Blood glucose Regulation Dr veerendra


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  • TAG(adipocytes) –-------Hormone sensitive lipase--- Fatty acid + DAG
  • The principle action of Insulin is to inhibit hormone sensitive lipase and inhibit/reduce the release of FFA.In adipose tissue and skeletal muscle lipoprotein lipase is activated in response to insulin, the resulting FFA are taken up to form TAG stores. Glycerol remained in the blood is used for glycogen synthesis or lipogenesis.
  • Ra Rate of appearance, Rd – Rate of disappearance
  • Blood glucose Regulation Dr veerendra

    2. 2. Normal Blood glucose levels Fasting levels: 70-110 mg/dL Postprandial : up to 140 mg/dL Maintained with in physiological limits by 1. Rate of Glucose entrance into blood circulation 2. Rate of its removal from the blood stream.
    3. 3. Rate of glucose entrance in to the blood by: 1. Absorption from intestine 2. Hepatic glycogenolysis 3. Gluconeogenesis 4. Glucose obtained from other carbohydrates, eg: fructose, galactose etc
    4. 4. Rate of Removal of Glucose from blood depends on: 1. 2. 3. 4. 5. Oxidation of glucose by tissue to supply energy Hepatic glycogenesis Glycogen formation in muscles Conversion of glucose to fats in adipose tissues Synthesis/formation of fructose in seminal fluid, lactose in mammary gland, synthesis of glycoproteins. 6. Formation of ribose sugars and nucleic acid synthesis.
    5. 5. Blood glucose levels in Fasting state Also called as post absorptive state. Aprrox 12-14 hrs after the meal. Only source of glucose – Liver glycogen Muscle glycogen ??
    6. 6. Blood glucose levels in postprandial state Condition following ingestion of food. Absorbed monosaccharides are utilised for oxidation to provide energy. Remaining in excess is stored as glycogen in the Liver and Muscle. 40% of the glucose absorbed is used for lipogenesis and remaining is used for synthesis of glycoproteins and glycolipids.
    7. 7. Response to low Blood Glucose In the fasting state there will be decreased blood glucose levels. This stimulates the secretion of Glucagon from pancreas. The Glucagon released into the blood will stimulate hepatic glycogenolysis and gluconeogenesis, there by increasing the blood glucose levels. Once the blood glucose levels raises to the normal levels, the stimulus for the release of Glucagon will diminish.
    8. 8. Response to Elevated Blood Glucose In the post prandial state (after a meal)  Remember there are two separate signaling events  First signal is from the ↑ Blood Glucose to pancreas  To stimulates insulin secretion in to the blood stream  The second signal from insulin to the target cells  Insulin signals to the muscle, adipose tissue and liver to permit to glucose in and to utilize glucose  This effectively lowers Blood Glucose
    9. 9. Blood glucose regulation
    10. 10. Glucose Entry in to the Cell • Insulin/GLUT4 is not the only pathway • Insulin-dependent, GLUT 4 - mediated – Cellular uptake of glucose into muscle and adipose tissue (40%)  InInsulin-independent glucose disposal (60%) - GLUT 1 – 3 in the Brain, Placenta, Kidney – SGLT 1 and 2 (sodium glucose symporter) – Intestinal epithelium, Kidney
    11. 11. Hormonal Regulation of Blood glucose There are two categories of endocrine influences. a) Hormone which will decrease the blood glucose levels : Insulin b) Hormones which will increase the blood glucose levels: Glucagon, Epinephrine, Cortisol, Thyroid hormones.
    12. 12. Action of Insulin on Carbohydrate metabolism Diminishes the supply of glucose to the blood by • Facilitates the conversion of glucose to glycogen for storage in the liver and muscle by Activation of glycogen synthase. • Decreases the breakdown and release of glucose from glycogen by the liver by Inhibition of glycogen phospharylase activity. • Diminishes gluconeogenesis by Inhibiting – – – – pyruvate carboxylases activity PEP carboxykinases. Fructose 1,6 bisphosphatase. glucose 6 phosphatase.
