Insulin

Insulin

Insulin is a hormone that facilitates the penetration of glucose and amino acids through cell membranes of skeletal and heart muscle. Insulin was first extracted successfully from the pancre-atic islets by a young Canadian surgeon Frederick G Banting, together with a medical student Charles H Best, in 1921. They were helped in their quest by JRR Macleod, a professor of physiology, and JB Collip, a chemist. Therefore when the Nobel prize in Medicine (Physiology) was awarded to Banting and Macleod in 1923, there was a furore prompting Banting to share his prize with Best, while Macleod shared his with Collip.

Preparations

The various preparations of insulin currently available are mentioned (along with some relevant properties) in Table 31.3.

Uses

Subcutaneous administration of insulin is the primary treatment for all patients with IDDM (insulin-dependant diabetes mellitus or Type I DM), and for patients with NIDDM (non-insulin-dependant diabetes mellitus or Type II DM), that is not adequatelycontrolled by diet or oral hypoglycaemics, and for patients with post-pancreactectomy diabetes or gestational diabetes.

Toxicokinetics

Insulin is usually administered by subcutaneous injection. Commercial preparations are available for either subcutaneous or intravenous injection which differ in respect to onset and dura-tion of action. The onset and duration of action vary considerably depending on the preparation (Table 31.3). Insulin is not absorbed from the GI tract. Metabolism to the extent of 50% of the admin-istered dose occurs in the liver. The half-life of insulin is about 20 minutes if it has been injected IV, while it is 2 hours by the subcutaneous or intramuscular route. Insulin is 5% protein bound.

Insulin is reabsorbed in the proximal renal tubule (upto 98%), and 60% is returned to the venous blood. Less than 2% is excreted unchanged.

Adverse Effects

Hypoglycaemia: This remains one of the potential hazardsof insulin therapy, and is invariably the result of inadvertent overdose. Symptoms will depend on the extent of overdose and the time elapsed since administration (Table 31.4). Prolonged hypoglycaemia can produce behaviour disturbances, convul-sions, coma, and death. Irreversible neurologic sequelae are likely to occur when the duration of untreated hypoglycaemia approaches 7 hours following overdose. Sequelae may include amnesia, dementia, and confusion. While there is little corre-lation between insulin dose and severity of hypoglycaemia, serious sequelae are common when insulin is combined with other agents such as barbiturates.

Sensitivity reactions: These are more common with bovinepreparations than with porcine insulin, while human insulin is associated with negligible incidence of allergic reactions. Cutaneous manifestations are most common, while in some cases there may be systemic effects. In a few cases, insulin resistance may be encountered due to IgG antibodies.

Lipoatrophy and lipohypertrophy: The former is said to be avariant of an immune response to insulin, while the latter is because of lipogenic action of high local concentrations of insulin. Both are rare with purified insulin preparations. It is advisable to rotate the site of injection frequently to avoid these effects.

Insulin oedema: Sodium retention consequent to insulin admin-istration can result in oedema, abdominal bloating, weight gain, and blurred vision.

Drug Interactions

The hypoglycaemic action of insulin is enhanced by fasting, alcohol, barbiturates, salicylates, MAOIs, beta blockers, ACE inhibitors, and benzodiazepines. It is depressed by glucagon, adrenaline, oestrogens, adrenocortical hormones, INH, chlor-promazine and thyroxine.

Clinical (Toxic) Features

Acute Poisoning:

General—

·              Patients with intermediate or extended insulin overdose may not develop symptoms for 18 to 36 hours except for vomiting and lethargy. With long acting insulin, there is a compensatory mechanism in the first 24 hours which a compensatory mechanism in the first 24 hours which helps to maintain normoglycaemia. Later this is exhausted, leading to irreversible brain and myocardial damage due to severe hypoglycaemia.

·              After an insulin overdose, upto 12 days of treatment may be required before insulin needs return to normal. Non-diabetic patients are found to be more likely to present with hypogly- caemia, and develop recurrent hypoglycaemia despite oral intake and IV glucose infusion following intentional misuse.

·              Hypoglycaemia can occur with therapeutic doses of insulin in diabetics on an uncontrolled diet, with too much exercise, or in patients with brittle diabetes. It is difficult to predict the minimum toxic or lethal dose of insulin and severity of intoxication must be based on clinical findings.

