单单单单单单单单单单单单单 Pathophysiology of T2 Diabetes and its Clinical implications. INTESSAR SULTAN MD, MRCP PROF. OF MEDICINE @ TAIBA UNIVERSITY. CONSULTANT ENDOCRINOLOGIST@ DC, KFH, MADINAH.
Lecture By Prof.Intessar Sultan Taibah Universty,Consultant Endocrinology,KFH,Madina
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1. Pathophysiology of T2 Diabetes and its Clinical
implications. INTESSAR SULTAN 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. .
3. NORMAL FUEL METABOLISM
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.
7. BRIAN Do not store glucose Dependent on glucose
8. Mechanisms and sources of glucose release in the
post-absorptive state Renal contribution: 2.02.5 mol/(kgmin)
(2025%) Hepatic contribution: 7.58.0 mol/(kgmin) (7580%) Hepatic
glycogenolysis: 4.55.5 mol/(kgmin) (4550%) Renal gluconeogenesis:
2.02.5 mol/(kgmin) (2025%) Hepatic gluconeogenesis: 2.53.0
mol/(kgmin) (2530%) Overall rate of glucose release: ~10
mol/(kgmin)
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 6070% is stored (glycogen) 30-40%
oxidized for immediate energy needs. Produce postprandial blood
glucose 90120 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.
14. HORMONAL REGULATION OF FUEL METABOLISM
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
17. Insulin secretion
18. 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.
19. 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
20. 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:
7283.
21. Insulin Secretion Fig. 47-1
22. 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 (U / ml) Plasma insulin (U/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: 491502.
23. Overview of Insulin and Action
24. Insulin Preparations Fig. 47-3
25. 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.
26. 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;131:281303;
Wright EM. Am J Physiol Renal Physiol 2001;280:F10F18.
27. 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
28. 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;131:281303; Wright EM. Am J Physiol Renal Physiol
2001;280:F10F18.
29. 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
30. 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;131:281303; Wright EM. Am J Physiol Renal Physiol
2001;280:F10F18.
31. 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;131:281303; Wright EM. Am J Physiol Renal Physiol
2001;280:F10F18.
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 4 Glucose filtration/ reabsorption
FPG, fasting plasma glucose. Adapted from: DeFronzo RA. Ann Intern
Med 1999;131:281303; Wright EM. Am J Physiol Renal Physiol
2001;280:F10F18.
33. 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;131:281303; Wright
EM. Am J Physiol Renal Physiol 2001;280:F10F18.
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;131:281303; Wright
EM. Am J Physiol Renal Physiol 2001;280:F10F18.
37. 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
kidneys 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.
39. Mechanism of action-SU repaglinide (36 kD) Kir 6.2
nateglinide SUR depolarization SUR ATP glimipiride65 kD
glyburide140 kD
40. Mechanism of action- acarbose Reversible inhibition of
oligosaccharide breakdown by -glucosidases Acarbose Acarbose
Oligosaccharide Small intestine mucosa
41. SGLT-2 INHIBITORS
42. 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;14:78290.
43. Counter regulatory hormones
44. 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.
45. 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.
46. Cortisol. increases at times of stress. stimulate
gluconeogenesis. slower than glucagon not effective in protecting
against acute hypoglycemia.
47. 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.
48. T1D and advanced T2D: counterregulatory deficiencies and
impaired symptomatic awareness
49. VISCIOUS CIRCLE Hyperglycemia : Glucotoxicity : more hyper
Hypogycemia-associated autonomic failure (HAAF): more hypo
50. 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.
51. Reversible!! Avoidance of even mild hypoglycemia for 24
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.
