Background: The potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene has recently received much attention as a candidate susceptibility gene for type 2 diabetes mellitus, especially in Asian populations. We previously reported that Kcnq1 mutant mice exhibit reduced insulin secretion and hyperglycemia due to a decrease in pancreatic β-cell mass. Through in vivo and in vitro analyses, we ascertained that this mechanism is the result of the downregulation of the non-coding RNA ‘Kcnq1ot1,’ which is expressed in the paternal allele of the Kcnq1 gene region, causing an increase in the expression of the cell cycle inhibitor cyclin dependent kinase inhibitor 1C (Cdkn1c). It was found that decreased Kcnq1ot1 expression resulted in pancreatic β-cell failure; however, the degree of pancreatic β-cell volume reduction was not severe. Methods: We induced obesity in Kcnq1ot1 truncation mice by feeding them a high-fat diet and evaluated pancreatic β-cell mass. Results: In the present study, we reveal that CCAAT/enhancer binding protein beta (C/EBPβ), which is expressed at higher levels in pancreatic β-cells in obese individuals, further increases the expression of Cdkn1c, which is upregulated by the Kcnq1 gene mutation. We found that simultaneous Cdkn1c hypomethylation and C/EBPβ overexpression in pancreatic β-cells causes a synergistic decrease in pancreatic β-cell mass. Conclusion This finding suggests that the synergistic effect of genetic factors such as Kcnq1 gene mutations and environmental factors such as obesity and overeating, which lead to increased expression of C/EBPβ, contribute to the regulation of pancreatic β-cell mass. This study is the first to show that the Kcnq1 gene is related to pancreatic β-cell mass through genetic-environment interactions.

PURPOSE: Atrial natriuretic peptide (ANP) has a variety of pharmacologic effects, including natriuresis, diuresis, vasodilatation, and suppression of the renin-angiotensin system. A recent study showed that ANP infusion improved hypoxemia and pulmonary hypertension in a lung injury model. On the other hand, the pulse contour cardiac output (PiCCO(TM)) system (Pulsion Medical Systems, Munich, Germany) allows monitoring of the intravascular volume status and may be used to guide volume therapy in severe sepsis and critically ill patients. MATERIALS AND METHODS: We treated 10 pulmonary edema patients without heart disease with human ANP (HANP). The patients were divided into two groups: a group with normal Intrathoracic Blood Volume (ITBV) (900-1100 mL/m2) (n = 6), and a group with abnormal ITBV (n = 4), as measured by the PiCCOtrade mark device; the extravascular lung water (EVLW) and pulmonary vascular permeability index (PVPI) in the two groups were compared. RESULTS: The average patient age was 63.9 +/- 14.4 years. The normal ITBV group showed significant improvement of the EVLW (before, 16.7 +/- 2.7 mL/kg; after, 10.5 +/- 3.6 mL/kg; p = 0.0020) and PVPI (before, 3.2 +/- 0.3; after, 2.1 +/- 0.7; p = 0.0214) after the treatment. The abnormal ITBV group showed no significant improvement of either the EVLW (before, 16.3 +/- 8.9 mL/kg; after, 18.8 +/- 9.6 mL/kg; p = 0.8387) or PVPI (before, 2.3 +/- 0.8; after, 2.7 +/- 1.3; p = 0.2782) after the treatment. In both groups, the EVLW and PVPI were strongly correlated with the chest X-ray findings. CONCLUSION: We conclude that HANP supplementation may improve the EVLW and PVPI in pulmonary edema patients without heart disease with a normal ITBV. The PiCCO(TM) system seems to be a useful device for the management of pulmonary edema.
Aged ; Atrial Natriuretic Factor/administration & dosage/*therapeutic use ; Cardiac Output/*drug effects/*physiology ; Female ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Monitoring, Physiologic/*instrumentation ; Pulmonary Edema/*drug therapy/*physiopathology