MTC Module 3 Hormone Regulatio.pdf

7/27/2019 MTC Module 3 Hormone Regulatio.pdf

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1. Besides glucose, what else can stimulate insulin?: Insulin is also released by the amino acids, leucine and arginine but their effect

much smaller than glucose

2. Describe gluconeogenesis in Type I Diabetes: Despite an already high blood glucose, the constant influx of fatty acids from adipocyt

and amino acids from muscle cells enhances gluconeogenesis in the liver. Since hyperglycemia cannot stimulate the release of insulin from

the pancreas of a Type I diabetic patient, gluconeogenesis proceeds uncontrolled. Excess ive acetyl CoA formed in l iver mitochondria from

fatty acid causes ketone body formation.

3. Describe glycosylation of collagen in diabetes: In late diabetes, glycosylation of type IV collagen of the basement membrane of the

kidney glomeruli causes diabetic nephropathy. Glycosylation causes crosslinking of the collagen that decreases its turnover. The basemen

membrane thickens and inhibits proper filtering.

4. Describe glycosylation of Hb in Diabetes.: -In diabetes, prolonged increase of blood glucose causes glycosylation of several proteins.

The glycosylated proteins gradually lose their function.

-High glucose levels in diabetes glycosylate hemoglobin. The N-terminal valine of the hemoglobin subunit combines with glucose to form

Schiff base (aldimine). This binding process is slow and reversible. The aldimine is converted to a ketoamine that is irreversibly bound to

hemoglobin. Glycosylated hemoglobin survives for the life span of the RBC.

-Glycosylated hemoglobin levels are used to monitor the long-term compliance of patients with their diet and therapy. Weeks after an

improperly high glucose diet or refusal of insulin therapy, urinary glucose excretion decreases, but glycosylated Hb (HbA1C) level remains

elevated.

5.

Describe glycosylation of LDL in diabetes: Hyperglycemia also causes glycosylation of LDL. Glycosyl lysine, normally absent, isdetected in glycosylated LDL. LDL receptors do not bind glycosylated LDL efficiently, and the cellular uptake of glycosylated LDL is delay

Decreased intracellular cholesterol permits increased cholesterol synthesis within cells, particularly the hepatocyte. Decreased uptake an

increased synthesis result in high blood cholesterol and atherosclerosis.

6. Describe insulin action in adipocytes: In adipocytes, insulin causes increased triglyceride storage through increased glucose uptake

GLUT4, increased fatty acid intake from lipoproteins, a nd dephosphorylation of hormone-sensitive lipase. Entering glucose produces

DHAP which is then reduced to glycerol-3- P. Gly-3-P is used with fatty acids to form triglycerides. GLY-3-P formation from glucose is vit

because adipocytes lack the enzyme, glycerol kinase. High intracellular energy stimulates lipoprotein lipase formation. LPL liberates fatty

acids from chylomicron and VLDL particles. These are taken up by adipocytes. Decreased activity of hormone sensitive lipase ensures

increased lipogenesis.

7. Describe insulin action in muscle: In the muscle, insulin promotes protein synthesis. Recruitment of GLUT4 increases glucose uptak

into the muscle cell, providing energy for increased protein synthesis. High glucose in muscle also stimulates glycogen storage.

8. Describe insulin action in the liver: In the liver, insulin causes the activation of glucokinase and dephosphorylation of importantenzymes to promote storage of energy as glycogen a nd triglycerides for export as VLDL particles.

9. Describe ketone bodies in diabetes: The increase of -hydroxybutyrate and acetoacetate in the blood causes one of the most severe

complications of diabetes. In starvation, moderately increased ketoacids become an essential source of energy for the brain. In uncontroll

diabetes, ketoacid levels rise much higher than in starvation causing a severe increase in the proton concentration of cells and blood.

Prolonged ketoacidosis leads to acidotic coma. In some cases, a patient may develop hyperosmolar coma due to accumulation of excessive

glucose.

10. Describe liver glycogen in diabetes: In diabetes, the liver stores little glycogen. G6P levels are usually high, which ordinarily favors

glycogenesis. However, glycogen accumulation does not occur because glycogen synthase is phosphorylated and loses activity; glycogen

phosphorylase is also phosphorylated and gains activity.

