FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1

Fibroblast growth factor 21 (FGF21)-mediated weight loss and improvements in glucose metabolism correlate with increased uncoupling protein 1 (Ucp1) levels in adipose tissues, suggesting that UCP1-dependent thermogenesis may drive FGF21 action. It was reported that FGF21 is equally effective at reducing body weight and improving glucose homeostasis without UCP1. We find while FGF21 can lower body weight in both wild-type and Ucp1 knockout mice, rapid clearance of glucose by FGF21 is defective in the absence of UCP1. Furthermore, in obese wild-type mice there is a fall in brown adipose tissue (BAT) temperature during glucose excursion, and FGF21 improves glucose clearance while preventing the fall in BAT temperature. In Ucp1 knockout mice, the fall in BAT temperature during glucose excursion and FGF21-mediated changes in BAT temperature are lost. We conclude FGF21-mediated improvements in clearance of a glucose challenge require UCP1 and evoke UCP1-dependent thermogenesis as a method to increase glucose disposal

Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs

Functional cytochrome P450 1A enzymes are induced in mouse and human islets following pollutant exposure

Aims/hypothesis: Exposure to environmental pollution has been consistently linked to diabetes incidence in humans, but the potential causative mechanisms remain unclear. Given the critical role of regulated insulin secretion in maintaining glucose homeostasis, environmental chemicals that reach the endocrine pancreas and cause beta cell injury are of particular concern. We propose that cytochrome P450 (CYP) enzymes, which are inv

Effects of Various Alpha-1 Antitrypsin Supplement Dosages on the Lung Microbiome and Metabolome

Patients with Alpha-1 Antitrypsin Deficiency (A1AD) have abnormally low levels of the protein Alpha-1 Antitrypsin (AAT) in their blood, because of a double mutation that makes the protein misfold and instead collect in the liver (sometimes even causing cirrhosis). The currently accepted single dosage (SD) of AAT supplements does not produce AAT blood concentrations anywhere near normal levels; they typically only reach the effect of having a single mutation. Some have therefore advocated for a double dosage (DD) of these treatments, which generally would be enough to approach these normal concentrations. Levels of cytokines, produced by the immune system in response to an attack, have already been observed to drop dramatically when A1AD patients consuming single dosage started taking double dosage, and then either remain the same or increase again upon return to a single dosage regimen. In this study we administer the same dosage sequence to A1AD patients (SD, DD, SD) for one month each and view the effects on their lung microbiome and metabolome. We analyze both at the end of each stage, comparing and contrasting and discovering potential biomarkers for each stage, and concluding with a discussion of potential implications