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We report simulation results of photonuclear reactions in the atmosphere triggered by a downward terrestrial gamma ray flash in lightning. Possible channels of reactions in the atmosphere and their cross‐sections are verified with the ENDF/B‐VII.1 library. Monte Carlo simulations with two stages are then performed with the Geant4 framework. In the first stage, electrons following the relativistic runaway electron avalanche spectrum are produced in a mass model of the atmosphere, and production of photoneutrons and β+‐decay nuclei is calculated based on the nuclear data library. In total 1 × 1013 neutrons and 4 × 1012β+‐decay nuclei are produced by 1018 energetic electrons above 1 MeV. In the second stage, propagation of the photoneutrons and positrons from the β+‐decay nuclei in the previous stage is calculated. As a result, we model on‐ground distributions of fluxes and energy spectra for neutrons, neutron‐related gamma rays, and annihilation ones. The simulation model is to be compared with photonuclear events detected in low‐charge‐center winter thunderstorms. Plain Language Summary: Lightning discharges occasionally emit a powerful flash of gamma rays called terrestrial gamma ray flashes. Gamma rays in terrestrial gamma ray flashes have high energies enough to react with atmospheric nuclei such as nitrogen and oxygen. The nuclear reactions in the atmosphere produce neutrons and unstable isotopes that emit positrons. In this paper, we utilize a Monte Carlo simulation framework, calculate a series of reactions and processes in the atmosphere, and then construct a distribution model of neutrons, neutron‐related gamma rays, and positron‐related ones at ground level. The obtained model can be compared with recent observations of nuclear reactions during winter thunderstorms in Japan. Key Points: Possible channels of atmospheric photonuclear reactions in lightning are surveyed from a nuclear‐reaction data libraryMonte Carlo calculations are performed to simulate photoneutron and β+‐decay‐nuclide productions in the atmosphereOn‐ground distributions of fluxes and spectra for neutrons, neutron‐related gamma rays, and annihilation gamma rays are modeled [ABSTRACT FROM AUTHOR]

During a winter thunderstorm on 6 February 2017 in Japan, photonuclear reactions such as 14N(γ, n)13N were triggered by a downward terrestrial gamma‐ray flash (TGF), as reported by Enoto et al. (2017, https://doi.org/10.1038/nature24630). In the present paper, we compare the observation with a simulation model of downward TGFs and subsequent photonuclear reactions constructed by the first paper of the series and Wada, Enoto, Nakazawa, et al. (2019, https://doi.org/10.1103/physrevlett.123.061103). The observation and model consist of three components: annihilation gamma rays from positrons produced by β+‐decay nuclei, deexcitation gamma rays originating from neutron captures, and radiation doses by TGF photons. Each component of the observation is reproduced by the simulation model, and we constrain a relation between the number of avalanche electrons and their production altitude of the downward TGF. The constraints by three components match within an order of magnitude. The downward TGF is estimated to comprise (0.5–2.5) × 1019 avalanche electrons above 1 MeV produced at an altitude of 1.4–2.7 km. Despite differences in altitude, direction, and season, downward TGFs in winter thunderstorms are thought to have the same mechanism of electron acceleration and multiplication in lightning as TGFs observed by in‐orbit satellites. Plain Language Summary: Lightning flashes are sometimes accompanied by strong high‐energy emission called "terrestrial gamma‐ray flashes" (TGFs). The energy of gamma rays in TGFs is high enough to trigger nuclear reactions with atmospheric nuclei such as nitrogen and oxygen. The nuclear reactions produce neutrons and unstable isotopes that emit positrons. In the companion paper of this series, we calculated the nuclear reactions and propagation processes of their products such as positrons and neutrons and modeled their characteristics at ground level by simulations. In the present paper, the simulation model is compared with the actual observation of a TGF and nuclear reactions during winter thunderstorms in Japan. The model successfully reproduces the observation and estimate the production altitude the number of energetic electrons involved in the TGF. Key Points: A simulation model of photonuclear reactions in lightning is compared with an observation during a winter thunderstorm reported by Enoto et al. (2017, https://doi.org/10.1038/nature24630)Three detected signatures originating from positrons, neutrons, and TGF photons are reproduced by the simulation modelA downward TGF triggering photonuclear reactions comprised 1018 to 1019 avalanche electrons produced at 1.4–2.7 km above sea level [ABSTRACT FROM AUTHOR]

