• Biomolecules & Therapeutics
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• v.26 no.2
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• pp.201-209
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• 2018

G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.

• Journal of Ginseng Research
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• v.32 no.3
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• pp.187-193
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• 2008

The present study was designed to investigate the anti-diabetic effect and mechanism of Korean red ginseng in C57BL/KsJ db/db mice. The db/db mice were divided into three groups: diabetic control group (DC), Korean red ginseng group (KRG, 100 mg/kg) and metformin group (MET, 300 mg/kg), and treated with drugs once per day for 10 weeks. Compared to the DC group, fasting blood glucose levels were decreased by 19.8% in KRG-, 67.7% in MET-treated group. With decreased plasma glucose and insulin levels, the insulin resistance index of the KRG-treated group was reduced by 27.6% compared to the DC group. The HbA1c levels in KRG and MET-treated groups were also decreased by 11.0% and 18.9% compared to that of DC group, respectively. Plasma triglyceride and non-esterified fatty acid levels were decreased by 18.8% and 16.8%, respectively, and plasma adiponectin and leptin levels were increased by 20.6% and 12.1%, respectively, in the KRG-treated group compared to those in DC group. Histological analyses of the liver and fat tissue of mice treated with KRG revealed significantly decreased number of lipid droplets and decreased size of adipocytes compared to the DC group. From the pancreatic islet double-immunofluorescence staining, we observed KRG has increased insulin contents, but decreased glucagon production. To elucidate action mechanism of KRG, effects on AMP-activated protein kinase (AMPK) and its downstream target proteins responsible for fatty acid oxidation and gluconeogenesis were explored in the liver. KRG activated AMPK and acetyl-coA carboxylase (ACC) phosphorylations, resulting in stimulation of fatty acid oxidation. KRG also caused to down regulation of SREBP1a and its target gene expressions such as FAS, SCD1 and GPAT. In summary, our results suggest that KRG exerted the anti-diabetic effect through AMPK activation in the liver of db/db mice.

• Korean Journal of Veterinary Pathology
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• v.2 no.1
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• pp.17-24
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• 1998

This is the first report of c-Jun protein expression and mRNA in a pancreatic islet in a nonobese diabetic(NOD) state mice. In this experiment NOD mice with insulin-dependent diabetes mellitus type I at age 16 weeks(n=7) just before death(n=4) were used. The control group consist of prediabetic NOD(8 weeks n=7) and ICR(8 weeks n=7 and 16 weeks n=7) mice. c-Jun positive cells in the pancreatic islet of NOD mice were localized in the same positions as a-glucagon producing cells. immunoreactivity was negative in the prediabetic NOD(8 weeks) and ICR(8 weeks and 16 weeks) mice. The number of c-Jun positive cells in mice with severe diabetic state just before death were significantly decreased when compared to NOD(16 weeks) mice. Expression of c-Jun in mRNA level was assessed by RT-PCR method. The levels of mRNA in NOD(16 weeks) mice group were elevated in total pancreatic tissues. The present results suggest that the induction of proto-oncogene protein may be of significance in assessing cell specific injury and may play a functional role between pancretic islet $\alpha$-cells and $\beta$-cells in the diabetic state.

• The Korean Journal of Zoology
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• v.34 no.4
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• pp.433-451
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• 1991

척추동물(7목 23종)의 췌장에서 insulin( B)세포, glucagon(A)세포, somatostatin( D)세포 및 pancreatic polypeptide( PP)세포 등을 면역세포화학법으로 동정하여 이들의 출현율, 분포양상 및 형태 등을 계통별로 비교하였다. 파충강의 거북목, 양서강의 유미목 및 어강의 악상대목 들을 제외한 모든 종에서 췌도의 형성을 관찰할 수 있었으며, 췌도를 구성하는 내분비세포의 크기에는 계통간의 차이가 있었다. B세포는 파충강의 것이 가장 크고, 양서강, 어강의 순이 었으며 A와 PP세포는 양서강, 파충강 및 어강의 순서였다. D세포는 양서강의 것이 가장 윤고, 다음이 어장이었으며, 파충강의 것이 가장 작았다. 이들 세포의 모양은 B세포의 경우 양서강과 어장에서는 원형, 난원형 및 방추형이었으며, 파충강에서는 원추형 및 단기형 등 다양한 모습이었다. A세포는 어강에서는 원헝, 난원형 및 방추형이 고르게 나타났고, 파충강과 양서 강에서는 원주형, 다각형 및 쐐기형이 나타났다. D세포는 모든 동물에서 원형, 난원형 및 방추형이 관찰되었고, 특히 파충강에서는 원추형및 쐐기형도 나타났다. PP세포는 주로 방추형 및 반원형이 대다수이였으며 간혹 원형 또는 다각형 등의 모습도 나타났다. 각 내분비세포의 출현율은 파충강 열 어강 들에서는 B, A, D 및 PP세포 순이었으나, 양서 강에서는 B, A, PP 및 D세포 순으로 나타났다. B와 PP세포는 양서강, 어강 및 파충강 순서로 출현하였고, A세포는 파충강, 어강 및 양서강의 순서이었으며 D세포는 어강, 파충강 및 양서강의 순서였다. 췌도 내에서의 세포의 분포 위치는 세포의 종류에 따라 차이를 보여 B세포의 경우 대다수 동물들에서 중앙부에 균등하게 분포하였으나 A, D및 PP세포는 주로 췌도 주변부에 분포하였고, 어강에서의 D세포는 췌도 중앙부에서도 관찰되었다. 일반적으로 파충강 및 양서 강에서는 외분비 선포조직에서초 내분비세포들이 출현하였으나, 어강에서는 내분비세포가 전혀 출현하지 않았다. 양서강 및 어강 들의 일부 수에서는 췌관상피에서도 드물게 나타났다.

