glucose regulation

Hormonal Production and Regulation

• Hypothalamus: Key organ producing hormones such as Dopamine, PRH, TRH, CRH, GHIH, and GnRH, influencing the anterior pituitary's activities.
• Anterior Pituitary: Responds to hypothalamic signals, releasing significant hormones including prolactin, TSH, ACTH, GH, FSH, and LH, which impact various other glands and tissues.
• Thyroid Gland: Responsible for producing Thyroid hormones, essential for metabolism and growth.
• Adrenal Cortex: Produces Cortisol, a crucial hormone involved in stress response and metabolism regulation.
• Liver: Synthesizes IGFs (Insulin-like Growth Factors), which play a role in growth hormone signaling and tissue growth.
• Gonads' Endocrine Cells: Produce sex hormones like Androgens, Estrogens, and Progesterone, important for reproductive functions and secondary sexual characteristics.

Mechanism of Hormonal Action

• Endocrine Target Cells: Directly receive and respond to the hormones they secrete, ensuring that localized effects occur in specific tissues.
• Non-Endocrine Targets: React indirectly to hormonal signals, as their responses are influenced by hormonal effects on other organs and tissues, providing a broader systemic response.

Regulation of Fat-Soluble Hormones

• The release of fat-soluble hormones is primarily regulated by relay hormones, indicating a hierarchical control system within hormonal signaling pathways.

Glucose as the Primary Energy Substrate

• Glucose is essential for supplying energy, particularly for the brain and nervous system.
• Plasma glucose levels are rigorously regulated to support energy metabolism across various tissues.

Digestion and Absorption Overview

• Fats are metabolized into free fatty acids and glycerol.
• Carbohydrates are converted into glucose during digestion.
• Proteins are broken down into amino acids for various metabolic processes.

Metabolic Processes

• Fat Stores Management:

  • Lipolysis: Breakdown of stored free fatty acids for energy.
  • Lipogenesis: Conversion of excess free fatty acids into fat reserves.

• Glucose Pool Regulation:

  • Glycogenesis: Storage of glucose as glycogen in liver and muscle tissues.
  • Glycogenolysis: Release of glucose from glycogen stores when energy is needed.
  • Gluconeogenesis: Production of glucose from amino acids to maintain energy supply.

Amino Acid and Protein Utilization

• Protein Synthesis: Amino acids are used to build proteins necessary for body functions.
• Protein Breakdown: Proteins can be degraded into amino acids for alternative energy sources.
• Gluconeogenesis also utilizes amino acids to form glucose.

Energy Reliance and Excess Nutrient Management

• The brain relies on glucose exclusively for metabolic activities.
• Most body tissues utilize glucose as a primary energy source.
• The body manages excess nutrients by either storing them in various forms or excreting them through urine.

Glucose as the Primary Energy Substrate

• Glucose is essential for supplying energy, particularly for the brain and nervous system.
• Plasma glucose levels are rigorously regulated to support energy metabolism across various tissues.

Digestion and Absorption Overview

• Fats are metabolized into free fatty acids and glycerol.
• Carbohydrates are converted into glucose during digestion.
• Proteins are broken down into amino acids for various metabolic processes.

Metabolic Processes

• Fat Stores Management:

  • Lipolysis: Breakdown of stored free fatty acids for energy.
  • Lipogenesis: Conversion of excess free fatty acids into fat reserves.

• Glucose Pool Regulation:

  • Glycogenesis: Storage of glucose as glycogen in liver and muscle tissues.
  • Glycogenolysis: Release of glucose from glycogen stores when energy is needed.
  • Gluconeogenesis: Production of glucose from amino acids to maintain energy supply.

Amino Acid and Protein Utilization

• Protein Synthesis: Amino acids are used to build proteins necessary for body functions.
• Protein Breakdown: Proteins can be degraded into amino acids for alternative energy sources.
• Gluconeogenesis also utilizes amino acids to form glucose.

Energy Reliance and Excess Nutrient Management

• The brain relies on glucose exclusively for metabolic activities.
• Most body tissues utilize glucose as a primary energy source.
• The body manages excess nutrients by either storing them in various forms or excreting them through urine.

