6th Unit / Ch 23 Metabolic Effects of Insulin and Glucagon Flashcards
Insulin 23 1.1
How is the inactive precursor of insulin processed to produce the functional, mature product shown?
First made as preproinsulin on the RER of Pancreatic B cells. In the RER lumen and golgi, it is cleaved to form mature insulin which has 2 chains (A and B) linked by 2 disulfide bonds, and a C-peptide.
Note: C peptide levels reflect endogenous synthesis and secretion and are not found injectable insulin.
Insulin 23 1.2
How does a rise in blood glucose lead to insulin secretion from pancreatic B cells?
Glucokinase in the B cells acts as a sensor, reacting to a systemic increase in glucose. The ATP generated by catabolism of its product (glucose 6-P) in glycolysis closes ATP-sensitive K+ channels, depolarizing the cell membrane, which, in turn, opens voltage-gated Ca2+ channels. Ca2+ influx causes
insulin-containing vesicles to be exocytosed from the B cells.
[Note: Sulfonylureas increase insulin secretion by closing ATP-sensitive K+ channels and areused to treat T2D .]
Insulin 23 1.3
Why does the same amount of glucose given orally induce a greater insulin response than if given IV?
Glucose ingestion causes the small intestine to release the peptides GLP-1 and GIP, which increase B-cell sensitivity to glucose, causing an anticipatory rise in blood insulin and, thus, they are termed “incretins.” This does not occur in response to glucose injection.
Metabolic Effects of Insulin 23 2.1
In which tissues are the effects of insulin denoted by arrows in the green boxes most prominent? What is the major stimulator of insulin secretion?
Insulin increases (1) glucose uptake in muscle and adipose via recruitment of **GLUT-4** to the cell membrane; (2) glycogenesis in liver and muscle via activation of GS;
(3) amino acid uptake and protein synthesis in most
tissues; and (4) fat synthesis in liver, lactating mammary glands and, to a lesser extent, adipose tissue via
activation of ACC.
[Note: Insulin affects enzymatic activity by covalent (phosphorylation/dephosphorylation) and transcriptional regulation.] A rise in blood glucose is the major stimulator of insulin secretion as shown.
Metabolic Effects of Insulin 23 2.2
Contrast the effects of insulin on HSL (Hormone-sensitive lipase) and LPL (Lipoprotein lipase).
Insulin decreases the activity of intracellular HSL and increases the activity of membrane-associated extracellular
LPL, enzymes that degrade TAGs stored in adipocytes and carried in circulating LP particles (CMs and VLDLs),
respectively. Insulin activates a phosphatase that dephosphorylates (inactivates) HSL. In contrast, insulin
increases expression of the gene for LPL in adipocytes. [Note: Insulin decreases LPL expression in muscle.]
Metabolic Effects of Insulin 23 2.3
Insulin promotes endergonic pathways of nutrient storage. How does the body mobilize these stores in the
event of sudden physiologic stress?
- *Physiologic stress** (e.g., infection, hypoxia, and strenuous exercise) results in secretion of the
- *catecholamines** epinephrine and norepinephrine, which cause rapid mobilization of energy-yielding fuels
(e. g., glucose from glycogenolysis and FAs from lipolysis). They also inhibit insulin secretion.
Mechanism of Insulin Action 23 3.1
What happens to the inactive insulin receptor (shown) upon insulin binding? How are
the receptors regulated?
When insulin binds to its membrane receptor, the series of events shown occur. The process is regulated
through internalization of the insulin–receptor complex, after which the insulin is degraded in the
lysosomes, and the receptor is either recycled or degraded. Elevated insulin levels promote receptor
degradation.
Mechanism of Insulin Action 23 3.2
What effect does insulin have on muscle and adipocyte cell membranes? Is the same
effect seen on hepatocyte membranes?
Insulin receptor binding initiates a signaling cascade that includes Protein kinase B (PKB), also known as ( Akt ) axactivation, which causes
GLUT-4 recruitment from the intracellular vesicular pool to muscle and adipocyte cell membranes, thereby
enabling facilitated uptake of glucose. In contrast, hepatocytes contain the insulin-insensitive GLUT-2.
Mechanism of Insulin Action 23 3.3
What effect does blunting receptor responsiveness to insulin have on blood glucose
levels in affected individuals?