• Journal of Nutrition and Health
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• v.38 no.8
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• pp.613-625
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• 2005

This study was designed to evaluate impact of kinds of dietary grain and dietary lipid level on the glucose metabolism and antithrombogenic capacity in obesity induced rats. Total of 80 Sprague-Dawley male rats were raised for one month with control diet containing $50\%$ (w/w) well-milled rice powder and $20\%$(w/w) of dietary lipids. The rats were blocked into 8 groups and raised for two months with diets containing well-milled rice, brown rice, black rice, or glutinous barley powder and 8 or $20\%$(w/w) of dietary lipids. The contents of total dietary fiber in experimental grains were in following order; glutinous barley > black rice > brown rice > well-milled rice. Weekly food intake were lower in glutinous barley group among all experimental groups. Body weight gain was high in high level of fat groups ($50\%$w/w) than medium level of fat groups ($8\%$ w/w). Plasma glucose concentration was not different significantly in each groups. But brown rice group was a little lower than others. Plasma insulin concentration was lower in black rice and glutinous barley group than rice group. Plasma glucagon concentration did not differ significantly among all experimental groups. Hexokinase activities in skeletal muscle are different significantly according to level of dietary fat and grain variety factors. Brown rice group was significantly highest among all experimental groups in hexokinase activity. Plasma $TXB_2$ concentrations in black rice and glutinous barley groups were lower as compared to rice and brown rice groups. Plasma 6-keto-$PGF_{1\alpha}$ concentrations in glutinous barley group was higher as compared to others. In conclusion brown rice has a little lowering effect glucose concentration. Black rice and glutinous barley intakes enhance antithromboenic capacity. It is suggested that the intakes of mixed gains are recommend.

• YAKHAK HOEJI
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• v.50 no.6
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• pp.386-392
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• 2006

Pramlintide, a synthetic analogue of human hormone amylin, is the first of a new class of amylinomimetic compounds. Present study was undertaken to compile and analyze the clinical trials of pramlintide, and thereby to facilitate the design of the bridging study for the earlier introduction of the drug, which might be needed by diabetes patients in Korea. Sixty-two articles from Pubmed and MEDLINE search were used to analyze the trials of pramlintide along with prescribing information and New Drug Application packet obtained form the manufacturer. The efficacy of the new drug was attributed to three mechanisms: delay of gastric emptying time, inhibition of post-prandial glucagon secretion, and reduction of food intake by enhanced satiety. Clinical trials consistently identified the effectiveness of the drug for the treatment of type 1and type 2 diabetes who have failed to achieve glycemic control despite optimal therapy with insulin. However, the six pivotal Phase III clinical trials were peformed with mostly caucasian and some black and hispanic people. None of the trials documented the proportion of either Asian or Korean participants. Since Korean diabetes patients show different epidemiology and characteristics in their disease state, it appears that the bridging study of pramlintide should be designed in the level of full scale Phase III clinical trial along with pharmacokinetic and pbarmacodynamic studies.

• Asian-Australasian Journal of Animal Sciences
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• v.32 no.5
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• pp.648-656
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• 2019

Objective: An experiment was conducted to determine the effect of reduced energy density of close-up diets on metabolites, lipolysis and gluconeogenesis in cows during the transition period. Methods: Thirty-nine Holstein dry cows were blocked and assigned randomly to three groups, fed a high energy density diet (HD, 1.62 Mcal of net energy for lactation $[NE_L]/kg$ dry matter [DM]), a medium energy density diet (MD, $1.47Mcal\;NE_L/kg\;DM$), or a low energy density diet (LD, $1.30Mcal\;NE_L/kg\;DM$) prepartum; they were fed the same lactation diet to 28 days in milk (DIM). All the cows were housed in a free-stall barn and fed ad libitum. Results: The reduced energy density diets decreased the blood insulin concentration and increased nonesterified fatty acids (NEFA) concentration in the prepartum period (p<0.05). They also increased the concentrations of glucose, insulin and glucagon, and decreased the concentrations of NEFA and ${\beta}-hydroxybutyrate$ during the first 2 weeks of lactation (p<0.05). The plasma urea nitrogen concentration of both prepartum and postpartum was not affected by dietary energy density (p>0.05). The dietary energy density had no effect on mRNA abundance of insulin receptors, leptin and peroxisome proliferator-activated $receptor-{\gamma}$ in adipose tissue, and phosphoenolpyruvate carboxykinase, carnitine palmitoyltransferase-1 and peroxisome proliferator-activated $receptor-{\alpha}$ in liver during the transition period (p>0.05). The HD cows had higher mRNA abundance of hormone-sensitive lipase at 3 DIM compared with the MD cows and LD cows (p = 0.001). The mRNA abundance of hepatic pyruvate carboxy-kinase at 3 DIM tended to be increased by the reduced energy density of the close-up diets (p = 0.08). Conclusion: The reduced energy density diet prepartum was effective in controlling adipose tissue mobilization and improving the capacity of hepatic gluconeogenesis postpartum.

