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reviews Farewell to Diabetes: A Scientific Breakthrough Kazi Ullah, ‘14 and Malack Hamade, ‘13

Piercing an index finger to test for hyperglycemia is a tale familiar to every diabetic. Depending on the severity and type of diabetes, the frequency of monitoring blood sugar levels can vary anywhere from once a week to ten times a day with every diabetic. The burden of living with such an invasive disease coupled with the staggering number of a reported 350 million people who suffer from it worldwide has encouraged extensive investment in diabetic research. [1] While the cause at the heart of the problem is essentially one, initiatives in researching diabetes have spurred from many fields including genetics, neurobiology and cell differentiation, to name a few. Chronicled in this article are the latest of these initiatives, revolutionary approaches to what may be the next big discoveries in curing diabetes since the extraction of insulin in 1921.

Overview A simple sugar, glucose is obtained from our diets and circulates through our bloodstream as an accessible energy source for our cells. In order for cells to metabolize glucose, the pancreas must first secrete insulin, a hormone that induces the transcription and insertion of GLUT family transporters into cell membranes. These transporters then allow glucose molecules to diffuse across the plasma membrane of cells to be metabolized. When regulated, glucose is essential for the body’s metabolic processes and everyday functions. If left to accumulate in the bloodstream, glucose becomes the root cause of severe symptoms such as ketoacidosis, blindness and renal failure—all characteristic of diabetes. Diabetes Mellitus is marked by the sufferer’s inability to properly process insulin. In type I diabetes, the patient’s T-cells attack the insulin-producing beta-cells in the islets of Langerhans in the pancreas, depleting the patient of an insulin source. This type is also referred to as insulin-dependent diabetes and is often seen in children and young adults. The other type, type II diabetes, is the more common form of diabetes in the United States; it is a condition in which the cells of the body grow increasingly irresponsive to the insulin being produced. Type II diabetic cells are said to be insulin resistant. Comorbidity with obesity is usually the case, if not the cause, of type II diabetes. [1]

Hope In 2006, a study identified two mutations in the trpv1 gene as potential causes of autoimmune diabetes. Defects in neurons expressing trpv1 gene led to minimal secretion of substance P—a compound critical to islet cell regulation of insulin—from the nerve terminals of the pancreas. When comparing the nerves

(which express the TRPV1 receptor) of diabetes-prone mice to that of healthy mice, it was found that the nerves in diabetesprone mice did not produce sufficient amounts of Substance P. This inability to produce Substance P led to hyper-insulinemia and consequently, insulin resistance and islet cell destruction in autoimmune diabetes. [2] Direct injection of Substance P into the pancreas kept nonobese mice healthy for up to three weeks, and some even for months. The suggestion was promising: restoring the function of the TRPV1 neuron could result in the reversal of autoimmune diabetes. While genetic observations were critical to the findings in the aforementioned study, a team of researchers at Stony Brook University took genetic practices even further by demonstrating a complete reversal of hyperglycemia in diabetic mice subjects through the use of induced-pluripotent stem cells. An induced pluripotent stem cell, or iPS cell, is created from an adult cell such as a liver, stomach or other mature cell through the introduction of genes that reprogram the cell and virtually transform it into an embryonic stem cell. This enables the iPS cell to transform from an undifferentiated state to any of the 220 types of cells in the human body. [3] In the study, iPS cells were differentiated into insulin-secreting beta-like cells; cells triggered by the presence of glucose. The beta-like cells were transplanted into the portal veins of thirty mice—half of them type I diabetic and the other half type II—and allowed to engraft. The hyperglycemia in both mouse models was corrected and by the 12th week, 15 mice were able to remain “normoglycemic.” Although thirteen mice died in total by the end of the study, six of them were intentionally killed for histological purposes. And of the surviving mice, only two had relapsed into hyperglycemia after 8 weeks, an extremely promising statistic. [4] In the four months the type I diabetic mice were followed, glucose levels dropped rapidly and remained stable post-transplantation [4]. In the type II diabetic mouse models, the transplanted iPS cell-derived beta-like cells increased the amount of insulin significantly. An average 4.35-fold increase in insulin levels was observed in treated mice compared to levels in untreated mice indicating that transplanted cells are able to prevent insulin resistance and beta-cell failure. Conclusively, the study hinted that an iPS cell-derived beta-like cell therapy is able to correct for a hyperglycemic phenotype by restoring insulin secretion and consequentially, normal glucose levels [4]. An immunology study conducted in 2003 used splenocytes, splenic white blood cells, to eliminate autoimmunity and restore normal glycemic levels in mice. Splenocytes impede T-cells from attacking islets by presenting partially or fully matched MHC Class I antigens. The antigen specific-cytotoxic

The Stony Brook Young Investigators Review, Fall 2011


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Fall 2011  

Fall 2011