Type 2 diabetes (T2D) is diagnosed at the onset of hyperglycemia, by which time insulin-producing beta-cells have reached a tipping point of failure to secrete enough insulin to compensate for insulin resistance. Many pharmaceutical endeavors focus on stimulating insulin release at a late stage of type 2 diabetes when insulin secretion is failing. An alternative approach is to focus on islets at an earlier disease stage when insulin secretory capacity is still intact, but islets are overstimulated. Overstimulated islets are highly sensitive to glucose stimulation: secreting excessive insulin in low glucose, secreting inadequate insulin in high glucose, and showing disruptions in normal rhythmic insulin release. The central hypothesis of this proposal is that maintaining pulsatility is key to normal islet function in the body; restoring pulsatility in diabetic islets by reducing the excessive rate at which glucose stimulates insulin release will improve islet viability and function.
Specific Aims :
Aim 1) Importance of pulsatility: A novel perifusion system developed in the PI's lab will force intermittent periods of rest and activity on islets to generate ?forced oscillations?. This direct manipulation of the cellular processes that generate pulses will determine whether pulsatility is required for optimal islet health and function, and if so, which processes in the stimulus-secretion pathway are requisite for maintaining optimal function.
Aim 2) Resting to restore: Islets isolated from diabetic mice and humans will be treated with compounds that will mildly reduce excessive rates of activity at multiple points in the stimulus-secretion pathway (glucose-uptake, glycolysis, KATP-channel activity, calcium influx) to determine which interventions are effective at (a) restoring pulsatility and/or (b) improving islet function. Significance: the proposed work directly addresses for the first time whether pulsatility is required for optimal islet function and will establish whether treatments designed to promote `beta-cell rest' improve islet function in early T2D by restoring normal glucose-sensing and endogenous pulsatility. This work could help to redefine therapeutic approaches in early T2D.

Public Health Relevance

Type 2 diabetes (T2D) is a devastating metabolic disorder causing high blood sugar that affects over 25 million Americans and consumes nearly 1 in 5 health care dollars. During the development of T2D, obesity initially leads to higher than normal levels of insulin to help maintain normal blood sugar in the face of poor insulin signaling (insulin resistance), but this also disrupts the normal rhythms of insulin release from beta-cells, which may lead to reduced insulin release over time, causing T2D. We propose that reducing the sensitivity of insulin-producing cells to sugar will restore normal rhythmic responses that control to blood sugar and help to prevent the beta-cell failure that leads to T2D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Academic Research Enhancement Awards (AREA) (R15)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Wang, Xujing
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Ohio University Athens
Other Basic Sciences
Schools of Osteopathic Medicine
United States
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