Aims G protein-coupled receptor/free fatty acid receptor 1 ( GPR40/ FFAR1) regulates free fatty acid-induced insulin secretion. This study has been performed to clarify whether or not loss of GPR40/ FFAR1 function exacerbates diabetes, that is, whether GPR40 has an essential physiological role in the development of diabetes or not. Methods We generated GPR40/ FFAR1 knockout ( KO) mice and analysed their phenotypes in vitro and in vivo under the condition of dietary or genetically induced insulin resistance. Results GPR40/ FFAR1 KO mice kept on a high-fat diet became obese, developed glucose intolerance to a similar degree as GPR40/ FFAR1 wild-type ( WT) mice. In addition, the phenotype of KO mice harbouring diabetogenic KK background genes showed glucose intolerance at a level similar to level for control KK mice. In both mouse models with insulin resistance, insulin secretion after oral glucose load and homeostasis model assessment-insulin resistance ( HOMA-IR) did not change between GPR40/ FFAR1 KO and WT mice. Although glucose-induced insulin secretion under high palmitate concentration was significantly lower in KO than in WT islets, pancreatic insulin content and insulin secretion stimulated with glucose alone were not different between KO and WT mice. Conclusions GPR40/ FFAR1 has a major role in regulating fatty-acid-mediated insulin secretion, but the lack of GPR40/ FFAR1 does not exacerbate glucose intolerance and insulin resistance induced by high-fat diet or diabetogenic KK gene. Our findings indicate that loss of GPR40/ FFAR1 function does not play an important role in inducing or exacerbating diabetes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Alogliptin, a highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, enhances incretin action and pioglitazone enhances hepatic and peripheral insulin actions. Here, we have evaluated the effects of combining these agents in diabetic mice.Experimental Approach: Effects of short-term treatment with alogliptin alone (0.01%-0.1% in diet), and chronic combination treatment with alogliptin (0.03% in diet) and pioglitazone (0.0075% in diet) were evaluated in db/db mice exhibiting early stages of diabetes.Key Results: Alogliptin inhibited plasma DPP-4 activity up to 84% and increased plasma active glucagon-like peptide-1 by 4.4- to 4.9-fold. Unexpectedly, alogliptin alone lacked clear efficacy for improving glucose levels. However, alogliptin in combination with pioglitazone clearly enhanced the effects of pioglitazone alone. After 3-4 weeks of treatment, combination treatment increased plasma insulin by 3.8-fold, decreased plasma glucagon by 41%, both of which were greater than each drug alone, and increased plasma adiponectin by 2.4-fold. In addition, combination treatment decreased glycosylated haemoglobin by 2.2%, plasma glucose by 52%, plasma triglycerides by 77% and non-esterified fatty acids by 48%, all of which were greater than each drug alone. Combination treatment also increased expression of insulin and pancreatic and duodenal homeobox 1 (PDX1), maintained normal beta-cell/alpha-cell distribution in islets and restored pancreatic insulin content to levels comparable to non-diabetic mice.Conclusions and Implications: These results indicate that combination treatment with alogliptin and pioglitazone at an early stage of diabetes improved metabolic profiles and indices that measure beta-cell function, and maintained islet structure in db/db mice, compared with either alogliptin or pioglitazone monotherapy. [ABSTRACT FROM AUTHOR]