    13. 13. Increases the rate of utilization of glucose by tissues by Facilitates the transport of glucose into muscle and adipose cells(GLUT 4). Activating the Oxidation of glucose for energy production Increased glycogenesis – activating glycogen synthase
    14. 14. Action of Insulin on Lipid metabolism • Increased lipogenesis (by activation of acetyl CoA carboxylase) • Inhibition of FFA mobilization from adipose tissue via suppression of lipolysis by inhibiting activity of hormone sensitive lipase • Inhibition of plasma FFA uptake and oxidation via suppression of lipolysis • Inhibition of hepatic VLDL synthesis Suppression of circulating ketone body concentrations • Activation of adipose lipoprotein lipase
    15. 15. Role of Insulin Protein Metabolism and Growth – Increases transport of amino acids – increases mRNA translation and new Proteins, – A direct effect on ribosomes – Increases transcription of selected genes, – Especially enzymes for nutrient storage – Inhibits protein catabolism – Acts synergistically with growth hormone
    16. 16. Regulation of Insulin Secretion Summary of feedback mechanism for regulation ↑ blood glucose ↓ ↑ insulin ↓ ↑ transport of glucose into cells, ↓ gluconeogenesis, ↓ glycogenolysis ↓ ↓ blood glucose ↓ ↓ insulin
    17. 17. Lack of insulin – Occurs between meals, and in diabetes. – Transport of glucose and amino acids into the cells decreases, leading to hyperglycemia. – Hormone sensitive lipase is activated, – Causing TG hydrolysis and FFA release. – ↑ FFA conversion in liver → – Phospholipids and cholesterol → – Lipoproteinemia, – FFA breakdown leads to ketosis and acidosis.
    18. 18. Role of Glucagon • Metabolic Effects of Glucagon – – – – Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism (ketogenesis)
    19. 19. Metabolic Effects of Glucagon 20
    20. 20. Insulin – Anabolic and Glucagon - Catabolic Metabolic Action Insulin Glucagon Glycogen synthesis ↑ ↓ Glycolysis (energy release) ↑ ↓ Lipogenesis ↑ ↓ Protein synthesis ↑ ↓ Glycogenolysis ↓ ↑ Gluconeogenesis ↓ ↑ Lipolysis ↓ ↑ Ketogenesis ↓ ↑
    21. 21. Counter Regulatory Hormones • Early response – Glucagon – Epinephrine • Delayed response – Cortisol – Growth hormone
    22. 22. Counter Regulatory Hormones • Glucagon – Acts to increase blood glucose – Secreted by alpha cells of the pancreas – Chemical structure 29 amino acids – Derived from 160 aminoacid proglucagon precursor
    23. 23. Glucagon Secretion Stimulation of Glucagon secretion – Blood glucose < 70 mg/dL – High levels of circulating amino acids – Especially arginine and alanine – Sympathetic and parasympathetic stimulation – Catecholamines – Cholecystokinin, Gastrin and GIP – Glucocorticoids
    24. 24. Role of Glucagon • Metabolic Effects of Glucagon – – – – Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism (ketogenesis)
    25. 25. Role of Epinephrine Epinephrine – The second early response hyperglycemic hormone. – This effect is mediated through the hypothalamus in response to low blood glucose – Stimulation of sympathetic neurons causes release of epinephrine from adrenal medulla . – Epinephrine causes glycogen breakdown, gluconeogenesis, and glucose release from the liver. – It also stimulates glycolysis in muscle – Lipolysis in adipose tissue, – Decreases insulin secretion and – Increases glucagon secretion.
    26. 26. Role of Cortisol and GH • These are long term hyperglycemic hormones • Activation takes hours to days. – Cortisol and GH act to decrease glucose utilization in most cells of the body – Effects of these hormones are mediated through the CNS.
    27. 27. Cortisol • Cortisol is a steroid hormone – It is synthesized in the adrenal cortex. – Synthesis is regulated via the hypothalamus (CRF) and anterior pituitary (ACTH). • Clinical correlation: Cushing’s Disease
    28. 28. Growth Hormone (GH) • GH is a single chain polypeptide hormone. • Source is the anterior pituitary somatotrophs. • It is regulated by the hypothalamus. • GHRH has a stimulatory effect. • Somatostatin (GHIF) has an inhibitory effect. • Clinical correlation: Gigantism and Acromegaly cause insulin resistance.
    29. 29. Responses to decreasing Glucose levels Response Glycemic theshhold Physiological effects Role in counter regulation ↓ Insulin 80 - 85 mg% ↑ Ra (↓ Rd) Primary First Defense ↑ Glucagon 65 - 70 mg% ↑ Ra ↑ Epinephrine 65 - 70 mg% ↑ Ra ↓ Rd Critical Third Defense ↑ Cortisol, GH 65 - 70 mg% ↑ R a ↓ Rd Not Critical ↑ Food ingestion 50 - 55 mg% Primary Second Defense ↑ Exogenous < 50mg% no Glucose cognitive change