11. Describe pyruvate kinase and PDH in diabetes: Phosphorylation of pyruvate kinase and pyruvate dehydrogenase directs metabolis

toward constant gluconeogenesis. Gluconeogenesis continually replenishes G6P that forms glucose.12. Describe sorbitol in diabetes: -In diabetes, a high concentration of glucose activates aldose reductase which converts glucose (an

aldehyde) to sorbitol (an alcohol). Sorbitol, in a manner similar to the formation of galactitol in galactosemia patients, produces cataract

In muscle cells, the lack of insulin in diabetes decreases glucose uptake. The resulting energy shortage slows protein synthesis. A normal

rate of protein breakdown causes a net decrease in N balance and the release of amino acids into the blood. The muscle cells are also unab

to recruit GLUT4. With less glucose available, pyruvate formation is reduced. Thus, alanine released from muscles of a diabetic patient

arises primarily from proteins, and not from glycolysis.

-The released amino acids are taken up by the liver and serve as precursors for gluconeogenesis.

13. Describe the binding of insulin to its receptor: The binding of insulin to its receptor activates tyrosine activity in the B chain of the

receptor. Activated tyrosine kinase autophosphorylates 5 critical tyrosine residues on the B subunit. The activated tyrosine kinase then

phosphorylates IRS-1 (Insulin receptor substrate) which is the first intracellular transducer of the insulin effect. IRS-1 interacts with a

series of proteins to stimulate glucose transport and glycogen synthesis.

MTC Module 3: Hormone Regulation of Tissue MetabolismStudy online at quizlet.com/_cpua4


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14. Describe the effects of epinephrine on adipocytes: In adipose tissue, epinephrine promotes the action of PKA which stimulates

hormone sensitive lipase. Extra fatty acids are mobilized for liver energy use. PKA also inactivates acetyl CoA carboxylase, thereby shuttin

down fatty acid synthesis.

15. Describe the effects of epinephrine on glucose metabolism.: In stress, epinephrine rapidly redirects the energy metabolism in ord

to maintain the blood sugar levels for usage by the brain.

16. Describe the effects of epinephrine on muscle: Its major effects in muscle tissue are to stimulate glycogenolysis by promoting the

synthesis of cAMP and the activation of protein kinase A (PKA). PKA helps to stimulate glycolysis by phosphorylation of the tandem

enzyme. The tandem enzyme forms F-2,6-BP which activates PFK-1. Increased lactate production is used for glucose production by the liv17. Describe the effects of glucagon on muscle and liver: -Glucagon has no effect on muscle, because muscle cells possess very few

glucagon receptors. "Anti-insulin" effects in muscle are elicited by epinephrine.

-In the liver, glucagon phosphorylates key enzymes to promote glycogenolysis and gluconeogenesis.

18. Describe the effects of glucocorticoids on adipocytes: In adipocytes, glucocorticoids decrease glucose transport (GLUT4) and the

expression of lipoprotein lipase. There is reduced lipogenesis since less glycerol-3-P is available. Lipolysis continues normally resulting i

increased release of fatty acids and rising serum FA levels. Glucocorticoid effects on adipocytes in different areas of the body are variable.

19. Describe the effects of glucocorticoids on liver: In liver, glucocorticoids increase expression of PEPCK and transaminases leading

increased gluconeogenesis. The elevated G-6-P stimulates glycogen synthetase. The synthesis of urea cycle enzymes increases.

20. Describe the effects of glucocorticoids on muscle: In muscles, glucocorticoids reduce glucose uptake and protein synthesis. Protein

degradation continues normally resulting in release of amino acids and rising serum amino acid levels. The expression of transaminases

increases.

21. Describe the physiological effect of glucagon: Under hypoglycemic conditions, glucagon stimulates catabolism of triglycerides and

glycogen. It stimulates gluconeogenesis, which corrects for hypoglycemia. Glucagon utilizes a G-protein transducer (adenylate cyclase -

cAMP). In adipocytes, glucagon stimulus activates hormone sensitive lipase to break down stored triglycerides into glycerol and fatty acid

The fatty acids are released into the blood, transported by albumin, and taken up by the liver to provide energy for gluconeogenesis.

