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.

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