TRESIBA® FLEXTOUCH®

Indications

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus

Dosage

Children: Refer to the BNF for Children for the appropriate dosing recommendations based on the child's age and

Adults: Refer to the BNF for specific dosing guidelines depending on the individual's blood glucose levels, age, and weight.

Mechanism of action

Degludec binds to the insulin receptor (IR), a heterotetrameric protein composed of two extracellular alpha units and two transmembrane beta units. The binding of degludec to the alpha subunit of IR activates the intrinsic tyrosine kinase activity of the beta subunit. This leads to autophosphorylation of the receptor and subsequent phosphorylation of several intracellular substrates, including insulin receptor substrates (IRS) and other signaling molecules such as PI3 kinase and Akt. This cascade enhances glucose uptake by tissues, particularly muscle and adipose tissues, and promotes various metabolic processes.

Pharmacodynamics

Insulin is a natural hormone produced by the pancreatic beta cells, crucial for regulating glucose homeostasis. In individuals without diabetes, insulin levels rise postprandially, facilitating glucose uptake and storage as glycogen in liver and muscle tissues. Insulin also plays a role in lipid metabolism and protein synthesis. As a long-acting insulin analogue, degludec provides a consistent insulin level over 24 hours, reducing the risk of hypoglycemia and allowing for improved flexibility in meal timing.

Pharmacokinetics

Degludec has a prolonged duration of action, with effects lasting up to 24 hours. Its onset of action is typically between 1 to 2 hours. Due to its unique formulation, degludec exhibits a flat and predictable pharmacokinetic profile, which minimizes fluctuations in blood glucose levels. The pharmacokinetics of degludec is influenced by its self-association in subcutaneous tissue, leading to a slow and steady release into circulation, thus providing a stable insulin effect.

Contra-indications

• Hypersensitivity to degludec or any of its components
• Severe hypoglycemia

Adverse effects

• Hypoglycemia
• Weight gain
• Injection site reactions
• Allergic reactions
• Lipodystrophy

Interactions

• Other antidiabetic agents may increase the risk of hypoglycemia
• Beta-blockers may mask the symptoms of hypoglycemia
• Thiazide diuretics, glucocorticoids, and thyroid hormones may increase blood glucose levels

Precautions

• Monitor blood glucose regularly
• Adjust doses carefully when used in conjunction with other medications affecting glucose metabolism
• Caution in patients with renal or hepatic impairment

Pregnancy

Insulin detemir is generally considered safe in pregnancy, as insulin does not cross the placenta. However, blood glucose control is crucial for maternal and fetal health.

Breast-feeding

Insulin detemir is excreted in breast milk in small amounts, but it is not expected to affect the nursing infant. Blood glucose monitoring is advised.

Storage

Store in a refrigerator (2-8°C). After first use, it may be stored at room temperature (below 30°C) for up to 56 days.

Formulations

• Injection solution (100 units/ml)
• Pen device for subcutaneous use

Indications

• Diabetes mellitus (type 1 and type 2)
• Diabetic ketoacidosis
• Hyperglycemia due to other conditions
• Management of blood glucose levels during surgery
• Continuous subcutaneous insulin infusion therapy

Dosage

Children: For children aged 1-17 years, insulin is administered immediately before meals or when necessary shortly after meals, according to individual requirements. Specific dosing should be determined based on blood glucose monitoring and should be referred to the BNF for Children for precise guidance.

Adults: The dosage of insulin varies based on individual needs and is typically guided by blood glucose monitoring. It is recommended to consult local protocols for specific dosing instructions.

Mechanism of action

Insulin has a direct inhibitory effect on lipase, which is involved in the mobilization of fatty acids. In the absence of insulin, there is an abnormally high rate of conversion of protein to glucose, primarily in the liver. Insulin stimulates glycogen synthesis and enhances facilitated diffusion of glucose and the active transport of amino acids, although the exact mechanisms for these actions are not fully understood.

Pharmacodynamics

Insulin's primary pharmacodynamic effect is the reduction of blood glucose levels. It promotes the uptake of glucose by cells, increases glycogen synthesis in the liver, and inhibits gluconeogenesis. Insulin also influences lipid metabolism by inhibiting lipolysis and encouraging fat storage. Additionally, insulin enhances protein synthesis by promoting amino acid uptake into cells.

Pharmacokinetics

Insulin is administered by injection and is rapidly absorbed into the bloodstream. Its onset, peak, and duration of action depend on the formulation used (e.g., rapid-acting, short-acting). The half-life of insulin is typically around 5 to 10 minutes, but its effects can last several hours depending on the formulation. It is metabolized primarily in the liver and kidneys.

Contra-indications

• Hypersensitivity to insulin or any of its excipients
• Hypoglycemia

Adverse effects

• Hypoglycemia
• Injection site reactions
• Weight gain
• Allergic reactions
• Edema
• Lipodystrophy

Interactions

• Metreleptin may increase the risk of hypoglycemia when used with insulin
• Fibrates may increase the risk of hypoglycemia when used with insulin
• Macrolides may increase the risk of severe hypoglycemia when used with insulin
• Clarithromycin may increase the risk of severe hypoglycemia when used with insulin

Precautions

• Monitor blood glucose levels regularly, especially when changing insulin preparations
• Use caution in patients with renal impairment, as insulin clearance may be reduced
• Patients should be advised about the risks of hypoglycemia and how to manage it
• Should be used with caution in patients with cardiovascular disease

Pregnancy

Insulin is generally considered safe for use during pregnancy, but dosages may need to be adjusted.

Breast-feeding

Insulin is compatible with breastfeeding; insulin does not pass into breast milk in significant amounts.

Storage

Store unopened vials or pens in a refrigerator (2-8°C). Once opened, insulin can be stored at room temperature (below 25°C) for up to 28 days, depending on the formulation.

Formulations

• Insulin human 500 units/ml solution for injection
• Insulin human 100 units/ml solution for injection
• Insulin porcine 100 units/ml solution for injection

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 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.

Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In nondiabetic individuals, the pancreas produces a continuous supply of low basal insulin levels and spikes of insulin following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to an 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 the 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 mimics the basal insulin levels 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.

Mechanism of action

INSULIN HAS DIRECT INHIBITORY EFFECT ON LIPASE CONCERNED WITH MOBILIZATION OF FATTY ACIDS, WHILE GROWTH HORMONE, GLUCOCORTICOIDS, THYROID HORMONES & CATECHOLAMINES ENHANCE LIPOLYSIS. IN ABSENCE OF INSULIN THERE IS ABNORMALLY HIGH RATE OF CONVERSION OF PROTEIN TO GLUCOSE. ... PROTEINS & AMINO ACIDS ARE CONVERTED TO GLUCOSE @ ABNORMALLY HIGH RATE IN INSULIN DEFICIENCY. THE LIVER IS SITE OF CONVERSION. PROTEIN & AMINO ACIDS ARE MOBILIZED FROM PERIPHERAL TISSUES. INSULIN ACTS TO.../STIMULATE/ GLYCOGEN SYNTHESIS. MECHANISM OF IMPORTANT ACTIONS OF INSULIN TO ENHANCE FACILITATED DIFFUSION OF GLUCOSE & ACTIVE TRANSPORT OF AMINO ACIDS ARE NOT KNOWN.