• Archives of Obesity and Metabolism
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• v.1 no.2
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• pp.78-82
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• 2022

Liraglutide (Saxenda^R) is prescribed to induce and sustain weight loss in obese patients. The starting dose of liraglutide is 0.6 mg/day for 1 week, which is increased by 0.6 mg/day every week until the full maintenance dose of 3 mg/day is achieved. Such dose titration is needed to prevent side effects, which primarily include gastrointestinal problems such as nausea, diarrhea, constipation, vomiting, dyspepsia, and abdominal pain. A 35-year-old, reportedly healthy obese man receiving liraglutide treatment for obesity visited the emergency room complaining of generalized weakness and dizziness accompanied by repeated diarrhea and vomiting. He reported over 20 episodes of diarrhea starting the day after liraglutide dose escalation from 1.2 mg/day to 1.8 mg/day. Laboratory findings suggested pre-renal acute kidney injury, including serum creatinine 4.77 mg/dl, blood urea nitrogen (BUN) 37 mg/dl, estimated glomerular filtration rate (eGFR) 15 ml/min/1.73 m², and Fractional excretion of sodium 0.08. After volume repletion therapy, his renal function recovered to a normal range with laboratory values of creatinine 1.08 mg/dl, BUN 14 mg/dl, and eGFR 88 ml/min/1.73 m². This case emphasizes the need for caution when prescribing glucagon-like peptide-1 receptor agonists, including liraglutide, given the risk of serious renal impairments induced by volume depletion and dehydration through severe-grade diarrhea and vomiting.

• The Journal of Internal Korean Medicine
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• v.41 no.6
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• pp.1078-1088
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• 2020

Objective: The purpose of this study was to investigate the effect of amorfrutin of licorice for Type2 diabetes mellitus. Method: The PubMed, CNKI, Wanfang, OASIS, NDSL, J-STAGE, and CiNii databases were searched from the beginning of the search to September 20, 2020, with no limits on language. Extractions and selections from the literature were made by two authors. The study included in vivo experiments with amorfrutins in high-fat diet-induced obesity C57BL/6 mice and leptin receptor-deficient db/db mice and in silico studies. Results & Conclusion: Four studies were finally selected. We confirmed that amorfrutin treatment considerably improved insulin sensitivity and glucose tolerance and reduced plasma insulin and glucose. Amorfrutins bind to and selectively activate Peroxisome Proliferator-Activated Receptor Gamma (PPARγ), which plays an important role in glucose metabolism. Amorfrutins also strongly bind to the glucagon receptor (GCGR) and work as antagonist. Using the amorfrutins from licorice could therefore be helpful in treating type2 diabetes mellitus.

• Molecules and Cells
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• v.45 no.4
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• pp.180-192
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• 2022

Nuclear receptor coactivator 6 (NCOA6) is a transcriptional coactivator of nuclear receptors and other transcription factors. A general Ncoa6 knockout mouse was previously shown to be embryonic lethal, but we here generated liver-specific Ncoa6 knockout (Ncoa6 LKO) mice to investigate the metabolic function of NCOA6 in the liver. These Ncoa6 LKO mice exhibited similar blood glucose and insulin levels to wild type but showed improvements in glucose tolerance, insulin sensitivity, and pyruvate tolerance. The decrease in glucose production from pyruvate in these LKO mice was consistent with the abrogation of the fasting-stimulated induction of gluconeogenic genes, phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose-6-phosphatase (G6pc). The forskolin-stimulated inductions of Pck1 and G6pc were also dramatically reduced in primary hepatocytes isolated from Ncoa6 LKO mice, whereas the expression levels of other gluconeogenic gene regulators, including cAMP response element binding protein (Creb), forkhead box protein O1 and peroxisome proliferator-activated receptor γ coactivator 1α, were unaltered in the LKO mouse livers. CREB phosphorylation via fasting or forskolin stimulation was normal in the livers and primary hepatocytes of the LKO mice. Notably, it was observed that CREB interacts with NCOA6. The transcriptional activity of CREB was found to be enhanced by NCOA6 in the context of Pck1 and G6pc promoters. NCOA6-dependent augmentation was abolished in cAMP response element (CRE) mutant promoters of the Pck1 and G6pc genes. Our present results suggest that NCOA6 regulates hepatic gluconeogenesis by modulating glucagon/cAMP-dependent gluconeogenic gene transcription through an interaction with CREB.