I. Physiology of Insulin Secretion

Question 1

Total weight of endocrine pancreas

Answer 1

1g (under 3% of the pancreas volume)

Question 2

Most abundant cell type in the pancreas

Answer 2

Beta cells (60% of islet cells)
- Represent higher proportion of all endocrine cells in smaller islets, which are in closer contact with blood vessels

Question 3

Transporter of glucose into beta cells

Answer 3

Isoform 2 of the glucose transporter (GLUT2)

Question 4

First rate-limiting step in glucose metabolism

Answer 4

Phosphorylation of glucose to glucose-6-phosphate by glucokinase

Question 5

Enzyme responsible for first rate-limiting step in glucose metabolism

Answer 5

Glucokinase (functions as a glucose sensor)

Question 6

Glucose metabolism raises ___ production

Answer 6

ATP

Question 7

Elevated ATP production after glucose metabolism leads to ___

Answer 7

PRIMARILY: Closure of ATP-sensitive potassium channels and membrane depolarization

Other functions: Also serves as a major permissive factor for movement of insulin granules and for priming of exocytosis

Question 8

Closure of ATP-sensitive potassium channels and membrane depolarization leads to ___

Answer 8

Calcium entry through voltage-dependent calcium channels and elevation of calcium

Question 9

Calcium entry through voltage-dependent calcium channels and elevation of calcium leads to ___

Answer 9

Exocytosis of insulin from readily releasable granules

Question 10

Effect of sympathetic stimulation on beta-cell function (through alpha2 receptor-mediated norepinephrine release)

Answer 10

Inhibits insulin secretion and potentiates glucagon secretion

Question 11

Effect of parasympathetic stimulation on beta-cell function (through M3 muscarinic-mediated acetylcholine release)

Answer 11

Enhances insulin AND glucagon release

Question 12

When is the full complement of beta-cell mass established?

Answer 12

Within the first 5 years of life

Question 13

Average lifetime of beta cells

Answer 13

25 years (at islet periphery, a specialized microenvironment or neogenic niche harbors a population of transcriptionally immature (virgin) beta cells, which constitute a lifelong reservoir of new beta cells)

Question 14

Estimated pancreatic insulin content

Answer 14

200 to 250 units (a 10-day supply for a healthy lean adult)

Question 15

Physical description of an insulin secretory granule

Answer 15

300-350 nm in diameter, with electron-dense core composed of tightly packed crystals of insulin hexamers stabilized by one calcium and two zinc ions

Question 16

Functional description of an insulin secretory granule

Answer 16

1) only a small fraction (much less than 1%) is secreted in response to acute in vitro glucose stimulation
2) granule half-life is less than 5 days (with intracellular degradation starting already within about 3 days)
3) younger granules are fewer but more mobile than older granules even if they come from deep in the cytoplasm and thereform form a readily releasable pool

Question 17

The estimated pancreatic insulin content is adequate for how many days supply in a health lean adult?

Answer 17

10 days

Question 18

How much (in percentage) of the granules is secreted in response to acute in vitro glucose stimulation?

Answer 18

<1%

Question 19

Half life of beta cell secretory granule

Answer 19

5 days (with intracellular degradation starting already within about 3 days)

Question 20

Method for assessing insulin secretion in vivo

Answer 20

Measurement of C-peptide

1) C-peptide is co-secreted with insulin in equimolar amounts as a consequence of proinsulin cleavage
2) C-peptide is NOT extracted by the liver
3) C-peptide clearance - half of which occurs through the kidney - is approximately constant in any given individual

Question 21

TRUE or FALSE: C-peptide is extracted by the liver

Answer 21

False

Question 22

Primary clearance of C-peptide

Answer 22

Renal

Question 23

What do you call the mathematical procedure in which insulin secretion is calculated?

Answer 23

Deconvolution (reconstructs the pancreatic insulin secretion rate in pmol/min as it occurs before hepatic insulin degradation)

Question 24

How much of C-peptide is degraded by the kidneys?

