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www.excemed.org
IMPROVING THE PATIENT’S LIFE THROUGH
MEDICAL EDUCATION
Pathophysiology of type 2 diabetes
Bruno Almeida M.D., M.Sc. Clinical Nutrition,
PhD Student
October 2015
DISCLOSURES
• I have no actual or potential conflict of interest in relation to this program/presentation;
• Speaker: Merck Serono, Lilly, Novonordisk, Novartis;
Man evolution
National Geographic – August 2004
Atlas IDF. 2014 Update
WORLD DIABETES PREVALENCE
WORLD DIABETES PREVALENCE
Atlas IDF. 2014 Update
/12 Persons have
diabetes
50%
Don´t now that have
diabetes
Every
7 seconds
1 person die of
diabetes
Definition
• Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action or both.
• The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels.
ADA position statement. Diabetes Care 2009; 31(S1): S55-S60
Old view: predominantly insulin resistance and relative (rather than absolute) insulin deficiency. Current view: progressive insulin secretory defect on the background of insulin resistance.
Type 2 Diabetes
• The most prevalent form of diabetes (accounts up to 90-95% of all the forms of diabetes)
ADA Position Statement. Diabetes Care 2009; 31(S1): S55-S60
ADA Position Statement. Diabetes Care 2014; 37(S1): S14-S78
Glucose influx and outflow
• Any rise in glycaemia is the net result of glucose influx exceeding glucose outflow from the plasma compartment.
• In the fasting state, hyperglycemia is directly related to increased hepatic glucose production.
• In the postprandial state, further glucose excursions result from the combination of insufficient suppression of this glucose output and defective insulin stimulation of glucose disposal in target tissues.
Inzucchi E, et al. Diabetes Care 2012; 35:1364-79
Hypoglycaemic hormone
Hyperglycaemic hormones
14
The hormonal regulation of glucose metabolism
15
Effects of insulin on glucose influx/outflow
Increases glycogen synthesis Decreases glycogenolysis Inhibits gluconeogenesis
Increases the uptake of glucose by stimulating the exposure of GLUT4 in cell membrane
Stimulates glycolysis
Kahn R, et al. Joslin’s Diabetes Mellitus, 2005. Dimitriadis G, et al. Diabetes Res Clin Pract 2011; 93 (S1):S52-S59
• Interaction between genes and environment can lead to obesity and insulin resistance.
• Genetically susceptible β- cells are unable to
compensate the increased secretory demand, resulting in type 2 diabetes.
Adapted from Kahn, Hull, et al 2006
Etiology of type 2 diabetes
17
The β-cell in type 2 diabetes: function
HOMA: homeostasis model assessment
0
20
40
100
–4 6 –10 –8 –6 –2 0 2 4
80
60
–12 8
Diabetes diagnosis
Years to diagnosis
-c
ell function (
%,
HO
MA)
Adapted from: Lebovitz, Diabetes Reviews 1999;7:139–53
(data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:1249–58)
At the time of diagnosis patients with T2D already show an impaired β-cell function, that progressively decreases during the disease
18
The β-cell in type 2 diabetes: mass
0
0,5
1
1,5
2
2,5
3
NGT IFG T2D NGT T2D LADA
Lean Obese
-50%
-63%
-c
ell v
olu
me (
%)
Butler AE et al. Diabetes 2003; Leslie RD e Pozzilli P, J Clin Endocrinol Metab 2006; Deng S et al. Diabetes 2004
19
The loss of β-cell mass and function results in the progressive insulin secretory defect…
Hours
0
200
400
600
800
6.00 10.00 14.00 18.00 22.00 2.00 6.00
Breakfast Lunch DInner
normal
type 2 diabetes
Insu
lin s
ecr
eti
on
(p
mo
l/m
in)
Polonsky KS et al. N Engl J Med, 1988
…on the background of insulin resistance
IR: Insulin Resistance PG: Plasma glucose IS: Insulin Secretion
• Increased insulin resistance in muscle, liver and adipose tissue
causes hepatic glucose overproduction, impaired glucose uptake
from muscles and increased plasma levels of FFA
Taylor R Diabetologia 2008; 51: 1781-89
21
The twin vicious cycle of insulin resistance leading to T2D
Plasma glucose
Taylor R Diabetologia 2008; 51: 1781-89
22
Obesity and insulin resistance
1998
2009
OMINOUS OCTET
DeFronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
Diabetes. 2009;58:773-795
25 -60 0 60 120 180 240
Insulin
Glucagon
Glucose
meal
T2D
Controls
Impaired insulin secretion
Increases in glucagon levels
t
De Fronzo’s octet: increased glucagon
Muller WA et al. N EnglJ Med. 1970
The role of the adipose tissue
• Glucose derived from diet or endogenous sources stimulates insulin secretion.
