Poorly controlled diabetes 'bad to the bone'

The source of the diabetic nerve pain and degeneration begins with a special fusion of bone marrow and nerve cells that lead to nerve death and dysfunction – proving that diabetes is indeed "bad to the bone," said researchers from Baylor College of Medicine in two recent reports.

"The excess blood sugar levels in diabetes cause the bone marrow cells to become promiscuous, traveling to nerve and other tissue cells and fusing to them. When the bone marrow cells fuse to neurons (nerve cells) and cells of the nervous system, they cause the cells to die early and malfunction," said Dr. Lawrence Chan, professor of medicine – endocrinology and director of the federally funded Diabetes and Endocrinology Research Center at BCM.

"Diabetic neuropathy is one of the most common and most devastating complications of diabetes. The fact that it begins with the effects of poorly controlled diabetes on a population of bone marrow cells shows the ruinous potential of this unique cell population in people with this disease."

A report on this work appears online in the FASEB Journal.

An estimated 25.8 million people in the United States have diabetes and 7 million may not know of their disease. It is a leading cause of new cases of blindness and kidney failure and the seventh leading cause of death in the nation. More than 50 percent of people with diabetes suffer neuropathy associated with the disease.

It is known that activation of an enzyme called neuronal poly(ADP-ribose) polymerase-1 (PARP-1) is a major determinant of whether people or animals develop diabetic neuropathy. As a proof of principle, Chan and his colleagues took bone marrow from normal mice susceptible to diabetic neuropathy because their cells produced PARP-1 and transplanted it into mice resistant to the neuropathy. The transplanted marrow made the mice susceptible to the diabetic neuropathy. When they transplanted marrow from mice that did not produce PARP-1 into mice susceptible to the neuropathy, the mice that received the transplant were protected against the problem.

In the test tube, they put bone marrow cells in a high-glucose environment and watched as some began to produce the hormone proinsulin that is a precursor to insulin. Proinsulin production turned out to be a biomarker for the "bad" bone marrow cells.

If that fraction of cells is further incubated in high glucose in the test tube, the cells fuse with nerve cells, causing the neurons to begin the process of programmed cell death and to malfunction. That results in the diabetic neuropathy that is so common in patients whose diabetes if difficult to control.

These experiments indicated that these abnormal bone marrow-derived cells that produce PARP-1 promotes diabetic neuropathy by promoting the fusion of the bone marrow cells with neurons, leading to early nerve cell death and dysfunction.

"These experiments show the relationship between neuropathy and bone marrow cells in this disease, demonstrating that uncontrolled diabetes is, indeed, bad to the bone," said Chan.

Others who took part in this research include Tomoya Terashima and Hideto Kojima of BCM and Shiga University of Medical Science in Otsu, Japan.

Funding for this work came from the National Institutes of Health, the Betty Rutherford Chair for Diabetes Research from St. Luke’s Episcopal Hospital, and the T.T. & W.F. Chao Global Foundation.

Chan holds the Betty Rutherford Chair for Diabetes Research from St. Luke’s Episcopal Hospital.