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Changes in intracellular calcium (Ca2+) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca2+‐binding protein that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro‐inflammatory cytokine tumor necrosis factor α, in a manner dependent on nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB). We found that NFκB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca2+ levels, and decreased inositol 1,4,5‐trisphosphate‐mediated Ca2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca2+. Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up‐regulated by stress‐induced NFκB signaling and that NCS1 influences cell survival and motility through effects on Ca2+ signaling and Akt pathway activation. This study investigates the underlying mechanism by which the calcium (Ca2+)‐binding protein NCS1 promotes increased tumor aggressiveness. We characterize NCS1 as a stress response protein that is up‐regulated by exogenous stressors, including the cytokine tumor necrosis factor α, through a nuclear factor kappa‐light‐chain‐enhancer of activated B cells‐dependent mechanism. Increased NCS1 expression leads to disrupted intracellular Ca2+ signaling and activation of the protein kinase B pathway, leading to increased cell survival and migration.

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E2 (PGE2), has shown great promise as a biomarker of β-cell dysfunction in T2D. PGE2 synthesis, secretion, and downstream signaling are all upregulated in pancreatic islets isolated from T2D mice and human organ donors. In these islets, preventing β-cell PGE2 signaling via a prostaglandin EP3 receptor antagonist significantly improves their glucose-stimulated and hormone-potentiated insulin secretion response. In this clinical cohort study, 167 participants, 35 non-diabetic, and 132 with T2D, were recruited from the University of Wisconsin Hospital and Clinics. At enrollment, a standard set of demographic, biometric, and clinical measurements were performed to quantify obesity status and glucose control. C reactive protein was measured to exclude acute inflammation/illness, and white cell count (WBC), erythrocyte sedimentation rate (ESR), and fasting triglycerides were used as markers of systemic inflammation. Finally, a plasma sample for research was used to determine circulating PGE2 metabolite (PGEM) levels. At baseline, PGEM levels were not correlated with WBC and triglycerides, only weakly correlated with ESR, and were the strongest predictor of T2D disease status. One year after enrollment, blood glucose management was assessed by chart review, with a clinically-relevant change in hemoglobin A1c (HbA1c) defined as ≥0.5%. PGEM levels were strongly predictive of therapeutic response, independent of age, obesity, glucose control, and systemic inflammation at enrollment. Our results provide strong support for future research in this area.

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes 1 – 3 , the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation—all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment—reversing hepatic steatosis and glucose intolerance—were abrogated in Insp3r1 (also known as Itpr1 )-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes. A role and mechanism of action are identified for INSP3R1 in the stimulation of hepatic gluconeogenesis and mitochondrial oxidation by glucagon, suggesting that INSP3R1 may be a target for ameliorating dysregulation of hepatic glucose metabolism.

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases.

While it is well-established that alterations in the portal vein insulin/glucagon ratio play a major role in causing dysregulated hepatic glucose metabolism in type 2 diabetes (T2D)1–3, the mechanisms by which glucagon alters hepatic glucose production and mitochondrial oxidation remain poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing hepatic adipose triglyceride lipase activity, intrahepatic lipolysis, hepatic acetyl-CoA content, and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation, mediated by stimulation of the inositol triphosphate receptor-1 (InsP3R-I). Chronic physiological increases in plasma glucagon concentrations increased mitochondrial hepatic fat oxidation and reversed diet-induced hepatic steatosis and insulin resistance in rats and mice; however, the effect of chronic glucagon treatment to reverse hepatic steatosis and glucose intolerance was abrogated in InsP3R-I knockout mice. These results provide new insights into glucagon biology and suggest that InsP3R-I may be a novel therapeutic target to reverse nonalcoholic fatty liver disease and T2D.