Evans R, et al. Nat Rev Endocrinol 2004; 10: 1-10
• Insulin promotes glucose uptake by skeletal muscle and fat, opposes hepatic glycogenolysis and gluconeogenesis, and inhibits fat lipolysis.
• Free fatty acids liberated from adipose tissue contribute to insulin resistance in skeletal muscle and liver.
• Additional fat-derived signals, including TNF-α, resistin and visfatin, modulate insulin sensitivity and fatty acid metabolism in muscle and liver.
Evans R, et al. Nat Rev Endocrinol 2004; 10: 1-10
The role of the adipose tissue
Incretins
• Insulin response in humans is greater after the oral ingestion of glucose than after the intravenous infusion of glucose. This phenomena is known as “incretin effect”.
• GIP and GLP1 are two hormones, namely the incretins,
secreted by the gut (GIP in the jejunum and GLP-1 in distal ileum) that are responsible for the incretin effect.
• Incretins have a short half-life in-vivo because they are rapidly metabolized by an enzyme called DPP4.
Meier JJ. Nat Rev Endocrinol 2012; 8: 728-742
29
Total GLP-1, controls
Total GLP-1, T2D
Intact GLP-1, controls
Intact GLP-1, T2D
0
10
20
30
0 50 100 150
Tempo (min)
GLP
-1 (
pm
ol/
l)
*
* *
P <0,05
Vilsbøll T, et al. Diabetes. 2001
In T2D the secretion of GLP-1 after a meal is impaired
The role of the kidney
• The kidney filters 162 g ([glomerular filtration rate 180 l/day] [fasting plasma glucose 900 mg/l]) of glucose every day.
• The sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load.
• SGLT2 inhibitors promote the renal excretion of glucose and thereby lower elevated blood glucose levels in patients with type 2 diabetes.
• The glucose-lowering effect is independent of insulin (beta cell
function and insulin sensitivity).
David K McCulloch. UpToDate 2014.
SGLT2
Sodium-glucose transporters
SGLT1
1. Chao EC, Henry RR. Nat Rev Drug Discov 2010;9:551–9; 2. Mather A, Pollock C. Kidney Int Suppl 2011;120:S1–S6; 3. Wright EM, et al. J Intern Med 2007;261:32–43.
Main uptake mechanism for glucose and galactose in the intestine
S2 and S3 segments of the proximal renal tubule are responsible for the remaining 10% of the renal glucose
High-affinity (Km=~0.5 mM), low-capacity transporter, which transfers glucose and sodium with a Na+:glucose coupling ratio of 2:1
Almost completely expressed in the brush-border membrane of proximal renal tubular cells in the S1 and S2 segment
Responsible for 90% of the total renal glucose reabsorption
Low-affinity (Km=~2 mM), high-capacity transporter, which transfers glucose and sodium with a Na+:glucose coupling ratio of 1:1
Intestine Kidney
Neurotrasmitter dysfunction
Murray, S. et al. Nat. Rev. Endocrinol. 2014,
Abbreviations: ARC, arcuate nucleus of the hypothalamus; DAT, dopamine active transporter; DRD1, dopamine D1 receptor; DRD2, dopamine D2 receptor; LHA, lateral hypothalamic area; MOR, μ-opioid receptor; NAc, nucleus accumbens; TH, tyrosine hydroxylase; VTA, ventral tegmental area
Major complications of diabetes
Diabetic
retinopathy
Leading cause of
blindness in adults1,2
Diabetic
nepropathy
Principal causa de
doença renal
terminal3,4
Cardiovascular
disease
Stroke
Aumento de 2 a 4 vezes da mortalidade CV e de AVC5
Diabetic
neuropathy
Principal causa
não traumática de
amputações das
extremidades
inferiores7,8
Oito em cada dez
indivíduos com
diabetes morrem por
eventos CV6
1. UKPDS Group. Diabetes Res 1990;13(1):1–11; 2. Fong DS, e colab. Diabetes Care 2003;26(Suppl 1):S99–S102; 3. Hypertension in Diabetes Study. J Hypertens 1993;11(3):309–317; 4. Molitch ME, e colab. Diabetes Care 2003;26(Suppl 1):S94–S98; 5. Kannel WB, e colab. Am Heart J 1990;120(3):672–676; 6. Gray RP, e colab. In Textbook of Diabetes 2nd Edição, 1997; 7. King’s Fund. London: British Diabetic Association, 1996; 8. Mayfield JA, e colab. Diabetes Care 2003;26(Suppl 1):S78–S79
Conclusions
• The pathophysiology of type 2 diabetes is complex and involves multiple molecular pathways in various organs.
• The decreased insulin secretion by the pancreas, on the background of insulin resistance in the liver and muscles, have historically played a key role in the determination of hyperglycaemia in type 2 diabetes.
• In the last few years increasing evidences showed that also other organs like the gut, the kidney and the brain are involved in the pathogenesis of type 2 diabetes and are currently targeted by available and developing therapies for subjects affected by type 2 diabetes.