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Articles by L. H. Philipson
Total Records ( 3 ) for L. H. Philipson
  S Rajan , S. C Eames , S. Y Park , C Labno , G. I Bell , V. E Prince and L. H. Philipson

Permanent neonatal diabetes mellitus is a rare form of insulin-requiring diabetes presenting within the first few weeks or months of life. Mutations in the insulin gene are the second most common cause of this form of diabetes. These mutations are located in critical regions of preproinsulin and are likely to prevent normal processing or folding of the preproinsulin/proinsulin molecule. To characterize these mutations, we transiently expressed proinsulin-GFP fusion proteins in MIN6 mouse insulinoma cells. Our study revealed three groups of mutant proteins: 1) mutations that result in retention of proinsulin in the endoplasmic reticulum (ER) and attenuation of secretion of cotransfected wild-type insulin: C43G, F48C, and C96Y; 2) mutations with partial ER retention, partial recruitment to granules, and attenuation of secretion of wild-type insulin: G32R, G32S, G47V, G90C, and Y108C; and 3) similar to (2) but with no significant attenuation of wild-type insulin secretion: A24D and R89C. The mutant insulin proteins do not prevent targeting of wild-type insulin to secretory granules, but most appear to lead to decreased secretion of wild-type insulin. Each of the mutants triggers the expression of the proapoptotic gene Chop, indicating the presence of ER stress.

  L. E Fridlyand , N Tamarina and L. H. Philipson

Oscillatory phenomenon in electrical activity and cytoplasmic calcium concentration in response to glucose are intimately connected to multiple key aspects of pancreatic β-cell physiology. However, there is no single model for oscillatory mechanisms in these cells. We set out to identify possible pacemaker candidates for burst activity and cytoplasmic Ca2+ oscillations in these cells by analyzing published hypotheses, their corresponding mathematical models, and relevant experimental data. We found that although no single pacemaker can account for the variety of oscillatory phenomena in β-cells, at least several separate mechanisms can underlie specific kinds of oscillations. According to our analysis, slowly activating Ca2+-sensitive K+ channels can be responsible for very fast Ca2+ oscillations; changes in the ATP/ADP ratio and in the endoplasmic reticulum calcium concentration can be pacemakers for both fast bursts and cytoplasmic calcium oscillations, and cyclical cytoplasmic Na+ changes may underlie patterning of slow calcium oscillations. However, these mechanisms still lack direct confirmation, and their potential interactions raises new issues. Further studies supported by improved mathematical models are necessary to understand oscillatory phenomena in β-cell physiology.

  J. P Lopez , J. R Turner and L. H. Philipson

A key step in regulating insulin secretion is insulin granule trafficking to the plasma membrane. Using live-cell time-lapse confocal microscopy, we observed a dynamic association of insulin granules with filamentous actin and PIP2-enriched structures. We found that the scaffolding protein family ERM, comprising ezrin, radixin, and moesin, are expressed in β-cells and target both F-actin and PIP2. Furthermore, ERM proteins are activated via phosphorylation in a glucose- and calcium-dependent manner. This activation leads to a translocation of the ERM proteins to sites on the cell periphery enriched in insulin granules, the exocyst complex docking protein Exo70, and lipid rafts. ERM scaffolding proteins also participate in insulin granule trafficking and docking to the plasma membrane. Overexpression of a truncated dominant-negative ezrin construct that lacks the ERM F-actin binding domain leads to a reduction in insulin granules near the plasma membrane and impaired secretion. Conversely, overexpression of a constitutively active ezrin results in more granules near the cell periphery and an enhancement of insulin secretion. Diabetic mouse islets contain less active ERM, suggestive of a novel mechanism whereby impairment of insulin granule trafficking to the membrane through a complex containing F-actin, PIP2, Exo70, and ERM proteins contributes to defective insulin secretion.

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