INTEGRATION OF METABOLISM biochemistry.pptx

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1. INTEGRATION OF METABOLISM AHMED QAISER CN6

2. GLUCAGON Glucagon is a peptide hormone secreted by pancreatic α cells. Alongside other hormones like epinephrine, norepinephrine, cortisol, and growth hormone, it counters many actions of insulin. Its primary function is to regulate blood glucose levels by stimulating hepatic glycogenolysis and gluconeogenesis. Comprising 29 amino acids, it exists as a single polypeptide chain. Glucagon is synthesized from a larger precursor molecule, preproglucagon , through specific proteolytic cleavages. Unlike insulin, its amino acid sequence is consistent across mammalian species. Preproglucagon processing yields different products in various tissues, such as GLP-1 in intestinal L cells. Glucagon, similar to insulin, has a short half-life.

3. Stimulation of Glucagon Secretion The α cell responds to various stimuli signaling actual or potential hypoglycemia. Glucagon secretion increases in response to low blood glucose, amino acids, and catecholamines

4. Stimulation of Glucagon Secretion Low Blood Glucose: Decreased plasma glucose concentration is the primary trigger for glucagon release. Elevated glucagon levels during overnight or prolonged fasting prevent hypoglycemia. Amino Acids: Amino acids, such as arginine, from protein-rich meals stimulate glucagon release. Glucagon prevents hypoglycemia resulting from increased insulin secretion following a protein meal.

5. Stimulation of Glucagon Secretion Catecholamines : Elevated levels of circulating epinephrine from the adrenal medulla, norepinephrine from sympathetic innervation of the pancreas, or both, stimulate glucagon release. During physiological stress, heightened catecholamine levels can override the effect of circulating substrates on α cells, leading to elevated glucagon levels regardless of blood glucose concentration. In such situations, glucagon levels rise in anticipation of increased glucose utilization, while insulin levels decrease

6. Inhibition of glucagon secretion Glucagon secretion is significantly decreased by elevated blood glucose and by insulin. Both substances are increased following ingestion of glucose or a carbohydrate-rich meal.

7. Metabolic Effects of Glucagon Carbohydrate Metabolism: Glucagon administration via intravenous route induces an immediate elevation in blood glucose levels. This rise stems from enhanced breakdown of liver glycogen and increased hepatic gluconeogenesis

8. Metabolic Effects of Glucagon Lipid Metabolism: Glucagon primarily inhibits fatty acid synthesis by phosphorylating acetyl-CoA carboxylase (ACC), reducing malonyl CoA production. Reduced malonyl CoA levels alleviate the inhibition on long-chain fatty acid β- oxidation. While glucagon plays a role in adipose tissue lipolysis, catecholamines are the primary activators of hormone-sensitive lipase, leading to fatty acid release. The liberated fatty acids are taken up by the liver and oxidized to acetyl CoA, contributing to ketone body synthesis.

9. Metabolic Effects of Glucagon Protein Metabolism: Glucagon enhances amino acid uptake by the liver from muscle, thereby increasing carbon skeletons availability for gluconeogenesis. Consequently, plasma amino acid levels decrease

10. Mechanism of action of glucagon Glucagon binds to high-affinity G protein–coupled receptors specifically located on the cell membrane of hepatocytes. These receptors are distinct from those binding insulin or epinephrine and are absent in skeletal muscle. Upon glucagon binding, adenylyl cyclase activation occurs in the plasma membrane. Adenylyl cyclase activation leads to an elevation in cyclic adenosine monophosphate ( cAMP ) levels. Increased cAMP activates cAMP -dependent protein kinase A, leading to enhanced phosphorylation of specific enzymes or proteins. This phosphorylation cascade modulates the activities of key regulatory enzymes involved in carbohydrate and lipid metabolism. For example, in glycogen degradation, the cascade of enzymatic activities results in phosphorylation-mediated activation or inhibition of relevant enzymes.

11. HYPOGLYCEMIA Hypoglycemia characterized by CNS symptoms (e.g., confusion, coma) and blood glucose ≤ 40 mg/dl. Emergency: CNS relies on glucose for energy; hypoglycemia can lead to cerebral dysfunction and brain death. Hormonal Response: Elevated glucagon and catecholamines , reduced insulin release. Management: Immediate glucose administration required to prevent complications. Importance: Recognizing and treating hypoglycemia promptly is crucial to prevent serious CNS and health consequences.

12. Symptoms of hypoglycemia Adrenergic Symptoms: Anxiety, palpitations, tremors, sweating. Mediated by catecholamine release (primarily epinephrine). Regulated by the hypothalamus in response to abrupt drops in blood glucose levels. Neuroglycopenic Symptoms: Headache, confusion, slurred speech, seizures, coma, death. Result from impaired delivery of glucose to the brain ( neuroglycopenia ). Occur with gradual decline in blood glucose, often below 40 mg/dl. Deprives the CNS of fuel, triggering neuroglycopenic symptoms without an adequate adrenergic response.

