Question

Describe in detail the action of insulin. Be sure to include a description of what it is (what kind of biomolecule/class of hormone), how its secretion is regulated, where specifically it is secreted from, its general effects on body cells, and finally each of its specific effects (if it has any) on: skeletal muscle, the liver, adipose tissue, and blood glucose levels.

Answer 1

Structure of Insulin
Insulin is a peptide hormone consisting of two chains, A and B, which are connected by disulfide bridges. The molecular weight of insulin is 6,000:
1. The A chain contains 21 amino acids and B chain 30
amino acids.
2. The final structure of insulin is determined by the
N­terminal and C­terminal amino acids of A chain, and the hydrophobic character of the amino acids at the C­terminal of B chain.
3. However, the hydrophobic character of the amino acids at the C­terminal of B chain is important for bio­ logical activity of insulin.

Secretion of Insulin
Insulin secretion is greatly influenced by plasma glucose concentration. Elevation of glucose level in plasma is an important stimulator of insulin secretion. It is produced in the pancreas by the Islets of langerhans.

Regulation of Insulin Secretion
Insulin secretion is mainly regulated by the feedback con­ trol signal provided by nutrients level in plasma. When the nutrients are more, insulin secretion increases to facilitate their metabolism and use, and when nutrients are less, insulin secretion is less.

Plasma Glucose
Glucose is the most important stimulator of insulin secre­ tion. With the rise in plasma glucose level, there is almost a linear rise in plasma insulin concentration in the range of 50–300 mg% of plasma glucose. Insulin secre­ tion is almost nil below 50 mg% and no extra secretion above 300 mg% of plasma glucose. The secretion of insulin in response to rise in plasma glucose concentration occurs in two phases.
First Phase Response
Immediately following the rise in plasma glucose (in response to i.v. glucose infusion), insulin secretion increases rapidly to reach a peak within 1–2 minutes and then decreases to basal level in another 2 to 3 minutes.
1. This is the first and rapid phase of insulin secretion in response to sudden increase plasma glucose concen­ tration.
2. The first phase response is due to release of already synthesized and stored insulin from granules of b cells.

Second Phase Response
In the next phase, the rise in plasma insulin concentration occurs slowly that reaches a peak in about 60 minutes and then remains elevated for 3–5 hours. The second and slow phase insulin response is due to stimulation of insulin synthesis and secretion.

Mechanism of Glucose-induced Insulin Secretion
Glucose enters betacells of pancreas via GLUT 2:
1. In the b­etacells, glucose is utilized by glycolytic enzymes to pyruvate that enters TCA cycle to produce ATP.
2. Increased intracellular ATP inhibits ATP-sensitive K+ channels, which increases cytosolic K+ by decreasing K+ efflux.
3. This depolarizes the b cells, which in turn opens the Ca++ channels. Ca++ influx increases cytoplasmic Ca++ that facilitates Ca++-mediated exocytosis of insulin granules.
4. Plasma K+ is a natural regulator of insulin secretion. Hypokalemia decreases insulin secretion.

Response depends on route of administration: The insulin response to plasma glucose depends on the route of glucose administration:
The response of insulin secretion to orally adminis-tered glucose is more than the glucose administered intravenously.
When given orally, glucose stimulates secretion of hor­ mones from gastrointestinal tracts. Many GI hormones such as gastrin, secretin, enteroglucagon, GLP1, and GIP are insulinogenic.
They stimulate insulin secretion in addition to its secretion that occurs due to rise in plasma glucose

In Liver
In liver, insulin promotes glucose storage and prevents its production by following mechanisms:
1. Insulin facilitates glucose entry into the hepatic cell by
inducing the action of the enzyme glucokinase. Glucoki­nase catalyzes phosphorylation of glucose to glucose­ 6­phosphate. Thus, by facilitating glucose entry into the cells and also simultaneously converting glucose into glucose-6 phosphates, insulin keeps cytoplasmic glu­ cose concentration at lower level. Therefore, facilitated diffusion of glucose into the cell continues.
2. It stimulates glycolysis by activating the enzymes phosphofructokinase and pyruvate kinase. These actions convert glucose into pyruvic and lactic acids. Pyruvate and lactate are also oxidized by insulin as it stimulates pyruvate dehydrogenase activity. Thus, insulin decreases the cellular concentration of glucose and consequently helps in its facilitated diffusion into the cell.
3. It promotes glycogen synthesis in liver. In the liver cells, it activates the enzyme glycogen synthase com- plex that promotes formation of glycogen. Thus, it pro­ motes storage of glucose in the form of hepatic glycogen.
4. It inhibits hepatic glycogenolysis, and therefore it decreases hepatic glucose output. Insulin achieves it by inhibiting the activity of the enzymes glycogen phosphorylase and glucose-6-phosphatase.

5. It also inhibits gluconeogenesis. This is achieved by two mechanisms: (i) insulin inhibits gluconeogenic enzymes (pyruvate carboxylase, phosphoenolpyruvate carbox- ykinase, and fructose-1, 6-diphosphatase), and (ii) insulin decreases hepatic uptake of gluconeogenic amino acids

In Adipose Tissue
Insulin stimulates entry of glucose into the adipose tissue cells by activating GLUT 4 and hexokinase activity:
1. In fat cells, glucose is then converted into a-glycero-
phosphate (a­GP). The a­GP is used for the esterifica-
tion of fatty acids.
2. It also promotes storage of fatty acids as triglycerides.

In Skeletal Muscle
Insulin facilitates transport of glucose into the muscle cells by activating GLUT 4 and hexokinase activity:
1. In muscle cell, glucose is oxidized by activation of the
enzyme pyruvate dehydrogenase.
2. Glucose is also stored as muscle glycogen, which is
stimulated by insulin.

On blood glucose levels

Binding of insulin with receptors rapidly mobilizes glucose transport into the muscle and adipose tissue cells. This process of glucose entry in to the cell is increased by about 20 times by the activation of a glucose carrier system in the plasma membrane:
Insulin rapidly recruits the glucose transporter 4 (GLUT­4), which is specifically meant for insulin­stimu­ lated glucose uptake in skeletal and cardiac muscle, adipose tissue and other tissues.Due to this mechanism the blood glucose levels will reduce.