Glucose as the Primary Energy Substrate

• Glucose is essential for supplying energy, particularly for the brain and nervous system.
• Plasma glucose levels are rigorously regulated to support energy metabolism across various tissues.

Digestion and Absorption Overview

• Fats are metabolized into free fatty acids and glycerol.
• Carbohydrates are converted into glucose during digestion.
• Proteins are broken down into amino acids for various metabolic processes.

Metabolic Processes

• Fat Stores Management:

  • Lipolysis: Breakdown of stored free fatty acids for energy.
  • Lipogenesis: Conversion of excess free fatty acids into fat reserves.

• Glucose Pool Regulation:

  • Glycogenesis: Storage of glucose as glycogen in liver and muscle tissues.
  • Glycogenolysis: Release of glucose from glycogen stores when energy is needed.
  • Gluconeogenesis: Production of glucose from amino acids to maintain energy supply.

Amino Acid and Protein Utilization

• Protein Synthesis: Amino acids are used to build proteins necessary for body functions.
• Protein Breakdown: Proteins can be degraded into amino acids for alternative energy sources.
• Gluconeogenesis also utilizes amino acids to form glucose.

Energy Reliance and Excess Nutrient Management

• The brain relies on glucose exclusively for metabolic activities.
• Most body tissues utilize glucose as a primary energy source.
• The body manages excess nutrients by either storing them in various forms or excreting them through urine.

Metabolic Processes After a Meal

• The gastrointestinal (GI) tract absorbs nutrients such as glucose (including galactose and fructose), triacylglycerols, and amino acids immediately post-meal.
• Muscle tissues convert absorbed glucose into glycogen for storage and utilize available amino acids for protein synthesis.
• Almost all body tissues utilize the absorbed glucose as an immediate source of energy.
• The liver performs multiple critical functions, including:
  • Utilizing absorbed glucose as an energy source.
  • Converting glucose into storage forms: glycogen and triacylglycerols.
  • Processing absorbed amino acids to produce urea (a waste product) and keto acids.
• Adipose (fat) tissue primarily processes fatty acids released by the liver to generate triacylglycerols and monoglycerides.
• Blood glucose levels are tightly regulated by the hormones insulin and glucagon, which play essential roles in balancing energy homeostasis.

Metabolic Processes After a Meal

• The gastrointestinal (GI) tract absorbs nutrients such as glucose (including galactose and fructose), triacylglycerols, and amino acids immediately post-meal.
• Muscle tissues convert absorbed glucose into glycogen for storage and utilize available amino acids for protein synthesis.
• Almost all body tissues utilize the absorbed glucose as an immediate source of energy.
• The liver performs multiple critical functions, including:
  • Utilizing absorbed glucose as an energy source.
  • Converting glucose into storage forms: glycogen and triacylglycerols.
  • Processing absorbed amino acids to produce urea (a waste product) and keto acids.
• Adipose (fat) tissue primarily processes fatty acids released by the liver to generate triacylglycerols and monoglycerides.
• Blood glucose levels are tightly regulated by the hormones insulin and glucagon, which play essential roles in balancing energy homeostasis.

Glucose Homeostasis: Cellular Metabolism

• Glycerol, amino acids, and glucose are metabolically converted to pyruvate.
• Pyruvate conversion leads to the production of Acetyl CoA, a crucial metabolic intermediate.
• Fatty acids are also transformed into Acetyl CoA, linking lipid metabolism to energy production.
• Acetyl CoA enters the Citric Acid Cycle, also known as the Krebs cycle, resulting in the production of ATP, carbon dioxide (CO2), and high-energy electrons along with protons (H+).
• High-energy electrons and protons are utilized in the Electron Transport System (ETS) to generate additional ATP, molecular oxygen (O2), and water (H2O).
• Although glucose metabolism yields less ATP per unit than lipid metabolism, it is more efficient and faster in the conversion process.

Insulin and Glucagon Overview

• Insulin and glucagon are hormones with opposing functions.
• Insulin is released when blood glucose levels are high, while glucagon is secreted when glucose levels are low.

