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Insulin and glucagon control fuel flow and utilization
Three principal tissue types involved:
Metabolite targets include:
Effects
- Liver, Muscle, Adipose
- Glucose, Amino acids, Free fatty acids, Ketoacids
- Insulin: anabolic; lower glucose, AA, FFA, ketoacids; stim liver form glycogen, muscle form glycogen and protein, adipose form fat
- Glucagon: catabolic; increase glucose, ketoacids; stim liver gluconeogenesis, break down glycogen, adipose lipolysis
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The bulk of the pancreas serves _____. The endocrine functions are performed by _____, small groups of cells scattered through the pancreas, representing about 2% of pancreatic mass.
- an exocrine organ
- Islets of Langerhans
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Cell types of the Islets of Langerhans:
- Alpha cells (a-cells, A cells): 20% of islet, secrete glucagon. Inc. plasma glucose and mobilize hepatic glycogen & fat.
- Beta cells (b-cells, B cells): 60-75% of islet, secrete insulin. Inc. cellular glucose uptake and deposition of glycogen & fat.
- Delta cells (d-cells, D cells): <5% of islet, secrete somatostatin. Dec. insulin & glucagon secretion and exocrine gastric secretions.
- F cells: <5% of islet, secrete pancreatic polypeptide. Dec. food absorption.
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Synthesis of insulin
- 1. transcription and translation of the signal sequence
- 2. translocate to RER, continue translation the full sequence, pre-proinsulin, cleavage of signal sequence, forming proinsulin
- 3. in golgi, cleavage of C-peptide, A-B chains bind forming active insulin
- 4. packaged in secretory granules, C-peptide and insulin, high Zn stabilize the peptide
- 5. release into blood
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The half-life of insulin in the circulation is ____.
~5 min
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C-peptide offers a useful measure of ______ in patients under ______, because it is released in direct proportion to endogenous insulin generation but is not present in the injected insulin.
- pancreatic Beta cell function
- insulin therapy
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The principal mechanism for control of plasma glucose levels:
Normally _____ plasma lvl
As glucose increases, ______ secretion is stimulated.
When plasma glucose falls below the normal range, ______ secretion is increased.
- 5.5 mM (100 mg/dL)
- insulin
- glucagon
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________ condition occurs during a long term fast, and insulin lvl ___________.
- Hypoglycemic
- drops below baseline level
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Mechanism of glucose regulation of insulin secretion
- Glucose enters Beta-cells via GLUT2 transporters
- glycolysis & citric acid cycle
- increased ATP lvl
- inhibits ATP-sensitive K+ channels, shuts off K+ efflux
- depolarizes the B cell
- stim Ca2+ influx
- stim release of insulin by exocytosis
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Factors affecting insulin secretion: stimulators
- GLUCOSEAmino acids (leucine, arginine, others)
- β-Keto acids
- Glucagon, GLP-1, GIP
- Sulfonylureas (blocks KATP channels)
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Factors affecting insulin secretion: inhibitors
- 2-Deoxyglucose
- Somatostatin
- α-Adrenergic agonists
- Diazoxide (opens KATP channels)
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Insulin action on cells: Binding of insulin to its receptor causes ________ of the receptor, which then acts as a _______ that phosphorylates ______, which then _______ in other proteins and enzymes. Numerous target enzymes are ultimately activated or inactivated, and the result is to stimulate _______. Transport of amino acids, potassium, magnesium, and phosphate is facilitated by other mechanisms. The synthesis of various enzymes is induced or suppressed by changes in gene expression.
- autophosphorylation
- tyrosine kinase
- tyrosines in insulin receptor substrates
- phosphorylate serine and threonine residues
- glucose metabolism
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Mechanism of insulin activation of glucose transport: Cycling of _____ through _____ in insulin-sensitive tissues. Activation of the insulin receptor causes activation of _____, which speeds translocation of the _____. The GLUT4 transporters then mediate glucose transport into the cell.
- GLUT 4 transporters
- endosomes
- phosphoinositide 3-kinase
- GLUT4-containing endosomes into the cell membrane
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Glucose transporter families
- Active Na+-glucose cotransport: SGLT1 and 2 - active glucose absorption in gut and kidney
- Facilitated diffusion GLUT:
- GLUT2: B cells of islets, liver
- GLUT4: Insulin-stimulated glucose uptake; located in Skeletal and cardiac muscle, adipose tissue, other tissues
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Principal actions of insulin: Rapid (seconds)
Increased transport of glucose, amino acids, and K+ into insulin-sensitive cells
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Principal actions of insulin: Intermediate (minutes)
- Stimulation of protein synthesis
- Inhibition of protein degradation
- Activation of glycolytic enzymes and glycogen synthase
- Inhibition of glycogen phosphorylase and gluconeogenic enzymes
- Increased lipogenesis, inhibition of lipolysis
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Principal actions of insulin: Delayed (hours)
Increase in mRNAs for lipogenic and other enzymes
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Glucagon is a _____ hormone synthesized in the ____ cells of the _____ pancreas.
