• Credits

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

• Q. What is the effect of Insulin on the endothelium?

  • It has Dual action
    • It increases the release of Nitrous oxide (NO) from the endothelium
    • It is release Endothelin-1 a vasoconstrictor from the endothelium

• Q. What is the effect of Insulin on Vascular smooth muscles?

  • Produces NO in vascular smooth muscles leading to dilatation

• Q. What are the effects of insulin on the heart?

  • Increases Glucose uptake by the heart
  • Increases Cardiac glycogen storage
  • Helps in cardiac contractility
  • Helps in cardiac tissue growth
  • Improves vascular perfusion by dilatation of coronaries

• Q. What is the impact of Insulin on kidney and circulating volume?

  • It increases sodium and water reabsorption from the kidney and increases circulating volume

• Q. What is the impact of insulin on the Sympathetic nervous system (SNS)?

  • Activates the SNS and leads to increase vasoconstriction

• Q. What is the net effect of insulin on blood pressure?

  • There are both vasodilatory and vasoconstrictive effects of insulin
  • The overall net effect is no change in blood pressure because of the insulin

• Q. Summarize the CV effects of Insulin?

  • 

• **Insulin resistance and cardiovascular effects **

• Q. What is the overall take on the link between Insulin resistance and cardiovascular disease ?

  • The link between Insulin resistance and Cardiovascular disease is an area of debate.
  • While the theoretical concept and some indirect clinical data (especially the IRIS trial) show a link between the two, many direct study show only circumstantial and weak link

• Q. Why is there increase CV risk in patients with insulin resistance?

  • Because insulin resistance is associated with Endothelial dysfunction

• Q. Why does endothelial dysfunction occur in Insulin resistance (IR)?

  • This is a very important concept
  • With Insulin resistance there is selective resistance to the PI3K pathway
  • However, flux through the MAPK pathway is preserved
  • Hence there is less NO production but ET1 production is preserved
  • This is the basis of cardiovascular dysfunction that occurs in diabetics

• Q. What is the role of FFA in cardiovascular damage due to IR?

  -
  - IR= Insulin resistance; FFA = Free Fatty acid; SNS = Sympathetic nervous system; ROS=Reactive oxygen species; CV = Cardiovascular

• Q. What is the impact of Glucose Toxicity (Glucotoxicity) on CV dysfunction?

  • 

• Q. What is the role of adipocytes?

  • 

• Q. What is the net effect of IR on blood pressure?

  • Because of
    • Increase ET1
    • Increase salt and water retention
    • Absence of NO
  • There is a net increase in blood pressure in IR

• Q. Summarize the effect of IR on the CV system?

  • Endothelial dysfunction → reduces NO and increase ET1 → net increase of BP
  • Lipotoxicity
  • Glucotoxicity
  • Production of inflammatory adipokines
  • Increase renal sodium resorption
  • Activation of the sympathetic nervous system

• **Therapeutic interventions **

• #Clinicalpearl

  • Insulin resistance and metabolic syndrome is very well known to have increased CV risk

• Q. Do lifestyle interventions improve the CV risk produced by IR?

  • Yes
  • Lifestyle measures increase adiponectin and improve CV dysfunction produced by IR

• Q. What is the effect of Thiazolidinones on CV function in IR?

  • TZD improve adiponectin levels and improve endothelial dysfunction
  • They should produce the cardioprotective effect

• Q. IS there any study which has shown this cardiovascular benefit of Pioglitazone?

  • Yes – The PROactive study ^[1]
    • The results of the study show that pioglitazone had only a modest, and not statistically significant, 10% reduction in the risk of the primary composite endpoint, which consisted of all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, and revascularization or amputation.
    • However, the “main secondary endpoint,” consisting only of certain of the primary outcome measures, namely all-cause mortality, myocardial infarction, and stroke, was significantly reduced by 16%.
  • Another study showing the particular outcome in question is the IRIS trial
    • "In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo" ^[2]

• Q. What is the effect of Metformin in this pathway ?

  • Metformin activates the AMPK pathway leading to increase flux through the PI3k pathway leading to increase NO production
  • Hence it will have a benefit on the CV system

• Q. What is the effect of ACEI/ ARB in this scenario?

  • Improves BP
  • Improves endothelial dysfunction
  • Increase adiponectin
  • Reduces CV risk
  • Improve glycemia

• Q. What about statins?

  • They reduce inflammatory cytokines and improve Endothelial function
  • But no effect on insulin resistance

• Q. What is the effect of beta-blockers in this?

  • Beta-blocker worsen insulin sensitivity
  • However alpha1 blocker improve Insulin sensitivity
  • Hence carvedilol which has alpha1 properties is a good beta-blocker for diabetics

• Q. Summarize the effects of various therapeutic interventions on Insulin Resistance and the Cardiovascular system?

  • Lifestyle measures – improve endothelial function
  • TZD – improve –PROactive trial and IRIS trial
  • Metformin – improve
  • ACEI/ ARB- improve
  • Statin- no effect on IR but improve endothelial function
  • Beta-blocker- worsen, carvedilol may improve

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