VPHY 4200 Case 9

cardiomegaly

abnormal enlargement of the heart

ulcer

open sore or lesion in the skin or mucous membrane--can occur in DM patients because it is very difficult for healing materials to be delivered when there is edema, which leads to a bacterial infection

edema

abnormal accumulation of fluid in interstitial spaces of tissues, caused by the increased hydrostatic P of blood vessels in DM patients

60

beta cells make up about ?% of the Islets of Langerhans

25

alpha cells make up about ?% of the Islets of Langerhans

10

delta cells make up about ?% of the Islets of Langerhans

insulin, amylin

What do beta cells secrete?

glucagon

What do alpha cells secrete?

somatostatin

What do delta cells secrete?

amylin

peptide hormone co-secreted with insulin from beta cells in pancreas; plays a role in glycemic regulation

insulin, somatostatin

the close proximity of Islet cells allows for cell-cell communication, for ? to inhibit glucagon secretion, and for ? to inhibit insulin & glucagon secretion

100/1

ratio of insulin/amylin secreted from beta cells is about ?

slowing down, promoting, spikes

amylin plays a role in glycemic regulation by (slowing down/speeding up) gastric emptying, (inhibiting/promoting) satiety, and preventing post-prandial (dips/spikes) in blood glucose levels

disulfide bonds

alpha-chains and beta-chains must be linked by ? to be bioactive

preproinsulin

insulin mRNA is translated as a single chain called ?

proinsulin

removal of the signal peptide from preproinsulin during insertion to the ER yields ?

C peptide

in the ER, proinsulin is exposed to endopeptidases that excise the ? -> mature insulin

insulin, C peptide

in the synthesis of insulin, secretion of ? and ? are equi-molar

importance of C peptide levels

C peptide (exogenous insulin doesn't have it)

an individual's concentration of ? indicates the amount of endogenous insulin formed

T

T/F: all living cells have membrane potential

excitable cells

cells that are electrically excitable to change Vm from resting membrane potential (Vr) to action potential

neurons, muscle (all types), beta

important examples of excitable cells include ?, ? cells, and pancreatic ? cells

permeability

the fluctuation of Vm is due to changes in the membrane's ? to specific ions (Na+, K+, Ca2+)

Na+/K+ pumps (move more cations out of cell than in)

resting membrane potential is about -60 to -80 mV due to ?

GLUT-2

glucose enters beta cells through ?

facilitated diffusion

The movement of glucose into beta cells through GLUT-2 is what type of transport?

increase

Does glycolysis increase or decrease the ATP/ADP ratio?

ATP-sensitive K+ channels

ATP binds to ?, which close the channel for K+ -> no efflux of K+ -> increased membrane potential (depolarization)

Ca2+

depolarization by ATP binding to ATP-sensitive K+ channels causes voltage-dependent ? channels to open -> influx of those ions -> insulin secretion

open

at rest, ADP binds to ATP-sensitive K+ channels -> K+ channels remain (open/closed)

closed

in the glucose-stimulated state, ATP-sensitive K+ channels are (open/closed)

close, insulin

oral hypoglycemic drugs (sulfonylureas, meglitinides) (open/close) K+ channels -> depolarization -> greater ? secretion -> hypoglycemic effects

GLUT-4

insulin secretion triggers insertion of ? transporters to the cell membrane of insulin-sensitive cells

cardiac, skeletal, adipocytes

insulin-sensitive cells are found in ? muscle, ? muscle, and ?

glucose

GLUT-4 is the determinant of ? homeostasis

insulin, exercise, hypoxia

GLUT-4 is rapidly translocated to the cell surface in response to ?, ?, or ?

fast

glucose uptake into cells is (slow/fast)

80

GLUT-4 facilitates glucose uptake in ?% of body tissues (skeletal muscle cells, cardiac cells, and adipose cells)

brain neurons, pancreatic beta cells, intestinal mucosa, kidney tubules, RBCs

body tissues that don't express GLUT-4

amino acids, K+, PO42-

a fast effect of insulin is that it increases membrane permeability to ?, ?, and ? into cells

intermediate, phosphorylation

a (slow/intermediate/fast) effect of insulin is that it changes cellular enzyme activities by ?

proteins

a slow (hours to days) effect of insulin is the formation of new ? (growth effects)

liver, skeletal

insulin causes an increase in glycogenesis -> increased entry of glucose into ? cells and ? muscle cells

5

?% of liver mass consists of stored glycogen

activates

insulin (activates/inhibits) lipogenesis

hormone-sensitive lipase

insulin decreases lipolysis by decreasing activity of ?, which hydrolyzes triglycerides (into monoacylglycerol + free fatty acid)

glucokinase, synthase

insulin increases glycogenesis in the (liver) by increasing ? (enzyme) and increasing glycogen ? (enzyme)

fatty acids, increased

once glycogen storage mechanisms in the liver are saturated, insulin causes conversion of glucose into ? to increase -> (increased/decreased) VLDL production in the liver

VLDL

transports newly synthesized triacylglycerol molecules from the liver to peripheral tissues (adipose cells) in the bloodstream

IGF-1 (insulin-like growth factor 1), IGF-2 (insulin-like growth factor 2)

insulin is a member of a family of structurally and functionally similar molecules (?, ?, and relaxin) that have growth-promoting activities

vasodilator, endothelium

insulin exerts (vasodilator/vasoconstrictor) action in the vascular ? as a result of increased nitric oxide production

increase (especially arginine and lysine)

amino acids (increase/decrease) insulin secretion

sympathetic

? nervous system stimulation decreases insulin secretion

parasympathetic

? nervous system stimulation increases insulin secretion

incretin hormones

hormones that stimulate an increase of insulin from the beta cells of the pancreas; they slow gastric emptying and inhibit glucagon release

