Diabetes which is scientifically known as Diabetes mellitus, primarily manifests as excessive blood glucose levels mostly due to the decreased production of Insulin. Diabetes mellitus is diagnosed When the fasting blood glucose level is more than 126 mg/dl.
In India, Genetics is the primary cause of diabetes, followed by an increasingly sedentary lifestyle and a high-calorie diet that is growing in middle-class families in India. 7% of the adult population is suffering from a metabolic disorder called Diabetes mellitus.
There are two types of Diabetes mellitus:
A. Type 1
B. Type 2.
Type 1 diabetes is treated by insulin treatment, whereas in type 2, Insulin treatment is used when oral therapy of hypoglycaemic agents is found to be ineffective.
Classification of drugs:
Anti-diabetic drugs are used to treat diabetes, also known as antihyperglycemic agents.
Primarily, anti-diabetic drugs are classified according to the route of administration, i.e., oral and parenteral.
Oral anti-diabetic drugs are classified as:
- Drugs that act by other mechanisms
- Drugs which act by releasing insulin.
Parenteral anti-diabetic drugs are classified as:
- Insulin
- Amylin analogues
- GLP-1 analogues
Drugs that act by releasing insulin:
These anti-diabetic drugs release insulin by inhibiting ATP-sensitive K+ channels, causing depolarization of beta cells, opening ca 2+ channels leading to the entry of ca2+ into beta cells, which results in the release of insulin from granules.
Drugs are further classified into Meglitinides and Sulfonylureas:
Meglitinides:
It is also called D-phenylalanine analogues of anti-diabetic drugs. These drugs have the same mechanism of action of releasing insulin by inhibiting ATP-sensitive K+ channels, having quick and short-lasting action.
Nateglinide:
It acts by inhibiting beta cells KATP channels, giving it faster-acting and shorter-lasting action. It is advisable to ingest nateglinide 10 minutes before a meal. Nateglinide is a D-phenylalanine derivative.
Repaglinide:
It is given orally. It acts by depolarization of K+ resulting in insulin release. It is rapidly metabolized and quickly absorbed. It shows less fast action and shorter-lasting anti-diabetic action than Nateglinide. This drug is avoided in liver disease.
Sulfonylureas:
First-generation anti-diabetic drugs: chlorpropamide, tolazamide, acetohexamide, and tolbutamide.
Second-generation anti-diabetic drugs: glyburide, glimepiride, and glipizide
All these drugs have side effects such as hypoglycaemia and hypersensitivity. They should be avoided in nursing mothers due to the secretion of sulfonylureas in the milk. Chlorpropamide has been discontinued due to frequent hypoglycaemia, cholestatic jaundice, and alcohol flush.
Drugs acting by other Mechanisms:
Thiazolidinediones:
Currently, Pioglitazone is the only one Thiazolidinedione currently available. Without circulating insulin, it reduces blood glucose and HbA1C. Primarily Pioglitazone is used for insulin resistance with other insulin-releasing anti-diabetic drugs like Sulfonylureas. It has shown non-effectiveness in beta cell failure. Weight gain and CHF are its major side effects.
Biguanide:
In the 1950s, Phenformin and Metformin are two Biguanide anti-diabetic drugs that were introduced. Phenformin has been banned in India since 2003 due to lactic acidosis.
Metformin:
Metformin is different from Sulfonylureas due to having a less frequent cause of hypoglycaemia. Not only in diabetes, but Metformin has also shown improvement in lipid profile in type 2 diabetics. It has also been effective for weight loss.
Biguanide
Biguanide acts by activation of AMPK. It does not have any serious side effects excluding Phenformin.
α-Glucosidase inhibitors Acarbose reversibly inhibits alpha-glucosidases, resulting in a decrease in the digestion of starch and sucrose, reducing postprandial glycemia, without a significant increase in insulin. It reduces cardiac events in diabetics.
Amylin analogues:
Amylin acts to reduce the secretion of glucagon in the brain from alpha cells.
Pramlintide:
It is a synthetic amylin analogue which can be injected s.c. before meal, which helps to suppress glycaemic peaks in type 1 and type 2 diabetes as well. With anti-diabetic effects,
Insulin:
To correct the metabolic abnormalities, regular insulin is used. Insulin is administered externally due to inadequate production of it. Insulin primarily works in or is found extracellularly.
The synthesis of insulin occurs in beta cells of pancreatic islets. Insulin acts on a receptor called a receptor tyrosine kinase. This receptor has 2 extracellular α and 2 transmembrane b subunits. The binding site of insulin is carried by the beta subunit while tyrosine protein kinase activity is carried by alpha subunits. When insulin binds with alpha subunits, it activates the receptor and binds with insulin molecules, activating tyrosine kinase, resulting in the phosphorylation of tyrosine by pairs of beta subunits. Phosphorylation and dephosphorylation result in the stimulation or inhibition of enzymes involved in the rapid metabolic action of insulin.
The regulation of glucose levels in the bloodstream is carried out by insulin, which also regulates the storage of glucose in muscles, the liver, and adipose tissue.
Complications of insulin therapy:
• Hypoglycemia is the most common complication of insulin, treated by glucagon (i.v.), glucose, and glucose (oral or i.v.).
• From conventional preparations, Lipoatrophy (Allergic reactions) can occur.
• Edema can be caused due to Sodium and water retention; however, it has been rarely reported.
Glucagon:
Cleavage of a large peptide prohormone is the derivation of glucagon, like insulin. Most of the action of glucagon is opposite to that of insulin. Glucagon enhances Glycogenolysis and gluconeogenesis in the liver resulting in hypoglycemia. Glucagon cannot be given orally due to it getting a break in the liver. Kidney and plasma. It acts by its own receptor and coupling Gs protein resulting in activation of adenylyl cyclase and increases cAMP in the liver.
To manage diabetes, it is advisable to improve lifestyle and diet rather than just sticking to medicine. It has been studied that lifestyle change can have a huge effect on diabetes.
Reference:
KD Tripathi, Essential of Medical pharmacology- seventh edition – pg no 258-281.
Gobind Rai Garg Sparsh gupta – Review of pharmacology – pg no 235-289.
Harsh Mohan- Textbook of pathology-seventh edition- pg no 808-812.
