pathophysiology of diabetes by dr shahjada selim
TRANSCRIPT
Pathophysiology of Type 2 Diabetes
Dr Shahjada Selim Assistant Professor
Department of EndocrinologyBangabandhu Sheikh Mujib Medical University, Dhaka
Email: [email protected]
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.
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