Disrupted Insulin Signaling Causes Pain Hypersensitivity In Diabetes

Improper insulin signaling in pain sensory nerve fibers may be responsible for the chronic pain associated with diabetes according to new research led by Dr Seol Hee Im and Dr Michael Galko from the University of Texas MD Anderson Cancer Center. The currently held theory states that pain associated with is a secondary effect of micro-vessel (vascular) changes and toxicity of high blood sugar levels to nerve damage. However, latest research using a fruit fly model suggests that disrupted insulin signaling in pain sensory neurons may be actually responsible. The findings of the study are published in the open access journal Disease Models & Mechanisms.

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Reason for Study

• The mechanisms of diabetes-induced pain remain still largely unclear. Till date, most studies have used vertebrate animal models such as mice to determine how increased sugar levels might be affecting blood vessels and nerves.
• However, a wider investigation into whether other factors and tissues could be involved in the development of disease-associated pain symptoms has not been undertaken still.

The team hope to address this gap and determine whether other mechanisms could be at play in this disabling condition and gain insight into the pathogenesis of diabetic pain through the use of the fruit fly model.

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Details of Study

The fruit fly model for diabetic pain study described in this research publication is not new but an extension of well-established fruit fly models used in previous diabetes research, as well as assays for measuring pain in fly larvae.

The crucial questions that the study team hoped to answer were

• whether the pain hypersensitivity in persons with diabetes is related to defects in insulin signaling in sensory neurons
• whether this pain can be modeled in fruit flies

To answer these critical questions, the team employed three types of fruit fly models with different attributes namely

• one model with a genetic disruption of insulin signaling
• two more fruit fly models with established type 1 and type 2 diabetes respectively

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Key Findings of Study

• In the fruit fly model with disrupted insulin signaling, the team found to their surprise that the insulin receptor protein showed activity in pain sensory neurons instead of functioning in metabolic tissues such as muscle and fat.
• The faulty insulin receptor function in these flies caused persistent hyper-activation of the neurons and pain hypersensitivity.
• In both the genetic knock-down, as well as type 2 diabetes model flies, the scientists were able to reverse pain hypersensitivity by increasing insulin signaling in the pain sensory neurons.

Thus the findings of the study suggest that impaired insulin signaling may be responsible for pain hypersensitivity in diabetic patients and reversing it may reduce or prevent the pain.

The leaders of the study team, Dr Seol Hee Im and Dr Michael Galko from the University of Texas MD Anderson Cancer Center, explain that, "Only very recently have researchers started to pay attention to the loss of insulin signaling in the pain sensory neurons. This is a gap that our work has helped to fill in - the Drosophila model has allowed tissue-specific manipulation of insulin signaling and measurement of the ensuing effects on pain sensitivity."

About Fruit Flies

Fruit flies or Drosophila melanogaster are not new to research and have been used in genetic and developmental biological research for ages. Additionally, they have been used as a model organism for several aspects of diabetes research, including studies into the molecular mechanisms of maintaining optimal glucose levels, insulin production and sensitivity. They have also been used to study other diabetes-associated complications such as metabolic syndromes and obesity induced heart disease.

Diabetic Pain

The condition predominantly affects the lower legs and feet. Symptoms may vary from mild to painful, debilitating and even fatal. Symptoms include pain and tingling and numbness in the feet and legs. Treatment includes managing blood sugar levels and using drugs to control symptoms.

Future Research Plans

• The team plans to use the type 2 diabetes fly model to determine specifically which genes are necessary to maintain persistent hypersensitivity in pain sensory neurons for possible targeting in future.

Drs Im and Galko say, "Such screens can be either genetic or chemical in nature and could be performed in our models of genetic mutants or tissue-specific Insulin receptor knockouts as well. We can also expand our analysis to other sensory modalities such as cold or mechanical and chemical stimuli, as diabetes patients also experience these hypersensitivities."

• The role of insulin signaling in diabetic neuropathy and diabetic pain could be extended into vertebrate models to learn if the role of insulin signaling in pain fibers is preserved across species.

"By linking the function of insulin signaling and persistent pain, our study brings a new focus onto diminished insulin signaling in the pain sensory neurons in diabetic patients", explains Dr Im.

He is hopeful that their efforts could further extend to translational research and eventually contribute towards the development of effective and better treatment for diabetic neuropathy.

Reference

1. Caleb W. Grote, Douglas E. Wright, "A Role for Insulin in Diabetic Neuropathy" Front Neurosci (2016) doi: 10.3389/fnins.2016.00581

Source-Medindia