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Biochemical Changes of Diabetes Mellitus

Regulation to Glucose Level


Too Low
Release 4 Hormones (
Glucose)
Glucagon
Cortisol
Epinephrine, Norepinephrine
GH
Liver (4 things)
Gluconeogenesis
Glycogen Breakdown
Ketone Bodies
FFA Acetyl CoA

Glucose Homeostasis
Balance between 2 sets of factors

Rate of Supply of glucose to blood

Rate of Removal of glucose from blood


Plasma 4.0 6.7 mM (70-120 mg/dL)

Addition in Blood
Absorption from intestine
Hepatic Glycogenolysis
Gluconeogenesis in Liver
Glucose obtained from other
CHO

Removal from Blood


Hepatic Glycogenesis
Glycogenesis in Muscles,
Tissues
Conversion to Fat
Oxidation of Glucose

Synthesis of Glycoprotein,
Glycolipid, Lactose, Ribose,
Fructose
Synthesis of Non-Essential a.a.
Fate of Glucose and its Utilization
Oxidation

Glycolysis (Embden-Meyerhof Pathway)

HMP-Shunt Pathway

Uronic Acid Pathway


Storage as Glycogen (Glycogenesis)
Conversion to Fats (Lipogenesis)
Converstion to Amino Acids
Conversions to other Carbohydrates

Ribose, Deoxyribose

Fructose

Galactose

Too High
Release Insulin
Glucose filtered into Kidney
(excretion in the urine)

Liver (3 things)
Gluconeogenesis
Glycogen Synthesis
Ketone Bodies

Disorders of Glucose Homeostasis


Hyperglycaemia
Hypoglycaemia
Diabetes Mellitus
Insulin Secreting Tumour
(Insulinoma)
Non-Diabetic causes
Postprandial
Factitious
Drug related
Non-Pancreatic Endocrine
Disease
Pancreatic Disorder
Stress
Renal Threshold, Glycosuria

Diabetes Mellitus
Definition
Metabolic disorder of Multiple Etiology
Characterized by
Chronic Hyperglycaemia
Disturbances of Carbohydrate, Fat, Protein Metabolism
Results from
Defects in Insulin Secretion
Defects in Insulin Action
Classification
Type 1 (T1DM)
Type 2 (T2DM)
Gestational Diabetes (GDM) CHO intolerance,
Hyperglycaemia, Pregnancy
Type 1 (T1DM)
Type 2 (T2DM)
cell destruction
Insulin Resistance
Leading to Absolute Insulin
(predominantly)
Deficiency
Relative Insulin Deficiency
Autoimmune
Secretory Defect
Idiopathic
(with/ without Insulin
Resistance)
Genetic defects of -cell
function
Genetic defects in Insulin
Action
Disease of Exocrine Pancreas
Endocrinopathies
Drug, Chemical Induced
Infection
5 10% of Diabetic Population
Older onset (40 y/o)
Juvenile Onset Diabetes
Majority (90% of Diabetics)
No pancreatic reserve of
Some Residual Pancreatic
Insulin
function
(must receive Insulin Therapy)
Prone to develop Ketosis
Wide fluctuation in blood
Obese, Sedentary Lifestyle
glucose
Prone to Toxic Ketones in
Blood
Diabetes Mellitus

Criteria for Diagnosis of DM, Impaired Glucose


Homeostasis
Diabetes Mellitus
Impaired Glucose
Homeostasis
+ve findings from any 2 tests
Impaired Fasting Glucose
Symptoms of DM + [Plasma
FPG 110-126 (6.1 - 7.0
Glucose] 200mg/dL (11.1
mmol/L)
mmol/L)
Impaired Glucose
FPG 126 mg/dL (7.0
Tolerance
mmol/L)
2h PPG 140-200 (7.75 11.1
mmol/L)
2h PPG 200 mg/dL (11.1
mmol/L)
after 75g Glucose Load
Normal
FPG < 110 mg/dL (6.1 mmol/L)
2h PPG < 140 mg/dL (7.75 mmol/L)
Oral Glucose Tolerance Test
Principle
Glucose Load [Blood Glucose]

Initiates Insulin Release from Pancreas (Islet cells)

