Research Spotlight

Testa, G., G. J. McKenna, R. T. Gunby, T. Anthony, E. C. Koon, A. M. Warren, J. M. Putman, L. Zhang, G. dePrisco, J. M. Mitchell, K. Wallis, G. B. Klintmalm, M. Olausson and L. Johannesson (2018). “First live birth after uterus transplantation in the United States.” Am J Transplant Mar 25. [Epub ahead of print].

Full text of this article.

Uterus transplantation has proven to be a successful treatment for women with absolute uterine infertility, caused either by the absence of a uterus or the presence of a nonfunctioning uterus. We report the first birth of a healthy child following uterus transplantation in the United States, from a recipient of a uterus allograft procured from an altruistic living donor. Two major modifications from the previously reported live births characterized this uterus transplant. First, the transplanted uterus relied upon and sustained the pregnancy while having only the utero-ovarian vein as venous outflow. The implication is a significantly simplified living donor surgery that paves the way for minimally invasive laparoscopic or robot-assisted techniques for the donor hysterectomy. Second, the time from transplantation to embryo transfer was significantly shortened from prior protocols, allowing for an overall shorter exposure to immunosuppression by the recipient and lowering the risk for potential adverse effects from these medications.

Pollom, R. K., T. Costigan, L. B. Lacaya, L. L. Ilag and P. A. Hollander (2018). “Similar Efficacy and Safety of Basaglar((R)) and Lantus((R)) in Patients with Type 2 Diabetes in Age Groups: A Post Hoc Analysis from the ELEMENT-2 Study.” Diabetes Ther 9(2): 827-837.

Full text of this article.

INTRODUCTION: To compare efficacy and safety of Basaglar((R)) [insulin glargine 100 units/mL; LY insulin glargine (LY IGlar)] to Lantus((R)) [insulin glargine 100 units/mL; SA insulin glargine (SA IGlar)] in older (greater than or equal to 65 years) or younger (less than 65 years) patients with type 2 diabetes (T2D). METHODS: This subgroup analysis of a phase 3, randomized, double-blind, multinational, 24-week study compared LY IGlar and SA IGlar on several clinical efficacy (change in glycated hemoglobin (A1c), basal insulin dose, weight) and safety outcomes (incidence of adverse events, insulin antibodies, hypoglycemia incidence and rates) in patients either greater than or equal to 65 or less than 65 years. RESULTS: Compared with patients aged less than 65 years (N = 542), patients aged greather than or equal to 65 years (N = 214) had a significantly longer duration of diabetes; lower baseline A1c and body weight; and body mass index; and were more likely to report prestudy SA IGlar use. Compared to patients less than 65 years, patients greater than or equal to 65 years needed a lower basal insulin dose and experienced lower body weight gain. There were no significant treatment-by-age interactions for the clinical efficacy and safety outcomes, indicating that there was no differential treatment effect (LY IGlar vs SA IGlar) for patients greater than or equal to 65 years vs those less than 65 years. Moreover, within each age subgroup, LY IGlar and SA IGlar were similar for all clinical efficacy and safety outcomes. CONCLUSIONS: LY IGlar and SA IGlar exhibit similar efficacy and safety in patients with T2D who are greater than or equal to 65 years and in those less than 65 years. TRIAL REGISTRATION: ClinicalTrials.gov trial registration: NCT01421459.

Panda, S. K., V. Facchinetti, E. Voynova, S. Hanabuchi, J. L. Karnell, R. N. Hanna, R. Kolbeck, M. A. Sanjuan, R. Ettinger and Y. J. Liu (2018). “Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models.” J Clin Invest Apr 3. Epub ahead of print].

Full text of this article.

Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.

Packer, M. and D. W. Kitzman (2018). “Obesity-Related Heart Failure With a Preserved Ejection Fraction: The Mechanistic Rationale for Combining Inhibitors of Aldosterone, Neprilysin, and Sodium-Glucose Cotransporter-2.” JACC Heart Fail Mar 7. [Epub ahead of print].

Full text of this article.

Obesity-related heart failure with a preserved ejection fraction (HFpEF) is an important phenotype prevalent in the community, especially in people with metabolic disorders (e.g., dyslipidemia, diabetes). These individuals exhibit a marked expansion of plasma volume, but ventricular distensibility is limited, most likely as a result of cardiac microvascular rarefaction acting in concert with myocardial and pericardial fibrosis. Consequently, the increase in plasma volume causes a disproportionate increase in cardiac filling pressures, leading to heart failure, even though systolic ejection is not impaired. The features of this syndrome appear to be related (in part) to the overproduction of adipocyte-derived cell-signaling molecules, including aldosterone and neprilysin. The resulting sodium retention and plasma volume expansion is exacerbated by their mutual actions to promote cardiac and systemic inflammation and fibrosis. Inhibitors of aldosterone, neprilysin and the sodium-glucose transporter-2 (SGLT2) can ameliorate the plasma volume expansion and pro-inflammatory and profibrotic pathways, potentially opposing the action of diverse adipocytokines. All 3 classes of drugs can reduce the quantity of visceral adipose tissue and ameliorate its abnormal biological properties. This mechanistic framework is supported by the results of large-scale randomized trials with mineralocorticoid receptor antagonists and SGLT2 inhibitors and is being further tested in an ongoing large-scale trial of neprilysin inhibition. The promise of using mineralocorticoid receptor antagonists, neprilysin inhibitors, and SGLT2 inhibitors (alone or in combination) in the management of obesity-related HFpEF suggests that physicians might finally have a phenotype of HFpEF that they can understand and treat.

Packer, M. (2018). “Role of the sodium-hydrogen exchanger in mediating the renal effects of drugs commonly used in the treatment of type 2 diabetes.” Diabetes Obes Metab 20(4): 800-811.

Full text of this article.

Diabetes is characterized by increased activity of the sodium-hydrogen exchanger (NHE) in the glomerulus and renal tubules, which contributes importantly to the development of nephropathy. Despite the established role played by the exchanger in experimental studies, it has not been specifically targeted by those seeking to develop novel pharmacological treatments for diabetes. This review demonstrates that many existing drugs that are commonly prescribed to patients with diabetes act on the NHE1 and NHE3 isoforms in the kidney. This action may explain their effects on sodium excretion, albuminuria and the progressive decline of glomerular function in clinical trials; these responses cannot be readily explained by the influence of these drugs on blood glucose. Agents that may affect the kidney in diabetes by virtue of an action on NHE include: (1) insulin and insulin sensitizers; (2) incretin-based agents; (3) sodium-glucose cotransporter 2 inhibitors; (4) antagonists of the renin-angiotensin system (angiotensin converting-enzyme inhibitors, angiotensin receptor blockers and angiotensin receptor neprilysin inhibitors); and (5) inhibitors of aldosterone action and cholesterol synthesis (spironolactone, amiloride and statins). The renal effects of each of these drug classes in patients with type 2 diabetes may be related to a single shared biological mechanism.