Insulin resistance condition in which the receptor is mutated is it just a feedback mechanism of less use of ATP??
Dear Pranab
Good day. As for as mechanism of insulin resistance in type-2 diabetes mellitus is concerned, I think the basic evidence emerged when researchers observed that hyperglycemia was associated with higher than normal insulin, which implied that the hyperinsulinemia was unable to dispose of the glucose. This led to the concept of “insulin resistance”.
Now your question needs underlying mechanism in subjects with insulin resistance. Coming to this, first its not just ATP to blame, the defects seem to have molecular basis leading to changes in both insulin receptor and further downstream effect.
The normal physiological insulin-insulin receptor pathway is depicted as: (ATTACHED AS FIGURE-1)
So pathology can result from beta cell dysfunction, insulin release kinetics, insulin, insulin receptor and further downstream actors.
1- Vollenweider P et al have demonstrated defects in downstream pathways affecting insulin receptor substrate (IRS) related phosphatidylinositol 3 (PIP3) activation, which further inhibits the PKC protein due to decrese tyrosine kinase phosphorylation.
Reference: Vollenweider P et al. Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. Diabetes. 2002 Apr;51(4):1052-9.
2- Another pathway highlighted along with Vollenweider et al is that of p42(MAPK) & p44(MAPK) tyrosine phosphorylationwhich can lead to decrease glucose related uptake of glucose.
Reference: del Aguila LF et al. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Physiol.1999 May;276(5 Pt 1):E849-55.
3- Mutations in insulin receptor are also common in diabetes.
Reference: Kusari J et al. Insulin resistance and diabetes due to different mutations in the tyrosine kinase domain of both insulin receptor gene alleles. J Biol Chem. 1991 Mar 15;266(8):5260-7.
4- Apart from glucose insulin resistance is also implicated in disturbing lipid metabolites leading to their ectopic deposition and poor folding of several protein and effects on immune response with increase release of inflammatory cytokines.
Reference: Samuel VT et al. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012 Mar 2;148(5):852-71. doi: 10.1016/j.cell.2012.02.017.
Finally pubmed data search as ome of which I have highlighted will provide you with enormous specific defects in insulin release in type-2 diabetes. Moreover, the evolving field of molecular pathology is discovering newer and newer mutations which actually play the producer and director’s role behind these apparent mechanisms. Much more to decipher in terms of molecular parthenogenesis.
Regards
Dr Sikandar
this review article could be helpful in your question
Article Mechanisms of insulin resistance in obesity
Abberation in glucose transport and dysfunction of PI3-kinase-Akt pathway forms the basis of type-2-diabetes. Please refer article: "Insulin Receptor Signaling in Normal and Insulin-Resistant States" Cold Spring Harb Perspect Biol. 2014 Jan; 6(1): a009191. doi: 10.1101/cshperspect.a009191. Several other articles on Pi3-kinse-Akt pathway you can check on PUBMED.
Thank you all respected individuals for answering and putting recommendations. I may need a further clarification after going through again.
Dear
You are welcome? but it would be more suited to you if you take one area at a time. The research work with regards to insulin resistance has multiple dimensions and as we say for diabetes as "Mother of all diseases" suits pretty well for insulin resistance.
So you can further shortlist your area of interest
Regards
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