Blood glucose levels rise with decreased responsiveness of the insulin receptor as a result of decreased
uptake by adipocytes and muscle cells because of a decrease in GLUT-4 on their surface.
Glucagon 23 4.1
What are the major stimulators of glucagon secretion? What inhibits its secretion?
Epinephrine and norepinephrine, produced from Tyr in the adrenal medulla and sympathetic nervous system, stimulate glucagon secretion from pancreatic a cells. Amino acids (e.g., Arg) derived from a protein-containing meal also will induce glucagon release. [Note: Glucagon prevents the hypoglycemia that would
otherwise result from postprandial insulin secretion.] Insulin and glucose are negative regulators of the secretory pathway for glucagon.
Glucagon 23 4.2
What is the major difference between preproglucagon and preproinsulin processing?
Preproinsulin is made and processed (cleaved) to insulin only in pancreatic B cells.
In contrast, preproglucagon is made in pancreatic a cells and in cells of the intestine and the brain. It undergoes tissue-specific processing that generates glucagon only in pancreatic a cells and GLP-1 in intestinal L cells and brain cells.
Glucagon 23 4.3
A popular approach for losing weight is a high-protein, low-carbohydrate diet.
Why might such a diet be effective?
With a high-protein, low-carbohydrate diet, the free amino acids released from the protein component stimulate pancreatic glucagon secretion. The low level of carbohydrate minimizes the insulin response and reduces the rate of anabolic
pathways. If sustained, these conditions lead to increased lipolysis, FA B-oxidation, and ketogenesis. The increased rate of TAG degradation results in weight loss.
Metabolic Effects of Glucagon 23 5.1
In which tissue are the effects of glucagon denoted by arrows in the green boxes most prominent?
Glucagon’s primary target is the liver, where it acts to maintain blood glucose levels. Like insulin, glucagon has covalent and transcriptional effects.
[ Note: Skeletal muscles do not express the
glucagon receptor.]
Metabolic Effects of Glucagon 23 5.2
How do glucagon and epinephrine work together to ensure short-term glucose homeostasis?
Why are they termed “counterregulatory” hormones?
Glucagon bound to its membrane GPCR on hepatocytes promotes FA -oxidation, ketogenesis,
glycogenolysis, and gluconeogenesis, effects mediated through protein phosphorylation by PKA.
[Note: Hepatic FA oxidation supplies ATP and NADH for gluconeogenesis and acetyl CoA for ketogenesis.]
Epinephrine inhibits insulin secretion and, when bound to its GPCR, is the primary signal in
adipocytes for the PKA- mediated activation of HSL and subsequent lipolysis that provides FAs to the liver.
It also promotes glycogenolysis. Glucagon and epinephrine (and norepinephrine, cortisol, and growth
hormone) are termed “counterregulatory” hormones because they oppose the actions of insulin.
Metabolic Effects of Glucagon 23 5.3
Why might inactivating mutations to the glucagon receptor (e.g., as seen in Mahvash disease)
cause hypoglycemia?
Impaired signaling by the glucagon GPCR (Protein Coupled Receptor), as in Mahvash disease ,will decrease the body’s ability to maintain appropriate blood glucose levels through glycogenolysis and gluconeogenesis, thereby resulting in hypoglycemia.
[Note: In Mahvash disease, mutations in the receptor prevent its trafficking to the plasma
membrane thereby trapping it in the RER.]
Hypoglycemia 23 6.1
Complete the chart to show the actions of cortisol, epinephrine, and glucagon in
hypoglycemia.
In hypoglycemia (a blood glucose level sufficiently low to cause symptoms) cortisol activates gluconeogenesis, epinephrine activates glycogenolysis, and glucagon activates both. Glucagon and epinephrine work through **cell membrane GPCRs,** whereas cortisol (a steroid hormone) works through a **nuclear receptor**.
Hypoglycemia 23 6.3
What is the basis of ethanol-related hypoglycemia?
The basis of ethanol-related hypoglycemia is the rise in the NADH/NAD + ratio as a
result of ethanol metabolism by ADH and ALDH, enzymes that oxidize ethanol and acetaldehyde, respectively, as their coenzyme NAD+ is reduced. The NADH formed favors
the reduction of pyruvate to lactate and OAA to malate, diverting these intermediates of gluconeogenesis into alternate pathways and decreasing glucose synthesis as shown.
