Makindo Medical Notes

Insulin Production

• The gene for insulin is located on Chromosome 11. Messenger RNA (mRNA) is produced from this gene and exits the nucleus through nuclear pores to the rough endoplasmic reticulum (RER).
• In the RER, transfer RNA (tRNA) uses the mRNA template to form a chain of amino acids, creating pre-pro-insulin, which is converted to pro-insulin and transported to the Golgi apparatus. Here, it is processed and packaged into secretory granules.
• Pro-insulin is cleaved to produce insulin and C-peptide, which are released from the pancreas' beta cells into the bloodstream. Approximately half of the insulin is utilized in the liver via the portal venous system, with the remainder circulating systemically.

Insulin Receptor

• The insulin receptor, located on the short arm of Chromosome 19, consists of two alpha subunits that bind insulin and two beta subunits that span the cell membrane.
• Upon insulin binding, a conformational change activates tyrosine kinase, leading to increased expression of GLUT-4 glucose transporters on the cell surface and enhanced glucose uptake.

Glucose Transporters and Their Functions

• GLUT-1: Facilitates basal glucose transport in cells not stimulated by insulin.
• GLUT-2: Transports glucose into beta cells, essential for insulin release regulation.
• GLUT-3: Allows non-insulin-mediated glucose uptake in the placenta and neurons.
• GLUT-4: Present in muscle and adipose tissue, responsible for most peripheral actions of insulin.

Mechanism of Insulin Release in Beta Cells

• Beta cells have GLUT-2 receptors that facilitate glucose entry. Metabolized glucose generates ATP, which closes K⁺channels, depolarizing the cell membrane and leading to calcium influx and increased insulin release.
• Sulfonylureas can also close K⁺channels, enhancing insulin release. The level of glucose entering the beta cells directly correlates with the amount of insulin released.

Insulin Release Patterns

• Insulin is released from beta cells into portal circulation in a biphasic pattern: an initial surge lasting around 10 minutes, followed by sustained release based on glucose levels.
• Insulin enhances glycogenesis, lipogenesis, and protein synthesis, supporting the storage of carbohydrates, fats, and proteins. Basal insulin release is supplemented by prandial peaks, mimicked in modern therapy with a basal-bolus regimen using long-acting and short-acting insulins.

Indications for Insulin Therapy

• Type 1 Diabetes: All patients require insulin to prevent diabetic ketoacidosis (DKA).
• Type 2 Diabetes: Insulin is initiated when dietary adjustments and medications are insufficient. It may also be used perioperatively or during illness when oral intake is compromised.

Insulin Administration Methods

• Basal-bolus regimen: Involves long-acting insulin once daily, with short-acting insulin before meals to mimic natural patterns, commonly used in Type 1 diabetes.
• Syringe driver: Employed in hospitals for tight control in patients with variable needs, such as in ICU or perioperative settings, with frequent glucose monitoring.

Different Forms of Insulin

• Rapid-onset insulin: Examples include Humalog, Novorapid, Actrapid. Administered at mealtime to match glucose intake.
• Isophane insulin: Peaks variably at 4-12 hours and is favored for its cost-effectiveness.
• Pre-mixed insulin: Contains both short-acting and medium-acting insulin (e.g., NovoMix 30 combines 30% short-acting and 70% long-acting insulin).
• Long-acting insulin analogs: Examples include Glargine and Determir, often administered at night.

Long-Term Insulin Regimens

• BD Biphasic: A twice-daily premixed insulin regimen for regular lifestyles, applicable in both Type 1 and Type 2 diabetes.
• QDS Regimen: Involves ultra-fast insulin before meals and long-acting insulin at bedtime, common in Type 1 diabetes for more flexibility.
• Once-daily (OD) long-acting insulin: Typically used in Type 2 diabetes when transitioning from oral medication. Metformin may be continued for tighter control.

Different Long-Acting Insulins

• Glargine: Administered at bedtime for both Type 1 and Type 2 diabetes, with no peak to reduce nocturnal hypoglycemia risk.
• Insulin Detemir: Similar to Glargine, often used in Type 2 diabetes, especially in obese patients for better glycemic control.

Cases — Insulin Management in Type 1 and Type 2 Diabetes

• Case 1 — New diagnosis of Type 1 diabetes 💉: A 16-year-old boy presents with weight loss, polyuria, and ketosis. HbA1c 96 mmol/mol. Diagnosis: Type 1 diabetes. Managed with a basal–bolus insulin regimen (long-acting insulin once daily + rapid-acting insulin with meals) plus structured education (e.g. DAFNE programme).
• Case 2 — Established Type 1, insulin adjustment 🍽️: A 25-year-old woman with Type 1 diabetes reports frequent post-meal hyperglycaemia despite correct basal dosing. HbA1c 72 mmol/mol. Diagnosis: inadequate bolus-to-carbohydrate ratio. Managed by adjusting rapid-acting insulin doses using carbohydrate counting, with ongoing specialist nurse input.
• Case 3 — Type 2 diabetes starting insulin ⚠️: A 60-year-old man with Type 2 diabetes (10 years) is on maximum metformin and gliclazide but has HbA1c 85 mmol/mol. Fasting glucose consistently >12 mmol/L. Diagnosis: Type 2 diabetes requiring insulin initiation. Managed with once-daily intermediate-acting insulin (NPH) at night, continuing metformin.
• Case 4 — Frailty and insulin simplification 👴: An 82-year-old woman with Type 2 diabetes and recurrent hypos on basal–bolus insulin is admitted with falls. HbA1c 49 mmol/mol. Diagnosis: over-intensive insulin regimen in frailty. Managed by simplifying to once-daily basal insulin only, aiming to avoid hypoglycaemia and prioritise safety.
• Case 5 — Insulin pump therapy ⚙️: A 34-year-old man with Type 1 diabetes has recurrent nocturnal hypoglycaemia and poor HbA1c despite multiple daily injections. Diagnosis: Type 1 diabetes with poor control on basal–bolus regimen. Managed with continuous subcutaneous insulin infusion (insulin pump) and continuous glucose monitoring.

Teaching Point 🩺: - Type 1 diabetes → always insulin-dependent (basal–bolus preferred, pumps for selected cases). - Type 2 diabetes → insulin if lifestyle + tablets fail, or in acute illness/pregnancy. - Regimens: basal–bolus, twice-daily mixed insulin, once-daily basal, or pump therapy. - Always individualise: carb counting in young adults, simplification in frailty, continuation of metformin in T2DM.