• Credits

  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

• The Pancreatic Islet - structure, and function

• Q. Give some important facts about Islets?

  • Discovered by Langerhans
  • 100 microns in size
  • The human pancreas has 1 million islets

• **Islet anatomy **

• Q. How many islets in the human body?

  • 1 million
  • Pancreatic beta cells lie within islets of Langerhans.

• Q. Describe the structure of the islet of Langerhans?

  • They are 100 microns in size.
  • Beta-cell in the center surrounded by alpha cells, PP cell, and delta cells
  • Have a rich blood supply
  • Innervated by sympathetic and parasympathetic nerves

• Q. Which hormones are secreted by various cells within the islet of Langerhans?

  • Alpha cell – glucagon
  • Beta-cell- insulin- 70% - lie in the centre
  • Delta cell –stomatostain
  • PP cell- pancreatic polypeptide

• Q. Islets have a poor blood supply, True or false?

  • False
  • Islets have a rich blood supply
  • Receives 15% of blood supply of the pancreas
  • Each islet is supplied by an arteriole

• Q. Which nerves supply the islet?

  • Sympathetic and parasympathetic nerves supply the islets
  • Hence islets have a rich nerve supply also

• Intra-islet interactions

• Q. What is the mechanism by which the cells in the islets communicate with each other?

  • Gap junctions
  • Cell to cell communication by E-cadherin
  • Autocrine / paracrine communication

• Q. Give some examples of intra-islet communications?

  • Insulin regulates glucagon secretion- glucose glucagon axis
  • Glucagon regulates insulin secretion
  • Somatostatin regulates both insulin and glucagon

• **Glucose-glucagon axis **

• Q. Show some examples of intra-islet beta-cell – alpha cell communication in normal people and patients with diabetes?

  • Normal
    • Increase glucose à beta-cell → Increase insulin → alpha cell → reduced glucagon
  • In a patient with diabetes
    • Increase glucose → reduced beta-cell action→ little insulin → no action on alpha cell→ glucagon is high

• Q. What is the glucose-glucagon axis?

  • Impaired Glucose- glucagon axis is also responsible for increased risk of hypoglycemia in patients with type 1 diabetes.
  • In people with type 1 diabetes, the glucose- glucagon axis is lost
  • The increasing of glucose should lower glucagon, which does not happen – hence the risk of ketosis
  • And the falling of glucose should reduce glucagon, which does not occur and therefore increased the risk of hypoglycemia
  • Aberrant α-cell responses exhibit both fasting and post-prandial states: hyperglucagonemia contributes to fasting hyperglycemia caused by inappropriate hepatic glucose production and to post-prandial hyperglycemia owing to blunted α-cell suppression

• Q. Which drugs correct alpha cell dysfunction?

  • GLP1
  • DPPIV
  • SGLT1 + SGLT2 inhibitor- sotagliflozin

• Introduction to beta-cell physiology

  • Q. Is insulin seen only in mammals?

    • No
    • Insulin is an ancient hormone
    • Even the most primitive forms of vertebrates have insulin
    • Insulin is an evolutionary necessity for any animal which has a discontinuous supply of nutrition

  • Q. What happens to nutrition in a fasting state?

    • In a fasting state, the body tries to preferentially use lipid as a fuel in preference to glucose because glucose is limited
    • This is facilitated by the increased first-pass metabolism of insulin
    • Low insulin levels have a permissive effect for [lipolysis]

  • Q. What happens in a fed state?

    • In a fed state insulin is released in response to glucose. What this does is:
      • Pushes glucose to glucose-sensitive tissue reducing the blood glucose levels
      • Increases glycogen storage
      • Inhibits lipolysis

  • Q. Is insulin under the control of CNS?

    • Very limited insulin is under control of the CNS
    • Most of the control is locally from the gut
    • Insulin, however, is under the control of the gut hormones
    • This pushes the concept of the primitive nature of insulin

• Methods for assessment of Insulin secretion

  • Q. Where is insulin predominantly secreted?

    • Insulin is predominantly released into the portal circulation

  • Q. What is C-peptide ?

