Diabetes & Metabolism Journal

Original Article

Metabolic Risk/Epidemiology
A Prospective 1-Year Follow-Up of Glycemic Status and C-Peptide Levels of COVID-19 Survivors with Dysglycemia in Acute COVID-19 Infection: David Tak Wai Lui, Chi Ho Lee, Ying Wong, Carol Ho Yi Fong, Kimberly Hang Tsoi, Yu Cho Woo, Kathryn Choon Beng Tan; Received June 5, 2023 Accepted October 13, 2023 Published online March 11, 2024; DOI: https://doi.org/10.4093/dmj.2023.0175 [Epub ahead of print]

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We evaluated changes in glycemic status, over 1 year, of coronavirus disease 2019 (COVID-19) survivors with dysglycemia in acute COVID-19.
Methods
COVID-19 survivors who had dysglycemia (defined by glycosylated hemoglobin [HbA1c] 5.7% to 6.4% or random glucose ≥10.0 mmol/L) in acute COVID-19 were recruited from a major COVID-19 treatment center from September to October 2020. Matched non-COVID controls were recruited from community. The 75-g oral glucose tolerance test (OGTT) were performed at baseline (6 weeks after acute COVID-19) and 1 year after acute COVID-19, with HbA1c, insulin and C-peptide measurements. Progression in glycemic status was defined by progression from normoglycemia to prediabetes/diabetes, or prediabetes to diabetes.
Results
Fifty-two COVID-19 survivors were recruited. Compared with non-COVID controls, they had higher C-peptide (P< 0.001) and trend towards higher homeostasis model assessment of insulin resistance (P=0.065). Forty-three COVID-19 survivors attended 1-year reassessment. HbA1c increased from 5.5%±0.3% to 5.7%±0.2% (P<0.001), with increases in glucose on OGTT at fasting (P=0.089), 30-minute (P=0.126), 1-hour (P=0.014), and 2-hour (P=0.165). At baseline, 19 subjects had normoglycemia, 23 had prediabetes, and one had diabetes. Over 1 year, 10 subjects (23.8%; of 42 non-diabetes subjects at baseline) had progression in glycemic status. C-peptide levels remained unchanged (P=0.835). Matsuda index decreased (P=0.007) and there was a trend of body mass index increase from 24.4±2.7 kg/m² to 25.6±5.2 (P=0.083). Subjects with progression in glycemic status had more severe COVID-19 illness than non-progressors (P=0.030). Reassessment was not performed in the control group.
Conclusion
Subjects who had dysglycemia in acute COVID-19 were characterized by insulin resistance. Over 1 year, a quarter had progression in glycemic status, especially those with more severe COVID-19. Importantly, there was no significant deterioration in insulin secretory capacity.

Review

Pathophysiology
Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells: Seoil Moon, Hye Seung Jung; Diabetes Metab J. 2022;46(4):533-542. Published online July 27, 2022; DOI: https://doi.org/10.4093/dmj.2022.0070

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Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

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Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner
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Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells
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Interplay of skeletal muscle and adipose tissue: sarcopenic obesity
Min Jeong Park, Kyung Mook Choi
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Kun Cui, Zhizheng Li
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Xiaodan Zhang, Zirui Luo, Jiahong Li, Yaxuan Lin, Yu Li, Wangen Li
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Asie Sadeghi, Maryam Niknam, Mohammad Amin Momeni-Moghaddam, Maryam Shabani, Hamid Aria, Alireza Bastin, Maryam Teimouri, Reza Meshkani, Hamed Akbari
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Beta cell lipotoxicity in the development of type 2 diabetes: the need for species-specific understanding
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Original Article

Basic Research
DA-1241, a Novel GPR119 Agonist, Improves Hyperglycaemia by Inhibiting Hepatic Gluconeogenesis and Enhancing Insulin Secretion in Diabetic Mice: Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang; Diabetes Metab J. 2022;46(2):337-348. Published online January 21, 2022; DOI: https://doi.org/10.4093/dmj.2021.0056

