• Credits

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

• Q. Who was the first to give the concept of Glucose Toxicity (Glucotoxicity) ?

  • Rosetti and Defronzo

• Q. In current sense what is applicable to Glucose Toxicity (Glucotoxicity) ?

  • In this chapter it refers to excess glucose altering the mechanism of glucose itself
  • Basically it is high glucose producing Insulin resistance

• Q. What is the mass action of glucose ?

  • This concept if the key to understanding Glucose Toxicity (Glucotoxicity)
  • What is means is, that in presence of insulin, an increased level of glucose increases its own uptake and utilization
  • This is dependent for insulin dependent tissues and not for the tissues like brain
  • This is normal physiology in non-diabetic individuals
  • However, in diabetic individuals, the insulin production is reduced
  • Hence in such patients the glucose will increase and this hyperglycemia ideally would lead to increase glucose utilization overhwhealming the patient
  • This does not happen because of a protective mechanism which the body hass
  • In such scenario, the body increases the Insulin resistance leading to normalization of glucose utilization in insulin dependent tissues
  • So the insulin dependent tissues are spared of the effect of the hyperglycemia, but what about the non-insulin dependent tissues ?
    • Now this WILL be affected
    • The affect is however, restricted to tissues not protected by blood brain barrier - ie the brain again is spared
    • Which are these tissues ? The big three- kidney, retina and peripheral nerves !

• Q. What kind of Insulin resistance is seen in patients with Type 1 Diabetes ?

  • Insulin resistance is mainly seen at the skeletal muscles peripheral insulin resistance
  • It is believed most of the insulin resistance in this case is attributable to Glucose Toxicity (Glucotoxicity)

• Q. Does Chronic hyperglycemia itself cause Diabetes mellitus ?

  • Yes
  • This would be a consequence of Glucose Toxicity (Glucotoxicity)
  • Classical studies done in cats by Lukens and Dohan have shown that chronic hyperglycemia was responsible for causing permenent type 2 diabetes in these cats
  • Chronic hyperglyemia not only increases insulin resistance but also impairs beta-cell responsiveness to glucose
  • Studies have shown that hyperglycemia exposure to >68 hours leads to significant reduction of insulin secreation

  • Interestingly in most of the animal studies, use of phlorizin has been shown to restore the action- is there are role of SGLT2i in removing the Glucose Toxicity (Glucotoxicity) ?

• WHAT HAVE WE LEARNED SO FAR #Conceptual-Learning

  • Glucose toxicity is basically hyperglycemia reducing the body's ability to clear the hyperglycemia- hyperglycemia begetting hyperglycemia
  • Acute/Subacute hyperglycemia like in Type 1 Diabetes can cause peripheral insulin resistance
  • Chronic hyperglycemia - reduces beta-cell responsiveness to glucose-mediated insulin secretion

• Q. What are the potential mechanisms for Glucose Toxicity (Glucotoxicity) ?

  • 1. Extra glucose -→ converted to Lipid -→ Lipid flux produces Insulin resistance
  • 2. Increase Reactive oxygen species
  • 3. Increase flux through hexosamine linked glycation pathway

• Q. What is the importance of UDP-N-acetylglucosamine ?

  • This is a intermediate which is an important nutrient sensor
  • All the glucose and other nutrients are converted to UDP-N-Acetylgluosamine via the hexosamine pathway

• Q. What is the link between Oxidative stress and Beta-cells damage ?

  • Increased oxidative stress leads to Beta-cell dysfunction and damage
  • Remember oxidative stress also increases Insulin resistance

• Q. So in case of Glucose Toxicity (Glucotoxicity) , is the response to other nutrients preserved ?

  • This is the interesting part
  • In case of Glucose Toxicity (Glucotoxicity) , there is a loss of beta-cell response to glucose.
  • However, the beta-cell response to other nutrients which stimulate insulin release like Arginine is preserved and sometimes even exaggarated

• Q. What is the best example of Glucose Toxicity (Glucotoxicity) in Type 1 Diabetes ?

  • The "honeymoon period" in Type 1 Diabetes

• Q. How common is the honeymoon period ?

  • It is seen in almost 30% of patients with Type 1 Diabetes

• Q. What is an example of Glucose Toxicity (Glucotoxicity) in Type 2 Diabetes ?

  • The improvement in glycemic control and partial remission in Type 2 Diabetes because of Short term intensive insulin therapy is an example of Glucose Toxicity (Glucotoxicity) in type 2 diabetes

• #Clinicalpearl

  • Glucose Toxicity (Glucotoxicity) leads to insulin resistance in both type 1 as well as type 2 diabetes which can be reversed with good glycemic control

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