Unit VI- Insulin and Glucagon Flashcards Preview

MS 1 Unit VI Physiology > Unit VI- Insulin and Glucagon > Flashcards

Flashcards in Unit VI- Insulin and Glucagon Deck (31):
1

Metabolic reserves in 70kg man

-plasma/ecf glucose- 20g would last an hour
-glycogen- 100 g in liver; 200 in muscle- enough for part of one day
-protein- 10-12 kg, mostly skeletal muscle, about 1/2 available for energy needs before death from starvation due to respiratory muscle failure
-fat- 10 kg mostly in adipose tissue, lasts -40 days with water

2

Blood Glucose Homeostasis

-plasma glucose- 80-100 mg/dl or 4-5 mM
-all of peripheral tissues use glucose to produce ATP for energy but the brain is particularly dependent on plasma glucose
-insulin, glucagon, catecholamines, and gastro-intestinal hormones regulate the homeostasis of plasma glucose

3

Insulin

-synthesized by beta cells
-located in center of the Islets of Langerhans of the pancreas
-it is a anabolic hormone secreted in times of excess nutrient availability
-allows the body to utilize and store carbohydrates

4

Glucagon

-a catabolic hormone secreted during times of food deprivation
-glucagon along with the catecholamines epi and norepi allows utilization of stored nutrient reserves by mobilizing glycogen, fat and protein to serve as energy sources

5

Somatostatin

-a paracrine that inhibits the release of insulin and glucagon as well as gastrin, gastric acid secretion, and all gut hormones

6

The Brain

-relies almost exclusively on circulating glucose to meet its energy demands
-it consumed more than 20 percent of oxygen supply
-brain stores little glycogen and cannot oxidize fatty acids although it can utilize ketone bodies
-vulnerable to hypoglycemia, which can quickly produce coma and death

7

Islets of Langerhans

-normal pancreas 500,000 to several million islets, 1-2% of mass of pancreas
-each islet is highly vascularized and receives sympathetic and parasympathetic inputs
-insulin, proinsulin, and c-peptide secreted by beta cells (60%)in the center of islets
-glucagon synthesized and secreted by alpha cells (25%) at periphery
-somatostatin synthesized and secreted by delta cells dispersed in Islets' periphery
-F cells- in periphery secrete pancreatic polypeptide a gastro-intestinal hormone: inhibits gallbladder contraction and inhibits pancreatic exocrine secretion

8

Synthesis and degradation of Glucagon

-29 amino acid peptide of molecular weight 3500D, but synthesized as 160 amino acid pre-groglucagon
-postranslation processing yields glucagon, glicentin (69 aa), glicentin-like peptide, glucagon-like peptide 1 and 2
-glucagon circulates in the blood unbound to carrier proteins and has a half-life of only 3 to 4 min
-glucagon is degraded in the liver (80% and the kidney with very little excreted in the urine
-packaged and secreted like other peptide hormones

9

Stimulators of Glucagon Secretion

-Hypoglycemia (<50 mg/dl blood glucose)- most important
-increase in arginine and alanine-indicative of protein degradation
-exercise- liver supplies glucose to muscle
-stress- during healing after surgery

10

Inhibitors of Glucagon Secretion

-somatostatin- paracrine that inhibits release of insulin and glucagon, as well as gastrin, gastric acid secretion, and all gut hormones
-insulin- antagonist to glucagon
-hyperglycemia- above 200 mg/dl -max inhibition

11

Effects of Glucagon in Liver

-a catabolic hormone
-levels of glucagon rise during periods of food deprivation and consequently stored nutrient reserves are mobilized
-glucagon mobilized glycogen, fat and protein to increase blood glucose
-counter regulatory hormone that is released in times of stress to keep blood glucose high enough to support brain
-primary target is liver, where it antagonizes insulin
-stimulate glycogenolysis and gluconeogenesis
-increases lipolysis (breakdown trigylcerides into fatty acids and glycerol

