Short-Term Insulin Requirements Following Gastric Bypass Surgery in Severely Obese Women with Type 1 Diabetes

Background: In severely obese type 2 diabetes patients, gastric bypass surgery (GB) reduces body mass index (BMI) and hemoglobin A1c (HbA1c) and allows reduced doses of insulin and other medications. Data regarding the effects of GB on severely obese patients with type 1 diabetes are limited. Methods: Severely obese women with type 1 diabetes (n = 9) were studied immediately before and after GB (7.7 ± 5.8 weeks, mean ± SD). Results: On average, GB reduced mean BMI by 11 % and mean HbA1c by 0.9 % (from 8.0 to 7.1 %), with a parallel 38 % decrease in basal insulin requirements (expressed per kilogram of body weight). Conclusion: GB rapidly decreased BMI, HbA1c, and insulin requirements in severely obese women with type 1 diabetes. However, physiologic insulin replacement remains necessary in patients with type 1 diabetes

The TRPM7 interactome defines a cytoskeletal complex linked to neuroblastoma progression

Neuroblastoma is the second-most common solid tumor in children and originates from poorly differentiated neural crest-derived progenitors. Although most advanced stage metastatic neuroblastoma patients initially respond to treatment, a therapy resistant pool of poorly differentiated cells frequently arises, leading to refractory disease. A lack of insight into the molecular mechanisms that underlie neuroblastoma progression hampers the development of effective new therapies for these patients. Normal neural crest development and maturation is guided by physical interactions between the cell and its surroundings, in addition to soluble factors such as growth factors. This mechanical crosstalk is mediated by actin-based adhesion structures and cell protrusions that probe the cellular environment to modulate migration, proliferation, survival and differentiation. Whereas such signals preserve cellular quiescence in non-malignant cells, perturbed adhesion signaling promotes de-differentiation, uncontrolled cell proliferation, tissue invasion and therapy resistance. We previously reported that high expression levels of the channel-kinase TRPM7, a protein that maintains the progenitor state of embryonic neural crest cells, are closely associated with progenitor-like features of tumor cells, accompanied by extensive cytoskeletal reorganization and adhesion remodeling. To define mechanisms by which TRPM7 may contribute to neuroblastoma progression, we applied a proteomics approach to identify TRPM7 interacting proteins. We show that TRPM7 is part of a large complex of proteins, many of which function in cytoskeletal organization, cell protrusion formation and adhesion dynamics. Expression of a subset of these TRPM7 interacting proteins strongly correlates with neuroblastoma progression in independent neuroblastoma patient datasets. Thus, TRPM7 is part of a large cytoskeletal complex that may affect the malignant potential of tumor cells by regulating actomyosin dynamics and cell-matrix interaction

TRPM7 controls mesenchymal features of breast cancer cells by tensional regulation of SOX4

Mechanically induced signaling pathways are important drivers of tumor progression. However, if and how mechanical signals affect metastasis or therapy response remains poorly understood. We previously found that the channel-kinase TRPM7, a regulator of cellular tension implicated in mechano-sensory processes, is required for breast cancer metastasis in vitro and in vivo. Here, we show that TRPM7 contributes to maintaining a mesenchymal phenotype in breast cancer cells by tensional regulation of the EMT transcription factor SOX4. The functional consequences of SOX4 knockdown closely mirror those produced by TRPM7 knockdown. By traction force measurements, we demonstrate that TRPM7 reduces cytoskeletal tension through inhibition of myosin II activity. Moreover, we show that SOX4 expression and downstream mesenchymal markers are inversely regulated by cytoskeletal tension and matrix rigidity. Overall, our results identify SOX4 as a transcription factor that is uniquely sensitive to cellular tension and indicate that TRPM7 may contribute to breast cancer progression by tensional regulation of SOX4

Decreased insulin‐stimulated brown adipose tissue glucose uptake after short‐term exercise training in healthy middle‐aged men

Aims To test the hypothesis that high‐intensity interval training (HIIT) and moderate‐intensity continuous training (MICT) improve brown adipose tissue (BAT) insulin sensitivity. Participants and methods Healthy middle‐aged men (n = 18, age 47 years [95% confidence interval {CI} 49, 43], body mass index 25.3 kg/m2 [95% CI 24.1‐26.3], peak oxygen uptake (VO2peak) 34.8 mL/kg/min [95% CI 32.1, 37.4] ) were recruited and randomized into six HIIT or MICT sessions within 2 weeks. Insulin‐stimulated glucose uptake was measured using 2‐[18F]flouro‐2‐deoxy‐D‐glucose positron‐emission tomography in BAT, skeletal muscle, and abdominal and femoral subcutaneous and visceral white adipose tissue (WAT) depots before and after the training interventions. Results: Training improved VO2peak (P = .0005), insulin‐stimulated glucose uptake into the quadriceps femoris muscle (P = .0009) and femoral subcutaneous WAT (P = .02) but not into BAT, with no difference between the training modes. Using pre‐intervention BAT glucose uptake, we next stratified subjects into high BAT (>2.9 µmol/100 g/min; n = 6) or low BAT (<2.9 µmol/100 g/min; n = 12) groups. Interestingly, training decreased insulin‐stimulated BAT glucose uptake in the high BAT group (4.0 [2.8, 5.5] vs 2.5 [1.7, 3.6]; training*BAT, P = .02), whereas there was no effect of training in the low BAT group (1.5 [1.2, 1.9] vs 1.6 [1.2, 2.0] µmol/100 g/min). Participants in the high BAT group had lower levels of inflammatory markers compared with those in the low BAT group. Conclusions: Participants with functionally active BAT have an improved metabolic profile compared with those with low BAT activity. Short‐term exercise training decreased insulin‐stimulated BAT glucose uptake in participants with active BAT, suggesting that training does not work as a potent stimulus for BAT activation

The alpha-kinase family: an exceptional branch on the protein kinase tree

The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in the context of an alpha-helix. Although recent studies show that some members of this family can also phosphorylate residues in non-helical regions, the name alpha-kinase has remained. During evolution, the alpha-kinase domains combined with many different functional subdomains such as von Willebrand factor-like motifs (vWKa) and even cation channels (TRPM6 and TRPM7). As a result, these kinases are implicated in a large variety of cellular processes such as protein translation, Mg2+ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. Here, we review the current state of knowledge on different members of this kinase family and discuss the potential use of alpha-kinases as drug targets in diseases such as cancer