Makindo Medical Notes.com

Insulin production

• The gene for Insulin is coded on Chromosome 11. A template of the gene is made in messenger RNA and passes out via pores in the nuclear membrane to the rough endoplasmic reticulum.
• A chain of amino acids is made using transfer RNA and the messenger RNA template. The ribosomes form pre-pro-Insulin. This is then converted to pre-Insulin and enters the Golgi apparatus and transported closer to the cell membrane. The molecule is then converted to Insulin with loss of the connecting C-peptide and passed to the secretory granules or directly with a constitutive pathway.
• Released from the Beta-cells of the islets of langerhans of the pancreas. The hormone now passes out into the portal venous system and is carried to the liver where a vein radicle is part of the portal triad and 50% of the Insulin is used. It passes to the hepatic vein and into the inferior vena cava and systemic circulation

Insulin Receptor

• This is coded for on a short arm of 19. 2 alpha subunits which bind Insulin.
• Two Beta subunits that straddle the cell membrane.
• Binding leads to a conformational change and activation of tyrosine kinase which leads to increased expression of GLUT-4 glucose transporters on the cell surface and increased glucose uptake

Glucose transporters are formed by the action of Insulin

• GLUT-1 Basal glucose transport non Insulin-stimulated cells
• GLUT-2 Transports glucose into Beta-cell - needed to control Insulin release
• GLUT-3 non Insulin mediated glucose into placenta and neurons
• GLUT-4 muscle and adipose and accounts for most peripheral actions of Insulin

What happens in the Beta-cells ?

• They have GLUT-2 receptors for glucose entry
• The glucose is metabolised to produce ATP which shuts K⁺ channels
• Sulphonylureas also shuts the receptor causing the cell to depolarise and allow in calcium which stimulates a kinase and causes more Insulin release
• Basically the more glucose entering the more Insulin released

Insulin release

• Insulin is released by the beta cells of the Islets of Langerhans directly into the PORTAL circulation. Normal Insulin release is pulsatile with a biphasic response to a glucose load - there is an initial surge of Insulin release which lasts 10 minutes flowed then by a more sustained release that lasts as long as the glucose challenge. Insulin INCREASES glycogenesis, lipogenesis and protein synthesis and so enables us to store the dietary intake of carbohydrate, fat and protein. Starting Insulin is often associated with weight gain
• There is a basal level of Insulin release augmented by prandial peaks which is the regimen we try now to mimic by giving a basal-bolus of a long-acting Insulin such as determir or glargine and then giving short-acting Insulin around mealtimes. The daily pancreatic Insulin release depends on glucose intake and other factors and ranges from 30 to several hundred units per day

Indications

• Type 1 Diabetes - all require Insulin or else will develop diabetic ketoacidosis
• Type 2 Diabetes - where dietary and other drug measures are not controlling blood glucose. When oral intake not possible e.g. perioperative, illness. Insulin demand increases with illness or stress of surgery.

Administration

• Basal Bolus - a single day dose of long-acting supplemented with short-acting before meals. Attempts to mimic normal control. The usual for a Type 1 DM
• Syringe driver - in the hospital when "tight" control needed in those with varying or unpredictable needs. Demands repeated testing and finger-prick blood glucose. Used in CCU for MI patients or in ITU and sometimes the stroke unit. May be used perioperatively. Labour intensive in term of nursing time. Try to start a normal Insulin regimen as soon as possible.

Different forms of Insulin

• Rapid onset: Humalog/Novorapid/Actrapid: Give at start of meal, or just after so that it can match what is eaten.
• Isophane insulin (variable peak at 4–12h): favoured by NICE (it’s cheap!).
• Pre-mixed insulins combines short and medium acting e.g. NovoMix 30 = 30% short-acting and 70% long-acting. Can be given BD
• Long-acting recombinant analogues. Given at night. Glargine/Determir are examples.

Different Long term Insulin Regimens

• BD biphasic: twice daily premixed insulins by pen (e.g. NovoMix 30R). useful in type 1/2 DM with regular lifestyle.
• QDS regimen: before meals ultra-fast insulin + bedtime long-acting analogue: useful in type 1 DM for flexible lifestyle e.g. can adjust with meals/exercise.
• OD before-bed long-acting insulin: useful when switching from tablets in type 2 DM. Work up to slowly and give 1U/24h for every unit of BMI in adults. Consider retaining metformin if needed for tight control and patient is unable to use BD regimen
  • Glargine: used at bedtime in T1/2. No peak, so avoids nocturnal hypoglycaemia.
  • Insulin detemir: similar and can help control in obese Type 2 DM