B5.002 Diabetes Melltus Metabolism

Question 1

classify DM1

Answer 1

destruction of B cells, absolute insulin insufficiency

• autoimmune
• idiopathic
• typically occurs at a young age

Question 2

classify DM2

Answer 2

resistance to insulin and relative insulin insufficiency

• called adult onset or non insulin dependent
• genetic and lifestyle factors
• possible environmental factors

Question 3

who is at the highest risk for diagnosis of diabetes

Answer 3

1. Hispanic females
2. black females
3. Hispanic males
4. black males
5. white females
6. white males

Question 4

what % of patients with newly diagnosed diabetes are overweight or obese?

Answer 4

90%

-60% obese, 30% overweight

Question 5

core defects of DM2

Answer 5

insulin resistance

B cell dysfunction

Question 6

what % of patients with DM2 are insulin resistant

Answer 6

83%

• 54% resistance and low secretion
• 29% resistance and good secretion

Question 7

what is insulin sensitivity

Answer 7

amt of insulin required to stimulate whole body glucose uptake
DM2 pts need a 2x higher dose of insulin to elicit same response

Question 8

what organ plays the most major role in insulin resistance?

Answer 8

skeletal muscle

in DM2, not stimulated to uptake as much glucose in response to infused insulin (reduction from 5 mg/kg/min to 2)

Question 9

when glucose is consumed orally, what organs are the primary locations of glucose uptake?

Answer 9

1. splanchnic bed (liver and gut) 29%
2. skeletal muscle 26%
3. brain 23%

Question 10

what are the 2 major pathways for glucose transport into skeletal muscle

Answer 10

1. insulin receptor

2. contraction

Question 11

which transporter is present in skeletal muscle

Answer 11

GLUT4

Question 12

what is the effect of skeletal muscle contraction + insulin pathways both being activated

Answer 12

healthy people have an additive effect on glucose transport

people with insulin resistance experience a synergistic effect on glucose transport

Question 13

what is meant by synergistic effect of contraction + insulin

Answer 13

exercise prior to insulin infusion helps with insulin sensitivity and glucose uptake

Question 14

what are some possible mechanisms of insulin resistance in muscle

Answer 14

increase in adipose increases release of inflammatory cytokines and fatty acids (TGs)
leads to production of excess serine kinases which dephosphorylate components of the insulin pathway and blunt the signal transduction
oxidative stress also increases

Question 15

how are liver fat and insulin sensitivity related

Answer 15

increased liver fat leads to decreased insulin sensitivity

steatosis- >5% of liver is fat

Question 16

why do lipid intermediates contribute to insulin resistance

Answer 16

increased production of DAGs leads to and increase in serine kinases
kinases blunt insulin signal transduction pathway

Question 17

discuss effects of DM2 on post prandial glucose metabolism

Answer 17

glucose peaks at a higher level and takes longer to return to baseline
HGP never effectively turned off as it should be in healthy people

Question 18

what is the normal compensation for decreased insulin sensitivity

Answer 18

increased beta cell function (insulin production)

Question 19

what happens in people who progress from normal glucose tolerance to diabetes

Answer 19

beta cells not able to compensate for reduced insulin sensitivity
decreased sens and decreased B cell function when compared to non-progressors

Question 20

discuss the progression of insulin over time in a person with DM2

Answer 20

initially rises to compensate for declining sensitivity, but eventually begins to fall leading to an increased plasma glucose

Question 21

what is the difference in glucose and insulin responses in normal and obese people without DM

Answer 21

both have similar glucose responses

obese individuals require much higher insulin levels to achieve the same response

Question 22

what is a disposition index

Answer 22

insulin secretion x insulin sens

pts with DM2 have a slower rate of insulin production than those without diabetes

Question 23

what is a feature of resting glucose and insulin levels in pts with DM2

Answer 23

hyperglycemia and hyperinsulinemia even without meals

Question 24

how is CHD risk affected by IGT?

Answer 24

IGT can increase CHD even without progression to diabetes

diabetes worse than isolated IGT, but IGT increases all cause mortality by 20/1000

Question 25

what negative consequences are linked to hyperglycemia

Answer 25

oxidative stress

CVD

Question 26

how are plasma glucose levels tightly regulated

Answer 26

alterations in insulin secretion relative to underlying level of insulin sens

Question 27

do IFG and IGT always occur together?

Answer 27

no, can be separate and have separate pathologies

Question 28

what is HbA1c?

Answer 28

glucose chemically linked to Hb

Question 29

what causes B cell failure in DM2?

Answer 29

high circulating FFAs -> lipotoxicity
chronic hyperglycemia -> glucotoxicity
over secretion of insulin to compensate

Question 30

what distinguishes which B cells are unable to compensate for insulin resistance vs. which are able to sustain adaptation

Answer 30

robust vs susceptible B cells
factors include:
genetic and acquired defects
glucolipo detoxification
mitochondrial function
and other factors

Question 31

what is the incretin effect?

Answer 31

greater insulin/c-peptide response in oral vs. IV glucose delivery
as much as 50% of post prandial release of insulin depends on incretins

Question 32

modes of action of GLP-1

Answer 32

stimulates insulin secretion
suppressed glucagon secretion
slows gastric emptying
reduces food intake
increases B cell mass and maintains function
improves insulin sensitivity
enhances glucose disposal

Question 33

what are reasons GLP-1 levels are decreased in DM2 patients

Answer 33

reduced production
increased degradation (DPP4)

Question 34

discuss the incretin effect in normal vs DM2 patients

Answer 34

incretin effect reduced in DM2

DM2 patients make less incretins and are less sensitive to them

Question 35

what is one reason insulin injections don’t provide the same benefits as adequate endogenous insulin release?

Answer 35

portal vein carries insulin from pancreas to liver
portal vein experiences high insulin oscillations which stimulate the liver to clear 50-80% or insulin and store 30-50% of glucose
in peripheral vein injection of insulin, liver never sees the high insulin oscillations and therefore does not exhibit sufficient glucose storage
liver does not micromanage glucose as well due to this effect

Question 36

how do treatments for DM2 hold up over time?

Answer 36

all get worse over time as exhibited by HbA1c measures over 10 years

Question 37

why might HbA1c be an inadequate metric for outcome sin DM2?

Answer 37

fails to capture short term glycemic control and does not distinguish pre- and postprandial conditions

Question 38

what is a primary cause of DM2?

Answer 38

inactivity

increases risk in those w/ and w/o family history of diabetes

Question 39

what volume of activity is needed to offset DM2?

Answer 39

> 3500 steps per day confer protection

Question 40

how does interrupting prolonged sitting w brief walking and simple resistance affect DM2?

Answer 40

better glucose control
less insulin secretion
lower TGs

Question 41

why is C-peptide a better marker of insulin production than insulin

Answer 41

does not get degraded as quickly

Question 42

what factors negatively impact the response of DM2 to exercise?

Answer 42

duration of DM2
HbA1c levels
longer DM2 or higher glycemia means exercise is a less effective treatment