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER), plasma membrane, and primary cilia of all cell and tissue types. Loss-of-function mutations in the gene encoding for PC2, PKD2, lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. In the past decade, culminating evidence has indicated that ADPKD is characterized by altered metabolism of cystic kidney cells, though the specific mechanisms leading to this phenotype remained unclear, especially in the context of PC2-mediated ADPKD. One process by which cells regulate cell metabolism is through the formation of mitochondria-associated membrane (MAM) regions, which function to increase the efficiency of Ca2+ transfer from the ER into mitochondria, thus stimulating mitochondrial respiration. Through my thesis work I show that PC2 functions to reduce these inter-organelle contacts and consequently mitochondrial Ca2+ uptake and function. In cell culture models, PC2 knockdown led to a 50% increase in mitofusin 2 (MFN2) expression, an outer mitochondrial membrane GTPase that physically tethers mitochondria to the ER. Live-cell super-resolution and electron microscopy analyses revealed enhanced MFN2-dependent ER-mitochondrial tethering in PC2 knockdown cells. PC2 knockdown also led to increased ER-mediated mitochondrial Ca2+ signaling, bioenergetic activation, and mitochondrial density. In cell culture models and in mice with kidney-specific PC2 knockout, knockdown of MFN2 rescued defective mitochondrial Ca2+ transfer and diminished cell proliferation in kidney cysts. Consistent with these results, cyst-lining epithelial cells from human ADPKD kidneys had a twofold increase in mitochondria and MFN2 expression. Our data suggest that PC2 normally serves to limit key mitochondrial proteins at the ER-mitochondrial interface and acts as a checkpoint for mitochondrial biogenesis and bioenergetics. Loss of this regulation may contribute to the increased oxidative metabolism and aberrant cell proliferation typical of kidney cysts in ADPKD.Though PC2 plays a clear role in kidney physiology, it is a ubiquitously expressed protein. However, despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, and thus the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains incompletely understood. In this thesis, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases, overall providing new evidence for the importance of PC2 not only in the kidney, but in all tissue and cell types.

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E (PGE ), has shown great promise as a biomarker of β-cell dysfunction in T2D. PGE synthesis, secretion, and downstream signaling are all upregulated in pancreatic islets isolated from T2D mice and human organ donors. In these islets, preventing β-cell PGE signaling via a prostaglandin EP3 receptor antagonist significantly improves their glucose-stimulated and hormone-potentiated insulin secretion response. In this clinical cohort study, 167 participants, 35 non-diabetic, and 132 with T2D, were recruited from the University of Wisconsin Hospital and Clinics. At enrollment, a standard set of demographic, biometric, and clinical measurements were performed to quantify obesity status and glucose control. C reactive protein was measured to exclude acute inflammation/illness, and white cell count (WBC), erythrocyte sedimentation rate (ESR), and fasting triglycerides were used as markers of systemic inflammation. Finally, a plasma sample for research was used to determine circulating PGE metabolite (PGEM) levels. At baseline, PGEM levels were not correlated with WBC and triglycerides, only weakly correlated with ESR, and were the strongest predictor of T2D disease status. One year after enrollment, blood glucose management was assessed by chart review, with a clinically-relevant change in hemoglobin A1c (HbA1c) defined as ≥0.5%. PGEM levels were strongly predictive of therapeutic response, independent of age, obesity, glucose control, and systemic inflammation at enrollment. Our results provide strong support for future research in this area.

Over half of patients with type 2 diabetes (T2D) are unable to achieve blood glucose targets despite therapeutic compliance, significantly increasing their risk of long-term complications. Discovering ways to identify and properly treat these individuals is a critical problem in the field. The arachidonic acid metabolite, prostaglandin E[sub.2] (PGE[sub.2] ), has shown great promise as a biomarker of β-cell dysfunction in T2D. PGE[sub.2] synthesis, secretion, and downstream signaling are all upregulated in pancreatic islets isolated from T2D mice and human organ donors. In these islets, preventing β-cell PGE[sub.2] signaling via a prostaglandin EP3 receptor antagonist significantly improves their glucose-stimulated and hormone-potentiated insulin secretion response. In this clinical cohort study, 167 participants, 35 non-diabetic, and 132 with T2D, were recruited from the University of Wisconsin Hospital and Clinics. At enrollment, a standard set of demographic, biometric, and clinical measurements were performed to quantify obesity status and glucose control. C reactive protein was measured to exclude acute inflammation/illness, and white cell count (WBC), erythrocyte sedimentation rate (ESR), and fasting triglycerides were used as markers of systemic inflammation. Finally, a plasma sample for research was used to determine circulating PGE[sub.2] metabolite (PGEM) levels. At baseline, PGEM levels were not correlated with WBC and triglycerides, only weakly correlated with ESR, and were the strongest predictor of T2D disease status. One year after enrollment, blood glucose management was assessed by chart review, with a clinically-relevant change in hemoglobin A1c (HbA1c) defined as ≥0.5%. PGEM levels were strongly predictive of therapeutic response, independent of age, obesity, glucose control, and systemic inflammation at enrollment. Our results provide strong support for future research in this area.

