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Pathophysiology of diabetes final 2
1. Pathophysiology of T2 Diabetes and its
Clinical implications.
INTESSAR SULTAN
单击此处编辑母版副标题样式
MD, MRCP
PROF. OF MEDICINE @ TAIBA UNIVERSITY.
CONSULTANT ENDOCRINOLOGIST@ DC, KFH,
MADINAH.
2. 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.
.
4. 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
5. 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.
6. 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.
8. Mechanisms and sources of glucose
release in the post-absorptive state
Renal contribution:
2.0–2.5
μmol/(kg−min)
(20–25%)
Hepatic contribution:
7.5–8.0
μmol/(kg−min)
(75–80%)
Hepatic
glycogenolysis:
4.5–5.5
μmol/(kg−min)
(45–50%)
Renal
gluconeogenesis:
2.0–2.5
μmol/(kg−min)
(20–25%)
Hepatic
gluconeogenesis:
2.5–3.0
μmol/(kg−min)
(25–30%)
Overall rate of glucose
release:
~10 μmol/(kg−min)
9. 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 .
10. 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
11. 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
12. 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.
13. 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.
15. 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
16. Major Metabolic Effects of Insulin and Consequences of
Insulin Deficiency
Insulin effects: Stimulates glucose uptake into muscle and
adipose cells: lipogenesis + inhibits lipolysis
Consequences 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
19. 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.
20. 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
21. 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.
23. Loss of Early-phase Insulin Release in Type 2 Diabetes
Pattern of insulin release is altered early in Type 2 diabetes
120
100
20g
glucose
80
60
40
20
0
–30 0 30 60 90 120
Time (minutes)
Type 2 diabetes
Plasma insulin (µU / ml)
Plasma insulin (µU/ml)
Normal
120
20g glucose
100
80
60
40
20
0
–30 0 30 60 90 120
Time (minutes)
Adapted from Ward WK et al. Diabetes Care 1984; 7: 491–502.
26. 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.
27. Normal glucose homeostasis
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
FPG 90 mg/dL
Glucose
Glucose
filtration/
reabsorption
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.
28. 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
29. Pathophysiology of Type 2
diabetes
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
1
Insulin
FPG 90 mg/dL
Glucose
Glucose
filtration/
reabsorption
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.
30. Pathophysiology of Type 2 diabetes
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
31. Pathophysiology of Type 2
diabetes
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
1
FPG 90 mg/dL
2
Glucose
Glucose
filtration/
reabsorption
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.
32. Pathophysiology of Type 2
diabetes
3
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
1
FPG 90 mg/dL
2
Glucose
Glucose
filtration/
reabsorption
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.
33. Pathophysiology of Type 2
diabetes
3
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
1
FPG 90 mg/dL
2
Glucose
4
Glucose
filtration/
reabsorption
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.
34. Pathophysiology of Type 2 diabetes
3
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
1
FPG 180 mg/dL
2
GLUCOTOXICITY
Glucose
4
Glucose
filtration/
reabsorption
GLUCOSURIA
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.
35. Pathophysiology of Type 2 diabetes
3
Insulin-mediated glucose uptake by
skeletal muscle and adipose tissue
Glucagon
Insulin
1
FPG 180 mg/dL
2
GLUCOTOXICITY
Glucose
4
Glucose
filtration/
reabsorption
GLUCOSURIA
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.
38. KIDNEY
An adaptive response to
conserve glucose....
Glucose
...becomes maladaptive
in Type 2 diabetes
GLUCOSE
SGLT2 plays a crucial role in
renal glucose reabsorption
In Type 2 diabetes, the
kidney’s maximum glucose
reabsorption threshold is
exceeded, resulting in
glycosuria
This highlights renal glucose
reabsorption as a potential target
for treatment of Type 2 diabetes
Normal urine
GLUCOSURIA
SGLT2, sodium-glucose co-transporter-2.
