49: Insulin & Glucagon Flashcards
Describe stimulators and inhibitors of glucagon secretion and physiological effect of glucagon in liver.
Stimulators of Glucagon secretion:
- hypoglycemia (most important)
- increase in arginine & alanine (indicative of protein degradation)
- exercise
- stress
Inhibitors of Glucagon secretion:
- Somatostatin (it inhibits insulin, glucagon, gastrin, gastric acid secretion, & all gut hormones)
- insulin
- hyperglycemia
Glucagon is a catabolic hormone. Levels of glucagon rise during periods of food deprivation, and consequently stored nutrient reserves are mobilized. Glucagon mobilizes glycogen, fat and protein to produce a prompt increase in blood glucose concentration. Glucagon, along with catecholamines, growth hormone, and cortisol are counter-regulatory hormones that are released in times of stress such as exercise, illness, etc. to keep blood glucose levels high enough to support brain metabolism.
The primary target organ for glucagon is the liver, where glucagon antagonizes the action of insulin by stimulating glucose output via glycogenolysis (breakdown of stored glycogen into glucose) and gluconeogenesis (new synthesis of glucose from certain amino acids) and also increases lipolysis (breakdown of triglycerides into fatty acids and glycerol which forms glycerol-phosphate).
In adipose tissue, glucagon decreases glycolysis and promotes lipolysis and the release of fatty acids.
Injection of insulin leads to a decrease in blood glucose concentration. Hypoglycemia stimulates the secretion of growth hormone, glucagon, and epinephrine, all of which have counter regulatory effects to increase glucose levels in the blood.
Explain cleavage of proinsulin into insulin and C-peptide and clinical use of C- peptide.
**Proinsulin is cleaved into insulin and C-peptide. C-peptide has no known biological activity, but the level in blood is used to quantitate endogenous insulin production in patients receiving exogenous insulin.
Insulin is synthesized in a preproinsulin form. Proinsulin is packaged in the golgi and is processed during sorting to storage granules which also contain an endopeptidase with trypsin-like activity. Proinsulin and endopeptidase are secreted together. The secretory granules contain zinc which acts to join 6 insulin molecules into hexamers.
Today recombinant human insulin is most commonly used to avoid antibody reactions. Crystalline zinc insulin is the basic pharmaceutical preparation used to treat diabetes mellitus.
Insulin has a half-life of 5-8 minutes, and is degraded by insulinase in the liver, kidney and other tissues.
Explain how insulin secretion is regulated, the anabolic actions of insulin on liver, muscle, and fat.
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 minutes later.
After an IV dose of glucose, the first peak is the release of stored insulin. The peak falls in about 10 minutes. If the stimulus is maintained, insulin release increases gradually during the next hour. This later rise in insulin is known as the late phase of insulin release and probably reflects release of newly formed insulin—see pg. 111.
Mechanism of insulin secretion:
- Glucose enters the cell via a GLUT2 transporter which mediates diffusion of glucose into the cell.
- Increased glucose in cell stimulates glucose metabolism, increasing ATP.
- The increased ATP inhibits an ATP-sensitive K+ channel.
- Inhibition of the K+ channel causes membrane potential to depolarize (more positive).
- The depolarization activates a voltage gated Calcium channel in the cell membrane.
- The activation of the voltage gated Calcium channel allows Calcium influx into the cell & increases intracellular calcium. This initiates calcium induced calcium release.
- The elevated Calcium leads to exocytosis & release of Insulin into the blood. Insulin is released in secretory granules.
Response of Insulin after feeding:
Cephalic phase: gastric acid secretion & small rise in Insulin mediated by Vagus.
Intestinal phase: glucose absorption & rise in plasma glucose is primary stimulus for insulin secretion.
Incretins provide advance notice of feeding & stimulate insulin secretion—this is shown by oral glucose yielding more insulin than IV glucose.
Glucose-dependent insulinotropic peptide (GIP) is the only gastrointestinal (GI) hormone that is released in response to all three categories of nutrients-fat, protein, and carbohydrate. Oral glucose releases GIP, which, in turn, causes the release of insulin from the endocrine pancreas. This action of GIP explains why oral glucose is more effective than intravenous glucose in releasing insulin.
CCK, GIP (gastric inhibitory polypeptide), & glucagon like peptide increase insulin during feeding.
Stimulators of insulin secretion:
- Increase in serum: glucose, AA’s (arginine & lysine most potent), FFA’s, ketoacids, & ketone bodies.
- Increase in: GIP, Glucagon*, Gastrin, CCK, Secretin, Vasoactive intestinal peptide, epinephrine (B receptor), parasympathetic nervous system.
Inhibitors of insulin secretion:
- Decrease in: glucose, AA’s, FFA’s.
- Increase in Epinephrine (a-receptor), Somatostatin (main inhibitor).
In the liver, insulin stimulates glucose uptake and decreases glucose output. It stimulates formation of glycogen and inhibits glycogenolysis. It promotes glycolysis and lipogenesis. It decreases fat oxidation, gluconeogenesis, and ketogenesis. It promotes protein synthesis and inhibits protein breakdown and the urea cycle.
In muscle, insulin stimulates glucose uptake by increasing GLUT-4 and promotes glycogenesis while inhibiting glycogenolysis. It also promotes glycolysis, supplying acetyl CoA for fatty acid synthesis and lipogenesis. It stimulates amino acid uptake and protein synthesis and decreases proteolysis. So muscle can take up glucose.
