Ch. 19 Day 2 Flashcards by Bethany Smart

Is the primary control mechanism of metabolism exocrine or endocrine?

Endocrine

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Endocrine cells in pancreas secrete?

Insulin AND glucagon

Endocrine secretions come from Islets of Langerhans

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Alpha cells in pancreas secrete?

Glucagon

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Beta cells in pancreas secrete?

Insulin

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Describe the levels of glucose, insulin, and glucagon during the fasting and fed states during a CHO meal.

Fasting: decreased glucose, decreased insulin, increased glucagon

Fed: increased glucose, increased insulin, decreased glucagon

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Is glucagon catabolic or anabolic?

Catabolic
–levels increase during starvation, turned off by increasing insulin levels

*Insulin and glucose are anabolic

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When insulin turns something on, what turns it off?

glucagon

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When glucagon turns something on, what turns it off?

insulin

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Insulin dominates during the ____ (anabolic) state.

Fed

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Glucagon dominates during ____/____ (catabolic) state.

Fasting/starving

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When insulin is dominant in the body, what levels/processes increase and decrease?

Increases:

-GLUCOSE UPTAKE
-glycogenesis
-glycolysis
-lipogenesis
-TG storage
-protein synthesis

Decreases:

-blood glucose
-glycogenolysis
-gluconeogenesis
-FA oxidation
-TG hydrolysis
-protein catabolism
-ureogenesis
-ketogenesis

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When glucagon is dominant in the body, what levels/processes increase and decrease?

Increases:

-blood glucose
-glycogenolysis
-gluconeogenesis
-FA oxidation
-TG hydrolysis
-protein catabolism
-ureogenesis
-ketogenesis

Decreases:

-glycogenesis
-glycolysis
-lipogenesis
-TG storage
-protein synthesis

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Stimulation of Insulin Release

Increased plasma glucose

Increased plasma AAs

Incretin (hormone) release from small intestine (GLP-1, GIP) in response to CHO coming in

Parasympathetic, vagally-mediated reflexes originating in liver

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Inhibition of Insulin Release

Sympathetic stimulation - norepinephrine (e.g. “fight or flight”)

Stress - epinephrine, cortisol from adrenal gland
–fasting is a form of stress

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What are the 4 cellular mechanisms of insulin secretion?

1) Insulin binds to receptor w/ tyrosine kinase activity
2) phosphorylation-mediated activation of IRS’s
3) coupled to diverse array of signal transduction cascades
4) increased glucose uptake/utilization, increased expression of anabolic genes

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Insulin activates glucose uptake by inducing translocation of?

Glucose Transport Protein 4 (GLUT 4) to cell membrane

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Stimulation of Glucagon Release

Decreased plasma glucose

Increased plasma AA’s
–e.g. if increased dietary protein, but decreased dietary glucose

Increased sympathetic activity

Increased epinephrine release from adrenal

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Inhibition of Glucagon Release

Increased plasma glucose

Increased parasympathetic activity

Increased plasma insulin

Glucagon counteracts insulin effect on glucose uptake by?

Muscle and adipose

This serves to maintain blood glucose levels (during high protein low CHO meal)

What are the 5 steps of cellular mechanisms of glucagon action?

*Receptor is coupled to guanyl nucleotide (GTP) binding protein

1) activation of G protein activates A.C.
- -bound by glucagon

2) Activated A.C. produces cAMP
3) cAMP activates P.K.
4) P.K. phosphorylates P’ase kinase (activation) and glycogen synthase (inactivation)
5) P’ase kinase phosphorylates glycogen phosphorylase (activation

Diabetes

Dysfunctional hormonal control of metabolism

Hyperglycemia due to inadequate insulin secretion, decreased responsiveness to insulin, or both

Diabetes is a disease characterized by a CHRONIC PERSISTENT CATABOLIC STATE
–body thinks it’s starving

Diagnosed by measuring:

a) fasting levels of glucose in plasma
b) kinetics of glucose removal after defined oral glucose load - glucose tolerance test

The fasting blood glucose for non-diabetics (“normal”) is? The fasting blood glucose level for diabetics is?