22. Describe the physiological effects of insulin: Insulin decreases plasma glucose and stimulates anabolic processes. It causes

adipocytes to store free fatty acids as triglycerides, muscle cells to use the excess energy for the synthesis of proteins, and hepatocytes to

store excess glucose as glycogen as well as convert it to fatty acids.

23. Describe the structure of glucagon: Glucagon is synthesized in the a cells as proglucagon (MW = 9,000). Proglucagon is cleaved to

form glucagon (MW - 3,485). Glucagon is secreted from pancreatic -cells in response to low blood glucose levels. Glucagon is degraded

primarily in the kidneys.

24. Describe the structure of insulin: Insulin is a protein composed of an A-chain and a B-chain held together by 2 disulfide bonds.

Insulin is synthesized as a "pre- proinsulin," a single polypeptide chain. The "pre-" refers to a 23 amino a cid leader sequence on the

proinsulin. This leader sequence is cleaved within the rough endoplasmic reticulum to form proinsulin. Proinsulin is then transported by

microvesicles into the Golgi apparatus. The Golgi apparatus packages the proinsulin into secretory granules, which contain a protease tha

cleaves a C-peptide unit to form insulin. The secretory granules move to the cell membrane and release the insulin and C-peptide in a 1:1

ratio. C-peptide does not have biological activity, but is used diagnostically to indicate increased insulin production, such as occurs in an

insulinoma.

25. How does glucagon signal?: Glucagon signal through glucagon receptors on liver and adipose cells and cells of kidney cortex.

Glucagon activates Gs that stimulates adenylate cyclase to produce cAMP, which activates protein kinase A

Glycogenolysis

cAMP also activates cAMP responsive element binding protein(CREB) to activated gene transcription. CREB is phosphorylated by PKA

26. How is excess glucose stored?: Excess glucose is stored in adipose tissue as triacylglycerol (TG).

Since the adipose tissue has no glycerol kinase, glycerol 3-phosphate must be synthesized from glucose by glycolysis


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27.What are the abnormalities of Type I Diabetes?: 1. Lack of insulin reduces amino acid uptake and protein synthesis with increased

proteolysis.

a. Released amino acid with fatty acid used for energy production by muscle

b. Amino acid used for gluconeogenesis

c. During starvation muscle protein spared

2. Hyperglycemia caused by hepatic gluconeogenesis a nd reduced Glut4 glucose uptake muscle and adipose.

a. Very low insulin/glucagon increases gluconeogenesis and glycogenolysis.

b. Osmotic diuresis from glucosuria leads to hypovolemic shock because of sodium loss in urine.

c. During starvation blood glucose is at lower end of normal.

3. Ketoacidosis because of excessive lipolysis, resulting in release of fatty acids

a. Elevated acetyl CoA from -oxidation more severe in starvation

b. Because of high glucose, the brain uses more glucose than ketone contributing to ketoacidosis.

4. Hypertriglyceridemia caused by reduced lipoprotein lipase (LpL) activity

a. Reduced LpL leads to elevated plasma chylomicrons (Fed) and VLDL (fasting).

b. This often leads to Type V hyperliporoteinemia.

28.What are the abnormalities of Type II Diabetes?:A. Symptoms include polydipsia, polyuria, and polyphagia, classical triad , usua

accompanied by fatigue, weakness, and weight loss, which are mild than in Type I since the insulin/glucagon ratio is not as extreme.

B. Basal insulin levels are normal or high, but insulin resistance lead to hyperglycemia.

C. There is no ketoacidosis but hyperglycemia higher than Type I may lead to hyperosmolar nonketotic coma.

1. Obesitydown-regulationofinsulinreceptorsynthesis

2. Exercise up-regulates insulin synthesis.

D. Hyperglycemia must be managed by oral hypoglycemic agents

29.What are the long-term negative effects of hyperglycemia?: Prolonged hyperglycemia results in two mechanism of glucose damag

a. Glycosylation of basement membrane arterioles and capillaries, arthrosclerosis

b. Osmotic damage due to glucose conversion to sorbitol by aldose reductase, neither nerve, lens or kidney have

sorbitol dehydrogenase leading to nerve damage, cataracts, and kidney nephritis (oliguria-reduced urine

output , uremia-retention of waste products).c. Complications of insulin therapy are hypoglycemia and insulin induced coma.

