pathophysiology of diabetes by dr shahjada selim

Pathophysiology of Type 2 Diabetes

Dr Shahjada Selim Assistant Professor

Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka

Email: selimshahjada@gmail.com

DEFINITION

Diabetes mellitus (DM) is a state of chronic hyperglycemia due to defect in insulin secretion and or its action.

NORMAL FUEL METABOLISM

NORMAL FUEL METABOLISM

Fuel metabolism is regulated by complex system to: • Distribute nutrients to organs and tissues for mechanical or

chemical work, growth or renewal • Provide storage of excess nutrients: glycogen or fat • Allow release of energy from storage depots as needed during

fasting or high energy use

Carbohydrate Metabolism

• Glucose is a major energy source for muscles and the brain.

• The brain is nearly totally dependent on glucose

• Muscles use Glucose And Fat for fuel.• Main sources of circulating glucose are hepatic

glucose production, kidney and ingested carbohydrate.

Basal Hepatic glucose production: HGP

• After absorption of the last meal is complete, liver produce glucose to supply glucose needed for tissues that do not store glucose as brain.

• ~2 mg/kg body wt/min in adults.

BRIAN

• Do not store glucose• Dependent on glucose

Mechanisms and sources of glucose release in the post-absorptive state

Overall rate of glucose release:

~10 μmol/(kg−min)

Renal contribution:2.0–2.5 μmol/(kg−min)

(20–25%)

Hepatic contribution:7.5–8.0

μmol/(kg−min)(75–80%)

Renal gluconeogenesis:

2.0–2.5 μmol/(kg−min)

(20–25%)

Hepatic glycogenolysis:

4.5–5.5 μmol/(kg−min)

(45–50%) Hepatic

gluconeogenesis:2.5–3.0 μmol/(kg−min)

(25–30%)

High HGP In T2DM

• Insulin suppresses hepatic glucose production (HGP) • In T2D: impaired hepatic insulin action (Liver

resistance): increase BGP: high FBG: diagnosis• High HGP during fasting : hyperglycemia,

hyperlipidemia, and ketosis (RAMADAN FASTING).

• Metformin: act on liver resistance. Taken at PM , lowers liver production of glucose at night, lowers FBG .

Ingested carbohydrate

• 60–70% is stored (glycogen) • 30-40% oxidized for immediate energy needs.• Produce postprandial blood glucose 90–120 min after meal. • The magnitude and rate of rise in BG:

– size of the meal– physical state (solid, liquid, cooked, raw)– other nutrients: fat and fiber: slow digestion– amount and effect of insulin. – Type simple or complex: least effect – The rate of gastric emptying: delays PP surge with

hypoglycemia and rebound hyperglycemia

Protein Metabolism

Ingested protein is absorbed as amino acids:

• synthesis of new protein• oxidation to provide energy• conversion to glucose (gluconeogenesis)

during fasting: Alanine• In DM: gluconeogenesis: loss of weight

and Fatigue

Fat Metabolism

• Fat is the major form of stored energy as triglyceride in adipose tissue or muscle fat deposits.

• TG is converted to free fatty acids plus glycerol by lipolysis: transported to muscle for oxidation: ketone bodies acetoacetate and –hydroxybutyrate .

• Chronic nutritional excess: accumulation of stored fat, because ingested fat is not used and other excess nutrients (glucose) are used to synthesize fat: fatty liver.

CLINICAL IMPLICATIONS

• Elevated circulating free fatty acids from ingested fat or lipolysis may:

• induce hepatic insulin resistance at different sites: LIPOTOXICITY

• Increase basal HGP • Slow the postabsorptive decline in blood

glucose.

