Glucose Homeostasis & Fuel Metabolism - Dra. Flores - 2023-01.pdf

Glucose homeostasis & fuel metabolism Dr. Maritza Roxana Garcia Modified by Dra. Mariana Flores Objectives 01 Review metbolic pathways of glucose. 03 Know the specific enzymatic pathways that the muscle and brain utilize to obtain energy. 05 02 Understand the connections betwee protein, fats and car...

Glucose homeostasis & fuel metabolism Dr. Maritza Roxana Garcia Modified by Dra. Mariana Flores Objectives 01 Review metbolic pathways of glucose. 03 Know the specific enzymatic pathways that the muscle and brain utilize to obtain energy. 05 02 Understand the connections betwee protein, fats and carbohydrate metabolism for energy creation. 04 Recognize all steps for insulin secretion & activity mediated by insuline receptors. Comprehend glycemic reulation by the endocrine system and secondary mechanisms. Introduction The most important energy substrates are glucose and fatty acids. ENERGY SUPPLY After ingestion of food, the excess of glucose and fatty acids is stored, to be released again in case of need, thus providing continuous energy supply. The main pathways of fuel metabolism and the key metabolites Glucose Glucose is obtained from three sources: intestinal absorption of food, glycogenolysis, and gluconeogenesis. ✓Once transported into cells, can be stored as glycogen or it can undergo glycolysis to obtain pyruvate ✓Pyruvate can be reduced to lactate, transaminated to form alanine, or converted to acetyl coenzyme A (CoA). GLYCOLYSIS Further excess of glucose is converted to fatty acids, the ultimate long-term energy-storage material. Acetyl CoA can be oxidized in the TCA cycle, converted to fatty acids for storage as triglyceride, or serve as substrate for ketone bodies or cholesterol synthesis. Glycogen Synthesis/Glycogenolysis ✓First, a limited amount of glucose is stored as glycogen. ✓When glucose concentration in the extracellular fluid decreases, it is first replenished from the liver glycogen (sustain glucose supply for 16 h). Exam Like Question Which of the following molecules can't be use as substrates for gluconeogenesis? a)Alanine b)Lactate c)Glycerol d)Ketone Bodies e)Pyruvate Gluconeogenesis During prolonged fasting or extreme exercise: the synthesis of glucose from noncarbohydrate compounds, known as gluconeogenesis. The liver and kidneys contain the enzymes required for GLUCONEOGENESIS. Of the two organs, the liver is responsible for the bulk of glucose output; the kidney supplies only 10% to 20% of glucose production during fasting. The main substrates for gluconeogenesis: ✓lactate derived from anaerobic glycolysis ✓alanine from the amino acids released during the breakdown of muscle protein ✓glycerol from the breakdown of triacylglycerols in the adipose tissue. Fatty acids Fatty acids are the primary energy source during prolonged fasting and prolonged exercise In contrast to glucose, there is unlimited capacity for fat storage In extreme circumstances, people can fast for as long as 60–90 days. Fat is stored in the adipose tissue as triglycerides Excess amino acids taken in food are converted to carbohydrates Amino acids Amino acids → synthesis of body proteins. When energy needs increase (i.e., prolonged fast, illness, or injury), body proteins are degraded, and the released amino acids are converted into glucose through gluconeogenesis. Energy & the muscle ✓ Muscle uses both glucose and fatty acids as energy sources. ✓ Glucose is the preferred fuel for muscle use during the initial stages of exercise. ✓ During prolonged exercise, the main energy source is fatty acids. Muscle contributes to gluconeogenesis by releasing lactate and, alanine. Both are transported to the liver. Although glycogenolysis can occur in most tissues in the body, only liver and kidneys express the enzyme glucose-6phosphatase, which is required for release of cellular glucose into the bloodstream. Although the myocytes contain glycogen, they can only use it for