Endocrine System: Insulin and Glucose Regulation

Insulin and Glucose Lowering Agents

• The pancreas produces peptide hormones: insulin, glucagon, and somatostatin, which play a crucial role in regulating metabolic activities, particularly glucose homeostasis.
• Insulin is a small protein containing 51 amino acids arranged in two chains (A and B) linked by disulfide bridges.
• Proinsulin is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide.
• Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues.

Mechanism of Insulin Release

• Hyperglycemia results in increased intracellular ATP levels, which close ATP-dependent potassium channels, leading to depolarization of the beta cell and opening of voltage-gated calcium channels.
• The resulting increased intracellular calcium triggers the secretion of insulin.

Insulin Secretion

• Insulin is released from pancreatic beta cells at a low basal rate and at a much higher stimulated rate in response to various stimuli, including glucose, other sugars, amino acids, and hormones like glucagon-like polypeptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).
• Insulin secretion is also stimulated by high concentrations of fatty acids and β-adrenergic sympathetic activity.

Insulin Degradation

• The liver and kidney are the two main organs that remove insulin from the circulation, with the liver clearing 60% of the insulin released from the pancreas and the kidney removing 35-40% of the endogenous hormone.
• The half-life of circulating insulin is 3-5 minutes.

Insulin Receptor

• Insulin receptors are found on the membranes of most tissues, and the biologic responses promoted by these insulin-receptor complexes have been identified in the primary target tissues regulating energy metabolism, including liver, muscle, and adipose tissue.

Effects of Insulin on Its Targets

• Insulin promotes the storage of fat as well as glucose within specialized target cells and influences cell growth as well as the metabolic functions of a wide variety of tissues.

Diabetes Mellitus

• Diabetes mellitus is a rapidly growing health problem that affects more than 350 million people worldwide, with elevated blood glucose associated with absent or inadequate pancreatic insulin secretion with or without impairment of insulin action.
• The American Diabetes Association (ADA) recognizes four clinical classifications of diabetes: type 1, type 2, gestational diabetes mellitus, and other causes like genetic defects or medications.

Type 1 Diabetes

• Type 1 diabetes is characterized by selective B cell destruction (severe or absolute insulin deficiency) and is further subdivided into immune-mediated (type 1a) and idiopathic (type 1b) forms.
• Classical symptoms of type 1 diabetes include polydipsia, polyphagia, polyuria, and weight loss.
• Type 1 diabetes requires exogenous insulin to treat hyperglycemia and life-threatening ketoacidosis.

Self-Monitoring of Blood Glucose

• Capillary blood glucose measurements performed by patients themselves, as outpatients, are extremely useful in type 1 patients in whom "tight" metabolic control is attempted.
• Continuous glucose monitoring (CGM) systems are also available for clinical use, utilizing a subcutaneous sensor that measures glucose concentrations in the interstitial fluid for 3-7 days.

Medications for Hyperglycemia

• Human insulin is produced by recombinant DNA technology using strains of Escherichia coli or yeast that are genetically altered to contain the gene for human insulin.
• Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties.
• Insulin preparations vary primarily in their onset and duration of activity.

Pharmacokinetics

• Insulin is generally administered by subcutaneous injection, although an inhaled insulin formulation is also available.
• Sliding scale insulin regimens approximate daily insulin requirements, depending on pre-defined blood glucose ranges for pre-meal or night time insulin dose.

Sliding Scale Insulin Therapy

• Disadvantages of sliding scale therapy include:
  • Not covering insulin needs related to snacks or stress and other activity
  • Requiring carbohydrate counting
  • Being less effective in covering a pre-meal high blood sugar
  • Requiring a consistent diet and lifestyle
• Sliding scale protocols (Bolus) involve calculating the dose of insulin based on the carbohydrate content of the meal and the blood glucose level.

Dose Calculation

• The carbohydrate coverage dose is a bolus dose for food coverage, prescribed as an insulin-to-carb ratio.
• The total daily insulin requirement can be calculated using formulas such as Total units daily = weight in pounds / 4 or Total units daily = weight in kg x 0.55.