    • The pancreatic proinsulin is broken down into insulin and C-peptide
    • the C-peptide is released in equimolar concentration as insulin

  • Q. Why is C-peptide a better measure of insulin secretion?

    • This is because of the following reasons:
      • a) The amount of C-peptide that is released is equal to the amount of insulin release
      • b) C-peptide is NOT extracted by the liver, whereas the majority of endogenous insulin is extracted by the liver (remember insulin is released into the portal circulation)
      • c) C-peptide clearance occurs via the kidney - but this is constant. That means at any given point in time, the amount cleared by the kidney is constant to the amount which is being produced
      • d) Exogenous insulin does not impact the measured of c-peptide; hence c-peptide is a measure of endogenous insulin production

  • Q. Can you calculate the exact amount of insulin being secreted by measuring the C-peptide levels?

    • Yes.
    • Using a mathematical process can Deconvolution you can measure an approximate amount of insulin which is secreted by measuring the C-peptide

  • Q. What is Deconvolution ?

    • This is an algorithm based process in which the recorded data can be reversed engineered to find the original signal
    • This is based on the theory that the recorded data or signal is the original signal which is then filtered
    • So basically, by measuring the C-peptide, you can trace it back to its root and find the amount of insulin that is secreted

  • Q. How do you convert insulin secreation from microU/ml to pmol/l ?

    • 1 microU/ml = 6 pmol/lit

• ** Beta-cells response to intravenous glucose**

  • ** Hyperglycemic clamp **

    • Q. What is the Hyperglycemic clamp ?

      • This is a study done for assessing the first phase and second phase insulin response
      • Here, the person is given an acute burst of glucose
      • Initially, there is a sharp increase in glucose secretion. This is the First phase insulin secreation
      • Then there is a small dip in insulin release
      • This is followed by a slow and sustained release of insulin again- which is the second phase of insulin secretion

    • Q. What information do you get from the Hyperglycemic clamp ?

      • 1. We understand that the release of insulin from the beta-cell is dose-responsive depending on the glucose level
      • 2. Using Deconvolution we can measure the insulin secretion

    • Q. What does the slope of the insulin secretion in a hyperglycemic clamp suggest ?

      • The slope of the curve represents the beta-cell sensitivity to the glucose

    • Q. How much is insulin secretion is present and how much does it increase on glucose infusion in a non-diabetic individual ?

      • The baseline insulin secretion is 5 mmol/lit
      • This increases to 10 mmol/lit on response to glucose

    • Q. How will you interpret the data of First phase insulin secreation from the Hyperglycemic clamp ?

      • 1. The first phase insulin secretion is more or less constant and less dose-dependent
        • This is perhaps because this represents the preformed insulin which is released in anticipation
      • 2. Blunting of the first phase insulin secretion is an early marker of developing diabetes mellitus

    • ** Intravenous glucose tolerance test IVGTT

      • Q. What is IVGTT ?

        • This is another method for assessment of First phase insulin secreation
        • Here the glucose is infused IV and the insulin and c-peptide are measured at regular intervals
        • Here the First phase insulin secreation is similar to Hyperglycemic clamp but the subsequent response (second phase) is different because of the different methodology

      • Q. How is the Intravenous glucose tolerance test IVGTT ?

        • Here short bursts of glucose are given at regular interval instead of a glucose infusion as done in Hyperglycemic clamp

      • Q. What is acute insulin response ?

        • This is an index derived from Intravenous glucose tolerance test IVGTT for assessment of the First phase insulin secreation
        • This is the mean increment of insulin secretion over baseline in the first 8-10 minutes

      • Q. At an intracellular level, what is the difference in first phase and second phase response ?

        • The First phase insulin secreation is release of preformed insulin granules and dependent on exocytosis. Exocytosis is in turn dependent upon the intracellular calcium. Hence this phase of insulin secretion is dependent on the intracellular calcium
        • The second phase insulin secretion however is NOT dependent on intracellular calcium

      • Research question

        • Does hypoparathyroidism impact the First phase insulin secreation since calcium is required for this process ?

