• Credits

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

• Linked notes

  • Insulin resistance: Introduction, Definition and Quantification

• Q. Describe the Insulin siganlling pathway ?

  • Please see this video that describes the insulin signal transduction beautifully

graph TD
					A[Insulin] -->|Binds| B[Alpha Subunit IR]
					B --> |Transmit signal intracellularly|C[Activate Beta subunit of IR]
					C -->|Tyrosine kinase phosphorylates|D[Activate IRS1]
					D -->|Phosphorylates| E[Activate PI-3K]
					D -->|Phosphorylates| F[Activate MAP kinase]
					E --> G(Protein Synthesis)
					E --> H(Lipid synthesis)
					E --> |Via AKT| I(Glucose metabolism)
					I --> J(GLUT4 moves to Cell surface)
					I --> K(Glycogen formation)
					J --> L(Uptake of Glucose into the cell)
					F --> M(Cell growth)
					F --> N(Gene expression)
					M --> O(Implicated in cancer)

• Q. Describe the components that impact insulin resistance ?

  • Nutrient excess
  • Lack of exercise
  • Inflammation
  • Excess free fatty acid
  • Intramyocellular lipids
  • Mitochondrial dysfunction
  • Glucocorticoids
  • Sleep
  • Human placental lactogen

• Q. How does mTOR lead to insulin resistance ?

  graph LR
  	A[Excess nutrients activate mTOR] --> B[S6K] --> C[phosphorylation of IRS1] --> D[Insulin resistance]

• Q. What is the role of AMPK in this ?

  graph LR
  A[Exercise and metformin] --> B[increase AMPK inhibition of mTOR] --> C[reduces insulin resistance]

• Q. What is unfolded protein response ?

  graph LR
   A[Excess nutrients] --> B[ER Stress] --> C[excess unfolded protein] --> D[Janus kinase activiated] --> E[IRS1 phosphorylation] --> F[insulin resistance]

  • To know more about Unfolded protein response and ER stress please see our video on this topic

• Q. How does inflammation in adipocytes produce insulin resistance ?

  graph LR
  	 A[Excess white adipose tissue blood supply not able to keep up with it] --> B[hypoxia] --> C[Inflammation] --> D[TNF alpha release] --> E[Activate Janus kinase] --> F[IRS1 phosphorylation] --> G[Insulin resistance]

• Q. What is the Randle cycle ?

  • Excess Free fatty acids reduces Glucose metabolism

• Q. Describe the process of lipotoxicity and Randle cycle ?

  • Randle cycle:

    graph TD
    A[Increase Free fatty acid increase oxidation of FFA] --> B[increase citrate] --> C[inhibit PFK] --> D[inhibits glucose metabolism pathway] --> E[accumulation of G6P] --> F[reduced glucose uptake by GLUT4 in muscles]

• Q. How do glucocorticoids produce insulin resistance ?

  • Change in body composition → fat moves from periphery to centre
  • Increase Free fatty acid
  • Reduction of P13K

• Q. Summarize how obesity leads to insulin resistance ?

graph TD
        X[Obesity] --> A2[Excess white adipose tissue blood supply not able to keep up with it] --> B2[hypoxia] --> C2[Inflammation] --> D2[TNF alpha release] --> E2[Activate Janus kinase] --> F2[IRS1 phosphorylation] -->   Z[Insulin resistance]
        X --> L[Nutrient excess] --> A[Excess nutrients activate mTOR] --> B[S6K] --> F2 --> Z
        X --> M[Excess lipolysis] --> N[increased free fatty acid] --> Z
        X --> L --> B1[ER Stress] --> C1[excess unfolded protein] --> E2 --> F2 --> Z

• #Updates

  • Date: May 1st, 2021
  • Source: International Textbook of Diabetes Mellitus, 2 Volume Set, 4th Edition

• Q. Which is more likely to cause insulin resistance, Subcutenous fat or viceral fat ?

  • Viceral fat is known to produce insulin resistance
  • Eventually ovewhelming of fat storage in subcutenous regions - leads to spillover to viceral area- leading to more fat storage and insulin resistance

• Q. Does one impact the other - i.e. if for some reason, the patient cannot store subcutenous fat, there is more ectopic fat storage ?

