Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

Background: Postprandial syndrome is characterized by hunger, weakness and anxiety neurosis occurring after meals. Although abnormal glucagon response has been suggested, inaccuracies of the conventional glucagon measurement method have prevented from precise analysis. Recently, a more reliable dual-antibody sandwich enzyme-linked immunosorbent assay for glucagon has been developed. Methods:We conducted a 75 g oral glucose tolerance test (OGTT) extending to 4 hours in 14 patients with idiopathic postprandial syndrome. In addition to blood glucose and insulin, we have measured glucagon concentrations using the novel method and analyzed retrospectively.Results: Median (lower quartile, upper quartile) of age and BMI were 40 years old (30, 49) and 24.9 (23.1, 26.2), respectively. The OGTT revealed that one patient had a diabetic pattern, and two were glucose intolerant. Fasting insulin was 7.6 U/mL (6.8, 8.8) and reached 73.7 (54.3, 82.6) at 30 min. Insulin remained elevated until 180 min. The fasting glucagon was 21.1 pg/mL (16.1, 33.8), falling at 60 min to a nadir of 6.9 (3.5, 10.3), onethird of the baseline, then remaining suppressed until 180 min. Furthermore, we have found that two types of glucagon dynamics: one is lower fasting glucagon with further suppression and the other is normal or higher fasting glucagon with subsequent big drop.Conclusions: These data suggest that glucagon suppression is stronger in patients with idiopathic postprandial syndrome than in normal subjects previously reported. The present data will contribute to further understanding and future research of this syndrome.

The present investigation was performed to examine wether the polygraphic monitoring and recording method developed by SUGANO et al (1962) for mouse was applicable or not in determining the normal values in several physiological factors, i. e. body temperature, heart beat, respiratory rate, blood pressure and sedimentation rate of erythrocyte in chick.The summarized results were as follows :(1) The experiments were made by using white leghorn chicks belonging to the same strain.The age of the chicks distributed from 1 to 10 weeks old after hatch. Growth of the chicks used was recognized as normal, with reference to weekly increase of body weight. The sexual difference was found in the chicks older than 6 weeks.(3) The heart beat rate continued to increase to reach its maximum of 470 in 2 to 4 weeks old chicks and decreased to about 370 in the 10th week of age in which the sexual difference in the rate was detected, females showing higher values.(4) The respiratory rate showed a remarkably wide range of variation, but it presented a gradual decrease accompanying with growth until it dropped to about 40 in 10 weeks old chicks.(5) An increase of the blood pressure was presented during the initial six weeks of growth and it reached to its maximum value of 140mmHg in the 10th week.(6) The sedimentation rate of erythrocyte was 2.0 to 2.5mm per 30 minutes at the age of 6 to 10 weeks after hatch.Jap. J. Zootech. Sci., 37, (3) 93 1966. 3.

Glucose produces, through glycolysis, pyruvate, a substrate for mitochondrial metabolism. Mitochondrial metabolism generates signals for insulin exocytosis, which include ATP and other as yet unidentified molecules. Although important roles of mitochondrial metabolism of glucose for insulin secretion is established, roles of glycolysis are not completely understood. Does glycolysis merely produce pyruvate for mitochondrial metabolism or generate its own signal? To study this question, we have created mitochondrial pyruvate carrier 2 (Mpc2) knockout MIN6 cells by the Crispr technology. We first generated MIN6 cells expressing MPC2-Flag under the control of Tet3G transcriptional activator, to assure mitochondrial metabolism of glucose in a condition of Mpc2 alleles being knocked out. Then, stop codons followed by the zeocin or puromycin-resistant gene units were introduced in the second exons of the gene. We have confirmed a complete loss of endogenous MPC2 expression by Western blot analyses and these cells were maintained in the presence of doxycycline, expressing MPC2-Flag. Upon withdrawal of doxycycline, glycolytic flux estimated by 5-[3H]glucose utilization was unaltered at 5 mM glucose but reduced by 37.2% ± 1.2% (Mean ± SE, n = 3, p < 0.05) at 12.5 mM and 55.3% ± 9.6% (p < 0.05) at 20 mM. In MPC2-deficient MIN6 cells, glucose-stimulated insulin secretion was completely abolished at 12.5 and 20 mM glucose, while glutamine (5 mM) plus leucine (5 mM) induced insulin secretion was comparable to that by doxycycline-treated MPC2-Flag expressing cells. Interestingly, when MPC2-deficient MIN6 cells were activated with glutamine plus leucine, 5-20 mM glucose was able to cause further dose-dependent increases in insulin secretion with 1.9 ± 0.3-fold (n = 4, p < 0.05) augmentation at 20 mM. These data suggested that glycolysis generates signals for insulin secretion distinct from those produced by the mitochondria in glucose-stimulated insulin secreting cells. Disclosure H. Ishihara: Advisory Panel; Self; Astellas Pharma Inc. Research Support; Self; Daiichi Sankyo, Eli Lilly Japan K.K., Kowa Company, Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma K.K., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi. H. Nishioka: None. M. Yamana: None. A. Nagasawa: None. M. Kosuda: None. M. Koike: None. G. Kohno: None. H. Saito: None.

Tne purpose of the present experiment was to examine the changes of physiological values possibly produced by the medication of a few of agricultural chemicals such as Diethyl Pnitrophenyl monothiophosphate (Parathion) and 1, 2 dicarboethoxyethyl dithiophosphate (Marathion) and make a detailed analysis of the changes from the view point of polygraphy in growing chicks. The results obtained were as follows :(1) Principal symptoms appeared in Parathion and/or Marathion poisoning in chicks presented a similarity to those observed in adult fowls and mammals medicated with them. Urination, lacrimation, salivation, piloerection and defecation etc. were usualy detected and muscular tremor was also frequently recognized. The vigorous difficulty of breathing and convulsion produced by injection of a large quantity of the drugs were always followed by death. The toxic potency of Parathion was presumed to be about 10 times stronger than that of Marathion.(2) The injection of Parathion into the pectoral muscle produced a prompt decrease of the heart beat rate and respiration frequency and a sudden decline of blood pressure. In this case, the death occured usually in few minutes after medication, despite quantity of the chemicals injected being distributed over a wide range of 15 mg/kg to 60 mg/kg.(3) The drug effect was influenced by density of the solution injected. An adequate dose for observing the typical phenomena in phosphate poisoning was 720 mg/kg in Marathion and 60 mg/kg in Parathion, by which the chicks could be kept alive long enough to the observation time of about 60 minutes.(4) The changes in physiological measures in case of the poisoning by organic phosphate medication followed after the above-mentioned clinical or external phenomena. A prompt decrease of the heart beat and a rapid decline of the blood pressure appeared almost simultaneously. An acceleration of respiratory movement gave rise immediately to occure before the death and its abrupt cease accompanying with vigorous convulsion.(5) It seems that Parathion acts further stronger to 4 weeks old chicks than 6 or 8 weeks old chicks from the vieow point of length of their living time.Ja p. J. Zootech. Sci., 37, (3). 99 1966. 3.