books/bv
The formation of ketone bodies
Acetyl CoA, formed from pyruvate and fatty oxidation hydrolysis enters the TCA cycle. In diabetes or fasting,
oxaloacetate is consumed by the gluconeogenic pathway. There is reduced incorporation of acetyl CoA into citrate
(x) and hence acetyl CoA is converted to form ketone bodies.
http://www.ncbi.nlm.nih.gov/books/bv
The family of glucose transporters (GLUTs 1–5)
http://www.ncbi.nlm.nih.gov/books/bv
Therapies for DM - 1 Human insulin replacement
http://www.ncbi.nlm.nih.gov/books/bv
Therapies for DM - 1 Human insulin replacement
http://www.ncbi.nlm.nih.gov/books/bv
Increase in plasma insulin concentration after a sudden increase in
blood glucose to two to three times the normal range
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Approximate insulin secretion at different plasma glucose levels
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Approximate plasma glucagon concentration at different blood glucose
levels
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Changes in blood constituents in diabetic coma, showing normal values
(light bars) and diabetic coma values (dark bars)
Guyton & Hall. Textbook of Medical Physiology. Tenth Edition.
Action of insulin on the adipocyte
The effects of insulin on adipose tissue.
http://www.ncbi.nlm.nih.gov/books/bv
insulin signaling system in healthy normal glucose tolerant
A) and T2DM B) subjects.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 01
The triumvirate: insulin resistance in liver and muscle with impaired insulin
secretion represent the three core defects in T2DM. Reproduced with permission
from DeFronzo RA. Lilly lecture. The triumvirate: Beta-cell, muscle, liver.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 02
Effect of thiazolidinedione (TZD) treatment on beta cell function.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 03
Pioglitazone positively affects the insulin signaling system resulting in improved
glycemic control, generation of nitric oxide and decreased MAP kinase pathway
activation.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 04
Effect of thiazolidinediones (TZDs) on body fat distribution.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 05
GLP-1 levels decline as glucose tolerance deteriorates A), whereas GiP levels are
normal or elevated in patients with type 2 diabetes mellitus B).
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 06
Percentage (%) of subjects achieving select HbA targets with alogliptin in Phase 3 trials.
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 08
Necessity for hyperglycemic rescue* in Phase iii trials with
alogliptin
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 09
The ominous octet: pathophysiologic abnormalities in type 2 diabetes mellitus
Pioglitazone and alogliptin combination therapy in type 2 diabetes: a pathophysiologically sound Treatment - Vascular Health and Risk Management 2010:6 671–690 – Fig 10