Insulin

Insulin is a polypeptide hormone synthesized in the pancreas by β-cells, which construct a single chain molecule called proinsulin. 

Insulin, secreted by the β-cells of the pancreas in response to rising blood glucose levels, is a signal that glucose is abundant.

Insulin binds to a specific receptor on the cell surface and exerts its metabolic effect by a signaling pathway that involves a receptor tyrosine kinase phosphorylation cascade.

The pancreas secretes insulin or glucagon in response to changes in blood glucose.

Each cell type of the islets produces a single hormone: α-cells produce glucagon; β-cells, insulin; and δ-cells, somatostatin.

Insulin secretion

When blood glucose rises, GLUT2 transporters carry glucose into the b-cells, where it is immediately converted to glucose 6-phosphate by hexokinase IV (glucokinase) and enters glycolysis. The increased rate of glucose catabolism raises [ATP], causing the closing of ATP-gated K+ channels in the plasma membrane. Reduced efflux of K+ depolarizes the membrane, thereby opening voltage-sensitive Ca2+ channels in the plasma membrane. The resulting influx of Ca2+ triggers the release of insulin by exocytosis.

Insulin lowers blood glucose by stimulating glucose uptake by the tissues; the reduced blood glucose is detected by the β-cell as a diminished flux through the hexokinase reaction; this slows or stops the release of insulin. This feedback regulation holds blood glucose concentration nearly constant despite large fluctuations in dietary intake.

Insulin counters high blood glucose

Insulin stimulates glucose uptake by muscle and adipose tissue, where the glucose is converted to glucose 6-phosphate. In the liver, insulin also activates glycogen synthase and inactivates glycogen phosphorylase, so that much of the glucose 6-phosphate is channelled into glycogen.

Diabetes mellitus, caused by a deficiency in the secretion or action of insulin, is a relatively common disease. There are two major clinical classes of diabetes mellitus: type I diabetes, or insulin-dependent diabetes mellitus (IDDM), and type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), also called insulin-resistant diabetes. In type I diabetes, the disease begins early in life and quickly becomes severe. IDDM requires insulin therapy and careful, lifelong control of the balance between dietary intake and insulin dose.

Characteristic symptoms of type I (and type II) diabetes are excessive thirst and frequent urination (polyuria), leading to the intake of large volumes of water (polydipsia)

Type II diabetes is slow to develop (typically in older, obese individuals), and the symptoms are milder.

Essential vs. Nonessential Amino Acids

*The amino acids arginine, methionine and phenylalanine are considered essential for reasons not directly related to lack of synthesis. Arginine is synthesized by mammalian cells but at a rate that is insufficient to meet the growth needs of the body and the majority that is synthesized is cleaved to form urea. Methionine is required in large amounts to produce cysteine if the latter amino acid is not adequately supplied in the diet. Similarly, phenyalanine is needed in large amounts to form tyrosine if the latter is not adequately supplied in the diet.

Weak Acids and pKa

• The strength of an acid can be determined by its dissociation constant, Ka.

• Acids that do not dissociate significantly in water are weak acids.

• The dissociation of an acid is expressed by the following reaction: HA = H⁺ + A^- and the dissociation constant Ka = [H⁺ ][A^- ] / [HA]  

• When Ka < 1, [HA] > [H⁺ ][A^- ] and HA is not significantly dissociated. Thus, HA is a weak acid when ka < 1.

• The lesser the value of Ka, the weaker the acid.

• Similar to pH, the value of Ka can also be represented as pKa.

• pKa = -log Ka.

• The larger the pKa, the weaker the acid.

• pKa is a constant for each conjugate acid and its conjugate base pair.

• Most biological compounds are weak acids or weak bases.

Functions of  lipids

1. They are the concentrated fuel reserve of the body  (triacylglycerols).

2. Lipids are the constituents of membrane structure and regulate the membrane permeability (phospholipids  and cholesterol).

3. They serve as a source of fat soluble vitamins (A, D, E and K).

4. Lipids are important as cellular metabolic regulators (steroid  hormones and prostaglandins).

5. Lipids protect the internal organs, serve as insulating materials and give shape and smooth appearance to the body.

CLASSIFICATION OF ENZYMES

1. Oxidoreductases : Act on many chemical groupings to add or remove hydrogen atoms. e.g. Lactate dehydrogenase

2. Transferases Transfer functional groups between donor and acceptor molecules. Kinases are specialized transferases that regulate metabolism by transferring phosphate from ATP to other molecules. e.g. Aminotransferase.

3. Hydrolases Add water across a bond, hydrolyzing it. E.g. Acetyl choline esterase

4. Lyases Add water, ammonia or carbon dioxide across double bonds, or remove these elements to produce double bonds. e.g. Aldolase.

5. Isomerases Carry out many kinds of isomerization: L to D isomerizations, mutase reactions (shifts of chemical groups) and others. e.g. Triose phosphate isomerase

6. Ligases Catalyze reactions in which two chemical groups are joined (or ligated) with the use of energy from ATP. e.g. Acetyl CoA carboxylase

The input to fatty acid synthesis is acetyl-CoA, which is carboxylated to malonyl-CoA.

The ATP-dependent carboxylation provides energy input. The CO₂ is lost later during condensation with the growing fatty acid. The spontaneous decarboxylation drives the condensation. 

 fatty acid synthesis
acetyl-CoA + 7 malonyl-CoA + 14 NADPH → palmitate + 7 CO₂ + 14 NADP⁺ + 8 CoA

ATP-dependent synthesis of malonate:
8 acetyl-CoA + 14 NADPH + 7 ATP → palmitate + 14 NADP⁺ + 8 CoA + 7 ADP + 7 P_i

Fatty acid synthesis occurs in the cytosol. Acetyl-CoA generated in the mitochondria is transported to the cytosol via a shuttle mechanism involving citrate