Study Notes for Molecular Cell Biology Lecture #17: Receptor Tyrosine Kinases II

Molecular Cell Biology

Lecture Details

  • Lecture Title: Receptor Tyrosine Kinases II

  • Instructor: Mitra Esfandiarei, Ph.D.

  • Email: mesfan@midwestern.edu

  • Date: October 2, 2025

Learning Objectives

  • Understand how blood glucose regulates insulin release from beta cells.

  • Explain the specific role that GLUT2 plays in the insulin secretion pathway.

  • Understand the role of ATP production in insulin secretion from beta cells.

  • Explain the stages of insulin synthesis, processing, and secretion from beta cells.

  • Understand the differences between GLUT2 and GLUT4 glucose transporters.

  • Explain how the body responds to low blood glucose (hypoglycemia).

  • Understand the counter-regulatory roles of glucagon and epinephrine in relation to insulin.

  • Explain the impact of insulin on different tissues (e.g., liver, fat, and muscle).

  • Understand the role of insulin signaling and active Akt in decreasing lipolysis in adipose tissue, including the role of hormone-sensitive lipase (HSL).

  • Explain the consequences of chronic hyperinsulinemia.

  • Understand how insulin resistance can lead to inflammation in adipose tissue and the role of SOCS2 E3 Ligase in this process.

  • Understand the impact of hyperinsulinemia on IRS1/2 phosphorylation on serine sites and its inactivation, along with its role in insulin resistance.

  • Explain the role of mTORC1 in insulin resistance through p70S6K1 protein.

  • Understand how insulin resistance could lead to metabolic syndrome characterized by dyslipidemia and fatty liver disease.

  • Recognize the difference between primary and secondary dyslipidemia.

  • Understand how insulin resistance can simultaneously increase lipolysis in adipose tissue and lipogenesis in the liver and adipose tissue.

  • Explain how insulin induces lipogenesis in the liver through the SREBP-1 transcription factor.

Insulin Secretion from Pancreatic Beta Cells

  • GLUT2 Transporter Role:

    • GLUT2 allows bi-directional transport of glucose.

    • Facilitates glucose uptake during hyperglycemia and release during hypoglycemia.

    • Operates independently from insulin signaling.

Insulin Secretion Pathway Steps

  1. Insulin Gene Transcription:

    • Beta cells produce pre-pro-insulin mRNA.

  2. mRNA Export:

    • mRNA is exported to the cytoplasm and directed to the rough endoplasmic reticulum (ER) by its signal peptide.

  3. Translation:

    • Pre-pro-insulin is translated into the ER lumen.

  4. Processing:

    • The signal peptide is cleaved to form pro-insulin.

  5. Trafficking:

    • Properly folded pro-insulin is transported to the Golgi and then into immature secretory granules.

  6. Maturation:

    • Endoproteases PC1/2/3 cleave pro-insulin to produce mature insulin and C-peptide.

  7. Exocytosis:

    • Following glucose entry and membrane depolarization, mature granules containing insulin and C-peptide are released via exocytosis.

Summary of Insulin Secretion

  • After a meal, blood glucose concentration increases.

  • Beta cells possess GLUT2 transporters on their membranes sensitive to glucose levels.

  • Glucose entry increases ATP production, leading to the closure of ATP-gated potassium channels (KATP).

  • Decrease in potassium efflux causes beta cell depolarization, which stimulates insulin secretion into circulation.

  • Depolarization also opens voltage-gated calcium channels, resulting in calcium influx. Calcium ions are essential for insulin release.

Hypoglycemia & Counter-Regulatory Mechanisms

  • When insulin levels are too high and blood glucose drops excessively (hypoglycemia), counter-regulatory responses are triggered, including:

    • Glucagon:

    • Secreted from pancreatic alpha cells, stimulates glucose release from the liver via glycogenolysis and gluconeogenesis.

    • Epinephrine (Adrenaline):

    • Released from adrenal glands, promotes glycogen breakdown in liver and mobilizes fat from adipose tissue.

  • Symptoms of Severe Hypoglycemia:

    • Dizziness, confusion, seizures, and, in extreme cases, coma.

Comparison of Insulin and Glucagon

  • Insulin:

    • Raises blood sugar in response to high blood sugar levels.

    • Stimulates glycogen formation and glucose uptake from food.

    • Lowers blood sugar levels.

  • Glucagon:

    • Raises blood sugar by stimulating glycogen breakdown in the liver.

    • Lowers blood sugar through the promotion of insulin release from the pancreas.

Insulin’s Overall Metabolic Goals

  • Enhance glucose uptake by cells in various tissues.

  • Promote protein synthesis across tissues.

  • Promote glycogen synthesis (energy storage) particularly in liver and muscle.

  • Suppress glycogenolysis and gluconeogenesis, especially in the liver.

  • Promote lipogenesis in adipose tissue and liver.

  • Suppress lipolysis in adipose tissue.

