Biochemical Cha nges of Diabetes Mellitus

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 Removal from Blood

Absorption from intestine Hepatic Glycogenesis

Hepatic Glycogenolysis Glycogenesis in Muscles, Tissues

Gluconeogenesis in Liver Conversion to Fat

Glucose obtained from other CHO 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

Regulation to Glucose Level

Too Low Too High

Release 4 Hormones (↑ Glucose)

Glucagon

Cortisol

Epinephrine, Norepinephrine

GH

Release Insulin

Glucose filtered into Kidney

(excretion in the urine)

Liver (4 things)

↑ Gluconeogenesis

↑ Glycogen Breakdown

↑ Ketone Bodies

↑ FFA → Acetyl CoA

Liver (3 things)

↓ Gluconeogenesis

↑ Glycogen Synthesis

↓ Ketone Bodies

Disorders of Glucose H omeostasis

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

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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)

β cell destruction

Leading to Absolute Insulin Deficiency

Insulin Resistance (predominantly)

Relative Insulin Deficiency

Secretory Defect

(with/ without Insulin Resistance)

Autoimmune

Idiopathic

Genetic defects of β-cell function

Genetic defects in Insulin Action

Disease of Exocrine Pancreas

Endocrinopathies

Drug, Chemical Induced

Infection

5 – 10% of Diabetic Population

Juvenile Onset Diabetes

No pancreatic reserve of Insulin

(must receive Insulin Therapy)

Wide fluctuation in blood glucose

↑ Prone to Toxic Ketones in Blood

Older onset (≥40 y/o)

Majority (90% of Diabetics)

Some Residual Pancreatic function

↓ Prone to develop Ketosis

Obese, Sedentary Lifestyle

Diabetes Mellitus

Criteria for Diagnosis of DM, Impaired Glucose Homeostasis

Diabetes Mellitus Impaired Glucose Homeostasis

+ve findings from any 2 tests Impaired Fasting Glucose

FPG 110-126 (6.1 - 7.0 mmol/L) Symptoms of DM + [Plasma Glucose ]

≥ 200mg/dL (11.1 mmol/L) Impaired Glucose Tolerance

2h PPG 140-200 (7.75 – 11.1 mmol/L) FPG ≥ 126 mg/dL (7.0 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 β 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

Fasting ≤ 5.5 mmol/L 5.6 – 6.0 mmol/L ≥ 6.1 mmol/L

1h Post Glucose Load < 11.1 mmol/L < 11.1 mmol/L > 11.1 mmol/L

2h Post Glucose Load < 7.8 mmol/L 7.8 – 11.0 mmol/L > 11.1 mmol/L

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Insulin Secretion

Glucose Transported into β-cell by GLUT2

↓

Phosphorylation of Glucose → Glucose -6-Phosphate

(catalyzed by Glucokinase)

(rate-limiting step in glycolysis)

(effe ctively 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 β-cell ↓

↑ +ve charge

Cause β-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)

↓ [Fa5y 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-se nsitive Lipase

↓ [K+, Magnesium, Phosphate]

Uptake of K+, Magnesium, Phosphate (Muscle, Fat cells)

↓ [Ketone]

↓ Triglyceride Breakdown (Liver)

(↓ TG breakdown → ↓ FFA → ↓ β-oxidation → ↓ Acetyl-CoA → ↓ Ketone)

↓ [Glucagon]

Inhibits Glucagon Secretion from α-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 β-oxidation)

Hormones

• Glucagon

• Cortisol

• Cathecolamine (Adrenaline, Noradrenaline)

• Growth Hormone

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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 a ction 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 (β-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-Ba se Disturbance s

Type 1 Diabetes (↑ Anion Gap – Metabolic Acidosis – Diabetic Ketoacidosis)

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

TG Breakdown, β-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)

Large Vessel Disease Complications

(Macroangiopathy)

Proliferative Retinopathy

Macular Edema

(Vision Loss, Blindness)

Ischemic Heart Disease

(Large, Small Vessel Disease)

Stroke

Peripheral Neuropathy

Damaged Blood Vessels

(Foot Ulcers – Necrosis, Infection,

Gangrene)(Require Amputation)

Peripheral Vascular Disease

(Foot Ulcers)(Re quire Amputation)

Diabetic Nephropathy

(Renal Failure)

Sorbitol do not cross cell membranes

Accumulates Intracellularly

Produce Osmotic Stress

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