Lini

• Diabetes Mellitus (DM)


  Chronic Hyperglycemia: A key factor leading to complications, though the exact mechanisms of cellular and organ dysfunction remain unclear
• Epigenetic Modifications


  Lead to the formation of advanced glycation end products (AGEs) and the generation of reactive oxygen species (ROS), causing cellular damage and contributing to the pathology of diabetes
• Regulation of Insulin Secretion by Glucose Levels


  1. High Blood Glucose: Leads to increased glucose metabolism in pancreatic β cells, raising intracellular ATP levels

  2. ATP Effect: Closes K+ channels, causing membrane depolarization

  3. Ca2+ Influx: Voltage-gated Ca2+ channels open, increasing cytosolic Ca2+ levels, triggering insulin release via exocytosis
• Glucose Production in Fasting State

  1. Glycogenolysis: Liver glycogen is broken down to glucose-1-phosphate, then converted to glucose-6-phosphate, and finally to free glucose for release into the bloodstream

  2. Gluconeogenesis: Amino acids from protein degradation and glycerol from TAGs breakdown are used to synthesize glucose
• Fuel Utilization in Fasting State

  • Fatty Acids: The liver primarily uses fatty acids as a fuel source
  • Ketone Bodies: Excess acetyl-CoA is converted to ketone bodies, which are exported to tissues like the brain for energy during prolonged fasting
• Lipid Metabolism in Adipose Tissue During Diabetes

  1. Lipolysis: Increased breakdown of triacylglycerides (TAGs) into free fatty acids (FFAs) and glycerol

  2. Glucagon Activation: Glucagon binds to receptors on adipocytes, activating adenylyl cyclase via G protein, leading to cAMP production and PKA activation, which then phosphorylates hormone-sensitive lipase and perilipin, facilitating lipolysis

  3. Transport: FFAs are released into the bloodstream, bind to serum albumin, and are transported to other tissues for oxidation
• Accumulation of Acetyl-CoA in Liver During Diabetes

  1. Excess Glucose and Fatty Acids: Result in high levels of acetyl-CoA

  2. Ketogenesis: The liver converts acetyl-CoA into ketone bodies, which serve as an alternative energy source for peripheral tissues
• Chronic high levels of acetyl-CoA


  May contribute to metabolic disturbances through epigenetic modifications, such as histone acetylation
• Coordination of Glycolysis and Krebs Cycle

  1. ATP, Citrate, and O2 Levels: Coordinate the activity of glycolysis and the Krebs cycle to balance energy production and utilization

  2. Acetylation of Proteins: A post-translational modification that can regulate enzyme activity and metabolic pathways, similar to phosphorylation
• Histone and Protein Acetylation

  • Histone Acetylation: Modifies chromatin structure, influencing gene expression
  • Protein Acetylation: Regulates enzyme activity and metabolic pathways, affecting cellular functions and potentially contributing to disease states
• Ketogenic Diets


  1. Carbohydrate Suppression: Leads to increased reliance on lipids and proteins for fuel

  2. Mitochondrial Function: Ketogenic diets shift metabolism towards fat oxidation and ketone body production
• Key Metabolic Pathways in Ketogenic Diets

  • Fatty Acid Oxidation: Produces acetyl-CoA
  • Ketogenesis: Converts acetyl-CoA to ketone bodies in the liver
• Acetyl-CoA Accumulation in Diabetes Type II


  May lead to epigenetic changes, such as histone acetylation, affecting gene expression and potentially causing cellular de-differentiation and other pathological changes
• Accumulation of metabolic intermediates

  Can influence cell function and contribute to the development of complications
• Blood Levels of Metabolites During Starvation

  1. Glucose: Levels decrease as glycogen stores are depleted

  2. Ketone Bodies: Levels increase as fatty acids are mobilized and converted to ketone bodies

  3. Fatty Acids: Levels increase due to lipolysis in adipose tissue
• Events During Adaptation to Starvation

  1. Intestine and Portal Vein: Nutrient Absence - Low glucose and amino acids in the blood

  2. Pancreas: Low Insulin - Reduced release by beta cells, High Glucagon - Increased release by alpha cells

  3. Adipose Tissue: Fatty Acid Release - From triacylglycerol hydrolysis

  4. Liver: Glucose Release - From glycogen degradation and gluconeogenesis, Ketone Body Production - Increased synthesis and release

  5. Muscle: Fatty Acid and Ketone Utilization - Increased oxidation for energy, Amino Acid Release - For gluconeogenesis

  6. Brain: Glucose and Ketone Utilization - Oxidized to CO2 and water for energy