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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