  • Yes
  • There is a theory that suggests that if the patient cannot store more subcutenous fat, then they store ectopic fat and vice versa
  • This phenomenon is seen in lipodystrophic syndrome
  • It is also seen in Sumo wrestlers who are having more subcutenous and less ectopic fat and hence are more healthy
  • South-Asians have more viceral fat and have less ability to store subcutenous fat
    • This may be some sort of Lipodystrophy variant
    • This is why South Asians have poor metabolism compared to Caucasian
    • 
    • 

• Q. In terms of chronology what appears first- peripheral insulin resistance or central insulin resistance ?

  • Peripheral insulin resistance appears first and it is present for a long time before central insulin resistane (at the level of liver) appears
  • However the hepatic insulin resistance immediatley preceeds the development of type 2 diabetes
  • Hence NAFLD/NASH is a strong predictor for development of type 2 diabetes
  • 

• Q. Amongst the parameters of a liver profile, which parameters have a strong link with type 2 diabetes ?

  • ALT (SGPT)
  • GGT

• Q. Which is an emerging biomarker in this regards ?

  • Fetuin-A

    • It is a hepatokine
    • Proinflammatory and antiinflammatory attributes of fetuin-a: a novel hepatokine modulating cardiovascular and glycemic outcomes in metabolic syndrome - PubMed
      • Fetuin-A is a novel hepatokine. The number of biologic roles attributed to fetuin-A has increased exponentially in the past decade.
      • Fetuin-A is the endogenous ligand for Toll-like receptor-4 activation, for lipid-induced insulin resistance. Fetuin-A has inverse interaction with adiponectin. Increased fetuin-A is a risk factor for diabetes and fatty liver disease in normoglycemia and prediabetes
      • Decreased fetuin-A predicts increased disease activity in obstructive lung disease, Crohn's disease, and ulcerative colitis. Both elevated and reduced fetuin-A may be linked with increased cardiovascular events.
      • As a proinflammatory molecule, fetuin-A contributes to insulin resistance and is an important link between liver, adipose tissue, and muscles
      • Fetuin-A is neuroprotective and plays an important antiinflammatory role in sepsis and autoimmune disorders

  • Q. What is the role of SHBG in this ?

    • Low SHBG is a marker of Hepatic Insulin resistance
    • This is the pathogenesis implicated for PCOS
    • Low SHBG predicts the risk of developing type 2 diabetes in an individual

  • Q. What happens to adiponectin levels with increasing insulin resistance ?

    • Adiponectin levels reduce

  • Q. Is Adiponectin a good marker for insulin resistance ?

    • Probably not
    • No strong data exist for the same and its role in predicting diabetes is limited

  • Q. What is the "adiponectin paradox" ?

    • This is common with a lot of biomarkers seen in insulin resistance
    • In a physiological sense in a normal individual - a high adiponectin is protective for insulin resistance
    • However in a diseased individual it is associated with higher risk of complications

  • Q. In which other situations do you see an adiponectin paradox ?

    • natriuretic peptides
      • In normal individuals- BNP levels are protective from insulin resistance
      • In diseased individual (ie those with type 2 diabetes)- they are associated with adverse cardiovascular situations

  • Q. Which are the other emerging biomarkers ?

    • IL-6
    • PAI-I
    • Both of these are also associated with increased risk of type 2 diabetes

  • Q. What is the importance of microalbuminuria in this scenario ?

    • Microalbuminuria is a marker of vascular dysfunction in both - the patients with diabetes and also patients with insulin resistance not having diabetes

• #Updates

  • Date: May 1st, 2021
  • Source: International Textbook of Diabetes Mellitus, 2 Volume Set, 4th Edition

• Q. What are the changes in lipid profile in patients with Insulin resistance ?

  • Increased Triglycerides → Has stronger link to risk of developing diabetes
  • Reduced HDL → Has stronger association with Cardiovascular disease
  • Small dense LDL → Strong association with Cardiovascular disease

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