Abstract We and others previously reported increased signaling through the Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor (GPCR) for the arachidonic acid metabolite, prostaglandin E2 (PGE2), is associated with β-cell dysfunction of type 2 diabetes (T2D). Yet, the relationship between PGE2 production and signaling and β-cell function during the progression to T2D remains unclear. In this work, we assessed gene expression from a panel of cadaveric human islets from 40 non-diabetic donors with BMI values spanning the spectrum from lean to high-risk obesity. Interleukin-6 (gene symbol: IL6) and cyclooxygenase-2 (COX-2) (gene symbol: PTGS2) mRNA levels were positively correlated with donor body mass index (BMI), while EP3 (gene symbol: PTGER3) was not. IL6 was itself strongly correlated with PTGS2 and all but one of the other PGE2 synthetic pathway genes tested. About half of the islet preparations were used in glucose-stimulated- and incretin-potentiated insulin secretion assays using an EP3-specific antagonist, confirming functionally-relevant up-regulation of PGE2 production. Islets from obese donors showed no inherent β-cell dysfunction and were at least equally as glucose- and incretin-responsive as islets from non-obese donors. Furthermore, insulin content, a marker of islet size known to be associated with donor BMI, was also significantly and positively correlated with islet PTGS2 expression. We conclude up-regulated islet PGE2 production and signaling may be a necessary part of the β-cell adaption response, compensating for obesity and insulin resistance. Analysis of plasma PGE2 metabolite levels from a clinical cohort reveal these findings are not in conflict with the concept of further elevations in PGE2 production contributing to T2D-related β-cell dysfunction where islet EP3 expression has also been up-regulated. Figure1 Figure1 * Download figure * Open in new tab Competing Interest Statement RJF, HKS, CP, AR, JMH, DCP, RN, MD, SP, MP, DBD, and MEK declare that they have no conflicts of interest with the contents of this article. NAT is currently a Nanomedicine Innovation Center LLC employee (46701 Commerce Center Drive, Plymouth, MI 48170). AMW is currently an Allena Pharmaceuticals employee (One Newton Executive Park, Suite 202, Newton, MA 02462). ALB is currently a Pfizer employee (235 East 42nd Street, New York, NY 10017). This work was completed in full during their research training with Dr. Kimple and are not related to their current positions.

Progress in maternal child health has been hampered by poor rates of outpatient follow up for postpartum individuals. Primary care after delivery can effectively detect and treat several pregnancy-related complications and comorbidities, but postpartum linkage to primary care remains low. In this manuscript, we share the experience of implementing a novel mother-infant dyad program, the Multimodal Maternal Infant Perinatal Outpatient Delivery System (MOMI PODS), to improve primary care linkage and community resource access postpartum via integration into pediatric care structures. With a focus on providing care for people who are publicly insured, we designed a program to mitigate maternal morbidity risk factors in postpartum individuals with chronic disease or pregnancy complications. We discuss the systematic process of designing, executing, and evaluating a collaborative clinical program with involvement of internal medicine/pediatric, family medicine, and obstetric clinicians via establishing stakeholders, identifying best practices, drawing from the evidence base, designing training and promotional materials, training partners and providers, and evaluating clinic enrollment. We share the challenges encountered such as in achieving sufficient provider capacity, consistent provision of care, scheduling, and data tracking, as well as mitigation strategies to overcome these barriers. Overall, MOMI PODS is an innovative approach that integrates outpatient postpartum care into traditional pediatric structures to increase access, showing significant promise to improve healthcare utilization and promote postpartum health.