RESEARCH SUMMARY:
Selective destruction of pancreatic
islet β-cells.
Selective destruction of pancreatic
islet β-cells. The loss of insulin-secreting β-cells results
in an inability to regulate blood glucose levels. β-cell destruction
is characterized by the infiltration of macrophages, monocytes,
NK-cells, and T-lymphocytes into islets. Cytokines, released
during islet inflammation, are believed to participate in
-cell death, either by directly mediating β-cell lysis or indirectly
by regulating islet inflammation. Our studies have focused
on the mechanisms by which cytokines directly impair β-cell
function and induce islet destruction. We have shown that
the macrophage-derived cytokine, interleukin-1 (IL-1), directly
impairs β-cell function by stimulating the expression of inducible
nitric oxide synthase (iNOS) and the increased production
of the free radical nitric oxide. We have shown that nitric
oxide targets iron-sulfur-containing enzymes found in the
mitochondria, resulting in the inhibition of oxidative metabolism
and reduced cellular levels of ATP in islets. Nitric oxide
also targets DNA, inducing strand breaks. Human islets require
a combination of IL-1 and the T-lymphocyte cytokine IFN-γ
to stimulate iNOS expression and nitric oxide production,
and to inhibit glucose-stimulated insulin secretion. Our current
focus is to determine the signal transduction mechanisms by
which IL-1 and IL-1 + IFN-γ stimulate iNOS expression by rat
and human -cells, respectively, and to determine mechanisms
by which -cells recover from nitric oxide-mediated damage.
The interactions of both environmental and genetic factors appear to participate in the development of insulin-dependent diabetes mellitus (IDDM).
The risk of IDDM in Caucasians is 0.4%, and this figure rises to 6% for siblings of IDDM patients. However, the concordance rate for the development of IDDM by monozygotic twins is less than 40%. While familial clustering is consistent with a substantial genetic contribution, the low concordance rate of diabetes in monozygotic twins indicates the importance of environmental factors in IDDM. Viral infection is one environmental factor that has been implicated in the initiation of -cell damage during diabetes development. Double-stranded RNA (dsRNA) is an active component of a viral infection that stimulates antiviral responses in infected cells. Treatment of isolated rat islets with dsRNA, in combination with IFN-γ, results in an inhibition of insulin secretion and islet degeneration. The inhibitory and destructive effects of dsRNA + IFN-γ on islet function are dependent on both IL-1 and nitric oxide. Our current studies are designed to determine: 1) the mechanisms by which dsRNA impairs β-cell function; 2) if dsRNA mediates β-cell death and if this death is apoptotic or necrotic; and 3) the effects of a viral infection on the function and viability of isolated rat and human islets and primary β-cells. Immunological, biochemical, molecular, and transgenic approaches will be used to examine the mechanisms by which cytokines and viral infections mediate β-cell damage.
Figure: Our studies focus on mechanisms of pancreatic
beta cell destruction (orange cells), and the role of cytokines
such as IL-1 and IFN-gama in mediating beta-cell destruction.
We have shown that these cytokines stimulate beta cell production
of nitric oxide and that nitric oxide is one mediator of cytokine-induced
beta-cell damage.
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