PC1320 W3 Lecture 3a_Pharmacology of drugs for Diabetes

Learning Outcomes

• Understand roles of insulin in glucose metabolism

• Describe common strategies for reducing blood glucose in hyperglycaemia

• Explain mechanisms of action for drugs that lower elevated blood glucose

• Compare benefits and risks of these agents, including side effects and hypoglycaemia risk

Hormones

• Definition: Endogenous regulatory substances produced in organs, transported by blood to target cells.

• Functions: Stimulate specific cells/tissues into action.

• Examples: Insulin, testosterone, oestrogen, cortisol, thyroid hormones.

Diabetes: Dysregulation of Blood Glucose Levels

• Pancreatic Function:

  • Beta cells: Secrete insulin in response to elevated blood glucose.

  • Alpha cells: Secrete glucagon when blood glucose is low.

• Types of Diabetes:

  • Type 1 Diabetes Mellitus (DM):

    • Total insulin deficiency; typically autoimmune with familial links.

    • Early life onset.

  • Type 2 DM:

    • Reduced insulin production and insulin resistance; more common with age.

  • Gestational Diabetes:

    • Insulin resistance due to increased growth hormones; maternal and fetal hyperglycaemia.

Complications of Diabetes

• Microvascular Complications:

  • Retinopathy

  • Nephropathy

  • Neuropathy

• Macrovascular Complications:

  • Ischaemic heart disease

  • Atherosclerosis

  • Peripheral vascular disease

  • Stroke

Managing Elevated Blood Glucose Levels: Ominous Octet

• Multi-faceted treatment approaches:

  • Stimulate insulin production.

  • Improve cell sensitivity to insulin.

  • Delay carbohydrate absorption from the gut.

  • Prolong action of endogenous insulin.

  • Impair gluconeogenesis.

  • Replace endogenous insulin.

Overview of Newer Agents

• Key drug classes identified:

  • Metformin (Biguanide)

  • Insulin

  • Sulfonylureas (SU)

  • DPP-4 Inhibitors

  • SGLT-2 Blockers.

Insulin

• Anatomy of Pancreas:

  • Exocrine and endocrine functions.

  • Endocrine function performed by islets of Langerhans:

    • Alpha cells: Glucagon

    • Beta cells: Insulin

    • Delta cells: Somatostatin

    • F cells: Pancreatic polypeptide.

Insulin and Counter-Regulatory Hormones

• Insulin:

  • Prevents hyperglycaemia.

• Counter-Regulatory Hormones:

  • Counteract hypoglycaemia (insulin's effects):

    • Glucagon

    • Adrenaline

    • Somatostatin

    • Growth Hormone.

Actions of Insulin

• Increases glucose uptake (stimulated by acute blood glucose rise).

• Stimulated by incretins (GIP and GLP-1), suppresses blood glucose levels:

  • Increases glycogen synthesis.

  • Decreases glycogenolysis & gluconeogenesis.

Insulin Production and Release

• Released by beta cells in response to:

  • High blood glucose levels.

  • Presence of glucagon or protein in the small intestine.

• Inhibited by negative feedback:

  • Hypoglycaemia decreases insulin and glucagon release.

Insulin Mechanism of Action

• Binds to insulin receptors (type 3 kinase-linked).

• Immediate metabolic and longer-term genomic effects (growth, metabolism).

Hypoglycaemic Agents: Insulin

• Highest risk of hypoglycaemia.

• All forms of insulin require injection.

• Potential side effects:

  • Lipodystrophy

  • Weight gain

  • Allergic reactions.

Metformin: Biguanide

• Only available biguanide in Australia.

• Common first-line treatment for Type 2 Diabetes.

• Mechanisms:

  • Increases insulin sensitivity.

  • Suppresses hepatic glucose production.

  • Low likelihood of causing hypoglycaemia.

  • Promotes weight loss.

Metformin: Mechanisms of Action

• Increases glucose uptake & fatty acid oxidation.

• Decreases gluconeogenesis and absorption from the gut.

• Prevents post-meal hyperglycaemia.

• Does not cause hypoglycaemia or stimulate appetite.

Metformin: Side Effects

• Common: Nausea, vomiting, diarrhea, anorexia, Vitamin B12 absorption reduction.

• Rare: Acute hepatitis, rash, lactic acidosis.

Summary on Metformin

• Very low hypoglycaemia risk.

• Weight-neutral or weight-negative effects.

• Reduces hepatic glucose production and increases peripheral uptake.

Other Available Agents for Diabetes

• Classes:

  • Sulfonylureas

  • DPP-4 Inhibitors:

    • Increase insulin secretion; Example: glibenclamide, sitagliptin.

  • SGLT-2 Inhibitors:

    • Ex: Dapagliflozin, Dulaglutide.

• Mode of Action:

  • Sulfonylureas stimulate insulin secretion.

  • DPP-4 Inhibitors increase incretin hormones affecting insulin and glucagon.

  • SGLT-2 Inhibitors reduce glucose reabsorption.

• Hypoglycaemia Risk:

  • Sulfonylureas: High risk.

  • DPP-4 Inhibitors: Low risk.

  • SGLT-2 Inhibitors: Low risk when used alone.

Adverse Effects of Other Agents

• Sulfonylureas: Weight gain, hypoglycaemia risk, cardiovascular issues.

• DPP-4 Inhibitors: Headache, muscle pain.

• SGLT-2 Inhibitors: UTI, dehydration, nausea, vomiting.

Conclusion

• Continuous assessment of available diabetes management options is essential for patient care.