Fed State: Insulin Dominates

• Body converts excess glucose into energy for cellular metabolism.
• Prepares for potential energy shortages by:
  • Converting glucose to glycogen through glycogenesis for storage.
  • Promoting protein synthesis to support cellular functions.
  • Encouraging lipogenesis, the process of converting excess glucose to fat for long-term energy storage.

Fasting State: Glucagon Dominates

• Energy is urgently needed as blood glucose levels fall.
• Glycogen, the storage form of glucose, is broken down into glucose through glycogenolysis to release immediate energy.
• Gluconeogenesis occurs, producing new glucose from non-carbohydrate sources such as amino acids and glycerol.

Insulin and Glucagon

• Insulin and glucagon are hormones that have opposing functions regarding blood glucose levels.
• Insulin lowers blood glucose levels, while glucagon raises them.

Fed State: Insulin Dominates

• Blood glucose is reduced as it enters cells for energy production.
• Body prepares for periods of low food availability, often referred to as “lean years.”
• Excess glucose is converted to glycogen through glycogenesis for storage.
• Promotes protein synthesis and fat storage via lipogenesis.

Fasting State: Glucagon Dominates

• Glucagon is released when the body requires energy.
• Glycogen stored in the liver is broken down into glucose through glycogenolysis.
• Glucose is synthesized from non-carbohydrate sources via gluconeogenesis to maintain blood glucose levels.

Insulin and Glucagon Regulation

• The term "insula," meaning "island" in Latin, refers to the pancreatic islets where insulin and glucagon are produced.
• Blood glucose levels typically begin around 90 mg/100 ml, rising to approximately 130 mg/100 ml within the first hour post carbohydrate consumption.
• After reaching peak glucose concentration, blood glucose levels decline steadily over the subsequent five hours.

Blood Insulin Response

• Blood insulin levels are initially around 0 units/ml for about the first hour following a meal.
• Insulin levels then surge sharply, peaking at around 100 units/ml within the second hour post-meal.
• Following the peak, insulin levels gradually decrease over the next few hours.

Blood Glucagon Dynamics

• Blood glucagon starts at nearly 100 g/ml and remains stable for the initial hour after eating.
• After one hour, glucagon levels drop slightly to approximately 90 g/ml and remain consistent for the duration of the six-hour observation period.

Glycemic Control Mechanism

• The intake of carbohydrates elevates blood glucose, prompting the pancreas to secrete insulin.
• Insulin facilitates the uptake of glucose by body cells, effectively reducing blood glucose levels.
• Glucagon serves to prevent blood glucose from depleting too low by enhancing glucose production in the liver, maintaining necessary energy levels in the body.

Endocrine Response to Carbohydrate-Containing Meal

• Elevation of plasma glucose levels triggers the secretion of insulin from pancreatic β-cells, a primary mechanism for insulin release.
• Ingestion of glucose leads to the release of incretins, specifically GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide), which enhance insulin secretion.
• Autonomic nervous system may influence β-cell activity, suggesting a potential mechanism for stimulation; however, the precise processes remain unclear.

Incretins and Carbohydrate Metabolism

• Ingesting carbohydrates leads to an increase in glucose levels.
• The small intestine's brush border responds by elevating levels of two key incretins: GLP-1 and GIP.
• GLP-1 (Glucagon-like peptide-1) and GIP (Glucose-dependent insulin-releasing polypeptide) significantly stimulate pancreatic β cells to increase insulin secretion.
• This insulin response helps lower plasma glucose levels following carbohydrate intake.

Role of DPP-4 and Its Inhibitors

• GLP-1 and GIP are rapidly inactivated by the enzyme Dipeptidyl peptidase-4 (DPP-4).
• Inhibition of DPP-4 can prolong the activity of incretins, enhancing their effects on insulin secretion and glucose management.

Effects of Incretins on Various Tissues

• Increased levels of fat promote greater glucose uptake in tissues.
• Skeletal muscle exhibits elevated insulin sensitivity, resulting in enhanced glucose absorption.
• In the liver, GLP-1 and GIP lead to decreased glucagon levels, which decreases hepatic glucose production, further assisting in glucose homeostasis.