• Beta-cell response to oral glucose - The incretin Effect

  • Q. In terms of glucose responses what is incretin effect ?

    • The insulin response to oral glucose is much more pronounced compared to the insulin response to intravenous glucose. This is called the incretin effect

  • Q. Which are the incretin in hormones ?

    • GLP-1 - Released by the L cells of the pancreas
    • GIP - released by the K-Cells of the pancreas

  • Q. What is potentiation phenomenon ?

    • Potentiation phenomenon states that in an OGTT the glucose levels come back to normal in a short while because of the insulin. However, at the end of the period when the glucose comes back close to baseline, the insulin secretion was 70% higher compared to the baseline basal secretion.
    • For example
      • Basically if your glucose value at baseline is 90mg/dl
      • Your insulin secretion at that time is x
      • Now I do an OGTT
      • Your glucose levels peak and comes down to baseline
      • At this point of time the insulin secretion is x + 70x- i.e. higher than X
    • This is potentiation phenomenon
    • This is partly explained by incretin effect

  • Q. What is Staub-Traugott Phenomenon ?

    • From Wikipedia
      • Abraira and Lawrence describe the original discovery as being that "when glucose loads are given in succession, orally or intravenously, significant and progressive improvement in glucose tolerance will occur in normal and nonketotic diabetic subjects. This facilitated disposal of a glucose load is known as the Staub-Traugott phenomenon."
    • potentiation phenomenon is a form of this effect
    • Starvation, hypopituitarism and Diabetes leads to loss of this effect
    • Basically
      • If you do OGTT once- by potential phenomenon the higher amount of insulin remains at the end of the cycle
      • Now if you do it again, the remaining extra insulin helps clear the glucose much faster

  • Q. Is there a difference in insulin secreation in response to normal meal in during a 24 hour period ?

    • Yes
    • Insulin secretion in response to morning meals is higher compared to that during the rest of the day

• Beta-cell response to non insulin secretagogues

  • Q. Do we have an insulin response to proteins ?

    • Yes we do
    • Proteins cause an insulin secretion over 2-3 fold over baseline
    • The elevation remains for about 90-240 minutes
    • The elevation is mainly due to individual amino acids

  • Q. Which amino acids cause more insulin release and which are neutral ?

    • Insulinophilic amino acids- those which cause more insulin release
      • Phenylalanine
      • Glycine
    • Neutral
      • Arginine
      • Histidine
      • Tyrosine

  • Q. Which amino acid has a negative effect on insulin release ?

    • Homocysteine
    • This has a dose-dependent negative effect on insulin release

  • Q. Is the release of insulin in response to amino acids dependent on insulin resistance ?

    • Interestingly, No
    • The amino acid-derived insulin release is independent of Insulin resistance

  • Q. Q. Does NEFA (Non-esterified fatty acid) produce insulin release ?

    • Yes
    • Monounsaturated NEFA produces more insulin release than PUFA or Saturated NEFA
    • However, the effect may be lost in patients with type 2 diabetes

• Slow beta-cell response and adaptation mechanisms

  • Q. What are modes of insulin release in terms of speed of response ?

    • Whatever we have discussed so far are rapid responses of Beta-cells to glucose
    • We also have slower beta-cell responses
    • The second phase insulin secretion during a Hyperglycemic clamp is an example of the slow response

  • Q. Does the potentiation phenomenon apply here as well ?

    • Yes
    • The insulin release in response to subsequent bout of hyperglycemia is more than the first bout of hyperglycemia
    • This is as explained earlier the potentiation phenomenon

  • Q. Which amino acid produces a response similar to that seen with potentiation phenomenon ?

    • Arginine
    • This amino acid produces a robust insulin response above and beyond that see with glucose alone

  • Q. What is the disposition index ?

    • Disposition index is the product of insulin sensitivity multiplied by the insulin secretion
    • In the normal non-diabetic individual, this level remains constant

  • Q. What is the importance of disposition index ?

