I. Physiology of Insulin Secretion Flashcards
Total weight of endocrine pancreas
1g (under 3% of the pancreas volume)
Most abundant cell type in the pancreas
Beta cells (60% of islet cells)
- Represent higher proportion of all endocrine cells in smaller islets, which are in closer contact with blood vessels
Transporter of glucose into beta cells
Isoform 2 of the glucose transporter (GLUT2)
First rate-limiting step in glucose metabolism
Phosphorylation of glucose to glucose-6-phosphate by glucokinase
Enzyme responsible for first rate-limiting step in glucose metabolism
Glucokinase (functions as a glucose sensor)
Glucose metabolism raises ___ production
ATP
Elevated ATP production after glucose metabolism leads to ___
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
Closure of ATP-sensitive potassium channels and membrane depolarization leads to ___
Calcium entry through voltage-dependent calcium channels and elevation of calcium
Calcium entry through voltage-dependent calcium channels and elevation of calcium leads to ___
Exocytosis of insulin from readily releasable granules
Effect of sympathetic stimulation on beta-cell function (through alpha2 receptor-mediated norepinephrine release)
Inhibits insulin secretion and potentiates glucagon secretion
Effect of parasympathetic stimulation on beta-cell function (through M3 muscarinic-mediated acetylcholine release)
Enhances insulin AND glucagon release
When is the full complement of beta-cell mass established?
Within the first 5 years of life
Average lifetime of beta cells
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)
Estimated pancreatic insulin content
200 to 250 units (a 10-day supply for a healthy lean adult)
Physical description of an insulin secretory granule
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
Functional description of an insulin secretory granule
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
The estimated pancreatic insulin content is adequate for how many days supply in a health lean adult?
10 days
How much (in percentage) of the granules is secreted in response to acute in vitro glucose stimulation?
<1%
Half life of beta cell secretory granule
5 days (with intracellular degradation starting already within about 3 days)
Method for assessing insulin secretion in vivo
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
TRUE or FALSE: C-peptide is extracted by the liver
False
Primary clearance of C-peptide
Renal
What do you call the mathematical procedure in which insulin secretion is calculated?
Deconvolution (reconstructs the pancreatic insulin secretion rate in pmol/min as it occurs before hepatic insulin degradation)
How much of C-peptide is degraded by the kidneys?
~85% (15% of renal C-peptide uptake is excreted intact into the urine)
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)
C-peptide
Measurements of the ratio of urinary C-peptide 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)
Insulin clearance occurs through 2 principal routes depending on the site of entry of the hormone into circulation:
1) peripheral (or exogenous) pMCRI
2) prehepatic (or endogenous) eMCRI
How is peripheral (or exogenous) insulin clearance determined?
Ratio of exogenous insulin infusion rate to arterial plasma insulin concentration at steady state
How is prehepatic (or endogenous) insulin clearance determined?
Ratio between endogenous insulin secretion - reconstructed from C-peptide deconvolution - and arterial plasma insulin concentration at steady state
How to estimate fractional hepatic insulin extraction
Fractional difference of endogenous and exogenous insulin clearance
What is the fraction of portal insulin that is removed by the liver in its first pass?
65% (ranging between 50% and 70%)
What is the fraction of insulin that is removed by the liver overall (first pass plus recirculation)?
Approximately 80%
How is insulin cleared once in the systemic circulation?
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)
During FASTING, what is the relationship of fasting prehepatic insulin concentrations to peripheral insulin levels?
Linear fashion, with an average ratio of 4:1
In the FED state, what is the relationship of fasting prehepatic insulin concentrations to peripheral insulin levels?
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
Antidiabetic agent that is known to reduce insulin clearance
Sulphonylureas
Association of insulin clearance with insulin sensitivity - positive or negative?
Positive (regardless of the temporal sequence of changes in these two functions)
What is responsible for the tightest physiologic feedback on insulin secretion?