Insulin Receptor Structure

• Insulin receptor consists of a tetrameric protein structure.
• Composed of two alpha (α) subunits located on the cell membrane, which possess insulin binding sites.
• Contains two beta (β) subunits that span the membrane and are linked with tyrosine kinases.

Functionality of Insulin Receptor

• Functions primarily as a tyrosine-kinase receptor to mediate insulin's cellular effects.
• Upon insulin binding, the receptor activates its intrinsic kinase activity, leading to the phosphorylation of specific intracellular proteins.

Signal Transduction Pathways

• Major signaling pathway activated by insulin is the PI3-kinase and protein kinase B (Akt) pathway.
• This pathway plays a crucial role in mediating many of insulin's metabolic effects across different tissues.

Target Cells for Insulin Action

• Insulin receptors are present in liver, muscle, and adipose (fat) cells, making these tissues responsive to insulin.
• These cell types are critical for regulating glucose uptake and metabolism in response to insulin signaling.

The Insulin Receptor

• Composed of four subunits, known as a tetramer protein.
• Contains two α-subunits located on the cell membrane, responsible for binding insulin.
• Features two β-subunits that are transmembrane proteins linked to tyrosine-kinases, facilitating transduction of signals.
• Classified as a "tyrosine-kinase-receptor," which indicates it functions as a receptor-enzyme.
• Activates multiple signaling pathways, prominently the PI3-kinase - protein kinase B/Akt pathway, influencing various cellular responses.
• Expressed in key cell types: liver cells, muscle cells, and adipocytes, which are integral to the effects of insulin in the body.

Key Functions and Pathways

• Upon insulin binding, the receptor initiates a cascade of intracellular signaling.
• The PI3-kinase pathway is crucial for conveying insulin's metabolic actions, particularly in glucose uptake and metabolism.
• The receptor's activation leads to the phosphorylation of Akt, a vital protein for cell survival and metabolism regulation.

Insulin's Cellular Impact

• Insulin receptors are vital for the regulation of glucose levels in the bloodstream.
• The sensitivity of liver, muscle, and adipose tissues to insulin is essential for metabolizing sugars and fats, influencing overall energy balance in the body.

The Insulin Receptor

• Composed of a tetramer protein structure.
• Features two α-subunits located on the cell membrane, responsible for insulin binding.
• Contains two β-subunits that are transmembrane proteins linked to tyrosine-kinases.
• Classified as a "tyrosine-kinase-receptor," part of the receptor-enzyme family.
• Signaling pathways activated by the receptor primarily involve the PI3-kinase - protein kinase B/Akt pathway.
• Present in liver, muscle, and adipose tissue cells, which are the primary targets for insulin's effects.
• The kinase activity of the insulin receptor phosphorylates specific intracellular proteins, initiating a signal transduction cascade.

Cellular Uptake of Glucose

• Glucose concentration rise leads to increased insulin secretion by pancreatic beta cells, enhancing glucose uptake in tissues.
• Cell Membrane Dynamics*
• Inactive PI3-K is present before insulin signaling is activated.
• Active PI3-K is generated upon insulin receptor activation, playing a key role in glucose uptake.
• Active IRS-1 relays signals from the insulin receptor; its inactivity results in diminished signaling pathways.
• GLUT vesicles contain glucose transporters that are filled and ready for translocation.
• The translocation of GLUT vesicles to the cell membrane is crucial for glucose absorption.
• Increased glucose transport leads to higher levels of glucose in the cytoplasm for utilization and storage.

Key Molecules

• IRS-1 (Insulin Receptor Substrate-1): Mediator in insulin signaling pathways, connects insulin receptors to downstream signaling effects.
• PI3-K (Phosphatidylinositol 3-kinase): Enzyme involved in signaling that promotes glucose uptake and utilization.
• PKB (Protein Kinase B): Also known as Akt, involved in promoting glucose uptake and metabolic actions.
• GSK-3 (Glycogen Synthase Kinase-3): Inhibited by insulin signaling, facilitating glycogen synthesis by promoting glucose storage.
• GLUT (Glucose Transporter): Family of proteins responsible for transporting glucose across cell membranes, essential for cellular glucose uptake.

