Pathophys Diabetes Section I

Front 1

the most important stimulus for insulin secretion

Back 1

increased plasma glucose

Front 2

type 3 diabetes includes...

Back 2

2º causes e.g. pancreatic destruction

genetic defects in ß cell function (e.g. MODY) or insulin action

Front 3

type 4 diabetes includes...

Back 3

gestational diabetes

Front 4

amylin effects

(3)

Back 4

decreases:

-- glucagon release
-- gastric emptying
-- appetite

Front 5

pramlintide basic mechanism

which types of diabetes does it treat?

Back 5

decreases postprandial hyperglycemia

type 1 and type 2

Front 6

a synthetic amylin

Back 6

pramlintide

Front 7

pramlintide is effective because it is a ______ ______

Back 7

synthetic amylin

Front 8

how can we distinguish

an insulin-secreting tumor vs. hypoglycemia 2º exogenous insulin

Back 8

C-peptide is present in the insulinoma

Front 9

oral glucose vs. IV glucose

they affect the body differently

how extreme is the difference?

Back 9

oral glucose is more effective at stimulating insulin release

up to 3x more, Lenny said

Front 10

the incretin hormones

an important effect they have

which incretin does this the most?

Back 10

GIP
glucagon-like peptide-1
VIP

increase insulin release

GLP-1

Front 11

incretins increase insulin release by the ß cell

using what 2nd messenger?

Back 11

increased cAMP

Front 12

rising plasma glucose increases insulin release by what notable events in the ß cell?

7 steps

begin by describing how it enters the cell

Back 12

enters the ß cell by GLUT2

it's phosphorylated by glucokinase

undergoes glycolysis --> ATP

ATP closes ATP-sensitive K+ channels

which depolarizes the cell, thereby

activating Ca++ channels, so Ca++ enters the cell

which causes exocytosis of insulin

Front 13

C-peptide can help us distinguish between

exogenous insulin administration vs.

two other things

Back 13

insulin-secreting tumor

secretagogues

Front 14

people normally make about how much insulin every day?

Back 14

30 units/day according to Lenny

Front 15

besides the well-known mechanism, glucose also increases insulin secretion by ß cells by a misc. mechanism

Back 15

it increases ß cell production of IP3

IP3 mobilizes intracellular Ca++ stores from the ER

Ca++ stimulates insulin secretion

Front 16

genetics of MODY type 2

Back 16

autosomal dominant

mutation that causes reduced glucokinase activity

Front 17

major clinical features of MODY type 2

(4)

Back 17

insulin release is decreased

persistent hyperglycemia develops before 25 years of age


MODY does not feature:

insulin resistance
ketoacidosis

Front 18

various things that cause insulin release or are necessary for allowing it to happen

(8)

Back 18

glucose

amino acids, particularly arginine, leucine, lysine

ß2-adrenergic
M3 cholinergic

GIP
GLP-1

glucagon

normal serum K+ is necessary for insulin release and action in the periphery

Front 19

explain propranolol's effect on plasma insulin and glucose

what's the irony?

Back 19

propranolol is a ß-adrenergic antagonist, so it decreases hepatic gluconeogenesis

thus it can enhance the effect of hypoglycemic drugs

the irony:

ß2-adrenergic stimulation increases insulin release. so you might expect a ß blocker like propranolol to have a hyperglycemic effect by inhibiting insulin release

Front 20

MODY type 2's secretion of insulin in response to _ is impaired

Back 20

glucose only!

insulin secretion in response to glucose is impaired, because we have decreased action of glucokinase.

but we can still secrete insulin in response to amino acids, ACh, etc.

Front 21

some things that decrease insulin secretion

Back 21

alpha2-adrenergic stimulation e.g. by epinephrine

somatostatin

Front 22

insulin vs. glucagon

which one increases or decreases the other?

Back 22

insulin decreases glucagon release

glucagon stimulates insulin release

Front 23

6 antihyperglycemic effects of
GLP-1

Back 23

decreased:

gastric emptying
glucagon
hepatic glucose production

increased:

ß cell proliferation
insulin
insulin sensitivity

Front 24

a patient was recently diagnosed with hypertension. how might that affect their insulin levels, and why?

Back 24

they may be treated with a diuretic!

most diuretics decrease serum K+, causing

decreased insulin

and thereby increased glucose


Lenny said: most diuretics e.g. thiazides lower K+, and even if it stays in its reference range, lower K+ can decrease insulin secretion

Front 25

compare GIP vs. GLP-1

Back 25

GIP does not increase insulin secretion enough in type 2 diabetics to normalize plasma glucose


GLP-1 does

Front 26

insulin and glucagon

increase or decrease each other?

Back 26

insulin decreases glucagon

glucagon increases insulin

Front 27

hypokalemia increases or decreases insulin?

how?

Back 27

the K+ channel sends K+ out of the cell

hypokalemia makes it want to send K+ out of the cell even more

thus the cell is hyperpolarized by sending + charge out

and it is less easily depolarized by the closing of K+ channels

and thus Ca+ channels are less easily activated to bring Ca++ in, to cause insulin exocytosis

Front 28

chronic hyperglycemia has what effect on insulin?

this effect is termed

Back 28

decreases insulin release by up to 75%

glucotoxicity

Front 29

glucotoxicity means, briefly, that

Back 29

chronic hyperglycemia causes progressive impairment of insulin secretion

Front 30

glucotoxicity mechanisms

one that is very important

there are two others that aren't as important

Back 30

mitochondrial injury: glucose overloads glycolysis and oxidative damage to ß cells decreases ATP synthesis

-- decrease in size of insulin pool aka "ß cell exhaustion"

-- desensitization of ATP-dependent K+ channels in ß cells

Front 31

the gist of lipotoxicity in diabetes

Back 31

chronic increase in FFAs

causes decreased *glucose-stimulated* insulin secretion (i.e. the other mediators of insulin synthesis remain intact)

I *believe* that Lenny said this was by overrunning lipid metabolism, mitochondrial injury and oxidative damage. several mechanisms of lipotoxicity are mentioned in the atherosclerosis section

Front 32

type II diabetes is a disease that ultimately features insulin ___

Back 32

ultimately, insulin resistance AND deficiency

Front 33

_ type of insulin secretion is biphasic

Back 33

glucose-stimulated

Front 34

1st phase of glucose-stimulated insulin secretion

vs.

2nd-phase


what changes in plasma glucose trigger which phase?

where does the insulin come from?

Back 34

Phase 1: triggered by an abrupt increase in plasma glucose

Phase 2: triggered by a slow and sustained increase in plasma glucose


exocytosis of a readily releasable pool of insulin granules

exocytosis of a reserve pool of insulin granules

Front 35

which releases more insulin, phase 1 or phase 2?

Back 35

the vast majority is phase 2