13. Glucoregulatory systems Two systems respond to hypoglycemia: Pancreatic α cells release glucagon. Hypothalamic glucoreceptors detect low blood glucose. Hypothalamic response: Triggers catecholamine release via autonomic nervous system. Stimulates anterior pituitary to release ACTH and growth hormone. Counterregulatory Hormones: Glucagon, catecholamines , cortisol, and growth hormone. Oppose insulin action, maintaining blood glucose levels.

14. Activation and Role Activation of systems ensures glucose homeostasis during hypoglycemia. Glucagon promotes glycogenolysis and gluconeogenesis. Catecholamines increase glycogen breakdown and inhibit insulin secretion. Cortisol and growth hormone mobilize glucose and fatty acids for energy. Collective action prevents excessive glucose lowering and sustains CNS function.

15. Glucagon and epinephrine Glucagon and epinephrine play crucial roles in acute, short-term regulation of blood glucose levels. Glucagon: Stimulates hepatic glycogenolysis (breakdown of glycogen) and gluconeogenesis (production of glucose). Epinephrine: Promotes glycogenolysis and lipolysis (breakdown of fats). Inhibits insulin secretion and insulin-mediated glucose uptake by peripheral tissues.

16. Glucagon and epinephrine Critical Role in Hypoglycemia: Epinephrine assumes importance when glucagon secretion is deficient, such as in late-stage type 1 diabetes mellitus. Failure of Hypoglycemia Prevention: Occurs when both glucagon and epinephrine secretion are deficient. Collective action of these hormones is essential for maintaining blood glucose levels and preventing or correcting hypoglycemia.

17. Cortisol and growth hormone These hormones are less important in the short term maintenance of blood glucose concentrations. They do, however, play a role in the long-term (transcriptional) management of glucose metabolism

18. cortisol ► Cortisol is a hormone that affects almost every organ and tissue in your body. It plays an important role in helping you to : ► Respond to stress ► Fight infection ► Regulate blood sugar ► Maintain blood pressure ► Regulate metabolism, the process of how your body uses food and energy

19. CORTISOL Steroid glucocorticoid hormone secreted by adrenal cortex; has metabolic, anti- inflammatory, immunosuppressive, vascular effects Normal pulsatile secretion, approximately 10 surges in diurnal (daily) pattern Concentration highest in morning, lowest in evening. Diurnal pattern: maintained by hypothalamic suprachiasmatic nucleus; acts as central pacemaker for hypothalamic-pituitary-adrenal (HPA) axis; adrenals maintain diurnal pattern of sensitivity to ACTH

20. SECRETION REGULATION Stress (infection, trauma, initiation of "fight or flight" response, psychological stressors), ↑ sympathetic activity, physical activity.↓ blood glucose hypothalamus stimulated to release corticotropin -releasing hormone (CRH)→ anterior pituitary releases adrenocorticotropic hormone (ACTH ) → adrenal medulla secretes glucocorticoids (primarily cortisol ) → target tissues Negative feedback of cortisol to hypothalamic-pituitary axis→↓ cortisol

21. Major effects Metabolic :↑ blood glucose (considered diabetogenic hormone) by ↑ hepatic glycogenolysis , † lipolysis, ↑ protein catabolism, cellular insulin sensitivity. ↑ appetite Immune : intensity of immune, inflammatory responses by production of arachidonic acid metabolites (e.g. prostaglandin, thromboxane, leukotrienes), ↓ production of interleukins, interferon, tumor necrosis factor; I T cell proliferation; ↓ neutrophil phagocytosis

22. Major effects Vascular : involved in normal vascular blood pressure maintenance; supports vascular smooth muscle responsiveness to catecholamine vasoconstrictive effects Other : connective tissue fibroblast proliferation, bone formation, ↑ renal blood flow, erythropoietin release, alters sleep patterns

23. Metabolic Effects of Cortisol Cortisol promotes lipolysis for energy and gluconeogenesis to maintain blood glucose levels. Increases insulin resistance, leading to elevated blood glucose levels. Stimulates proteolysis in muscles and up-regulates alpha1 adrenergic receptors in blood vessels for vasoconstriction.

24. E pinephrine Also known as adrenaline Catecholamine Derived from phenylalanine and tyrosine

25. Effects of epinephrine Metabolism : glycogenolysis in liver and skeletal muscles . Hyperglycemia:mobalization of free faty acids ,increase metablic rate. Increase oxygen consumption.