Answer 24

~85% (15% of renal C-peptide uptake is excreted intact into the urine)

Question 25

Measurements of the ratio of urinary ____ to creatinine have been shown to be reasonably well correlated with postprandial C-peptide levels (indicator of residual beta-cell function in patients with T1D)

Answer 25

C-peptide

Question 26

Measurements of the ratio of urinary C-peptide to creatinine have been shown to be reasonably well correlated with ___

Answer 26

Postprandial C-peptide levels (indicator of residual beta-cell function in patients with T1D)

Question 27

Insulin clearance occurs through 2 principal routes depending on the site of entry of the hormone into circulation:

Answer 27

1) peripheral (or exogenous) pMCRI 2) prehepatic (or endogenous) eMCRI

Question 28

How is peripheral (or exogenous) insulin clearance determined?

Answer 28

Ratio of exogenous insulin infusion rate to arterial plasma insulin concentration at steady state

Question 29

How is prehepatic (or endogenous) insulin clearance determined?

Answer 29

Ratio between endogenous insulin secretion - reconstructed from C-peptide deconvolution - and arterial plasma insulin concentration at steady state

Question 30

How to estimate fractional hepatic insulin extraction

Answer 30

Fractional difference of endogenous and exogenous insulin clearance

Question 31

What is the fraction of portal insulin that is removed by the liver in its first pass?

Answer 31

65% (ranging between 50% and 70%)

Question 32

What is the fraction of insulin that is removed by the liver overall (first pass plus recirculation)?

Answer 32

Approximately 80%

Question 33

How is insulin cleared once in the systemic circulation?

Answer 33

Recirculated and further cleared by liver (overall contribution 80%), and, to a lesser extent, by skeletal muscle and the kidneys (In the fed state, contribution of skeletal muscle is decreased and that of the kidney is increased, but together still contribute no more than 20% to overall insulin clearance)

Question 34

During FASTING, what is the relationship of fasting prehepatic insulin concentrations to peripheral insulin levels?

Answer 34

Linear fashion, with an average ratio of 4:1

Question 35

In the FED state, what is the relationship of fasting prehepatic insulin concentrations to peripheral insulin levels?

Answer 35

Endogenous clearance is lower than in the fasting state as a consequence of saturation of liver extraction --> Ratio of prehepatic to peripheral insulin is progressively lower as pancreatic insulin release increases

Question 36

Antidiabetic agent that is known to reduce insulin clearance

Answer 36

Sulphonylureas

Question 37

Association of insulin clearance with insulin sensitivity - positive or negative?

Answer 37

Positive (regardless of the temporal sequence of changes in these two functions)

Question 38

What is responsible for the tightest physiologic feedback on insulin secretion?

Answer 38

Plasma glucose concentration

Question 39

TRUE or FALSE: Insulin action is functionally relatively stable within any given individual

Answer 39

TRUE (Insulin sensitivity vary by 30-80% during 24 hours of free living; can at best double with physiologic or pharmacologic intervention)

Question 40

TRUE or FALSE: Insulin secretion can vary manyfold in the same person in a matter of minutes

Answer 40

TRUE

Question 41

Direct technique of determining the insulin clearance, sensitivity, etc

Answer 41

Euglycemic hyperinsulinemic clamp

Question 42

3 main modes of beta-cell response

Answer 42

1) first-phase or acute insulin secretion 2) glucose sensitivity 3) potentiation of insulin secretion

Question 43

Describe first-phase insulin release

Answer 43

Sharp and short-lived peak of insulin secretion elicited by a brisk rise in glucose levels Magnitude depends on the size of the glucose stimulus Can also be represented as a function of the glucose rate of change (also called rate sensitivity, anticipation, or derivative component) Contributes an estimated one-tenth (about 3 nmol/m2) of suprabasal secretion during a 2-hour OGTT

Question 44

What is "potentiation"?