Insulin Reduces Lipolysis in Adipose Tissue

  • Insulin suppresses triglyceride breakdown (lipolysis) in adipose tissue, preventing fatty acid release into the bloodstream.

  • Mechanism of Action:

    • Activation of Akt via insulin signaling leads to phosphorylation and inactivation of PKA (Protein Kinase A).

    • Reduced PKA activation results in decreased HSL (Hormone-Sensitive Lipase) activity, which normally breaks down triglycerides into free fatty acids (FFAs) and glycerol.

    • Insulin inhibits HSL, resulting in reduced FFAs production, promoting glucose use as energy.

Consequences of Chronic Hyperinsulinemia

Overview of Hyperinsulinemia and Its Effect

  • Chronic hyperinsulinemia leads to insulin resistance in peripheral tissues, including muscle, liver, and adipose tissue via several mechanisms:

    1. Overstimulation of Insulin Receptors:

    • Persistent high insulin levels lead to receptor desensitization, reducing downstream signaling effectiveness.

    1. IRS Phosphorylation:

    • Insulin Receptor Substrate (IRS) is phosphorylated on serine residues instead of tyrosine, inhibiting PI3K/Akt pathway signaling.

    1. Inflammation:

    • Chronic insulin exposure induces pro-inflammatory cytokines that disrupt insulin signaling, particularly in adipose tissue.

Effects of Insulin Resistance

  • Impaired Glucose Uptake:

    • Leads to hyperglycemia due to inadequate cellular glucose uptake.

  • Pancreatic Compensation:

    • The pancreas compensates by secreting more insulin, resulting in hyperinsulinemia.

Inflammation in Insulin Resistance

  • Insulin resistance may provoke macrophage infiltration into adipose tissue, promoting inflammation:

    • Upregulation of Monocyte Chemoattractant Protein-1 (MCP-1) attracts inflammatory cells.

    • Inflammatory markers, including TNF-α, IL-6, and IL-1β, are released by inflamed adipocytes and macrophages.

    • Cytokines activate SOCS3 E3 Ligase, which promotes the degradation of IRS1/2, leading to further insulin signaling inactivation.

Impacts on Signaling Pathways

  • Chronic hyperglycemia and hyperinsulinemia result in overactivation of the PI3K/Akt/mTORC1 signaling pathway.

  • Mechanisms of Overactivation:

    • Overactive Akt phosphorylates mTORC1, which then phosphorylates and activates p70S6K1.

    • p70S6K1 induces a negative feedback loop on IRS1/2 through serine phosphorylation, inhibiting additional insulin signaling.

  • Consequences:

    • Reduced glucose uptake and increased glycogen storage contribute to chronic hyperglycemia.

Effect of Insulin Resistance on Adipocytes

  • In insulin-resistant adipocytes, signaling is defective, particularly at the IRS and Akt levels.

    • Reduces Akt activation and increases PKA activity, which stimulates HSL, thus increasing lipolysis.

    • Long-term insulin resistance leads to ineffective utilization of free fatty acids, resulting in adipocyte hypertrophy and obesity.

Insulin Resistance Effects on the Liver

  • Chronic hyperinsulinemia can result in non-alcoholic fatty liver disease (NAFLD) due to lipid accumulation in hepatocytes via increased lipogenesis and reduced clearance.

  • Insulin enhances SREBP-1c transcription factor activity, which upregulates enzymes like Acetyl-CoA Carboxylase (ACC) and Fatty Acid Synthase (FAS), promoting de novo lipogenesis.

  • Insulin resistance hampers very-low-density lipoprotein (VLDL) secretion, leading to triglyceride accumulation in the liver, oxidative stress, and additional inflammatory damage, potentially progressing to fibrosis and HCC (hepatocellular carcinoma).

The Paradox of Lipolysis and Lipogenesis

  • Insulin resistance leads to simultaneous lipogenesis and lipolysis; these occur within different tissues and at different times.

    • In Primary Dyslipidemia, lipolysis occurs in adipose tissue while lipogenesis occurs in the liver.

    • In Secondary Dyslipidemia, both tissues store excessive fats, damaging both liver and adipocytes.

Downstream Events of Hyperinsulinemia

Overview of Metabolic Impact

  1. Increased Glucose Uptake and Utilization:

    • Insulin stimulates GLUT4 translocation to plasma membranes, enhancing glucose uptake in skeletal muscle and adipose tissue, leading to increased glycolysis or glycogen storage.

  2. Suppression of Hepatic Glucose Production:

    • Insulin inhibits gluconeogenesis and glycogenolysis in the liver, reducing glucose release into the bloodstream while enhancing glycogen storage.

  3. Increased Lipogenesis and Fat Storage:

    • Insulin promotes de novo lipogenesis, converting excess glucose to fatty acids, potentially leading to hepatic steatosis and NAFLD.

  4. Amino Acid Uptake and Protein Synthesis:

    • Insulin stimulates amino acid uptake and activates mTORC1 pathway to promote protein synthesis (anabolism) while inhibiting degradation (catabolism).