(Approved investigational) Insulin Detemir (Approved investigational) DB01307 Category : Antidiabetic Agents Description : Insulin detemir is a long-acting human insulin analogue used to maintain basal levels of insulin in diabetic individuals. It is produced using recombinant DNA technology in yeast cells. This insulin analogue has a 14-C fatty acid, myristic acid, bound to the lysine amino acid at position B29. The myristoyl side chain increases self-association and albumin binding. This along with slow systemic absorption from the injection site prolongs distribution of the hormone into tissues and results in a long duration of action. Novo Nordisk markets insulin detemir under the trade name Levemir. Targets : Insulin receptor Half life : 5 - 7 hours depending on dose. The half life also differs between age groups (type 1 diabetes patients); Children (6-12 years) = 302 ± 100 minutes;; Adolescents (13-17 years) = 301 ± 107 minutes;Adults (18-65 years) = 425 ± 78 minutes

Mechanism of action : Insulin detemir binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slows its distribution into target tissues and prolongs its duration of action.

Pharmacodynamics : Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin. Sequence : Protein for Achain GIVEQCCTSICSLYQLENYCN ; Protein for B chain FVNQHLCGSHLVEALYLVCGERGFFYTPK Brand : Novo Nordisk's Levemir Indications : For the treatment of type 1 or 2 diabetes mellitus. May be used in combination with oral anti-diabetic agents in type 2 diabetic patients who are not in adequate metabolic control with oral anti-diabetic agents alone.

LEVEMIR (insulin detemir [rDNA origin] injection) is a sterile solution of insulin detemir for use as a subcutaneous injection. Insulin detemir is a long-acting (up to 24-hour duration of action) recombinant human insulin analog. LEVEMIR is produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification.Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a molecular formula of C267H402O76N64S6 and a molecular weight of 5916.9. Overdose : An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia

Dosage and administration : LEVEMIR is a recombinant human insulin analog for once- or twice-daily subcutaneous administration. Patients treated with LEVEMIR once-daily should administer the dose with the evening meal or at bedtime. Patients who require twice-daily dosing can administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose. The dose of LEVEMIR must be individualized based on clinical response.Blood glucose monitoring is essential in all patients receiving insulin therapy.Patients adjusting the amount or timing of dosing with LEVEMIR should only do so undermedical supervision with appropriate glucose monitoring. In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting insulin. As with all insulins, injection sites should be rotated within the same region (abdomen, thigh, or deltoid) from one injection to the next to reduce the risk of lipodystrophy. LEVEMIR can be injected subcutaneously in the thigh, abdominal wall, or upper arm. As with all insulins, the rate of absorption, and consequently the onset and duration of action, may be affected by exercise and other variables, such as stress, intercurrent illness, or changes in co-administered medications or meal patterns.

When using LEVEMIR with a glucagon-like peptide (GLP)-1 receptor agonist, administer as separate injections. Never mix. It is acceptable to inject LEVEMIR and a GLP-1 receptor agonist in the same body region but the injections should not be adjacent to each other. Initiation of LEVEMIR Therapy: The recommended starting dose of LEVEMIR in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Rapid-acting or short-acting, pre-meal insulin should be used to satisfy the remainder of the daily insulin requirements. The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled on oral antidiabetic medications is 10 Units (or 0.1-0.2 Units/kg) given once daily in the evening or divided into a twice daily regimen. The recommended starting dose of LEVEMIR in patients with type 2 diabetes inadequately controlled on a GLP-1 receptor agonist is 10 Units given once daily in the evening. LEVEMIR doses should subsequently be adjusted based on blood glucose measurements. The dosages of LEVEMIR should be individualized under the supervision of a healthcare provider.

General reference : www.rxlist.com www.drugbank.com http://www.rxlist.com/levemir-drug.htm http://www.drugs.com/dosage/levemir.html