Normal: 125 mg/dL

Gut microflora

Largest population of microbes in body

Regulatory role in METABOLIC and immune pathways: interactive host-microbiota metabolic, signaling, immune-inflammatory axes connecting gut, liver, muscle, brain

Type 1 Diabetes

Formerly juvenile-onset diabetes

MOST SEVERE FORM

Failure of pancreatic beta cells to produce/release insulin

Incompletely understood autoimmune destruction of beta cells, associated w/ genetic and/or environmental factors

Treatment: exogenous administration of insulin - resolves gluco-regulation, but other complications (ex: peripheral vascular disease) persist

Type 2 Diabetes

Formerly adult-onset diabetes, now insulin RESISTANT diabetes Accounts for about 90% of cases of diabetes worldwide Precise cause uncertain, but associated w/ OBESITY-INDUCED INFLAMMATION Progressive: insulin resistance in target cell --> compensatory hyper secretion of insulin --> eventual loss of beta cell function Tissues w/ most prominent insulin resistance: skeletal muscle, liver, adipose

Pathophysiological Consequences of Diabetes (see p. 43 in notes for complete list)

1. extreme thirst due to hyperosmolar state created by hyperglycemia 2. operating due to failure of insulin-dependent central satiety mechanisms to "see" glucose despite hyperglycemia 3. glycosuria (exceeding renal threshold for glucose reabsorption) 4. microvascular disease --> retinopathy, neuropathy, nephropathy 5. macrovascular disease --> accelerated CV disease, M.I., stroke 6. hyperglycemia 7. ketoacidosis

Insulin resistance --> Type 2 diabetes

Partly a response to obesity-induced inflammation originating from adipose tissue under conditions of increasing fat content Main trigger for inflammation appears to be simply increasing fat storage --inflamm. response can be shut down during weight loss Inflammatory factors circulate to ALL tissues and can produce significant metabolic dysfunction

Obesity-induced inflammation

Compromises insulin-dependent processes throughout body

What pathways link obesity to insulin resistance?

endocrine, inflammatory, and neuronal pathways

Precise mechanistic linkage between obesity and insulin resistance/diabetes not yet fully understood. But what do we know so far?

Only about 75% of severely obese patients insulin resistant; about 25% have normal insulin sensitivity Adipose from resistant vs non-resistant obese patients shows differences in specific cellular processes (e.g. TG storage/lipolysis, oxidant stress, mitochondrial function, and inflamm.) - reason(s) for these differences is unknown Deleterious effects of expanding adipose appears to depend upon location --visceral adipose associated w/ greater inflamm. response than in subQ adipose

Obesity/insulin resistance can produce significant derangements in body lipid/lipoprotein metabolism which can lead to?

Atherosclerosis and CV disease

What's a lipoprotein?

Large complex of lipid and proteins which serve as transport vehicle for lipids (TG, cholesterol, cholesteryl esters)

Chylomicrons

produced by and released by intestine (transports dietary lipids into body) increased TG

VLDL

very low density lipoprotein produced b liver (transports endogenous lipids) increased TG

IDL, LDL

intermediate density lipoprotein, low density lipoprotein derived from VLDL during its plasma passage and metabolism (transport cholesterol to periphery) increased cholesterol LDL is "bad cholesterol"

HDL

high density lipoprotein precursor produced by liver, picks up cholesterol from peripheral tissues, transports it to liver ("reverse cholesterol transport") increased cholesterol "good cholesterol"

Lipoprotein metabolism

healthy state depends on HDL/ldl; if instead we have hdl/LDL --> atherosclerosis Endogenous pathway depends on LDL levels

Dysfunctional lipoprotein metabolism can lead to?

Atherosclerosis Insulin resistance - 1) promotes VLDL production and secretion from liver - 2) decreases expression of liver LDL receptor - ->increased production + decreased disposal - 3) decreases plasma HDL

Increased VLDL in plasma =?

increased TG

Increased VLDL in plasma --> ?

increased LDL

When LDL levels remain elevated, increased amounts are taken up in artery walls --> ?

Atherosclerosis excess LDL taken up by blood vessels, promoting lipid deposition in artery walls as part of chronic inflammatory process (which is atherosclerosis)

Does atherosclerosis take time to develop or is it rapid?

Takes time to develop/build up

Metabolic Syndrome

Cluster of risk factors for diabetes and CV disease Index of visceral obesity 100+ mg/dL blood sugar indicative of prediabetes 150+ mg/dL TG and low HDL cholesterol highly indicative of insulin resistance