HORMONAL REGULATION OF FUEL METABOLISM

Insulin and Glucose Metabolism

Major Metabolic Effects of Insulin• Stimulates glucose uptake into muscle and

adipose cells: lipogenesis• Inhibits hepatic glucose production

Consequences of Insulin Deficiency

• Hyperglycemia osmotic diuresis and dehydration

Major Metabolic Effects of Insulin and Consequences of Insulin Deficiency

Insulin effects: Stimulates glucose uptake into muscle and adipose cells: lipogenesis + inhibits lipolysisConsequences of insulin deficiency: elevated FFA levels

Insulin effects: Inhibits ketogenesis• Consequences of insulin deficiency: ketoacidosis,

production of ketone bodies

Stimulates glucose uptake into muscle stimulates amino acid uptake and protein synthesis, inhibits protein degradation, regulates gene transcription • Consequences of insulin deficiency: muscle wasting

Insulin secretion

Basal Insulin• Constant low insulin levels• Prevent lipolysis and glucose production. • Low level of basal Insulin during exercise

making stored energy available. • Low basal insulin during fasting: increase

glucagon : glycogenolysis , lipolysis, and ketogenesis: hyperglycemia, hyperlipidemia, and ketosis.

Prandial insulin • Blood glucose is the dominant stimulus for

insulin secretion. • Postprandial secretion increases rapidly> basal

– Suppress glucose production– Supress lipolysis– stimulate uptake of ingested glucose by tissues

The Biphasic prandial Insulin Response

Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.

Insulin Secretion

Fig. 47-1

Adapted from Ward WK et al. Diabetes Care 1984; 7: 491–502.

Normal Type 2 diabetes120100

80604020

0

–30 0 30 60 90 120Time (minutes)

–30 0 30 60 90 120Time (minutes)

Plas

ma

insu

lin (µ

U/m

l) 120100

80

6040

200

20g glucose20g

glucose

Plas

ma

insu

lin (µ

U /

ml)

Pattern of insulin release is altered early in Type 2 diabetes

Loss of Early-phase Insulin Release in Type 2 Diabetes

Overview of Insulin and Action

Insulin Preparations

Fig. 47-3

Glucotoxicity

• Hyperglycemia inhibits insulin secretion and impairs insulin action.

• Oral agents that increase insulin secretion or improve action could be ineffective at higher levels of hyperglycemia.

• Treatment with insulin for a few days to reduce the marked hyperglycemia may make the patient more responsive to subsequent treatment with oral agents.

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

FPG 90 mg/dL

Normal glucose homeostasis

Pathophysiology in Type 2 DM 1.Decreased insulin and increased glucagon

secretion result in...2.elevated hepatic glucose output...3. reduced insulin-mediated glucose uptake 4.Hyperglycaemia 5.Renal glucose filtration and reabsorption is

increased up to the renal threshold for glucose reabsorption (180 mg/dL): glucosuria

6.Glucotoxicity of all organs, exposing the individual to the risk of complications and further impairing insulin secretion and action

Pathophysiology of Type 2 diabetes

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

FPG 90 mg/dL

Insulin resistance is the decreased

response of the liver and peripheral tissues (muscle, fat) to

insulin Insulin resistance is a primary defect

in the majority of patients with Type 2

diabetes

Pathophysiology of Type 2 diabetes

Pathophysiology of Type 2 diabetes

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

2

FPG 90 mg/dL

Pathophysiology of Type 2 diabetes

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

2

3

FPG 90 mg/dL

Pathophysiology of Type 2 diabetes

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

2

3

FPG 90 mg/dL

4

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

2

3

4

GLUCOSURIA

GLUCOTOXICITY

FPG 180 mg/dL

Pathophysiology of Type 2 diabetes

FPG, fasting plasma glucose.Adapted from: DeFronzo RA. Ann Intern Med 1999;131:281–303; Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.

Insulin

Glucose

GlucagonInsulin-mediated glucose uptake by skeletal muscle and adipose tissue

Glucose filtration/

reabsorption

1

2

3

4

GLUCOSURIA

GLUCOTOXICITY

FPG 180 mg/dL

Pathophysiology of Type 2 diabetes

Glucogen synthesis

Glucose oxidation

Glucogen catabolism

Hepatic glucose production

Adipocytes uptake TG

Lipid synthesis (lipoproteinesterase activity )Lipid mobilization (Hormone sensitive lipase )

ketone (acetone, acetoacetic acid,beta-hydroxybutyric acid)

DeFronzo RA. Diabetes. 2009;58:773-795.