In adipose tissue, insulin stimulates glucose uptake via GLUT-4 and increases glycolysis which produces alpha-glycerophosphate which in turn increases the esterification of fats. It also decreases lipolysis. It also stimulates the synthesis of lipoprotein lipase which moves to the surface of endothelial cells where it releases fatty acids from chylomicrons and VLDL.
Explain the glucose-tolerance test.
In the normal subject, glucose consumption should cause a sharp rise in insulin production, that is, more insulin is produced than there is glucose. Curves are same shape & insulin is on top of glucose.
In a subject with type 1 diabetes, with the same glucose load as the normal subject causes plasma glucose to rise to a higher level & to stay there longer. This is due to the fact that plasma insulin rises very little to the glucose challenge. The diagnosis of diabetes is made if the plasma glucose is higher than 200 mg/dc at the second hour.
Note that plasma glucose will still eventually fall. Normally, plasma glucose is regulated at a concentration of 80-100 mg/dl.
See pg. 119
Explain control of food intake and the roles of adiposity signals and satiation signals.
Hypothalmus primarily controls food intake via:
- Orixigenic factors (neurotransmitters that stimulate feeding) such as: neuropeptide Y
- Anorexigenic factors (neurotransmitters that inhibit feeding) include corticotropin releasing hormone (CRH), glucagon-like peptide 1 (GLP-1), alpha-melanocyte stimulating hormone (alpha-MSH), and cocaine- and amphetamine-regulated transcript (CART)
Satiation (Satiety) signals:
Satiation signals are secreted in response to food ingestion, act within the time frame of a single meal, and reduce meal size. They include GI distension triggers vagal afferents that suppresses hunger center. GI peptides reduce meal size: CCK, glucagon-like peptide-1 (GLP-1), glicentin, GLP-2, glucagon, peptide tyrosine-tyrosine (PYY including NPY), etc.
CCK: Secreted from I cells, CCK diffuses locally in a paracrine fashion to stimulate CCK-1 receptors on the branches of 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 (NTS) in the hindbrain and relayed to the hypothalamus.
Ghrelin is secreted from the oxyntic glands of the stomach. It is the only GI hormone that stimulates food intake. Ghrelin levels increase before meals and decrease after meals. It appears that ghrelin directly works in the arcuate nucleus (ARC) of the hypothalamus to enhance NPY/AgRP pathways and inhibit POMC/CART parthways.
Adiposity signals:
Leptin makes you feel full.
Leptin and Insulin: they are hormones secreted in proportion to the amount of fat in the body. Leptin is mainly derived from white adipocytes. Both hormones cross the blood-brain barrier and gain access to the hypothalamus to influence energy homeostasis. Hence, 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. First, Leptin and insulin stimulate proopiomelanocortin (POMC) neurons to produce alpha melanocyte stimulating hormone (alpha-MSH) as a neurotransmitter. Alpha-MSH binds on receptors (melanocortin 3 and melanocortin 4 receptors) on other hypothalamic neurons and elsewhere in the brain to reduce food intake.
Second, leptin and insulin inhibit agouti-related peptide (AgRP) and NPY containing neurons in the ARC. These neurons have similar projections as POMC neurons and antagonize alpha-MSH. NPY and AgR stimulate food intake.
Synthesis of adiposity & satiation signals in the hypothalamus.
Meal onset:
Controlled by social, cultural, and environmental factors. 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.
Satiation signals:
Satiation signals activate vagus nerve and pass the information to the nucleus of the solitary tract which in turn stimulate POMC/CART neurons in the ARC. Activation of POMC neurons in turn inhibit LHA neurons but stimulate TRH/CRH neurons in the paraventricular nucleus.
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.
Mutations that exemplify the importance of neuroendocrine 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 human.
Non-objective relevant material
Insulin is synthesized by beta cells, which are located at the center of the Islets of Langerhans of the pancreas. Insulin is an anabolic hormone secreted in times of excess nutrient availability. Insulin allows the body to utilize and store carbohydrates.
Glucagon is a catabolic hormone secreted during times of food deprivation. Glucagon, along with the catecholamines epinephrine and norepinephrine allows utilization of stored nutrient reserves by mobilizing glycogen, fat and protein to serve as energy sources.
Somatostatin is a paracrine that inhibits the release of insulin and glucagon, as well as gastrin, gastric acid secretion, and all gut hormones.
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 and amino acids although it can utilize ketone bodies. Brain is exceedingly vulnerable to hypoglycemia, which can quickly produce coma and death.
The Islets of Langerhans of the pancreas receive sympathetic and parasympathetic inputs. The beta cells secrete insulin. Glucagon is synthesized by alpha cells. Somatostatin is synthesized by delta cells. Pancreatic polypeptide, a gastro-intestinal hormone, is synthesized by F cells. Pancreatic polypeptide inhibits gallbladder contraction, and also inhibits pancreatic exocrine secretion, i.e. secretion of fluid and digestive enzymes into the pancreatic duct, during strenuous exercise or after ingestion of a protein-rich meal or during hypoglycemia.
Response of catecholamines and insulin during exercise: circulating epinephrine stimulates insulin secretion via a beta receptor on the pancreatic beta cells
But local autonomic adrenergic innervation releasing norepinephrine acts via an Alpha receptor and predominates
This results in insulin suppression and to prevent hypoglycemia caused by excessive uptake of glucose by muscle
Reduce insulin also permits liver to supply glucose to muscle and adipose tissue to supply fatty acids to muscle
Leptin, Insulin, CCK, & PPY decreased & remained low in obese people who lost weight. Grelin & hunger increased in people decreased & remained low in these people (@ end of diet & 1 yr later).