Cellular Uptake of Glucose

• Increased glucose levels stimulate insulin secretion.
• Insulin binds to its receptor, enhancing glucose uptake by cells.
• Insulin receptor substrate-1 (IRS-1) plays a crucial role in the signaling cascade activation.

Key Molecular Players

• Inactive P13-K transitions to active P13-K, triggering downstream signaling.
• PKB/Akt is activated, leading to translocation and release of glucose transporter (GLUT) vesicles to the cell membrane.
• P-Tyr IRS-1 facilitates further signaling to enhance glucose uptake by cells.

Mechanism of GLUT Vesicle Translocation

• GLUT vesicles migrate towards the cell membrane, increasing glucose transport capacity.
• This mechanism is vital for maintaining glucose homeostasis in the body.

Important Terms

• P13-K: Enzyme responsible for phosphorylating phosphatidylinositols, crucial for cell signaling.
• PKB (Akt): Important kinase in the signaling pathway promoting glucose uptake and glycogen synthesis.
• GLUT: Essential for glucose transport across the cell membrane.

Cellular Uptake of Glucose

• Increased glucose concentration stimulates insulin secretion from pancreatic β-cells.
• Insulin binds to its receptor on cell membranes, initiating glucose uptake mechanisms.
• The insulin receptor activates signaling pathways through the insulin receptor substrate-1 (IRS-1).
• Initially inactive phosphatidylinositol 3-kinase (P13-K) becomes active as a result of IRS-1 signaling.
• Active IRS-1 undergoes phosphorylation, leading to its activation and changing its status from inactive to active.
• Protein kinase B (PKB/Akt) is activated through the phosphorylation of IRS-1 and P13-K pathways.
• Activation of PKB/Akt inhibits glycogen synthase kinase-3 (GSK-3), influencing metabolic processes.
• Glucose transporter (GLUT) vesicles are mobilized and translocated to the cell membrane, facilitating glucose entry into cells.
• GLUT molecules in the cytoplasm are crucial for effective glucose transport across the cell membrane.

Glucose Homeostasis Overview

• Essential for maintaining stable blood glucose levels in the body.
• Involves multiple organs and signaling pathways, primarily the liver.

Hepatocyte Functions

• Contains a plasma membrane crucial for regulating substance transport.
• Protein Kinase A (PKA) is pivotal for glucose metabolism regulation.
  • Activates Phosphorylase b kinase, converting it from inactive to active form.
  • Activates Phosphorylase a, promoting glycogen breakdown.
  • Inactivates Glycogen Synthase I to inhibit glycogen synthesis.

Glycogen Management

• Glycogen serves as a major energy reserve, particularly in the liver.
• Glycogen Synthase D is the active form for glycogen synthesis; Glycogen Synthase Kinase regulates its activity.
• Increase in plasma glucose levels promotes DIABETOGENIC EFFECTS, highlighting the link between excess glucose and metabolic dysfunction.

Glycogenolysis Process

• Glycogenolysis involves the conversion of glycogen into glucose, predominantly occurring in the liver.
• Serves as a critical energy source during fasting situations when external glucose sources are limited.
• Glucagon binds to its receptor, activating the cAMP-PKA signaling pathway, resulting in enhanced glycogen breakdown for glucose availability.

Glycogenolysis

• Glycogenolysis is the process of converting glycogen into glucose, primarily occurring in the liver.
• This physiological response is critical during fasting when external glucose sources are unavailable.
• The binding of glucagon to its receptor initiates the cyclic AMP (cAMP) - protein kinase A (PKA) signaling pathway.
• Activation of PKA results in increased glycogen breakdown, ensuring a steady supply of glucose during periods of low availability.

Increased Plasma Glucose Levels: Diabetogenic Effects

• Glycogen synthase (GSK) is inactivated during glycogenolysis, which prevents glycogen synthesis while glucose is released.
• Dysregulation of glycogenolysis can lead to persistently high plasma glucose levels.
• Chronic elevated blood sugar can cause insulin resistance, paving the way for type 2 diabetes development.
• The coordinated regulation of glycogen phosphorylase (activates glycogen breakdown) versus glycogen synthase (inhibits glycogen storage) is essential for maintaining glucose homeostasis.