KIDNEY An adaptive response to

conserve glucose.......becomes maladaptive

in Type 2 diabetesGlucose

Normal urine GLUCOSURIA

GLUCOSE

SGLT2 plays a crucial role in renal glucose reabsorption

This highlights renal glucose reabsorption as a potential target for treatment of Type 2 diabetes

In Type 2 diabetes, the kidney’s maximum glucose reabsorption threshold is

exceeded, resulting in glycosuria

SGLT2, sodium-glucose co-transporter-2.

IncreasedHepatic

Glucose Production

Impaired Insulin Secretion

Hyperglycemia

Decreased GlucoseUptake

TZDsGLP-1 analoguesDPP-4 inhibitors

SulfonylureasThiazolidinediones

Metformin

MetforminThiazolidinediones

_

Pathophysiologic Approach to Treatment of T2DM

DeFronzo RA. Diabetes. 2009;58:773-795.

Mechanism of action-SU

nategliniderepaglinide (36 kD)

SUR

depolarization

ATPglimipiride（ 65 kD）

glyburide（ 140 kD）

Kir 6.2

SUR

Mechanism of action- acarbose

Acarbose

Oligosaccharide

Acarbose

Small intestinemucosa

Reversible inhibition of oligosaccharide breakdown by -glucosidases

SGLT-2 INHIBITORS

SGLTs

SGLT1 SGLT2

Site Mostly intestine with some in the kidney

Nearly exclusively in the kidney

Sugar specificity Glucose or galactose Glucose

Affinity for glucose HighKm = 0.4 mM

LowKm = 2 mM

Capacity for glucose transport Low High

Role Dietary glucose absorption Renal glucose reabsorption Renal glucose reabsorption

SGLT1/2, sodium-glucose co-transporter-1/2.Abdul-Ghani MA, et al. Endocr Pract 2008;14:782–90.

Counter regulatory hormones

Glucagon.

• The first line of defense against hypoglycemia in normals

• Glucagon rises rapidly when blood glucose levels fall and stimulates HGP.

• In type 1 diabetes, glucagon secretion in response to hypoglycemia may be lost.

Catecholamines.

• Produced at times of stress (“fight or flight”) • Stimulate release of stored energy. • Major defense against hypoglycemia in T1M

(POOR glucagon). • IF DEFECTIVE: Hypoglycemia unawareness:

severe and prolonged hypoglycemia: • Intensified glucose control only after a period

of hypoglycemia avoidance and restoration of catecholamine response.

Cortisol.

• increases at times of stress. • stimulate gluconeogenesis. • slower than glucagon• not effective in protecting against

acute hypoglycemia.

Growth hormone

• Slow effects on glucose metabolism.• major surge during sleep : rise in blood

glucose levels in the early morning: dawn phenomenon.

• In normal physiology, a slight increase in insulin secretion compensates

• In diabetes: variable morning hyperglycemia related to variable nocturnal growth hormone secretion.

T1D and advanced T2D: counterregulatory deficiencies and impaired symptomatic awareness

VISCIOUS CIRCLE

• Hyperglycemia : Glucotoxicity : more hyper

• Hypogycemia-associated autonomic failure (HAAF): more hypo

Hypoglycemia Unawareness

• No early warning symptoms of hypoglycemia • cognitive impairment may be first symptom • Clinical diagnosis• Reduced glucose thresholds for epinephrine-mediated warning

symptoms• Autonomic dysfunction: inadequate catecholamic release to

hypoglycemia.

Reversible!!

• Avoidance of even mild hypoglycemia for 2–4 weeks. • Adjustments in glycemic goals • Education to estimate and detect blood glucose level

fluctuations. • Increased monitoring of blood glucose • Modifying glycemic targets until hypoglycemia awareness is

regained. • Symptom recognition • AFTER regaining hypoglycemia awareness: reassess the

treatment plan to avoid episodes of hypoglycemia, especially• nocturnal hypoglycemia.

THANK YOU