Morris F. White
We investigate the molecular basis of insulin signal transduction to understand the pathophysiology of diabetes and related disorders, including obesity, infertility, and cardiovascular and retinal disease. Much of our work on signaling pathways that mediate the insulin response was fueled by our discovery of the insulin receptor substrate (IRS) protein family. Since diabetes is a complicated, multisystem disease, we use mice to integrate our molecular studies with physiology. Transgenic mice lacking the genes for Irs1 or Irs2 reveal a surprisingly close relation between the molecular regulation of insulin secretion and that of insulin action. We now understand that the IRS2-branch of the insulin/IGF signaling pathways controls pancreatic β-cell growth, function and survival. We are searching for ways to exploit the IRS2 signaling cascade to restore β-cell function and prevent or cure diabetes.
Diabetes is serious, but only one of the consequences of insulin resistance. While compensatory hyperinsulinemia prevents gross decompensation of glucose homeostasis, dysregulated insulin signaling is associated with a cohort of systemic disorders, including dyslipidemia, hypertension, cardiovascular disease, stroke, blindness, kidney disease female infertility, and neurodegeneration. Whether better management of inflammatory responses can attenuate insulin resistance and promote β-cell function is an important area of investigation. Finding drugs that promote IRS2 signaling might be a good starting point. However, too much insulin action might shorten our lives, so future work must better resolve the network of insulin responses that are generated in various tissues, and attempt to distinguish the ones that prolong health from the ones that diminish it.
White MF. Insulin signaling in health and disease. Science. 2003 Dec 5;302(5651):1710-1.
Hennige AM, Burks DJ, Ozcan U, Kulkarni RN, Ye J, Park S, Schubert M, Fisher TL, Dow MA, Leshan R, Zakaria M, Mossa-Basha M, White MF. Up-regulation of insulin receptor substrate-2 in pancreatic β-cells prevents diabetes. J Clin Invest. 2003 Nov;112(10):1521-32.
Giraud J, Leshan R, Lee Y-H, White MF. Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem. 2004 Jan 30;279(5):3447-54.