Answer 44

It is when the dose-response relationship between glucose level and insulin secretion is enhanced, as when prior exposure to glucose leads to a greater insulin secretion on subsequent exposure. It may be generated by a glucose "memory", incretins, or factors such as glucagon, cholinergic stimuli, other nutrients such as fructose, or drugs including sulfonylureas.

Question 45

TRUE or FALSE: Maintenance of glucose homeostasis depends not only on the absolute amount of insulin release but also on the time dynamics of the secretory response.

Answer 45

TRUE

Question 46

TRUE or FALSE: In hyperglycemic patients, fasting insulin secretion is generally lower than in normoglycemic subjects at each level of obesity.

Answer 46

FALSE. It is generally HIGHER.

Question 47

Frequency of detectable pulses of insulin concentration in the portal vein blood

Answer 47

5- to 14-minute intervals (Pulsatile secretion is disrupted in hyperglycemic states)

Question 48

Proposed marker of beta-cell function

Answer 48

Ratio of proinsulin to insulin concentrations (or absolute proinsulin concentration adjusted for insulin) in a fasting plasma sample

Question 49

Insulin secretory response to intravenous glucose - Hyperglycemic clamp (square wave of hyperglycemia)

Answer 49

Typically biphasic, with an initial sharp insulin secretory burst lasting about 5 to 8 minutes (first-phase secretion), followed by a transient decrease and then a progressive slow increase, which continues as long as hyperglycemia is maintained (second-phase secretion)

Question 50

TRUE or FALSE: The amount of insulin secreted during the first phase (also referred to as acute insulin response) is NOT dependent on the magnitude of the glucose rise.

Answer 50

FALSE. It IS dependent. In a typical +126 mg/dL hyperglycemic clamp, it is approximately 4 nmol per square meter of body surface area (~1 unit in a 70-kg adult).

Question 51

TRUE or FALSE: Attenuated first-phase insulin secretion is a very sensitive marker of early beta-cell dysfunction.

Answer 51

TRUE

Question 52

TRUE or FALSE: Higher glycemic plateaus elicit larger secretory responses (of insulin).

Answer 52

TRUE

Question 53

TRUE or FALSE: As multiple glucose steps are applied in sequence, the secretory response progressively increases.

Answer 53

FALSE If multiple glucose steps are applied in sequence, the first-phase response is progressively attenuated while second-phase secretion increase in proportion to the height of the glycemic plateaus.

Question 54

Insulin secretory response to intravenous glucose - Intravenous glucose tolerance test

Answer 54

Also with biphasic insulin response. In contrast to the hyperglycemic state, glucose concentrations fall rapidly after the initial peak, and second-phase secretion is NOT sustained but TRANSIENT with a multiphasic pattern.

Question 55

TRUE or FALSE: Prolonged (2-4 days) exposure to mild hyperglycemia markedly decreases insulin secretion.

Answer 55

FALSE Prolonged (2-4 days) exposure to mild hyperglycemia markedly enhances insulin secretion, with a steepening of the dose-response curve.

Question 56

When glucose is ingested, what is typical number of hours it takes for plasma glucose level to peak and return to baseline?

Answer 56

Plasma glucose levels typically peak at 0.5 to 1.0 hour and return to baseline by 2 hours post ingestion.

Question 57

What do you call the phenomenon wherein, with consecutive nutrient loads, the plasma glucose and insulin secretory responses are attenuated during the second, as compared with the first, meal

Answer 57

Staub-Traugott effect

Question 58

What causes the Staub-Traugott effect?

Answer 58

This is due to persistent suppression of endogenous glucose production by the hyperglycemia and hyperinsulinemia induced by the first load and to enhanced potentiation of insulin release.

Question 59

TRUE or FALSE: The beta cell protects against hypoglycemia during a prolonged fast but retains the potential to efficiently increase insulin production on refeeding.

Answer 59

TRUE

Question 60

TRUE or FALSE: If glucose is ingested rather than infused, insulin secretion is higher at the same glucose levels.