their own energy needs; they cannot release glucose because they lack the glucose-6-phosphatase https://www.youtube.com/watch?v=d-HgDkWK3P0 Energy & the Brain Glucose → only fuel used by the brain. The brain uses approximately 20% of all oxygen consumed by the body. During starvation, the brain adapts to the use of ketone bodies as an alternative energy source. Caloric restriction downregulates glucose metabolic pathway but upregulates ketogenic pathway Exam Like Question Which of the following is consider an anabolic hormone? a)Adrenaline b)Cortisol c)Growth Hormone d)Somatostatin e)Insuline Glucose homeostasis Under normal conditions, glucose concentration is tightly regulated by the NEUROENDOCRINE SYSTEM. Control of blood glucose is complex, involving interaction among liver, pancreas, muscle, adipose tissue, pituitary, adrenals, and bone. Glucose homeostasis is controlled by: ✓ Anabolic hormone insulin and, ✓Catabolic hormones (glucagon, catecholamines, cortisol, and Growth hormone). Insulin The switch from glycogen synthesis after meals to glycogen breakdown and gluconeogenesis is orchestrated by hormones of which insulin is centrally important. ✓Surge in insulin: activates glycogen synthesis enhances peripheral glucose uptake inhibits glucose production lipogenesis is stimulated lipolysis and ketogenesis are suppressed Increase protein synthesis and decrease proteolysis ✓ Plasma insulin concentrations increase to peak levels of 50 to 100 µU/mL after meals. ✓ During fasting, plasma insulin level falls to less than or equal to 5 to 10 µU/mL. ✓ Hormones including glucagon, catecholamines, cortisol, and growth hormone (GH) counteract the effects of insulin and promote glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. Insulin secretion Insulin Secretion Insulin secretion is controlled by glucose metabolism in the β-cell 1. The β cell takes up glucose using the membrane transporter GLUT-2. 2. On entering the cell, glucose is phosphorylated by glucokinase and enters glycolysis. 3. As glucose metabolism is stimulated, the ATP/ADP ratio in the cell increases. 4. This closes the ATP-sensitive potassium channels in the cell membrane, decreasing potassium efflux and depolarizing the cell. 5. This in turn opens the L-type calcium channels, allowing calcium ions to enter the cell. 6. This activates Ca2+ -dependent proteins that cause the release of secretory granules containing insulin. *Note that this substances can also stimulate insuline secretion: Amino acids, such as leucine, arginine, and lysine. Free fatty acids and ketone bodies Incretins such as gastrointestinal polypeptide (GIP), pancreatic glucagon and the glucagon-like peptides (GLP). decreasing potassium efflux and DEPOLARIZING the cell 5 4 3 1 2 6 Because Cpeptide is present in the same molar concentration as native insulin, it serves as a marker of βcell function. Insulin Receptor Insulin binds to its receptor, a tyrosine kinase expressed in many cell types. It then triggers a complex series of events: -Recognition of the activated insulin receptor substrate by intracellular signal transducing proteins, and activation of postreceptor signaling pathways. 1 2 1. Insulin attaches to the receptor. 2. It activates tyrosine kinase activity, causing the enzyme to autophosphorylate. 3. Phosphorylation induces a conformational change that enables recruitment of several proteins known as the insulin receptor substrates (IRS1–6) 4. IRS proteins bind to the now active tyrosine kinase receptor. IRS then serves as a loading dock for several different proteins. 5. Growth factor receptor–bound protein 2 (GRB2) is one of the proteins involved in signal transduction and will activate gene-modulating proteins that inhibit phosphoenolpyruvate carboxykinase (PEPCK). 