Aims: G protein-coupled receptor/free fatty acid receptor 1 (GPR40/FFAR1 ) regulates free fatty acid-induced insulin secretion. This study has been performed to clarify whether or not loss of GPR40/FFAR1 function exacerbates diabetes, that is, whether GPR40 has an essential physiological role in the development of diabetes or not., Methods: We generated GPR40/FFAR1 knockout (KO) mice and analysed their phenotypes in vitro and in vivo under the condition of dietary or genetically induced insulin resistance., Results: GPR40/FFAR1 KO mice kept on a high-fat diet became obese, developed glucose intolerance to a similar degree as GPR40/FFAR1 wild-type (WT) mice. In addition, the phenotype of KO mice harbouring diabetogenic KK background genes showed glucose intolerance at a level similar to level for control KK mice. In both mouse models with insulin resistance, insulin secretion after oral glucose load and homeostasis model assessment-insulin resistance (HOMA-IR) did not change between GPR40/FFAR1 KO and WT mice. Although glucose-induced insulin secretion under high palmitate concentration was significantly lower in KO than in WT islets, pancreatic insulin content and insulin secretion stimulated with glucose alone were not different between KO and WT mice., Conclusions: GPR40/FFAR1 has a major role in regulating fatty-acid-mediated insulin secretion, but the lack of GPR40/FFAR1 does not exacerbate glucose intolerance and insulin resistance induced by high-fat diet or diabetogenic KK gene. Our findings indicate that loss of GPR40/FFAR1 function does not play an important role in inducing or exacerbating diabetes., (© 2013 Blackwell Publishing Ltd.)

1. The level of glycated haemoglobin (GHb) in diabetic rats was measured using a newly developed automatic high-performance liquid chromatography (HPLC) with a boronate affinity column that requires only 2.5 min per sample for analysis. 2. Levels of GHb were 2.7% in normal 7-week-old Sprague-Dawley rats. These levels increased gradually following the abrupt induction of hyperglycaemia by intravenous injection of streptozotocin (STZ), reaching a maximal level of 10.1% after 6 weeks. 3. Glycosylated haemoglobin (HbA1) levels measured by cation-exchange chromatography were also increased by STZ treatment, although HbA1 values were lower than GHb measured by affinity column HPLC. 4. In Wistar fatty rats, GHb levels declined gradually over 5 weeks following the administration of pioglitazone (0.75 or 2.25 mg/kg per day) as a food admixture, which reduced plasma glucose (PG) levels to normal levels within 1 week. Glycated haemoglobin levels after 5 weeks treatment with pioglitazone correlated better with the area under the curve for PG over the entire 5 week treatment period than with the PG level at the end of treatment. 5. In addition, GHb determined by affinity column HPLC correlated well with HbA1 measured by cation-exchange chromatography, although the GHb value was higher than the HbA1 value. 6. Glycated haemoglobin levels in db/db and KKAy mice were higher than those in control normoglycaemic animals and were also higher than HbA1 values measured by the cation-exchange method, although the two values did show good correlation. 7. These results indicate that the newly developed affinity column HPLC system is useful for evaluating total GHb levels in rats as an index of antidiabetic treatment.

1. The effects of combined treatment with pioglitazone.HCl and metformin on diabetes and obesity were investigated in Wistar fatty rats, which are hyperglycaemic and hypertriglyceridaemic and have higher plasma levels of total ketone bodies than lean rats. 2. Plasma glucose was significantly decreased when pioglitazone.HCl or metformin was administered alone and combined treatment accentuated this decrease. The administration of pioglitazone.HCl, but not metformin, also decreased plasma levels of triglyceride and total ketone bodies. 3. The glycogen content of skeletal muscle was not increased by pioglitazone.HCl or metformin alone, but was increased by combined treatment (P=0.003, ANOVA). 4. Pioglitazone.HCl produced increased food intake and bodyweight in hyperphagic Wistar fatty rats; however, concurrent administration of metformin significantly ameliorated these pioglitazone.HCl-induced increases. 5. These results indicate that combined treatment with pioglitazone.HCl and metformin induces a marked hypoglycaemic effect accompanied by a reduction in plasma levels of total ketone bodies and prevention of excessive bodyweight gain in Wistar fatty rats. These favourable effects suggest that the combination would be beneficial in treating patients with type 2 diabetes.