    • In normal individuals the insulin release is proportionate to the glucose levels and dose-dependent
    • However, in insulin-resistant individuals, the beta-cell produce more insulin in response to the glucose because the patient is insulin resistant
    • Hence in such cases, glucose levels alone do not determine the insulin release
    • This is where the disposition index becomes useful
    • The reduced insulin sensitivity leads to increased insulin secretion, maintaining a normal disposition index in a normoglycemic individual. If the value declines, that means the insulin secretion cannot match the insulin resistance
    • This is a better measure of the insulin release in proportion to the glucose and also a good predictor of future diabetes risk

  • Q. Insulin resistance impacts fasting blood glucose more or post-meal glucose more ?

    • It impacts fasting blood glucose more
    • Remember the rule of thumb

      • Insulin resistance does NOT impact beta-cell sensitivity

    • So basically increased insulin resistance enhances the release of basal insulin secretion and First phase insulin secreation , it does not impact beta-cell sensitivity hence it does not have an impact on post-prandial insulin release (the second phase secretion)

• Beta-cell response to other hormones and nervous system

  • Q. What is the impact of somatostatin on glucagon and insulin release ?

    • Somatostatin inhibits both insulin and glucagon release

  • Q. What is the impact of Leptin on insulin secretion ?

    • Leptin inhibits insulin secretion

  • Q. What is the impact of Ghrelin on this pathway ?

    • Ghrelin inhibits GLP-1 insulinotropic action

  • Q. Who was the first to suggest that the Nervous system may have a role in the modulation of insulin secretion ?

    • Claude Bernard

  • Q. Broadly, what is the impact of autonomic nervous system on the release of insulin?

    • sympathetic system - inhibits insulin release
      • Specifically alpha-2 adrenergic receptor blocks the release of insulin
      • Beta-2 adrenergic receptor may enhance insulin release
    • parasympathetic system - enhances insulin release
      • Acetlycholine enhances intracellular calcium release- leading to more insulin release.

  • Q. What is Cephalic phase insulin release ?

    • Presence of a visual or olfactory stimulus can elicit insulin release even before the food enters the system
    • This is Cephalic phase insulin release and this is mediated by the innervation of pancreatic beta-cells by the nervous system

• Pulsatile secretion of insulin

  • Q. What is the nature of pulse secretion of insulin?

    • Pancreatic beta-cells act like Pacemakers
    • They release insulin in a pulsatile manner over every 4-6 minutes
    • There is also a slower ultradian periodicity of about 140 minutes
    • Both GLP-1 and Sulphonylurea can enhance the pulsatility

  • Q. What is the advantage of this pulsatile release ?

    • It is believed that this pulsatility has some autocrine role
    • Also it is shown that insulin required to maintain euglycemia is lower in those people in whom insulin is given in a pulsatile manner compared to continuous insulin infusion

• Beta-cells mass and function

  • Q. How can you reliably detect the amount of beta-cell mass ?

    • This can be reliably assessed only on autopsy

  • Q. What is the approximate beta-cell mass in a normal human ?

    • About 0.9 gram

  • Q. What is the impact of obesity on beta-cell mass ?

    • Obesity increases the beta-cell mass by 0.2 gram for every 10 points increase of BMI

  • Q. What is the impact of aging on beta-cell mass ?

    • The beta-cell mass increase up to 20 years of age
    • After this is it relatively stable in a non-obese, non-diabetic individual

  • Q. Is there a variation in beta-cell mass in humans?

    • Yes
    • Genetics may influence this
    • There is a wide variation in the mass ranging from 500-1500 million cells

  • Q. What is the impact on the overall asset quality of the beta-cell mass on humans?

    • The mass serves as a functional reserve for individual
    • It has almost two times the reserve capacity
    • This means up to 50% reduction in beta-cells can maintain euglycemia status
    • This has been seen in the pancreatectomy sample- you need to remove more than 50% of the pancreas to create hyperglycemia in a previously non-diabetic individual

    • In corollary in a patient diagnosed to have diabetes mellitus - at least 50% of beta-cells have already been lost by the time the patient develops hyperglycemia.

#Updates

• Source: Talk on "Assessment of Insulin Secretion and Sensitivity"
• Date: Monday, 10 May 2021

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