Biology subjects

McGraw, T. E.

Publications and source records attributed to McGraw, T. E..

3 recordsLinked to original sources

bioRxiv2020

A common human variant of GIPR improves systemic glucose homeostasis in a sexual dimorphic manner

Glucose-dependent insulinotropic polypeptide (GIP) has a role in controlling postprandial metabolic tone. In humans, a GIP receptor (GIPR) variant (Q354, rs1800437) is associated with a lower body mass index (BMI) and increased risk for Type 2 Diabetes. To isolate the contribution of GIPR in metabolic control, we generated a mouse model of the GIPR-Q354 variant (GIPR-Q350 mice). Female GIPR-Q350 mice are leaner than littermate controls, and male GIPR-Q350 mice are resistant to diet-induced obesity, in line with the association of the variant with reduced BMI in humans. GIPR-Q350 mice of both sexes are more glucose tolerant and exhibit an increased sensitivity to GIP. Postprandial GIP levels are reduced in GIPR-Q350 mice, revealing feedback regulation that balances the increased sensitivity of GIP target tissues to secretion of GIP from intestinal endocrine cells. The increased GIP sensitivity is recapitulated ex vivo during glucose stimulated insulin secretion assays in islets. Generation of cAMP in islets downstream of GIPR activation is not affected by the Q354 substitution. However, post-activation traffic of GIPR-Q354 variant in {beta}-cells is altered, characterized by enhanced intracellular dwell time and increased localization to the Trans-Golgi Network (TGN). Consequently, our data link altered intracellular traffic of the GIPR-Q354 variant with GIP control of metabolism. We propose that this change in spatiotemporal signaling underlies the physiologic effects of GIPR-Q350/4 and GIPR-E350/4 in mice and humans. These findings contribute to a more complete understanding of the impact of GIPR-Q354 variant on glucose homeostasis that could perhaps be leveraged to enhance pharmacologic targeting of GIPR for the treatment of metabolic disease.

physiology↗

bioRxiv2020

Evolution of immune escape mechanisms in the progression from preinvasive to invasive human lung adenocarcinoma.

The tumor microenvironment (TME) of lung adenocarcinoma (LUAD) precursor lesions has not been described. We interrogated by multiplex immunofluorescence the TME of preinvasive and invasive Stage 1A LUADs selected by computer tomography (CT) scan-density. Pure non-solid (p-NS) CT density nodules are preinvasive/minimally invasive, whereas solid CT density nodules are frankly invasive cancers. Our data reveal an intensely immune-suppressive immune TME in p-NS tumors characterized by an increase in Treg cells and a decrease in cytotoxic T cells relative to normal lung. The TME of the solid tumor group, more advanced lesions than the p-NS yet still early in disease development, were increasingly more immune-suppressive. Provocatively, there was a further increase in both Treg cells and cytotoxic T cells, establishing a nascent albeit ineffective anti-tumor immune response in transition from preinvasive p-NS to invasive solid tumors. Regulatory T cells play a dominant role throughout progression, while additional immune evasive mechanisms are employed at different stages of disease progression, including T cell exclusion from cancer cell nests early and activation of immune checkpoints later. Our study establishes that different immune-targeted strategies are required to intercept disease progression at these two distinct early points of lung cancer development. Statement of SignificanceUsing multiplexed IF, we compared the cellular composition and activation state of the tumor immune microenvironment between pre/minimally invasive and frankly invasive adenocarcinoma. We found a progressive increase in immunosuppressive mechanisms in association with disease progression suggesting that Interception strategies should be specifically tailored based on underlying immune escape mechanisms

cancer biology↗

bioRxiv2020

Insulin promoted mobilization of GLUT4 from a perinuclear storage site requires RAB10.

Insulin controls glucose uptake into muscle and fat cells by inducing a net redistribution of GLUT4 from intracellular storage to the plasma membrane (PM). The TBC1D4-RAB10 signaling module is required for insulin-stimulated GLUT4 translocation to the PM, although where it intersects GLUT4 traffic was unknown. Here we demonstrate that TBC1D4-RAB10 functions to control GLUT4 mobilization from a Trans Golgi Network (TGN) storage compartment, establishing that insulin, in addition to regulating the PM proximal effects of GLUT4-containing vesicles docking to and fusion with the PM, also directly regulates the behavior of GLUT4 deeper within the cell. We also show that GLUT4 is retained in an element/domain of the TGN from which newly synthesized lysosomal proteins are targeted to the late endosomes and the ATP7A copper transporter is translocated to the PM by elevated copper. Insulin does not mobilize ATP7A nor does copper mobilize GLUT4. Consequently, GLUT4 intracellular sequestration and mobilization by insulin is achieved, in part, through utilizing a region of the TGN devoted to specialized cargo transport in general rather than being specific for GLUT4. Our results define GLUT4-containing region of the TGN as a sorting and storage site from which different cargo are mobilized by distinct signals.

cell biology↗