30.What are the main causes of insulin resistance?: Some of the causes of insulin resistance are:

a mutant insulin molecule which is not recognized by the receptor,

a mutant receptor which is unable to recognize and bind insulin effectively,

the presence of anti-insulin antibodies which bind insulin and prevent its binding receptors,

the presence of anti-insulin receptor antibodies which attach to the receptor and prevent insulin binding to the receptor,

a mutation in the tyrosine kinase region of the receptor which prevents signal transduction,

a mutation in one of the proteins in the signal transduction pathway, and

a mutation in one of the effector metabolic proteins.

Some of the causes of insulin resistance are:

a mutant insulin molecule which is not recognized by the receptor,

a mutant receptor which is unable to recognize and bind insulin effectively, the presence of anti-insulin antibodies which bind insulin and prevent its binding receptors,

the presence of anti-insulin receptor antibodies which attach to the receptor and prevent insulin binding to the receptor,

a mutation in the tyrosine kinase region of the receptor which prevents signal transduction,

a mutation in one of the proteins in the signal transduction pathway, and

a mutation in one of the effector metabolic proteins.

31.What can cause a deficiency of cortisol?: Over use of glucocorticoids can cause deficiency of cortisol

32.What causes insulin resistance?: 1. faulty receptor, post-receptor signaling

2. defects in intermediary metabolism involved with glucose homeostasis, e.g. increased hepatic gluconeogenesis, decreased glucose

utilization by skeletal and adipose tissue,

increased lipolysis and blood fatty acid concentration


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33.What causes the release of fatty acids from adipose tissue?: The activation of the hormone sensitive lipase by epinephrine or

glucagon results in the release of triacylglycerol from adipose stores (5), which supply fatty acids to liver for fatty acid oxidation. Fatty aci

are also used by muscle and therefore spare blood glucose for use by the brain (3) and red blood cells (4). The use of muscle alanine and

other amino acids increases the synthesis of urea (10) to dispose of excess nitrogen

34.What causes Type II Diabetes?: Type II DM results from dysfunction pancreatic cells insulin deficiency and insulin resistance due t

reduced

responsiveness of target tissues (muscle and adipose). This condition is associated with obesity and if untreated can progress to fatty liver

hepatitis, cirrhosis, and eventually liver cancer.

35.What does glucagon work in concert with to increase cAMP?: Epinephrine and glucagon act synergistically to increase cAMP

cAMP levels are reduced by phosphodiesterase (caffeine inhibits PDE)

36.What does insulin signal through?: Insulin signals through tyrosine Kinase insulin receptors.

Insulin binding initiates insulin receptor dimerization and autophosphorylation of tyrosine residues that bind adaptor and exchange

proteins.

Two targets for phosphorylation by insulin receptor are insulin receptor substrate 1 and 2..

IRS1 controls lipogenesis by activation of SREBP1-2

of glucagon

IRS2 controls gluconeogenesis and in diabetes IRS2 loss of activity increase hepatic gluconeogenesis.

37.What happens after three days of starvation?:After 3 days of starvation, fatty acid oxidation increases dramatically and the

production of ketone bodies by the liver increases. Ketone bodies are used by the nervous system, and again spare blood glucose levels, a n

there use by muscle spares amino acids during starvation. The use of muscle amino acid decreases and thus gluconeogenesis. The decreasin amino acid usage decreases blood urea nitrogen. At this time, gluconeogenesis in the kidney accounts for approximately 40% of the blo

glucose. The kidney use of glutamine is important in neutralizing metabolic acidosis.

38.What happens when pancreatic cells are stimulated by glucose?: The stimulation of pancreatic cells by glucose results in a

"biphasic response" of insulin release. Phase I involves a rapid release of preformed, stored insulin. Phase II occurs 30 minutes after the

initial stimulation of glucose and results in the release of newly synthesized insulin. The pancreatic glucose transporter, GLUT2, and

glucokinase are the "glucose sensors" that regulate insulin secretion. In addition, the pancreatic cells must metabolize glucose and

change the ATP/ADP ratio as a consequence in order to secrete insulin. The mechanism involves the closing of a K+ channel by ATP, the

depolarization of the membrane, and an increase in intracellular Ca2+.

