Ch. 19 Day 2 Flashcards
Is the primary control mechanism of metabolism exocrine or endocrine?
Endocrine
Endocrine cells in pancreas secrete?
Insulin AND glucagon
Endocrine secretions come from Islets of Langerhans
Alpha cells in pancreas secrete?
Glucagon
Beta cells in pancreas secrete?
Insulin
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
Is glucagon catabolic or anabolic?
Catabolic
–levels increase during starvation, turned off by increasing insulin levels
*Insulin and glucose are anabolic
When insulin turns something on, what turns it off?
glucagon
When glucagon turns something on, what turns it off?
insulin
Insulin dominates during the ____ (anabolic) state.
Fed
Glucagon dominates during ____/____ (catabolic) state.
Fasting/starving
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
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
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
Inhibition of Insulin Release
Sympathetic stimulation - norepinephrine (e.g. “fight or flight”)
Stress - epinephrine, cortisol from adrenal gland
–fasting is a form of stress
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
Insulin activates glucose uptake by inducing translocation of?
Glucose Transport Protein 4 (GLUT 4) to cell membrane
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
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)
- extreme thirst due to hyperosmolar state created by hyperglycemia
- operating due to failure of insulin-dependent central satiety mechanisms to “see” glucose despite hyperglycemia
- glycosuria (exceeding renal threshold for glucose reabsorption)
- microvascular disease –> retinopathy, neuropathy, nephropathy
- macrovascular disease –> accelerated CV disease, M.I., stroke
- hyperglycemia
- 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