Answer 60

TRUE (due to incretins - GIP and GLP1)

Question 61

What are the 4 features of in vivo incretin effect that are reasonably well established?

Answer 61

1) GLP1 and GIP are released in phase with insulin and glucose concentrations 2) When gastric emptying is accelerated (e.g., following gastric bypass surgery), both the glucose and insulin peaks are anticipated and GLP1 levels are much higher if still synchronous with insulin 3) Glucose-induced and incretin-induced potentiation of insulin secretion - as resolved by modeling of isoglycemic experiments - have different time courses and relation to glucose tolerance 4) Strength of potentiation depends on the stimulus and the quality of beta-cell function

Question 62

TRUE or FALSE: Acute insulin response (AIR) is directly proportional to insulin sensitivity.

Answer 62

FALSE AIR has a RECIPROCAL relationship with insulin sensitivity. This likely reflects adaptation of the beta cell to impaired insulin action, which sets in as a steep increment in secretion as insulin sensitivity declines.

Question 63

TRUE or FALSE: Insulin resistance raises the setpoint of beta-cell function.

Answer 63

TRUE Insulin resistance raises the setpoint of beta-cell function, whereby absolute measures of insulin secretion (fasting, AIR, and postglucose) are chronically upregulated. (but postprandial glucose excursions are less influenced)

Question 64

TRUE or FALSE: The beta-cell mass in obese individuals is expanded.

Answer 64

TRUE (probably due to insulin resistance which raises the setpoint of beta cell function, and, hence, insulin secretion; but many of whom have normal beta-cell glucose sensitivity and glucose tolerance)

Question 65

Effect of mutation in one of at least six different genes of MODY (autosomal dominant mode)

Answer 65

Hyperglycemia of variable severity in young, nonobese subjects (typically younger than 25 years) with a multigenerational family history of diabetes

Question 66

Mutation in MODY2

Answer 66

Heterozygous private mutation of the gene (GCK) encoding glucokinase resulting in partial enzyme deficiency and a loss of beta-cell glucose sensitivity

Question 67

Mutations in MODY1, MODY 2, MODY3, MODY4, MODY5, and MODY 6

Answer 67

MODY 1 - HNF4 alpha MODY 2 - glucokinase MODY 3 - HNF1alpha MODY4 - insulin promoter factor 1 MODY 5 - HNF1beta MODY 6 (or BETA2) - neurogenic differentiation 1 transcription factor Causes loss of beta-cell glucose sensitivity on a graded glucose infusion test and rapidly progressing hyperglycemia, as well as beta-cell dysfunction.

Question 68

TRUE or FALSE: Transcription factors responsible for beta cells are also expressed in other tissues.

Answer 68

TRUE Because these transcription factors are also expressed in other tissues (liver and kidney), the mutations produce a clinical phenotype in which islet dysfunction is associated with other abnormalities, particularly microvascular complications.

Question 69

Insulin action

Answer 69

Plasma insulin lowers plasma glucose by promoting tissue glucose uptake (primary feedback), and restrains lipolysis and protein breakdown, thereby lowering circulating FFAs and amino acids (secondary feedback loop).

Question 70

How does insulin resistance affect insulin secretion.

Answer 70

It increases baseline secretory activity and increments the stimulatory signals (i.e., glucose, FFAs, and amino acids)

Question 71

TRUE or FALSE: Absolute insulin release is directly proportional to glucose sensitivity of the beta cell.

Answer 71

FALSE There is an OPPOSITE behavior of absolute insulin release and glucose sensitivity of the beta cell across stages of glucose tolerance. In impaired fasting glycemia, for example, insulin output is increased by 15%, insulin sensitivity (on an insulin clamp) is only slightly impaired, but glucose sensitivity is 30% lower.

Question 72

TRUE or FALSE: Beta-cell glucose sensitivity is a powerful negative predictor of incident T2D in nondiabetic cohorts above and beyond the impact of conventional risk factors (sex, age, BMI, family history, etc).

Answer 72

TRUE