39.What hormones regulate blood glucose?: Both glucagon and insulin are the major hormones that regulate the blood glucose levels

40.What hormones regulate glycogenolysis and gluconeogenesis?: Sixteen hours after a meal liver Glycogenolysis is at peak activity

with gluconeogenesis peaking after 30 hours. Glucagon is the major hormone that regulates both glycogen breakdown and glucose

production. During stress, epinephrine is the major hormone that regulates glucose production while in hypermetabolic states caused by

surgery, sepsis or trauma, epinephrine with the adrenal glucocorticoid, cortisol, controls gluconeogenesis.

41.What induces catecholamine release?: Hypoxia

Hypoglycemia

Exercise

Pain

42.What is Addison's Disease?: Addison's disease is due to lack of cortisol

(nerve endings)

SAM

- Weight loss, hypoglycemia, hypotension, lethargy

- Weakness, pigmentation

43.What is Cushing's Syndrome?: Cushing's syndrome is due to hypersecretion of ACTH and leads to symptoms- Hypertension, sodium retention, thinning skin

- Hypokalemic, truncal obesity, muscle weakness

- Bruising, glucose intolerance, osteoporosis

44.What is diabetes?: Diabetes mellitus is characterized by hyperglycemia resulting from insulin deficiency or an ineffectiveness in insulin

action on target organs. In the latter case, target organs manifest "insulin resistance." Diabetes, in most instances, can be diagnosed by

measuring the morning blood glucose after an overnight fast. In borderline cases, a glucose tolerance test is administered. Glucose is give

to the patient, and blood glucose levels are monitored. In diabetes, glucose levels will rise higher than normal, and stay elevated long afte

control's blood sugar has returned to normal.

45.What is glucagon?: -Major insulin counter-regulatory hormones

-Hypoglycemia stimulates release of glucagon, epinephrine, norepinephrine and cortisol


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46.What is the action of glucokinase?: Glucokinase phosphorylates glucose in hepatocytes and pancreatic cells. The glucokinases of t

2 cell types have slightly different sequences. Both have a high KM (5mmol/L) for glucose. The glucokinase gene utilizes different exon 1

coding regions for transcription in liver and cells. A glucose response element in the gene allows for glucose to initiate the expression of

an mRNA in the pancreas, which has a different exon 1 from the glucokinase produced in the liver. In this organ, an insulin response

element allows for insulin to produce an mRNA containing an alternate exon 1.

47.What is the effect of diabetes on liver enzymes?: Diabetes results in the phosphorylation of key enzymes in the liver, favoring

glycogenolysis, gluconeogenesis, and ketogenesis.

48.What is Type I Diabetes?: -Type I DM autoimmune destruction of pancreatic -cells with total absence of insulin. The human leukocyantigen

(HLA) are involved in cell destruction.

-Symptoms include polydipsia, polyuria, and polyphagia, classical triad , usually accompanied by fatigue, weakness, and weight loss.

49.What maintains metabolism during fasting?: During fasting the initial fuel used to maintain blood glucose for approximately 24

hours is glycogen (2). Within 24-48 hours gluconeogenesis maintains blood glucose levels from lactate (11) and muscle amino acids

50.What stimulates cortisol release?: Adrenocorticotropic hormone (ACTH) simulates cortisol release from adrenal cortex

51.What stimulates epinephrine and norepinephrine release?: -Neural signal stimulate epinephrine release from adrenal medulla

-Neural signal causes norepinephrine release from nerve endings.

52.What tissues need glucose?: All tissues of the body require glucose.

Both the red blood cell and brain need a continual supply of glucose.

The brain consumes 150 grams of glucose per day.

The smooth muscle also needs glucose for glycolysis and glycogen storage. The muscle can produce Glucose 6-phosphate, but cannot

contribute to blood glucose since it has no glucose 6-phosphatase.

53.When is glucagon released?: Glucagon is released by -cells and release inhibited by Glucose and insulin

Protein stimulate more and longer release of glucagon over insulin

54.When is insulin released?: After a meal the pancreas -cells releases insulin.

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MTC Module 3 Hormone Regulatio.pdf