Gluconeogenesis Overview

• Definition: Gluconeogenesis is the metabolic process of synthesizing glucose from non-glucose precursors.
• When it Occurs: Activated during fasting or when glycogen stores are low, and dietary glucose intake is insufficient.

Precursor Molecules

• Types of Precursors:
  • Glycerol: A byproduct of fat metabolism, can be converted into glucose.
  • Lactate: Produced during anaerobic respiration, serves as a source for gluconeogenesis.
  • Amino Acids: Particularly alanine and glutamine, can be transformed into glucose when needed.

Location of Gluconeogenesis

• Primarily occurs in the liver and kidney.
• These organs are uniquely equipped to convert the aforementioned precursors into glucose.

Hormonal Regulation

• Glucagon: A key hormone that stimulates gluconeogenesis, especially during low blood sugar levels.
• Cortisol: Another hormone that plays a role in promoting gluconeogenesis, particularly during stress.

Key Outcome

• The process results in the formation of glucose 6-phosphate, essential for energy production and maintaining blood sugar levels.

Diabetogenic Hormones

• Insulin functions to decrease blood glucose levels.
• Glucagon is known to increase blood glucose levels.
• Adrenaline contributes to the elevation of blood glucose.
• Cortisol plays a significant role in increasing blood glucose levels.

Diabetogenic Effects

• Blood glucose decreases following insulin secretion.
• Glucagon, adrenaline, and cortisol elevate blood glucose levels.
• Hormonal interactions can amplify the effects on blood glucose.

Hormonal Combinations and Effects

• Glucagon combined with epinephrine results in a sharp increase in blood glucose levels.
• The combination of glucagon, epinephrine, and cortisol leads to the highest and most sustained elevation in blood glucose.
• Cortisol by itself produces a slower and more gradual increase in blood glucose compared to its combinations with other hormones.

Fasting Overview

• Fasting triggers compensatory metabolic reactions aimed at utilizing energy from existing body reserves.
• Leads to a catabolic state, where stored food materials are degraded for energy production.
• Demonstrates similarities with metabolic responses in Diabetes Mellitus Type 1.

Fasted-State Metabolism

• Liver glycogen is converted into glucose to maintain blood sugar levels.
• Adipose tissues break down lipids into fatty acids, which are released into the bloodstream.
• Triglyceride stores in fat cells are mobilized for energy.
• Ketone bodies are produced from fatty acids, serving as an alternative energy source, especially for the brain.
• The brain primarily relies on glucose and ketones for its energy requirements.
• Muscle glycogen stores are also utilized during fasting but to a lesser extent than liver glycogen.

Diabetes Mellitus: Pathophysiology

• Diabetes Mellitus arises from impaired insulin regulation of plasma glucose levels.
• The fundamental issue can occur due to:
  • Insufficient insulin concentration in the plasma.
  • Insulin resistance, where insulin levels may be normal or elevated, but its effectiveness is diminished.

Consequences of Impairment

• Reduced glucose uptake in muscle, fat, and liver cells leads to increased plasma glucose levels.
• Prolonged high glucose concentration in plasma can result in severe health complications.

Diabetes Mellitus: Pathophysiology

• Insulin is crucial for regulating blood glucose levels.
• Loss of insulin functionality causes diabetes mellitus.

Basic Problem

• Two primary issues:
  • Decreased insulin concentration in the bloodstream.
  • Insulin resistance, where insulin levels may be normal or high, but its action is diminished.

Consequences of Insulin Deficiency

• Reduced glucose uptake occurs in key tissues:
  • Muscle cells
  • Adipose (fat) tissue
  • Liver cells
• Elevated plasma glucose concentrations result, leading to potential long-term complications.

Glucose Tolerance Test Overview

• Measures plasma glucose levels after oral glucose intake to assess glucose regulation.
• Key time points for measurement: 0, 1, and 2 hours post-glucose intake.
• Plasma glucose levels are indicated in mg/dL, with ranges from 50 to 250.

Diabetic Subject Characteristics

• Higher initial fasting plasma glucose concentration compared to normal subjects.
• Blood glucose levels remain elevated above normal thresholds even after 2 hours.
• Reflects impaired ability to regulate blood glucose after glucose consumption.