41. Mechanism of action- acarbose
Reversible inhibition of oligosaccharide
breakdown by -glucosidases
Acarbose
Acarbose
Oligosaccharide
Small intestine
mucosa
43. 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
High
Km = 0.4 mM
Low
Km = 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.
45. 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.
46. 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.
47. Cortisol.
•
•
•
•
increases at times of stress.
stimulate gluconeogenesis.
slower than glucagon
not effective in protecting against
acute hypoglycemia.
48. 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.
49.
50. T1D and advanced T2D: counterregulatory
deficiencies and impaired symptomatic awareness
52. 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.
53. 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.
The kidneys and the liver both contribute to the overall quantity of glucose produced by the body (approximately 10 μmol/kg min in total). The human liver and kidneys provide roughly equal amounts of glucose via gluconeogenesis in the post-absorptive state, but the overall production by the liver exceeds that of the kidney due to additional hepatic glycogenolysis.The liver releases the majority of glucose in the post-absorptive state (75–80%) by gluconeogenesis (25–30%)from precursors such as lactate, glycerol, alanineGlycogenolysis makes up the rest of the liver’s glucose production (45–50%, from breakdown of stored glycogen)The kidney, by contrast, contributes 20–25% of the overall glucose productionThe kidney stores very little glycogen and most renal cells lack the necessary enzyme for glucose release from glucagon; hence its glucose production comes entirely from gluconeogenesisReference:Gerich JE. Diabet Med 2010;27:136–42.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
<Note: Slide title is animated and cannot be viewed properly in slide notes view>Under normal conditions, glucose homeostasis is kept under tight control.The pancreas, skeletal muscle, liver, adipose tissue and kidney are all important in regulating plasma glucose concentrationsInsulin from the pancreas mediates glucose uptake by skeletal muscle and adipose tissue when blood glucose is high, whilst glucagon increases hepatic glucose secretion when blood levels are lowThe kidney mediates glucose filtration and reabsorptionIn Type 2 diabetes, a number of pathophysiological changes take place:Decreased insulin and increased glucagon secretion result in......elevated hepatic glucose output...... and reduced insulin-mediated glucose uptake in the peripheryAs a result, hyperglycaemia occursUnder these circumstances renal glucose filtration and reabsorption is increased up to the renal threshold for glucose reabsorption (about 180 mg/dL), above which glucosuria developsDevelopment of hyperglycaemia causes glucotoxicity, which affects all organs, exposing the individual to the risk of complications and further impairing insulin secretion and actionReferences:DeFronzo RA. Ann Intern Med 1999;113:281–303.Wright EM. Am J Physiol Renal Physiol 2001;280:F10–F18.
The adaptive response of the kidney – reabsorption of glucose to provide substrate for energy generation – is largely mediated by SGLT2. Under normal conditions, glucose is filtered and reabsorbed in the kidney, predominantly by SGLT2, and none appears in the urineThis response becomes dysregulated in Type 2 diabetes, when, due to greater expression of SGLT2 (in part a result of hyperglycaemia), glucose filtration and reabsorption is increased. However, excess glucose concentrations also exceed the maximum reabsorption threshold of SGLT2, resulting in glycosuriaIt is therefore possible that renal glucose reabsorption could be targeted to reduce plasma glucose concentrations in patients with Type 2 diabetes
At least five different genes encoding SGLTs have been identified in humans, but only two (SGLT1 and 2) have been well characterised.SGLT1 is a high-affinity, low-capacity transporter that is mostly expressed in the intestine, with lesser expression in the kidney. SGLT1 plays a role in absorption of glucose from both the diet and the glomerular filtrateSGLT2 is a low-affinity, high-capacity transporter that is exclusively expressed in the kidney. It is responsible for the majority (~90%) of glucose reabsorption from the glomerular filtrateReference:Abdul-Ghani MA, et al. EndocrPract2008;14:782–90.