Promote Uptake of Glucose into cells


Determine the Rate of [Blood Glucose]

Diagnosis of DM, Impaired Glucose Tolerance


Preparation of subject for OGTT

3 Days of Unrestricted Diet (contain 150g of


Carbohydrate)

Discontinue Medications that affect glucose metabolism for


3 Days
(Thiazides, OCP, Corticosteroid)

Avoid Exercise, Stress, Smoking, Coffee (before/ during


test)

Fasted Overnight (10 12 hours)

Test should be performed in the Next Morning (7 9 am)


(subject seated comfortably during test)
Procedure
Collect Blood for Basal [Glucose]
75g Glucose in 300ml of H2O orally (should be taken within 5
minutes)
Collect blood at 60, 120 minute after Oral Glucose Loading
Interpretation
Blood Sample
Normal
IGT
DM
5.5
5.6 6.0 mmol/L
6.1 mmol/L
Fasting
1h Post Glucose
Load
2h Post Glucose
Load

mmol/L
< 11.1
mmol/L

< 11.1 mmol/L

> 11.1
mmol/L

< 7.8
mmol/L

7.8 11.0
mmol/L

> 11.1
mmol/L

Insulin Secretion

Glucose Transported into -cell by GLUT2

Phosphorylation of Glucose Glucose-6-Phosphate


(catalyzed by Glucokinase)
(rate-limiting step in glycolysis)
(effectively trap glucose inside cell)

Glucose Metabolism Proceeds


(ATP produced in Mitochondria)

ATP:ADP ratio
ATP-gated K+ channels are closed
K+ (+ve charged) are prevented from leaving -cell

+ve charge
Cause -cell Depolarization

Voltage-gated Ca2+ channels open, Allow Ca2+ to Flow Into


Cell

Intracellular [Ca]
Trigger Secretion of Insulin (via exocytosis)

Effects of Insulin on Glucose Uptake, Metabolism

Insulin binds to receptor (1)

Start Protein Activation Cascades (2)

Translocation of GLUT-4 transporter to Plasma


Membrane
Influx of Glucose (3)
Glycogen Synthesis (4)
Glycolysis (5)
Fatty Acid Synthesis (6)

Effects of Insulin on Blood Levels of Important Materials


[Glucose]
Glucose Uptake into Muscle, Fat Cells (GLUT4 Transporter)
Glycolysis

Synthesis of 3 Glycolytic Enzymes in Liver


(Glucokinase, PFK, Pyruvate Kinase)

Stimulates PFK
(via production of F2, 6, BP)

Inhibition of Pyruvate Kinase in Liver


(via production of Protein Kinase A)
Glycogen Storage, Glycogen Breakdown in Liver, Muscle

Activate Glycogen Synthase (via dephosphorylation)


Gluconeogenesis in Liver, Kidney

Synthesis of 4 Gluconeogenetic enzymes (Liver, Kidneys)


o
Pyruvate carboxylase
o
PEPCK
o
Fructose-1-6-Bisphosphatase (Inhibit via
production of F26BP)
o
Glucose-6-Phosphatase (Liver only)
[Amino Acids]
Amino Acid Uptake (Muscle, Liver)
Protein Synthesis (Muscle, Liver)

Stimulate Transcription, Translation


Protein Breakdown (Muscle, Liver)
[Fatty Acid]
Fatty acid uptake (Adipose, Liver cells)

Activity of Lipoprotein Lipase on cell surface


Triglyceride Synthesis (Adipose, Liver cells)
Triglyceride Breakdown into FFA, Glycerol (Adipose, Liver
cells)

Inhibit hormone-sensitive Lipase


[K+, Magnesium, Phosphate]
Uptake of K+, Magnesium, Phosphate (Muscle, Fat cells)
[Ketone]
Triglyceride Breakdown (Liver)
( TG breakdown FFA -oxidation Acetyl-CoA
Ketone)
[Glucagon]
Inhibits Glucagon Secretion from -cells
Counter-Regulatory Hormones
Oppose action of Insulin
Excess production results in Hyperglycaemia
Starvation Hormones are released when glucose intake is
Stimulate Glucose production from

Glycogen (Glycogenolysis)

