A newborn baby needs to be given small amounts of water in addition to breastmilk to meet his/her needs

1. 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

2. DISCLOSURES
• I have no actual or potential conflict of interest in relation to
this program/presentation;
• Speaker: Merck Serono, Lilly, Novonordisk, Novartis;

3. Man evolution

5. National Geographic – August 2004

6. Atlas IDF. 2014 Update
WORLD DIABETES PREVALENCE

7. WORLD DIABETES PREVALENCE
Atlas IDF. 2014 Update

8. /12
Persons have
diabetes

9. 50%
Don´t now that have
diabetes

10. Every
7 seconds
1 person die of
diabetes

11. 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

12. 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

13. 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

14. Hypoglycaemic
hormone
Hyperglycaemic
hormones
14
The hormonal regulation of glucose metabolism

15. 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

16. • 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. 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
-cell
function
(%,
HOMA)
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. 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%
-cell
volume
(%)
Butler AE et al. Diabetes 2003; Leslie RD e Pozzilli P, J Clin Endocrinol Metab 2006; Deng S et al. Diabetes 2004

19. 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
Insulin
secretion
(pmol/min)
Polonsky KS et al. N Engl J Med, 1988

20. …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. 21
The twin vicious cycle of insulin resistance leading to
T2D
 Plasma
glucose
Taylor R Diabetologia 2008; 51: 1781-89

22. 22
Obesity and insulin resistance

23. 1998
2009

24. 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. 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

26. 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

27. • 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

28. 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. 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
(pmol/l)
*
*
*
P <0,05
Vilsbøll T, et al. Diabetes. 2001
In T2D the secretion of GLP-1 after a meal is impaired

30. 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.

31. 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

32. 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

33. 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

34. 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.