Plasma glucose concentration
TRUE or FALSE: Insulin action is functionally relatively stable within any given individual
TRUE (Insulin sensitivity vary by 30-80% during 24 hours of free living; can at best double with physiologic or pharmacologic intervention)
TRUE or FALSE: Insulin secretion can vary manyfold in the same person in a matter of minutes
TRUE
Direct technique of determining the insulin clearance, sensitivity, etc
Euglycemic hyperinsulinemic clamp
3 main modes of beta-cell response
1) first-phase or acute insulin secretion
2) glucose sensitivity
3) potentiation of insulin secretion
Describe first-phase insulin release
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
What is “potentiation”?
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.
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.
TRUE
TRUE or FALSE: In hyperglycemic patients, fasting insulin secretion is generally lower than in normoglycemic subjects at each level of obesity.
FALSE. It is generally HIGHER.
Frequency of detectable pulses of insulin concentration in the portal vein blood
5- to 14-minute intervals (Pulsatile secretion is disrupted in hyperglycemic states)
Proposed marker of beta-cell function
Ratio of proinsulin to insulin concentrations (or absolute proinsulin concentration adjusted for insulin) in a fasting plasma sample
Insulin secretory response to intravenous glucose - Hyperglycemic clamp (square wave of hyperglycemia)
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)
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.
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).
TRUE or FALSE: Attenuated first-phase insulin secretion is a very sensitive marker of early beta-cell dysfunction.
TRUE
TRUE or FALSE: Higher glycemic plateaus elicit larger secretory responses (of insulin).
TRUE
TRUE or FALSE: As multiple glucose steps are applied in sequence, the secretory response progressively increases.
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.
Insulin secretory response to intravenous glucose - Intravenous glucose tolerance test
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.
TRUE or FALSE: Prolonged (2-4 days) exposure to mild hyperglycemia markedly decreases insulin secretion.
FALSE
Prolonged (2-4 days) exposure to mild hyperglycemia markedly enhances insulin secretion, with a steepening of the dose-response curve.
When glucose is ingested, what is typical number of hours it takes for plasma glucose level to peak and return to baseline?
Plasma glucose levels typically peak at 0.5 to 1.0 hour and return to baseline by 2 hours post ingestion.
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
Staub-Traugott effect
What causes the Staub-Traugott effect?
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.
TRUE or FALSE: The beta cell protects against hypoglycemia during a prolonged fast but retains the potential to efficiently increase insulin production on refeeding.
TRUE
TRUE or FALSE: If glucose is ingested rather than infused, insulin secretion is higher at the same glucose levels.
TRUE (due to incretins - GIP and GLP1)
What are the 4 features of in vivo incretin effect that are reasonably well established?
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
TRUE or FALSE: Acute insulin response (AIR) is directly proportional to insulin sensitivity.
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.
TRUE or FALSE: Insulin resistance raises the setpoint of beta-cell function.
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)
TRUE or FALSE: The beta-cell mass in obese individuals is expanded.
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)
Effect of mutation in one of at least six different genes of MODY (autosomal dominant mode)
Hyperglycemia of variable severity in young, nonobese subjects (typically younger than 25 years) with a multigenerational family history of diabetes
Mutation in MODY2
Heterozygous private mutation of the gene (GCK) encoding glucokinase resulting in partial enzyme deficiency and a loss of beta-cell glucose sensitivity
Mutations in MODY1, MODY 2, MODY3, MODY4, MODY5, and MODY 6
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.
TRUE or FALSE: Transcription factors responsible for beta cells are also expressed in other tissues.
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.
Insulin action
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).
How does insulin resistance affect insulin secretion.
It increases baseline secretory activity and increments the stimulatory signals (i.e., glucose, FFAs, and amino acids)
TRUE or FALSE: Absolute insulin release is directly proportional to glucose sensitivity of the beta cell.
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.
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).
TRUE
