Unit VI- Insulin and Glucagon Flashcards
1
Q
Metabolic reserves in 70kg man
A
- 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
Q
Blood Glucose Homeostasis
A
- 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
Q
Insulin
A
- 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
Q
Glucagon
A
- 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
Q
Somatostatin
A
-a paracrine that inhibits the release of insulin and glucagon as well as gastrin, gastric acid secretion, and all gut hormones
6
Q
The Brain
A
- 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
Q
Islets of Langerhans
A
- 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
Q
Synthesis and degradation of Glucagon
A
- 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
Q
Stimulators of Glucagon Secretion
A
- 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
Q
Inhibitors of Glucagon Secretion
A
- 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
Q
Effects of Glucagon in Liver
A
- 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
Q
Processing of Proinsulin
A
- 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
Q
Control of Insulin Secretion
A
- 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
Q
Insulin Secretion by Beta Cells
A
- 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
Q
Response of Insulin after feeding
A
- 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
Q
Stimulators of Insulin Secretion
A
- 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
Q
Inhibitors of Insulin Secretion
A
- decrease glucose
- decrease amino acids
- decrease free fatty acids
- hormones: Somatostatin, epi (alpha)
- SNS
18
Q
Response of Catecholamines and Insulin During Exercise
A
- 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
Q
Anabolic Action of Insulin on Liver
A
- 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
Q
Anabolic Action of Insulin on Muscle
A
- 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
Q
Anabolic Action of Insulin on Adipocyte
A
- 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
Q
Glucose Tolerance Test
A
- 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
Q
Diseases Involving Abnormal Levels of Insulin and Glucagon
A
- 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
Q
Appetite signals
A
- 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