12

Processing of Proinsulin

-peptide comprised of two disulfide linked chains 51 amino acids, 6000D
-synthesized in preproinsulin
-proinsulin packaged in the golgi and is processed during sorting to storage granules which contain endopeptidase with trypsin-like activity, also have zinc which acts to join 6 insulin molecules into hexamers
-proinsulin is cleaved into insulin and C peptide
-C peptide is used to measure insulin production
-half life of 5-8 minutes, degraded by insulinase in liver, kidney and other tissues
-recombinant human insulin,crystalline zinx insulin

13

Control of Insulin Secretion

-after ingestion of food, the fast component or early phase of insulin release occurs within 10 minutes of ingestion of food, and peaks about 30-45 mins
-after an IV dose of glucose the first peak is the release of stored insulin
-the peak falls in 10 mins, if stimulus maintained insulin release increases gradually for hour- late phase of insulin release proabably newly formed insulin

14

Insulin Secretion by Beta Cells

-increased extracellular trigger the beta cell to secrete insulin
-glucose enters the cell via a GLUT2 transporter, which mediates facilitated diffusion of glucose into the cell
-the increased glucose influx stimulates glucose metabolism leading to an increase in ATP
-increased ATP inhibits ATP-sensitive K+ channel
-inhibition of this K channel causes Vm to become more positive (depolarization)
-voltage gated Ca2+ channel activated
-activation of Ca2+ channel promotes Ca2+ influx - Ca induced Ca release
-elevated Ca leads to exocytosis and release into the blood of insulin contained secretory granules
-galactose and mannose and certain amino acids can also stimulate fusion of vesicles that have pre synthesized insulin

15

Response of Insulin after feeding

-Cephalic phase- gastric acid secretion and small rise in plasma insulin mediated by vagus nerve
-intestinal phase- glucose absorption and rise in plasma glucose is primary stimulus for insulin secretion
-incretins provide advance notice of feeding and stimulate insulin secretion: oral glucose yields more insulin than IV
-CCK and GIP enhance insulin secretion
-glucagon-like peptide similary increases insulin during feeding

16

Stimulators of Insulin Secretion

-increase serum glucose
-increase serum amino acids (esp arginine and lysine)
-increase serum free fatty acids (ketoacids)
-increase ketone bodies
-hormones: GIP, Glucagon, gastrin, CCK, secretin, VIP, epi (Beta)
-parasympathetic NS

17

Inhibitors of Insulin Secretion

-decrease glucose
-decrease amino acids
-decrease free fatty acids
-hormones: Somatostatin, epi (alpha)
-SNS

18

Response of Catecholamines and Insulin During Exercise

-circulating epi stimulates insulin secretion via beta receptor on pancreatic beta cell
-local autonomic adrenergic innervation releasing norepi acts on alpha receptor and predominates
-net result is to suppress insulin secretion and to prevent hypoglycemia caused by excessive uptake of glucose by muscle
-reduced insulin also permits the liver to supply glucose to muscle, and adipose tissue to supply fatty acids to muscle

19

Anabolic Action of Insulin on Liver

-stimulates glucose uptake and decreases glucose output
-it stimulates formation of glycogen and inhibits glycogenolysis
-promotes glycolysis and lipogenesis
-decreases fat oxidation, gluconeogenesis, and ketogenesis
-promotes protein synthesis and inhibits protein breakdown and the urea cycle

20

Anabolic Action of Insulin on Muscle

-insulin stimulates glucose uptake by increasing GLUT-4 and promotes glycogenesis (glycogen synthesis) while inhibiting glycogenolysis (breakdown of glycogen)
-promotes glycolysis (glucose to pyruvate), supplying acetyl CoA for fatty acid synthesis and lipogenesis
-also stimulates amino acid uptake and protein synthesis and decreases proteolysis

21

Anabolic Action of Insulin on Adipocyte

-insulin stimulates glucose uptake via GLUT-4 and increases glycolysis which produces alpha-glycerophosphate which in turn increases the esterification of fats
-decreases lipolysis
-also stimulates the synthesis of lipoprotein lipase which moves to the surface of endothelial cells where it releases fatty acids from chylomicrons and VLDL

