Antihyperglycemic action of Insulin and normal glucose metabolism

Blood glucose levels are maintained within narrow limits. In healthy individual overnight fasting glucose level is 70-90 mg/dl and post prandial level after meal do not exceed 140 mg/dl -180 mg/dl. Normoglycemia is restored within 2-4 hours. Among the hormones that regulate glucose level, Insulin is the only hormone that lowers glucose level.

Symptoms of hypoglycemia are seen if blood glucose is <60 mg/dl and the symptoms of hyperglycemia occurs at 215 mg/dl – 235 mg/dl.  

Fig. Antihyperglycemic action of insulin

Antihyperglycaemic actions of insulin

1.      Reduces production of gluconeogenic precursors like glycerol, alanine and lactate

2.      Inhibit gluconeogenic enzymes

3.      Inhibit hepatic glycogenolysis and stimulate glycogenesis.

4.      Increase cellular glucose uptake mediated by insulin sensitive GLUT4

5.      Reduces competition for glucose oxidation by alternative fuels (Randle effect) by inhibiting NEFA (Non-esterified fatty acid) release from adipose tissue and reducing hepatic ketogenesis.

Fig. Oral Antihyperglycemic Agents

NORMAL GLUCOSE METABOLISM

Glucose is derived from 3 main sources:

1.     Gut: By absorption from diet. Glucose, fructose and galactose are the principle carbohydrates resulting from digestive process.

2.      Stored glycogen (liver).

3.      Gluconeogenesis from non carbohydrate source.

Gluconeogenesis occurs in liver (75-90%) and kidneys (10-25%) from amino acids, glycerol, lactate and pyruvate.

Hepatic glucose output is about 2 mg/kg/min in resting postabsorptive state. Glucose is stored as glycogen (15-25%) in liver and >50% in skeletal muscle and lesser amount in other tissues. A 70 kg man has 700-1000 g hydrated glycogen.

Glycogen in skeletal muscle provides fuel for muscle but do not contribute to blood glucose as it lacks G-6-phosphatase.

Glucose is the main fuel for 24 hours. During high intensity exercise and 4-6h postprandial it is the predominant fuel of the whole body. Glucose liberates 112.2 kcal or 6 moles ATP per mole of oxygen consumed.

Glucose is fully oxidized in liver, muscle and brain. Brain utilizes most of the glucose in fasting state (100-124 g/24 h). During fasting or resting, state skeletal muscle takes up 10-20% hepatic glucose output: this is converted to lactate, pyruvate, glycerol or carbon skeletons of amino acids and then returned to liver for gluconeogenesis. Fatty acids or their derivative ketone bodies are the prime fuel of resting muscle, heart and liver. RBC, skin, adipose tissue and renal medulla derive energy from anaerobic glycolysis to produce lactate and pyruvate even in resting state.