GIP (glucose-dependent insulinotropic peptide)

stimulated by glucose in the gut; triggers insulin secretion and decreases gastric motility

CCK (cholecystokinin), gastrin, secretin

the incretin hormones ?, ?, and ? (help digestion and absorption of carbohydrates, fatty acids, and amino acids) stimulate insulin secretion (to get nutrients into the cells)

GLP-1 (glucagon-like peptide 1)

an increase in blood glucose, amino acids, and fatty acids -> increased ?, which greatly stimulates insulin secretion (potent antihyperglycemic)

intestinal

GLP-1 is secreted by ? L cells as a gut hormone

DPP-4 enzyme

inactivates GLP-1; causes GLP-1 to have a short half-life (2 minutes)

DPP-4 inhibitors

drugs that decrease activity of the enzyme that inactivates GLP-1

osmotic

Why store glycogen rather than just glucose? Too much glucose will increase the ? P (same reason glucose trapping is necessary--if it didn't occur, glucose would move out of cells due to the high intracellular concentration)

glycogen synthase

a regulatory, insulin-sensitive enzyme that is required for glycogenesis

beta

2 metabolic defects of type 2 DM: insulin resistance and (later stage) ? cell dysfunction--impaired insulin secretion

less

an insulin-resistant cell will move (more/less) GLUT-4 to the membrane

30

obesity is defined as BMI > ?

HHS (hyperosmolar hyperglycemic state)

an acute complication of DM; hyperglycemia causes high osmolarity without significant ketoacidosis

increases

insulin (decreases/increases) uptake of K+ by cells

hyperkalemia

in the absence of insulin action, more K+ exits from cells into plasma, causing ?

depolarized, cardiac arrhythmia

consequences of hyperkalemia: cell membrane becomes (hyperpolarized/depolarized); at high levels, this causes ?

macrovascular, atherosclerosis

? complications cause diseases of large and medium blood vessels due to accelerated ?

microvascular

? complications consist of capillary dysfunction in target organs

atherosclerosis

condition in which fatty deposits called plaque build up on the inner walls of the arteries

coronary artery, stroke

macrovascular complications may cause ? disease, peripheral vascular disease, and/or ?

neuropathy, nephropathy, retinopathy

microvascular complications of DM

aldose reductase, ROS (reactive oxygen species), advanced glycation, protein kinase

proposed mechanisms of vascular damage from hyperglycemia: ? pathway and ?; ? end products theory; ? theory

polyol pathway

occurs in hyperglycemic state; glucose (+ aldose reductase + NADPH) --> sorbitol (+ sorbitol dehydrogenase + NAD+) --> fructose

NADPH

in a euglycemic state, glucose feeds into ATP production (glycolysis and Krebs cycle) and into the hexose monophosphate shunt (pentose phosphate pathway) to make ? and ribose

polyol

in a hyperglycemic state, ~30% of glucose feeds into the ? pathway

sorbitol, fructose

in the polyol pathway, glucose is converted into ?, which is then converted into ?

NADP+, NADH

along with fructose, the polyol pathway generates ? and ?

free radicals

chemical compounds with an odd number of electrons; extremely unstable and reactive; tend to acquire an electron from other substances, making them unstable

ROS (reactive oxygen species)

reactive chemical species containing oxygen; many of them are free radicals

glutathione

the "? system" is present in every animal cell and exerts antioxidant effects

NADPH

in the glutathione system, ? indirectly provides electrons for the reduction of H2O2, thus decreasing the reactive oxygen species

retina, kidney, nervous

the glucose uptake in cells of the ?, ?, and ? tissues are insulin-independent

NADPH, increased

an increase in blood glucose -> depletion of ? by aldose reductase -> inability to regenerate reduced glutathione -> (increased/decreased) oxidative stress reactions -> cell death

sorbitol, decreased

from the polyol pathway, an increased [?] -> (increased/decreased) nitric oxide -> vasoconstriction in neuronal tissue and eventually ischemia

increases

sorbitol does not diffuse through cell membranes easily -> high accumulation of sorbitol -> (increases/decreases) osmotic P -> water retention -> cell swelling -> damage -> cataract formation

NAD+

Glycolysis requires what electron carrier?

NAD+

lactate dehydrogenase regenerates ? to be used in glycolysis

electron

ROS are produced from ? leakage to form superoxide

superoxide dismutase (SOD)

an enzyme that destroys superoxide: O2- + O2- + 2H+ --> H2O2 + O2

increases

in DM patients, the polyol pathway increases NADH -> NADH/NAD+ redox imbalance, which (increases/decreases) electron leakage -> more ROS -> oxidative stress

ER stress, lipid peroxidation

hyperglycemia causes oxidative stress in other intracellular structures such as the endoplasmic reticulum (?) or plasma membrane (?)

decreased

the polyol pathway activation leads to (increased/decreased) NADPH/NADP+ ratio

non-alcoholic fatty liver (NAFLD)

a high level of fructose may cause ? disease

increase

high levels of fructose (increase/decrease) glycation

liver

in the ?, fructose -> increased production of glucose, VLDL, and ApoC -> increased lipogenesis -> non-alcoholic fatty liver disease