Normal Subject Characteristics

• Lower initial fasting plasma glucose concentration.
• Blood glucose levels return to normal ranges within 2 hours post-glucose intake.
• Demonstrates effective glucose regulation and tolerance.

Implications

• The graph illustrates the stark differences in glucose tolerance between diabetic and normal individuals.
• Highlights the importance of glucose tolerance testing in diagnosing and managing diabetes.
• Sustained high glucose levels in diabetics can lead to long-term health complications.

Insulin Resistance

• Insulin resistance occurs when cells become less responsive to insulin, leading to impaired glucose metabolism.
• Obesity is a significant contributing factor, resulting in elevated levels of free fatty acids (FFA) in the bloodstream.
• Elevated FFA induces the production of diacylglycerol, a lipid that disrupts normal signaling pathways.
• Diacylglycerol inhibits protein kinase C (PKC), an important enzyme for insulin signaling.
• Inhibition of PKC leads to the phosphorylation and subsequent inactivation of insulin receptor substrate-1 (IRS-1).
• Inactive IRS-1 prevents the activation of phosphatidylinositol 3-kinase (PI3-K), a key player in insulin signaling.
• Inactive PI3-K results in reduced activity of protein kinase B (PKB), also known as Akt.
• Inactivation of Akt impacts glycogen synthase kinase-3 (GSK-3), leading to its inhibition.
• Inhibition of GSK-3 decreases glucose uptake by the cells, ultimately contributing to insulin resistance.

Key Components of Insulin Signaling

• Free Fatty Acids (FFA): Unbound fatty acids that act as signaling molecules in insulin resistance.
• Protein Kinase C (PKC): Enzyme involved in insulin signaling and modulation of cellular functions.
• Insulin Receptor Substrate-1 (IRS-1): Critical protein connecting insulin receptors to downstream signaling pathways.
• Phosphatidylinositol 3-Kinase (PI3-K): Integral to insulin signaling, initiating a cascade that promotes glucose uptake.
• Protein Kinase B (PKB/Akt): Regulates various metabolic processes, including glucose storage and utilization.
• Glycogen Synthase Kinase-3 (GSK-3): Enzyme that influences glycogen synthesis and is affected by the insulin signaling cascade.

Summary

• The process of insulin resistance involves a series of molecular events often triggered by obesity and excessive FFA levels.
• Central to this mechanism is the disruption of insulin signaling pathways, leading to decreased glucose metabolism and increased risk of metabolic disorders.

Fasting and Metabolism

• Fasting triggers compensatory metabolic processes where energy is derived from existing body stores.
• CATABOLISM occurs as food stores are broken down into basic nutrients.
• Liver glycogen is converted into glucose during fasting.
• Adipose lipids are broken down into fatty acids, which then enter the bloodstream.
• Brain energy is dependent on glucose and ketone bodies.

Diabetes Mellitus: Pathophysiology

• Diabetes develops when insulin fails to effectively regulate plasma glucose levels.
• Basic issues include decreased insulin concentration or insulin resistance despite normal insulin levels.
• Consequences:
  • Reduced glucose uptake in muscle, fat, and liver cells.
  • Elevated plasma glucose levels leading to serious health issues over time.

Glucose Tolerance Test

• Diabetic individuals present with higher fasting plasma glucose and prolonged elevated levels post-glucose administration.
• Normal individuals show a quick return to normal glucose levels within 2 hours after glucose intake.

Insulin Resistance

• Obesity is linked to increased free fatty acids (FFA) impacting insulin action.
• Mechanisms include alterations in cell membrane dynamics and protein kinase C (PKC) pathways.

Hormonal Regulation of Energy Metabolism

• Hypothalamus produces hormones that signal the anterior pituitary, which releases various hormones affecting metabolism.
• Key hormones include:
  • Insulin (produced in the pancreas) and glucagon, which exert opposite effects on glucose metabolism.
• Fat-soluble hormones are primarily regulated by relay hormones.

