The Origin of Insulin Resistance in DM

Published on Mon, 10/23/2017

Insulin Resistance and Diabetes in DM are the Product of INSR Mis-Splicing, Right?

Insulin resistance, impaired glucose utilization by multiple tissues (particularly in skeletal muscle), and multi-systemic consequences of type 2 diabetes mellitus represent impactful metabolic alterations that contribute to morbidity and mortality in DM1 and DM2. Understanding the molecular mechanisms behind insulin resistance will foster better treatments for patients living with DM. It is easy to conclude that we already understand the basis of insulin resistance in DM1—that it is a direct consequence of an already well-established mis-splicing and predominance of the fetal insulin receptor (INSR) transcript. Yet, that assumption has not been directly tested.

The Real Story Appears to be More Complex

An MDF Fellow, Laura Renna, and her colleagues in Milan have recently published a study that provides new insights into the pathogenesis of insulin resistance and diabetes in DM1 and DM2. This research team took the novel approach of evaluating INSR transcript and protein, and the status of downstream insulin signaling pathway components, in DM patient muscle biopsies and myotubes differentiated ex vivo in order to better understand the molecular causes of the metabolic phenotype that characterizes DM.

Despite observation of mis-spliced INSR in all DM1 (65% fetal isoform) and DM2 (50% fetal isoform) muscle biopsies, levels of INSR protein were not reduced when compared with controls. However, basal phosphorylation levels of Akt/PKB, p70S6K, GSK3β and ERK1/2 were altered, indicating potential compromise of signaling pathways downstream of the INSR. In keeping with DM1 pathophysiology, distal muscles (tibialis anterior) exhibited greater signaling pathway impairment than proximal (biceps brachii). 

To facilitate studies aimed at a better understanding of events downstream of INSR protein, the research team utilized DM patient-derived myotubes. In patient myotubes, no differences in INSR protein levels were detected between DM1, DM2, and controls.  But, analyses of glucose uptake showed reduced insulin-mediated stimulation in DM myotubes. Moreover, activation of both IRS1-Akt/PKB and Ras ERK pathways was impaired. Thus, deficits in insulin signaling in DM may not be the sole consequence of INSR mis-splicing, but rather may be due to dysfunction in downstream signaling pathways.

Taken together, the cellular/molecular mechanisms underlying reduced insulin sensitivity in DM may be more complex that has been appreciated. The Milan research team assessed insulin signaling pathways and concluded that perturbations of post-INSR signaling may well be a key factor in development of insulin resistance in DM, irrespective of any changes in INSR transcript splicing. The pathophysiological mechanisms underlying these alterations in post-receptor signaling proteins are currently unknown.


Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.
Renna LV, Bosè F, Iachettini S, Fossati B, Saraceno L, Milani V, Colombo R, Meola G, Cardani R.
PLoS One. 2017 Sep 15;12(9):e0184987. doi: 10.1371/journal.pone.0184987.