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.