Cellular Actions of Insulin

• Insulin receptor consists of a tetramer structure with two α-subunits for binding and two β-subunits that contain tyrosine kinases.
• Insulin signaling affects liver, muscle, and adipose cells, crucial for glucose uptake and metabolism.
• Insulin receptor signaling often activates the PI3-kinase pathway leading to various metabolic responses.

Glucose Homeostasis Overview

• Glucose serves as the primary energy substrate, vital for brain function.
• Plasma glucose is meticulously regulated, especially after dietary intake.
• Nutrient digestion results in the breakdown of fats to fatty acids, carbohydrates to glucose, and proteins to amino acids.
• Excess nutrients can be stored, and metabolic pathways allow for glucose production from non-carbohydrate sources (gluconeogenesis).

Metabolic States Post-Meal

• After a meal, the GI tract absorbs glucose, triacylglycerols, and amino acids.
• Muscle cells convert glucose to glycogen for storage and utilize amino acids.
• The liver plays a central role in using glucose, producing glycogen, and converting amino acids for energy.
• Insulin promotes glucose uptake and reduces blood glucose levels, while glucagon maintains homeostasis during fasting states.

Glycogenolysis and Diabetes Connection

• Glycogenolysis occurs in the liver, breaking down glycogen to glucose during fasting states.
• Glucagon activates cAMP-PKA signaling, leading to glycogen breakdown and increased plasma glucose levels.
• Dysregulation in this process can result in insulin resistance and the development of type 2 diabetes.

Endocrine Responses to Carbohydrates

• Ingestion of carbohydrates leads directly to increased plasma glucose and insulin secretion from pancreatic β-cells.
• Incretins (GLP-1 and GIP) are released from the gut, enhancing insulin production and secretion.
• DPP-4 inhibitors can prolong the action of incretins, benefiting glucose regulation.### GLP-1, GIP, DPP-4
• GLP-1: Regulates glucose metabolism and insulin secretion.
• GIP: Stimulates insulin release in response to meals.
• DPP-4: Enzyme that inactivates GLP-1 and GIP, influencing glucose levels.

Cellular Actions of Insulin

• Insulin stimulates glucose uptake in fat and muscle tissues.
• Insulin reduces glucagon levels in the liver, decreasing glucose production.

Insulin Receptor Structure

• Comprised of two α-subunits for insulin binding and two β-subunits with tyrosine-kinase activity.
• Functions as a tyrosine-kinase receptor activating multiple signaling pathways, primarily the PI3-kinase - protein kinase B/Akt cascade.
• Found on liver, muscle, and adipose tissue, making these cells sensitive to insulin.

Cellular Uptake of Glucose Mechanism

• Increased glucose levels lead to elevated insulin secretion, triggering insulin receptor activation and subsequent glucose uptake.
• Pathway includes:
  • Activation of PI3-K, IRS-1, and PKB/Akt.
  • Translocation of GLUT vesicles to the cell membrane, facilitating glucose entry into the cytoplasm.

Glucose Homeostasis in Hepatocytes

• Hepatocytes contain proteins that regulate glycogen metabolism.
• Increases in plasma glucose levels can lead to diabetogenic effects.
• GSK inactivates glycogen synthase, promoting glycogen breakdown.

Glycogenolysis

• Process of breaking down glycogen to release glucose, occurring primarily in the liver.
• Activated by glucagon via the cyclic AMP (cAMP) and protein kinase A (PKA) signaling pathway, increasing glycogen breakdown during fasting.

Gluconeogenesis

• Synthesis of glucose from non-carbohydrate precursors like glycerol, lactate, and amino acids.
• Ensures glucose availability during fasting when glycogen stores are low.
• Occurs mainly in the liver and kidneys; regulated by hormones such as glucagon and cortisol.

Diabetogenic Hormones

• Insulin: Decreases blood glucose levels.
• Glucagon: Increases blood glucose levels.
• Adrenaline: Elevates blood glucose, especially during stress.
• Cortisol: Promotes higher blood glucose levels.

Blood Glucose Response to Hormones

• Glucagon alone causes sharp increases in blood glucose.
• Co-administration of glucagon with epinephrine amplifies the response.
• Cortisol adds a slower, sustained increase in blood glucose levels.