快樂小藥師 Im pharmacist nichts glücklich

Alessia Fornoni, M.D., Ph.D

N Engl J Med 2010; 363:2068-2069

Diabetic nephropathy is a chronic progressive disease that affects 20 to 40% of patients with diabetes mellitus. Clinical trials have shown that strict control of hyperglycemia and hypertension can slow the progression of diabetic nephropathy and that insulin resistance correlates with the onset and severity of albuminuria. This correlation has also been found in normotensive persons who do not have diabetes, suggesting that insulin resistance per se may cause albuminuria. On the basis of these observations, Welsh and colleagues1 recently investigated the role of insulin signaling in the kidney and report that podocyte-specific deficiency of insulin receptors leads to a glomerular lesion resembling diabetic nephropathy, but in the absence of hyperglycemia.

Insulin is known as the master regulator of glucose and lipid metabolism, a role that critically depends on its interaction with the insulin receptor, which is expressed primarily in muscle, fat, liver, and brain. The kidney has traditionally not been considered a target organ of insulin action, although evidence suggests that insulin sensitizers may be superior to other hypoglycemic agents in conferring protection against diabetic nephropathy. After describing a functionally intact insulin-signaling pathway in podocytes,2 Welsh and colleagues now show a direct effect of local insulin-receptor signaling on podocyte function in vitro and in vivo.

Podocytes are highly specialized cells of the kidney glomerulus that help to prevent proteinuria through complex regulation of the actin cytoskeleton in their foot processes. Welsh and colleagues engineered two mouse models in which the gene encoding the insulin receptor (Insr) could be deleted in a podocyte-specific manner. In mice in which the gene was deleted, albuminuria developed, along with effacement of the podocyte foot processes, apoptosis, thickening of the glomerular basement membrane, and increased glomerulosclerosis — all histologic features typical of diabetic nephropathy.

Analysis of glomeruli isolated from wild-type mice and mice with a podocyte-specific deletion of the insulin receptor that were treated with insulin showed that insulin signaling in podocytes occurs primarily through two pathways: one involving Pi3k (phosphatidylinositol 3-kinase) and Akt (the v-akt murine thymoma viral oncogene homologue 1 protein) and the other involving the Mapk42 or Mapk44 (mitogen-activated protein kinase 42 or 44)

Welsh and colleagues also found that insulin directly induces the short-term reorganization of the actin cytoskeleton of human podocytes in vitro, resulting in retraction of cellular processes and increased permeability. These findings are consistent with the clinical evidence that insulin infusion in normal persons causes transient proteinuria.3 If and how these pathways interact to cause diabetic nephropathy remains to be established.

Since unopposed stimulation of the Mapk pathway by means of compensatory hyperinsulinemia occurs in patients with insulin resistance, one could argue that the disease phenotype in the mutant mice may be more representative of insulin deficiency than insulin resistance. A key finding by Welsh and colleagues was the marked variability in severity of the renal phenotype of the mutant mice, consistent with the clinical evidence that diabetic nephropathy does not develop in every patient with a mutant insulin receptor.4 The finding that diabetic nephropathy developed in only one of two sisters carrying the same mutation in INSR 4 suggests that mutations affecting the insulin receptor may be insufficient to cause a pathologic renal phenotype in humans.

But why should insulin signaling be important for podocyte function? Does insulin result in increased uptake of glucose by the podocyte during the postprandial period to enable the podocyte to better deal with the increased filtration load, or does insulin affect the podocyte in ways that are independent of glucose uptake? Imaging of glucose metabolism in vivo has shown that the brain, skeletal muscle, and fat are primarily involved in glucose uptake, whereas the kidney parenchyma takes up significant amounts of glucose only under pathologic conditions,5 with only minimal renal physiologic uptake due to glucose excretion. It is possible that the podocyte insulin receptor serves primarily as a receptor for proteins involved in actin cytoskeleton remodeling and guidance of the foot processes, as it does in axon guidance.6 The fact that nephrin, a key regulator of podocyte permeability, is essential for insulin signaling in the podocyte supports this possibility.

The podocyte insulin receptor is therefore an attractive target for the development of new antiproteinuric agents. The work by Welsh and colleagues calls for further experimental studies to characterize the mechanisms by which insulin and the insulin receptor affect podocyte function and for randomized clinical trials to address the role of insulin sensitizers in the treatment and prevention of diabetic nephropathy and other glomerular diseases.