22

Glucose Tolerance Test

-when person ingests a glucose meal plasma rises slowly reflecting the intestinal uptake of glucose
-the pancreatic beta cells secrete insulin, and plasma insulin rises sharply
-with the same meal plasma glucose rises to a higher level and stays there long with a diabbetic
-plasma insulin rises very little in response to glucose challenge so the tissues fail to dispose of the glucose load as rapidly as normal
-diabetes- more than 200 mg/dL

23

Diseases Involving Abnormal Levels of Insulin and Glucagon

-insulin deficiency: Type I diabetes
-insulinemia- elevated levels of insulin in the blood- insulin shots and insulinoma
-glucagon deficiency- very very rare
-glucagonoma- high levels of glucagon in the blood- causes hyperglycemia

24

Appetite signals

-hypothalmus primarily controls food intake, although higher CNS centers and other areas of the brain also play a role
-orixigenic factors- neurotransmitters that stimulate feeding such as neuropeptide Y
-anorexigenic factors- neurotransmitters that inhibit feeding- include corticotropin releasing hormone, glucagon like peptide 1, alpha melanocyte stimulating hormone and cocaine and amphetamine-regulated transcript

25

Satiation (Satiety) signals

-GI distension triggers vagal afferents that suppresses hunger center
-GI peptides reduce meal size- CCK, GLP-1, glicentin, GLP-2, glucagon, PYY
-CCK is secreted from I cells, and diffuses locally to stimulate CCK-1 receptor on vagal sensory nerves
-the message that ingested fat/protein is being processed and will soon be absorbed is conveyed to the nucleus of the solitary tract in the hindbrain and relayed to the hypothalamus
-ghrelin is secreted from oxyntic (fundic) glands of stomach, only GI hormone that stimulates food intake, it works in the arcuate nucleus of the hypothalamus to enhance NPY/AgRP pathways and inhibit POMC/CART pathway

26

Adiposity signals

-leptin and insulin: they are hormones secreted in proportion to the amount of fat in the body
-leptin is derived from white adipocyte
-both hormones cross the blood brain barrier and gain access to the hypothalamus to influence energy homeostasis
-neurons sensitive to insulin and leptin receive a signal directly proportional to the amount of fat in the body
-for controlling energy homeostasis adiposity hormones activate neurons in the ARC of the hypothalamus
-leptin and insulin stimulate proopiomelanocortin neurons to produce alpha melanocyte stimulating hormone
-this then binds to receptors in brain to reduce food intake
-leptin and insulin also inhibit AgRP and NPY neurons (which stimulate food intake)

27

Meal onset

-controlled by social, cultural and environmental facotrs
-low leptin levels, hypoglycemia, hypoinsulinemia and conditions of negative energy balance all enhance NPY/AgRP expression in the ARC
-they activate orexin and MCH expression to increase the urge of food intake

28

Satiation signals

-activate vagus nerve and pass the info to the nucleus of the solitary tract which inturn stimulate POMC/CART neurons in the ARC
-activation of the POMC neurons in turn inhibit LHA neurons but stimulate TRH/CRH neurons in the paraventricular nucleus

29

Adiposity signals

-higher leptin or insulin signaling inhibits anabolic and activates catabolic circuits decreasing NPY/AgRP release and enhance activity of POMC/CART neurons with decrease in meal size

30

Mutations in control of food intake

-leptin and leptin receptor mutation cause obesity in human and in mice
-MC4R receptor mutations, receptor for alpha-melanocyte stimulating factor from POMC neurons cause obesity in humans

31

Long Term Persistance of Hormonal Adaptations to Weight Loss in Obese patients

-long term stategies to counteract hormonal response to diet programs may be needed to prevent obesity relapse
-leptin, insulin, CCK, peptide YY are reduced at completion of diet and stay there a year later
-ghrelin is increased and remains high and so does hunger