Protein (Gluconeogenesis)
Generation of Fatty Acids (via -oxidation)
Hormones

Glucagon

Cortisol

Cathecolamine (Adrenaline, Noradrenaline)

Growth Hormone

Failure of Metabolic Homeostasis in Diabetes Mellitus


Glucose Intolerance (All types of Diabetes)
Metabolism of Carbohydate, Fat, Protein are disturbed
Insulin Deficiency (Absolute, Relative)
Affect Glucose, Lipid, Protein, Potassium, Phosphate Metabolism
Indirectly influence H2O, Na+ Homeostasis
Severe cases of Untreated DM
Hyperglycaemia
Ketoacidosis
Triglycerides
Fatty Acids
Potassium
Phosphate
Disturbance of Acid-Base Balance
Disturbance of H2O, Na+ Metabolism
Long Term Effects of DM (Glucose Toxicity)
Progressive development of specific complications of

Retinopathy

Nephropathy

Neuropathy

Sexual Dysfunction

Risk
o
Cardiovascular Disease
o
Peripheral Vascular Disease
o
Cerebrovascular Disease
Biochemistry of Diabetes Mellitus
Hyperglycaemia
Hepatic Glucose Production

Gluconeogenesis, Glycogenolysis

Unopposed action of Glucagon, Adrenaline, Cortisol


Peripheral Uptake

Insulin Deficiency Inhibits cellular Glucose Uptake,


Glycolysis

Substrates other than Glucose (Fatty Acids, Ketones) are


substituted for energy production
Disturbances of Protein Metabolism
Catabolic State
Protein Wasting (due to Gluconeogenesis)
175g of Protein Destroyed, 100g of Glucose Produced
Disturbances of Fat Metabolism
Stimulate Lipolysis (Release of Fatty Acids into circulation)
Fatty Acids taken up by cells, converted to energy (-oxidation)
(Ketones, Triglycerides released from Liver in form of VLDL)
Insulin Deficiency

Inhibits Lipoprotein Lipase activity

Depresses clearance of VLDL, Chylomicrons

TG
TG Breakdown in Liver

FFA

Packaging of FFA into VLDLs, Chylomicrons


(for Delivery to Peripheral Tissues)
Hypertriglyceridemia
Packaging of FFA into VLDLs, Chylomicrons + Lipoprotein
Lipase Activity
Hyperkalemia
Direct action of Insulin = Cellular Uptake of K+
In Insulin Deficiency

K+ leaks out of cells

Results in Hyperkalemia
When Insulin Administered

Extracellular K+ returns to cells

Result in Severe Hypokalemia (unless K+ supplement are


administered)
Hyperphosphataemia
Insulin

Stimulating Glycolysis (utilize Inorganic Phosphate for ATP


production)

Cellular Phosphate Uptake


In Insulin Lack

Phosphate leaks of out cells

Results in Plasma levels of Phosphate


Acid-Base Disturbances
Type 1 Diabetes ( Anion Gap Metabolic Acidosis Diabetic
Ketoacidosis)

Plasma [Bicarbonate] to < 5mmol/L (pH as low as 6.80)


TG Breakdown, -oxidation of FFAs Acetyl CoA Ketone
formation
Sodium, Water Distrubances
Hyponatraemia
(due to Extracellular Osmolality Hyperglycaemia,
Hyperlipidaemia)
(H2O out of cells into Extracellular compartment Dilutional
Hyponatraemia)
Urinary Na+ loss (consequences of Osmotic Diuresis)
H2O intake (ill, confused patients)

Insulin Deficiency

Long Term of Diabetes


Small Vessel Disease
Complications
(Microangiopathy)
Proliferative Retinopathy
Macular Edema
(Vision Loss, Blindness)
Peripheral Neuropathy
Damaged Blood Vessels
(Foot Ulcers Necrosis,
Infection, Gangrene)(Require
Amputation)
Diabetic Nephropathy
(Renal Failure)

Large Vessel Disease


Complications
(Macroangiopathy)
Ischemic Heart Disease
(Large, Small Vessel Disease)
Stroke
Peripheral Vascular Disease
(Foot Ulcers)(Require
Amputation)

Sorbitol do not cross cell


membranes
Accumulates Intracellularly
Produce Osmotic Stress