• It is synthesized initially as a ______.
• Glucagon has a half-life of ___, and is degraded by ______.
- peptide
- Alpha
- endocrine
- preprohormone
- 5-10 min
- its major target organ, the liver
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organs other than the liver are exposed to relatively low levels of glucagon because
glucagon is released directly into the portal vein and is degraded by liver
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Glucagon release is inhibited by plasma glucose over a range between ________ to ____. Therefore, the regulation of glucagon by glucose is well tailored to its glycogenolytic and gluconeogenic actions to _______ from liver.
- hypoglycemic
- normal
- increase glucose release
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Stimulators of glucagon secretion
- Amino acids (particularly glucogenic AAs, eg. alanine, serine, glycine)
- Acetylcholine
- β-Adrenergic agonists
- Cortisol
- Exercise
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Inhibitors of glucagon secretion
- GLUCOSE
- Free Fatty Acids
- Ketones
- Somatostatin
- Insulin
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effect of glucagon:
- stimulate the generation of glucose from glycogen and amino acids in liver
- mobilize fatty acids and stimulate their conversion to ketoacids
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Somatostatin is produced in ______ of the pancreas, but is also formed in other locations including the ______. Its release is stimulated by ___________.
- Delta-cells
- hypothalamus
- the same stimuli that increase insulin secretion, particularly glucose and amino acids
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The principal effect of pancreatic somatostatin is to _________. This appears to rely on a _______ action, perhaps acting predominantly _______.
- inhibit the release of other islet hormones, most importantly insulin and glucagon
- paracrine
- within a single islet of Langerhans
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In the GI-tract, somatostatin has effects to _________.
decrease glucose transport across gut wall and to decreased blood flow
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Metabolic effects of epinephrine (NE has a lesser role in regulating metabolism):
- stims glucose production from gluconeogenesis (liver) and glycogenolysis (liver & muscle)
- Stim Lipolysis and ketogenesis
- stims lactic acid -> glucose, important to active muscles
- inhibits the action of insulin to stimulate glucose uptake (muscle and fat).
- OVERALL increases in plasma levels of glucose, free fatty acids, and ketoacids.
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The major effect of cortisol is to __________. The glucose is stored as ______ and released for use by other tissues
- stimulate the mobilization of amino acids (primarily from muscle, wasting of muscle) and their conversion to glucose (liver)
- glycogen
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Cortisol ____ the stimulation of glucose uptake by insulin in peripheral tissues (muscle and fat).
Cortisol causes _____ of fat from adipose tissue, but can also ______ in selected adipose tissue sites.
- inhibits
- mobilization
- facilitate fat storage
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Compare to glucagon, cortisol is
- same: hyperglycemic (it increases blood glucose).
- differ: unlike acute hyperglycemic hormones (glucagon and epinephrine), it stims the deposition of glycogen
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Leptin is a _____ hormone produced by ______. It is formed and secreted in proportion to _______, thus "report" the size of the adipose mass to the hypothalamus and other brain areas.
- peptide
- adipose tissue
- the amount of adipose tissue
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When excessive food intake leads to an increase in adipose mass, the plasma level of leptin _______, and this leads to a series of behavioral and metabolic changes designed to _______, such as to _________________.
- increases
- reduce adipose mass
- reduce appetite
- increase basal energy expenditure
- obligatory thermogenesis
- modulate the secretion of hormones to decrease lipogenic activity and increase lipolytic activity of adipose tissue
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Blood glucose
- GH +
- E +
- Cortisol +
- Glucagon +
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Glucose uptake
- GH -
- E -
- Cortisol -
- Glucagon none
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Glycogenesis
- GH +
- E -
- Cortisol +
- Glucagon -
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Glycogenolysis
- GH -
- E +
- Cortisol -
- Glucagon +
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Gluconeogenesis
- GH +
- E +
- Cortisol +
- Glucagon +
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Glycolysis
- GH -
- E +
- Cortisol -
- Glucagon -
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Protein
- GH +
- E none
- Cortisol -
- Glucagon -
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Fat
- GH -
- E -
- Cortisol +
- Glucagon -
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A common cause of hypoglycemia is ______. The brain is particularly sensitive to hypoglycemia, because ________.
- excess insulin due to improper self administration
- it has little stored carbohydrate and depends almost exclusively on glucose for its energy source
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