6. PI-3 kinase also becomes active after attaching to IRS, and this leads to inhibition of protein kinases and stimulation of protein phosphatases. -This results in increased glycogen synthesis and decreased glycogenolysis. -Also results in translocation of glucose transporter 4 (GLUT-4) to the membrane, facilitating glucose uptake. Insulin receptor signaling pathways 1 3 2 4 6 6 5 Decrease of gluconeogenesis GRB2 insulin signaling pathways inhibit fructose 1,6bisphosphatase & down-regulate the expression of phosphoenolpyruva te carboxykinase (pepck) *key rate-limiting steps of hepatic gluconeogenesis* Insulin signaling 1. IRS-1-PI3K-Akt pathway mediates the main metabolic effects of insulin and affects glucose transport through activation of protein kinase C (PKCs). 2. PI3K-independent pathway affects translocation of the GLUT-4 transporter to the cell membrane. 3. GRB2-SOS-Ras-MAPK pathway mediates mitogenic effects: cell growth proliferation and differentiation. *Muscle contraction during exercise increases expression of the GLUT-4 independently of insulin. The IRS-PI3K-Akt signaling pathway controls the metabolic effects of insulin ✓ IRS proteins recruit adaptor proteins→ phosphorylate the phosphatidylinositol 3-kinase (PI3K). ✓ Activation of PI3K → generates phosphatidylinositol -3,4,5triphosphate (PIP3 ). ✓ PIP3→ activates the 3′-phosphoinositide-dependent kinase 1 (PDK1) ✓ PDK1 → phosphorylates the Akt kinase (it is also called protein kinase B [PKB]). ✓ Akt + enhanced by a complex designated mTORC2→ regulates glycolysis, gluconeogenesis, and lipogenesis and suppresses glycogenolysis. ✓ This pathway also involves the activation of some isoforms of protein kinase C (PKC), known as atypical PKCs, which regulate glucose transport. The PI3K-independent pathway stimulates glucose transport ✓ Insulin receptor phosphorylates→ Cbl protein. ✓ Cbl protein → binds to Cbl-associated protein (CAP). ✓ CAP → binds to flotillin, a protein associated with lipid rafts in the cell membrane ✓ Flotillin → docks guanyl nucleotide exchange factor (C3G). ✓ C3G → activates the G-protein called TC-10. ✓ TC-10 → participates in the translocation of the GLUT-4 transporter to the cell membrane. Insulin resistance ✓ Insulin resistance: A key concept in glucose homeostasis ✓ Insulin resistance is a condition in which a given dose of insulin produces less-than-expected cellular response. ✓ The concept of insulin resistance is crucial to understanding the pathogenesis of type 2 diabetes. Alternative glucose homeostasis mechanisms ✓ The gut informs the brain of glucose and other macronutrient changes by secreting peptides including ghrelin, cholecystokinin (CCK), and glucagon-like peptide-1 (GLP-1). ✓ This create signals to peripheral tissues to alter their glucose uptake and/or secretion by both insulin-dependent and independent mechanisms. ✓ This signals are integrated by the brain and projected to the hypothalamus. https://www.researchgate.net/publication/279732627_Gutbrain_connection_The_neuroprotective_effects_of_the_anti-diabetic_drug_liraglutide Recently, bone has emerged as another endocrine “gland.” Osteocalcin, a bone-specific protein, was identified as a hormone that stimulates insulin sensitivity in peripheral tissues (liver, muscle, and adipose tissue) and insulin secretion by the pancreas. Exam Like Question A 12-year-old diabetic boy was playing with his friends. He received his normal insulin injection in the morning but continued playing through the lunch hour without a meal. He became increasingly confused and finally lost consciousness. He was immediately given an injection of glucagon from the emergency kit his father carried, and he recovered within minutes. What metabolic abnormality caused this kid’s symptoms? a) b) c) d) e) Hypoglycemia Hypernatremia Hypokalemia Hyperglycemia Hyperkalemia Metabolic effects of insulin Metabolism after an overnight fast (postabsorptive state) References ✓ Baynes, J., & Dominiczak, M. H. (2019). Medical biochemistry. Elsevier Health Sciences. ✓ Candeias et al. (2015). Gut-brain connection: The neuroprotective effects of the anti-diabetic drug liraglutide. World journal of diabetes. 6. 807-27. 10.4239/wjd.v6.i6.807.