pathophysiology of diabetes final 2

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Pathophysiology of T2 Diabetes and its Clinical implications.

INTESSAR SULTAN

MD, MRCP

PROF. OF MEDICINE @ TAIBA UNIVERSITY.

CONSULTANT ENDOCRINOLOGIST@ DC, KFH, MADINAH.

DEFINITION

Diabetes mellitus is metabolic disorder of multiple aetiology characterized by chronic

hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion,

insulin action, or both.

.

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 diabetes120

100

80

60

40

20

0

–30 0 30 60 90 120Time (minutes)

–30 0 30 60 90 120Time (minutes)

Pla

sma

insu

lin

(µ

U/m

l)

120

100

80

60

40

20

0

20g glucose20g

glucose

Pla

sma

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

SiteMostly intestine with some in the kidney

Nearly exclusively in the kidney

Sugar specificity Glucose or galactose Glucose

Affinity for glucoseHighKm = 0.4 mM

LowKm = 2 mM

Capacity for glucose transport

Low High

RoleDietary 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