• Credits

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

• Sources:

  • International Textbook of Diabetes Mellitus, 2 Volume Set, 4th Edition

• Q. What is the definition of insulin resistance?

  • Subnormal biological response to Insulin

• Q. Classify insulin resistance

  • Source of Insulin
    • Resistance to endogenous Insulin
      • Central or Hepatic insulin resistance
      • Peripheral insulin resistance
    • Resistance of exogenous Insulin
      • Psychological insulin resistance
      • Subcutenous insulin resistance syndrome

• Q. Do all patients with endogenous insulin resistance go on to develop type 2 diabetes?

  • Yes
  • Unless there is some lifestyle intervention which is made, they will all eventually progress to develop type 2 diabetes

• Q. What are the roles of Insulin beyond its impact on glucose?

  • 1. Suppression of free fatty acid from adipose tissue
  • 2. Limiting hepatic triglyceride synthesis
  • 3. Maintaining endothelial homeostasis
  • 4. Regulating thrombotic cascade
  • 5. Potential role of regulating inflammatory cascade

• Q. Insulin acts on which receptors?

  • Insulin receptors- IR-A and IR-B
  • IGR-1 Receptor
  • Hybrid receptors

• Q. Insulin resistance is a receptor or post-receptor defect?

  • It is a post-receptor defect

• Q. Give the pathway from Insulin resistance to the development of Type 2 diabetes mellitus?

  • 
  • 
  • 
  • 

• Q. What are the causes of Insulin resistance?

  • Primary causes- inherited syndromes

    • Leprechauns
    • Robson Mandall syndrome
    • Type A insulin resistance syndrome
    • Lipodystrophy

  • Secondary causes (Acquired)

    • Obesity and metabolic syndrome
    • Type 2 diabetes
    • PCOS
    • Hypertension
    • Type B insulin resistance syndrome
    • Other Endocrine disorders
      • Cushing's syndrome
      • Acromegaly
      • Glucagonoma
    • Drugs
      • Growth hormone
      • Glucocorticoids
    • Stress
    • Infection
    • Anorexia nervosa / malnutrition
    • Pregnancy
    • Inactivity
    • Chronic renal failure

• ** Quantification of insulin resistance**

• Q. Summarize the various methods for measurement of Insulin resistance?

  • 
  • Indirect methods
    • 1.IV glucose tolerance test
    • 2.Insulin indices- HOMA-IR, McAuley index, QUICKI
    • 3.Clinical – Metabolic syndrome criteria
    • 4.Others- Fasting TG, Fasting Insulin, TG/HDL ratio

• Q. What is the gold standard for the Quantification of insulin resistance?

  • Euglycemic hyperinsulinemic clamp

• Q. What are the different types of clamp techniques used?

  • Euglycemic clamp (also called Hyperinsulinemic clamp)
    • done to assess Insulin resistance
    • Here, the glucose level is kept steady
  • Hyperglycemic clamp
    • Done to assess beta-cell function
    • "how much insulin was released in response to hyperglycemia."
  • Hypoglycemia clamp
    • used to study counter-regulatory hormones

• Q. Describe the technique of Euglycemic clamp?

  • First insulin infusion is given to block the hepatic gluconeogenesis
  • Then glucose infusion is given and adjusted to maintain a steady-state of plasma glucose
  • When hepatic glucose is suppressed, the amount of glucose given from outside to maintain Euglycemia is the amount of glucose that goes to the muscles
  • Hence if more glucose is needed, then it means more glucose is going to the muscles, which means there is less insulin resistance
  • If less glucose needed is needed, it means less glucose is going to muscles, which means more Insulin resistance
  • 

• Q. What is the interpretation of GIR values in Euglycemic clamp?

  • Glucose infusion rate
    • More than 7.5 mg/min – normal
    • 4.0- 7.5 mg/min – variable
    • Less than 4.0 mg/min – insulin resistance

• Q. Describe the Hyperglycemic clamp?

  • Here, the glucose level is held at a higher rate of 125 mg/dl
  • Glucose infusion is given to maintain it at this level
  • This level of blood glucose would lead to endogenous insulin secretion
  • Now, if endogenous insulin secretion is higher – a higher amount of Glucose infusion rate will be needed to maintain this level of glycemia and vice versa

• Q. Describe the Insulin suppression test (also called the Insulin sensitivity test)?

  • Octreotide given to suppress endogenous insulin production
  • Now, Insulin infusion and Glucose infusion are given and the dose adjusted to achieve steady-state plasma glucose concentration (SSPG)
  • Once SSPG is achieved, the higher the SSPG higher the insulin resistance

• Q. What is the insulin tolerance test for Insulin resistance?

  • This is an outdated method
  • After an overnight fast, in an average individual, an intravenous bolus injection of a dose of regular Insulin of 0.1 U/kg of body weight will reduce the blood glucose level to a value of 50% or less of the initial value or may provoke frank hypoglycemia.
  • A patient with peripheral insulin resistance will require a higher dose of injected Insulin (≤0.2 U/kg) to produce this reduction in the fasting glucose level.
  • If the patient requires an insulin bolus of 0.3 U/kg or more to induce hypoglycemia, the diagnosis of extreme insulin resistance is certain.
  • Given the importance of the diagnosis, a serum insulin level should be obtained 10 minutes after insulin injection to confirm that Insulin entered the vascular compartment.

• Indirect methods

• Q. What are indices used in clinical practice for non-diabetic individuals?

  • Triglyceride - >130 mg/dl
  • TG / HDL ratio >3.0
  • Fasting insulin >15.7 uU/ml
  • Insulin indices
    • HOMA-IR
    • QUICKI
    • McAuley index
  • Using the diagnostic criteria for Metabolic syndrome

• Q. Is there any importance of fasting and postprandial insulin levels ? (in euglycemic patients)

  • This is now outdated
  • Some textbooks say the following is high
    • Fasting insulin >30 uU/ml
    • Postprandial >200 mU/ml

• Q. What dose of Insulin suggests insulin resistance?

  • A normal person secretes 25-40 units of Insulin a day which is 0.3-0.5 units/kg
  • Any person requiring >1.5-2 units/kg/day of Insulin (>60-100 units /day) should be evaluated for insulin resistance

• Q. How is HOMA IR calculated?

  • Fasting insulin (in mIU/ml) x Glucose (mmol/) / 22.5
  • Fasting insulin (in mIU/ml) x glucose (mg/dl) / 405

• Q. What is the cutoff for HOMA IR?

  • Prepuberty (SMR I) = >2.5
  • Pubertal children and adults (SMR II or higher) > 4.0

• Q. What is fullform of QUICKI ?

  • Quantitative Insulin sensitivity check index

• Q. What is the formula for QUICKI?

  • 1 / log(insulin in mIU/l) + log (glucose mg/dl)

• Q. What is the cutoff for QUICKI?

  • QUICKI index ranges from 0.45 in healthy individuals to 0.30 in people with diabetes;
  • Lower values indicate greater insulin resistance
  • Values below 0.339 in adults indicate insulin resistance

• Q. How is the McAuley index calculated, and what are its cut-offs?

  • It is based on TG and Insulin McAuley index =
  • 
  • (e = exponential, ln = log , TAG = triglyceride)
  • Value > 9.8 is considered to be high

• Q. Summarize the normal and abnormal values of various indices?

  • 

Linked notes:
- 2.0 Mechanisms for Insulin Resistance

#Updates

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

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