Diabetes-in-a-dish model uncovers new insights into the cause of type 2 diabetes

Date:
September 3, 2020
Source:
Joslin Diabetes Center
Summary:
Researchers have developed a novel 'disease-in-a-dish' model to
study the basic molecular factors that lead to the development
of type 2 diabetes, uncovering the potential existence of major
signaling defects both inside and outside of the classical
insulin signaling cascade, and providing new perspectives on
the mechanisms behind insulin resistance in type 2 diabetes and
possibly opportunities for the development of novel therapeutics
for the disease.



FULL STORY ========================================================================== Using cells taken from patients with type 2 diabetes and new techniques
to convert them into specialized precursors of muscle cells, researchers
have developed a novel 'disease-in-a-dish' model to study the basic
molecular factors that lead to the development of type 2 diabetes.


========================================================================== Defects in insulin signaling or insulin resistance in skeletal muscle is important in type 2 diabetes, but with this new approach the researchers
have uncovered the potential existence of major signaling defects both
inside and outside of the classical insulin signaling cascade.

They found that while a number of proteins involved in the action of
insulin were disrupted in cells originating from individuals with type
2 diabetes, the vast majority of changes detected were in proteins with
largely unknown roles in metabolism or diabetes.

The findings should provide new perspectives on the mechanisms behind
insulin resistance in type 2 diabetes and possibly opportunities for
the development of novel therapeutics for the disease.

The research program was led by C. Ronald Kahn MD, Chief Academic
Officer, Senior Investigator and Section Head, Integrative Physiology
and Metabolism at Joslin Diabetes Center, and Mary K. Iacocca Professor
of Medicine at Harvard Medical School. Their full research findings are published in the journal Cell Metabolism.

Focusing on reprogrammed induced pluripotent stem cells, or iPSCs, that
were derived from individuals with type 2 diabetes and healthy control subjects, the researchers managed to recreate a cell culture model with
many of the features of muscle insulin resistance that occur in humans
with diabetes.

They found that the cultured iPSC-derived myoblasts (an early precursor
to most muscle cell types) from individuals with type 2 diabetes mirrored
many of the impaired molecular responses to insulin and glucose that are
seen in humans with diabetes. This included defects in glucose uptake
and cellular metabolism.

Using a technique called phosphoproteomics that can measure chemical
changes in many thousands of proteins simultaneously, they then found alterations in multiple pathways both within and outside the classical
insulin signaling pathway in cells from individuals with type 2 diabetes compared to controls.

This included changes in the way DNA is converted to RNA and then into
protein, as well as changes affecting the function and transport of many
of these proteins within the cell. On that basis they suggest the work
points to a new and previously unrecognized layer of potential targets
for developing therapies towards type 2 diabetes.

Lead author Thiago Batista PhD said: "Our findings point to changes on
a multiplicity of pathways that are not explained by a single kinase or phosphatase whose function is to regulate cellular signaling. Finding
chemical factors that can alone impact the function of multiple kinases
and hence signaling pathways would be of great interest in the field."
Senior author C. Ronald Kahn added: "While we are interested in how
these newly identified pathways may contribute to disease progression,
future research should also aim at better understanding how this might
link to both genetic and environmental effects that increase the risks
for diabetes. This will open up a whole new range of diagnostic and
therapeutic possibilities for this common form of diabetes."

========================================================================== Story Source: Materials provided by Joslin_Diabetes_Center. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Thiago M. Batista, Ashok Kumar Jayavelu, Nicolai J. Wewer
Albrechtsen,
Salvatore Iovino, Jasmin Lebastchi, Hui Pan, Jonathan M. Dreyfuss,
Anna Krook, Juleen R. Zierath, Matthias Mann, C. Ronald Kahn. A
Cell- Autonomous Signature of Dysregulated Protein Phosphorylation
Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell
Metabolism, 2020; DOI: 10.1016/j.cmet.2020.08.007 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200903133023.htm

--- up 1 week, 3 days, 6 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1337:3/111)