MPP II 3.7 - ENDOCRINE PANCREAS PHYS. (PART I)

• Lecture 25 covers the endocrine pancreas pharmacology, focusing on insulin and diabetes mellitus.

Endocrine Pancreas Pharmacology

• Insulin, glucagon, and somatostatin are peptide hormones produced.
• These hormones are secreted from cells within the islets of Langerhans.
• β cells produce insulin, α cells produce glucagon, and δ cells produce somatostatin.
• Proper glucose homeostasis in the body is maintained by these hormones.

Diabetes Mellitus

• An estimated 25.8 million people in the United States and 347 million people worldwide have diabetes.
• Diabetes is a group of syndromes characterized by elevated blood glucose, due to relative or absolute insulin deficiency.
• The main types of diabetes include:
  • Type 1 (insulin-dependent),
  • Type 2 (non-insulin-dependent),
  • Gestational diabetes
  • Genetic defects or medications can also cause diabetes.
• A lack of insulin can cause hyperglycemia
• Retinopathy, nephropathy, neuropathy and cardiovascular complications can occur if left untreated.
• Administration of insulin or glucose-lowering agents can reduce mortality and morbidity.

Type 1 vs Type 2 Diabetes

• Type 1 diabetes typically presents during childhood or puberty, while type 2 is more common after age 35.
• Type 1 patients are commonly undernourished, while type 2 patients are often obese.
• Type 1 diabetes accounts for 5-10% of diagnosed cases, compared to 90-95% for type 2.
• Type 1 diabetes has a moderate genetic predisposition, while type 2 has a strong genetic component.
• Type 1 diabetes shows the destruction of insulin-producing β cells, while type 2 involves insufficient insulin production, insulin resistance, and other defects.

Type 1 Diabetes

• An absolute deficiency of insulin caused by the destruction of β cells is a characteristic.
• Loss of β-cell function is a result of autoimmune processes due to viruses or toxins.
• The Pancreas fails to respond to glucose.
• Classic insulin deficiency symptoms include polydipsia, polyphagia, polyuria, and weight loss.
• Treatment requires exogenous insulin to avoid hyperglycemia and ketoacidosis.
• Maintaining blood glucose close to normal and avoiding wide swings in glucose is the goal.
• It's important to avoid hypoglycemia.
• Constant β-cell secretion maintains low basal levels of circulating insulin during the normal postabsorptive period.
• Insulin secretion occurs within 2 minutes after a meal and lasts up to 15 minutes

Type 2 Diabetes

• Accounts for greater than 90% of cases.
• Influenced by genetic factors, aging, obesity, and peripheral insulin resistance.
• The metabolic alterations are milder than T1D but the long-term clinical consequences are similar.
• Causes include lack of sensitivity of target organs to insulin.
• Pancreas retains some β-cell function, but insulin secretion is insufficient to maintain glucose homeostasis
• The β-cell mass may gradually decline over time
• T2 diabetes patients are often obese.
• Obesity contributes to insulin resistance, which is considered the major defect of type 2 diabetes.
• Treatment includes weight reduction, exercise, and dietary modification to decrease insulin resistance and correct hyperglycemia.
• Most patients require oral glucose-lowering agents.
• Beta-cell function progressively declines and insulin therapy is often needed.

Insulin

• Two peptide chains connected by disulfide bonds comprise the polypeptide hormone.
• Insulin and C-peptide are formed when proinsulin undergoes proteolytic cleavage
• Both are secreted by the β cells.
• Insulin secretion is regulated by blood glucose levels and other hormones.
• Increased blood glucose triggers secretion
• Glucose is absorbed by the glucose transporter into the beta cells.
• Phosphorylation by glucokinase acts as a sensor.
• Products of glucose metabolism enter the mitochondrial respiratory chain and generate ATP.
• Blockade of K+ channels occurs when ATP levels rise.
• This leads to membrane depolarization and an influx of Ca2+.
• An increase in intracellular Ca2+ leads to pulsatile insulin exocytosis.
• Administered to replace absent insulin secretion in T1D
• It supplements in T2D when there is insufficient insulin secretion

Insulin Pharmacokinetics

• Human insulin is produced using recombinant DNA technology.
• This involves genetically altering E. coli or yeast 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.
• Insulin lispro, aspart, and glulisine have a faster onset and shorter duration of action than regular insulin.
• These do not aggregate or form complexes.
• Dose, injection site, blood supply, temperature, and physical activity can affect the onset and duration of various insulin preparations.

Insulin Adminstration

• Insulin is a polypeptide and is degraded in the GI tract if taken orally.
• Therefore, it is generally administered by subcutaneous injection
• Continuous subcutaneous insulin infusion is another method of delivery.
• The most serious and common adverse reaction is Hypoglycemia.
• Other adverse reactions include weight gain, local injection site reactions, and lipodystrophy.
• Diabetics with renal insufficiency may require a lower insulin dose.

Insulin Preparations

• Classified as rapid-, short-, intermediate-, or long-acting.
• Caution must be taken when adjusting.
• Four preparations fall into this category:
  • Regular insulin
  • Insulin lispro
  • Insulin aspart
  • Insulin glulisine
• Rapid-acting and Short-Acting:
  • Soluble Regula insulin
  • Modification of the AA sequence of regular insulin produces rapid acting analogs .

Rapid and Short acting continued

• Insulin aspart and insulin glulisine have similar properties to insulin lispro.
• Controls postprandial glucose and mimics mealtime release of insulin
• Administer during cases of quick correction of elevated glucose.
• Regular insulin should be administered 30 minutes before a meal.
• Rapid-acting insulin should be administered 15 minutes before or after the start of a meal.
• Rapid acting is commonly used in insulin pumps.

Intermediate-Acting Insulin

• Neutral protamine Hagedorn (NPH).
• Formed by adding zinc and protamine to regular insulin.
• This forms a complex that is less soluble, delaying absorption and prolonging duration.
• Used for basal (fasting) control in T1 or T2 diabetes.
• Usually given along with rapid- or short-acting insulin for mealtime control.
• Should not be used when rapid glucose lowering is needed.

Long-Acting Insulin

• Insulin glargine has a lower isoelectric point than human insulin.
• It forms a precipitate at the injection site that releases insulin over an extended period.
• Onset is slower than NPH insulin.
• It produces a flat, prolonged hypoglycemic effect with no peak.
• Insulin detemir has a fatty acid side chain that enhances association with albumin.
• Insulin glargine and insulin detemir are used for basal control and should only be administered subcutaneously.
• Long-acting should not be mixed in the same syringe with other insulins.
• This may alter the pharmacodynamic profile.

Insulin Combinations

• Premixed combinations of human insulins exist
• (70% NPH insulin plus 30% regular insulin.)
• Also available is 50% of each of the above agents.
• Premixed combinations decrease the number of daily injections.
• These make it more difficult to adjust individual components.

Standard Treatment vs Intensive Treatment

• Standard insulin therapy involves twice-daily injections.
• Intensive treatment utilizes three or more injections daily, with frequent blood glucose monitoring.
• The American Diabetes Association recommends a target mean blood glucose level of 154 mg/dL or less (HbA1c ≤ 7%).
• Intensive is more likely to achieve this goal.
• The frequency of hypoglycemic episodes, coma, and seizures is higher with intensive insulin regimens.
• Patients on intensive therapy show a reduction in retinopathy and nephropathy.
• Intensive therapy is not recommended for patients with long-standing diabetes, significant microvascular complications or advanced age.