Specific—

·              Eyes: Mydriasis, sluggish external ocular movements.

·              CNS: Drowsiness, confusion, headache, restlessness, extensor spasms, extensor plantar reflexes, absent gag reflex. Deep tendon reflexes may be normal, depressed or exaggerated. Generalised seizures may accompany severe hypoglycaemia following overdose. Aphasia, maniacal behaviour, and other personality changes secondary to hypoglycaemia can also occur.

·              Skin: Cold, clammy, pale, with profuse sweating.

·              Respiratory system: Breathing is deep and heavy, with periods of apnoea. Pulmonary oedema may occur.

·              CVS: Tachycardia.

·              Extremities: Pain, cramps, twitching.

·              Hypokalaemia may occur along with other electrolyte abnormalities following massive insulin overdose.  See also Table 31.4.

Chronic Poisoning

·              This is usually the result of chronic overtreatment with nsulin.

·              There is recurrent, episodic hypoglycaemia characterised by

o     Pallor, restlessness, stertorous respiration, depression, inattentiveness.

o     Sweating.

·              Nightmares, night sweats, difficulty in awakening.

·              Glycogen-laden hepatomegaly.

·              Morning hypothermia.

Diagnosis

·              Monitor blood sugar levels regularly. Plasma glucose levels of 30 mg/dL or lower are common following large over-dosage. Urinary glucose and acetone determination are also diagnostic for diabetic ketoacidosis. Immediate differentia-tion between hypoglycaemia and ketoacidosis is accom-plished by the use of a bedside blood glucose testing strip.

·              Plasma insulin levels do not correlate well with severity of hypoglycaemia.

·              Leukocytosis is commonly observed.

·              Potassium levels may be depressed.

·              ECG: Sinus tachycardia, occasional premature ventricular beats, elevated ST segments.

·              EEG: Slow diffuse waves without lateralising discharges.

·              Urinalysis: Albuminuria, hyaline casts.

·              Chronic insulin-induced hypoglycaemia is often associated with the presence of insulin-binding antibodies and low C-peptide levels.

Treatment

·              Stabilisation: Airway, breathing and circulation must be estab- lished and maintained. Endotracheal intubation and assisted ventilation may be necessary.

·              Antidote:Glucoseis the specific antidote and must be administered without delay.

·              Give 50 ml 50% dextrose as IV bolus upon admission.

·              Follow this up with continuous glucose infusion of 5% or 10% dextrose in water, sufficient to maintain slight hyperglycaemia.

·              Alternatively, if a patient is symptomatic, or has blood glucose level <60 mg/dL administer an IV bolus (50 ml) of 50% dextrose over a period of 2 to 3 minutes. Improvement will usually be seen in 5 to 10 minutes. A continuous IV infusion of 10 percent dextrose in water should be started following overdosage of longer acting insulin preparations given subcu- taneously. Monitor blood glucose levels regularly to maintain Oral glucose cannot be relied upon to maintain eugly- caemia.

·              Glucagon 1 to 2 mg, IM, may help in mobilising hepatic glycogen stores, but is not effective in the presence of prolonged hypoglycaemia, fasting, or alcohol abuse. Glucagon is only effective when the patient has adequate liver glycogen stores.

·              Adrenaline (1 : 1000), 1 mg, SC, can be beneficial in some cases.

·              Some investigators have achieved success by surgically excising visible injection sites down to the muscle layer. Cerebral oedema is treated with mannitol and dexamethasone.

• Hypokalaemia is managed by potassium supplements. Administer intravenous potassium chloride (20 to 60 mEq/L of fluid) to correct cardiac arrhythmias, muscle paralysis, or EKG changes secondary to hypokalaemia.

• Administer 300 grams daily or more of carbohydrates when the patient awakens, to supplement intravenous glucose and prevent secondary hypoglycaemia.

• Excision of the skin and fat down to the muscle wall of an insulin injection site using local anaesthetic has been utilised in the management of injected insulin overdoses.

• Haemodialysis does not appear to enhance elimination of insulin.

• Permanent brain damage has been reported following injec- tion of 800 and 3200 units of insulin in diabetic patients.

• At the same time, recovery has occurred following up to 3200 units in adults.