Oral Antidiabetics | Medical Science Optional Notes for UPSC PDF Download

Insulin

Insulin Mechanism of Action

Binding of insulin to its receptor triggers the activation of intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). IRS, along with other adaptor proteins, initiates a complex cascade of phosphorylation and dephosphorylation reactions, leading to the widespread metabolic and mitogenic effects of insulin.

• The activation of the PI-3-kinase (Phosphatidylinositol-3 kinase) pathway promotes the translocation of glucose transporters (GLUT4) to the cell surface. This crucial event facilitates glucose uptake by skeletal muscle and fat, inducing glycogen synthesis, protein synthesis, and lipogenesis.
• Simultaneously, activation of alternative insulin receptor signaling pathways, such as the MAP kinase pathway, induces cellular proliferation and growth. Additionally, these pathways regulate the expression of various genes in insulin-responsive cells.

Insulin Actions

Adverse Effects of Insulin

• Hypoglycemia
• Increased body weight
• Lipodystrophy at the injection site
• Pain and redness at the injection site
• Reduced potassium levels (Hypokalemia)
• Rare occurrences of allergic reactions
• Rare instances of edema

Insulin Analogues

The absorption, distribution, metabolism, and excretion (ADME) of naturally occurring insulin are altered by modifying the amino acid sequence of insulin through genetic engineering. These modified insulins are also referred to as insulin receptor ligands.

Types of Insulin

Newer Insulin Delivery Devices

• Pre-filled disposable syringes for insulin - These syringes come pre-loaded with specific types or combinations of regular and modified insulins.
• Pen devices - Resembling fountain pens, these devices utilize insulin cartridges for subcutaneous injection through a needle. Preset amounts (in 2 U increments) are administered by pushing a plunger, making them convenient for carrying and injecting.
• Inhaled insulin - An inhaled human insulin preparation was introduced in Europe and the USA but later withdrawn due to the risk of pulmonary fibrosis and other complications. The fine powder, delivered through a nebulizer, controlled mealtime glycemia but was not suitable for maintaining round-the-clock basal effects.
• Insulin pumps - These portable infusion devices, connected to a subcutaneously placed cannula, offer "continuous subcutaneous insulin infusion" (CSII). However, their cost, the need for strict adherence to diet and exercise, care of the device and cannula, and the risk of pump failure and site infection can be demanding for the patient.
• Implantable pumps - These pumps consist of an electromechanical mechanism that regulates insulin delivery from a percutaneously refillable reservoir.

Indications for Insulin Therapy

• Diabetes Mellitus Type 1
• Individuals recently diagnosed with diabetes exhibiting significantly elevated A1C levels (> 8.5%) or experiencing symptomatic diabetes
• Patients facing inadequate glycemic control (with the target A1C not achieved) after a 3-month treatment period using metformin or another antidiabetic medication
• Diabetes resulting from pancreatic insufficiency
• Diabetes during pregestational and gestational phases
• Individuals with end-stage renal failure (note: oral antidiabetic drugs are contraindicated in such cases)
• Emergency treatment for acute hyperkalemia involves administering a drip containing regular insulin and a glucose solution to reduce blood potassium levels.

Early Morning Hyperglycemia

Dawn phenomenon, a frequent issue, particularly in young individuals with type 1 diabetes, is characterized by early-morning hyperglycemia. This occurrence is attributed to the physiological rise in growth hormone levels during the early morning hours, stimulating hepatic gluconeogenesis. Insulin-dependent patients experience an increased demand for insulin, which cannot be adequately met, leading to elevated blood glucose levels in the morning.

Treatment involves assessing nocturnal blood glucose levels before initiating insulin therapy. Adjustments may include administering the long-acting insulin dose later, around 11 p.m., or increasing it under careful glycemic control. In children, treatment with an insulin pump may be considered.

The Somogyi effect is a rarer phenomenon marked by early-morning hyperglycemia resulting from counterregulatory hormone secretion triggered by nocturnal hypoglycemia following an evening insulin injection.

Treatment for the Somogyi effect entails reducing the evening dose of long-acting insulin.

Anti Diabetic Agents - Repeat

• Define insulin analogues and elaborate on their mechanism of action, highlighting their advantages over regular insulin (2009).
• Examine the mechanism of action of Rosiglitazone (2010).
• Provide a detailed discussion on the mechanism of action, clinical applications, and side effects of Metformin (2013/2018).
• Explore the mechanism of action and potential side effects of Sitagliptin (2015), as well as the mechanism of action and side effects of Sulfonylureas (2017).