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Background
We investigated the antidiabetic effects of DA-1241, a novel G protein-coupled receptor (GPR) 119 agonist, in vitro and in vivo.
Methods
DA-1241 was administrated to high-fat diet (HFD)-fed C57BL/6J mice for 12 weeks after hyperglycaemia developed. Oral/intraperitoneal glucose tolerance test and insulin tolerance test were performed. Serum insulin and glucagon-like peptide-1 (GLP-1) levels were measured during oral glucose tolerance test. Insulinoma cell line (INS-1E) cells and mouse islets were used to find whether DA-1241 directly stimulate insulin secretion in beta cell. HepG2 cells were used to evaluate the gluconeogenesis and autophagic process. Autophagic flux was evaluated by transfecting microtubule-associated protein 1 light chain 3-fused to green fluorescent protein and monomeric red fluorescent (mRFP-GFP-LC3) expression vector to HepG2 cells.
Results
Although DA-1241 treatment did not affect body weight gain and amount of food intake, fasting blood glucose level decreased along with increase in GLP-1 level. DA-1241 improved only oral glucose tolerance test and showed no effect in intraperitoneal glucose tolerance test. No significant effect was observed in insulin tolerance test. DA-1241 did not increase insulin secretion in INS-1E cell and mouse islets. DA-1241 reduced triglyceride content in the liver thereby improved fatty liver. Additionally, DA-1241 reduced gluconeogenic enzyme expression in HepG2 cells and mouse liver. DA-1241 reduced autophagic flow in HepG2 cells.
Conclusion
These findings suggested that DA-1241 augmented glucose-dependent insulin release via stimulation of GLP-1 secretion, and reduced hepatic gluconeogenesis, which might be associated with autophagic blockage, leading to improved glycaemic control.

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Youjin Kim, Si Woo Lee, Hyejin Wang, Ryeong-Hyeon Kim, Hyun Ki Park, Hangkyu Lee, Eun Seok Kang
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Review

Technology/Device
Assessment of Insulin Secretion and Insulin Resistance in Human: So Young Park, Jean-François Gautier, Suk Chon; Diabetes Metab J. 2021;45(5):641-654. Published online September 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0220

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Graphical Abstract Abstract PDF PubReader ePub

The impaired insulin secretion and increased insulin resistance (or decreased insulin sensitivity) play a major role in the pathogenesis of all types of diabetes mellitus (DM). It is very important to assess the pancreatic β-cell function and insulin resistance/ sensitivity to determine the type of DM and to plan an optimal management and prevention strategy for DM. So far, various methods and indices have been developed to assess the β-cell function and insulin resistance/sensitivity based on static, dynamic test and calculation of their results. In fact, since the metabolism of glucose and insulin is made through a complex process related with various stimuli in several tissues, it is difficult to fully reflect the real physiology. In order to solve the theoretical and practical difficulties, research on new index is still in progress. Also, it is important to select the appropriate method and index for the purpose of use and clinical situation. This review summarized a variety of traditional methods and indices to evaluate pancreatic β-cell function and insulin resistance/sensitivity and introduced novel indices.

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Original Articles

Basic Research
Notch1 Has an Important Role in β-Cell Mass Determination and Development of Diabetes: Young Sil Eom, A-Ryeong Gwon, Kyung Min Kwak, Jin-Young Youn, Heekyoung Park, Kwang-Won Kim, Byung-Joon Kim; Diabetes Metab J. 2021;45(1):86-96. Published online February 26, 2020; DOI: https://doi.org/10.4093/dmj.2019.0160

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Background

Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS).

Methods

Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and β-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion.

Results

NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and β-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice.

Conclusion

Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and β-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in β-cell mass determination and diabetes.

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N6-methylation of RNA-bound adenosine regulator HNRNPC promotes vascular endothelial dysfunction in type 2 diabetes mellitus by activating the PSEN1-mediated Notch pathway
Ying Cai, Tao Chen, Mingzhu Wang, Lihua Deng, Cui Li, Siqian Fu, Kangling Xie
Diabetes Research and Clinical Practice.2023; 197: 110261. CrossRef
Single‐cell RNA sequencing: Inhibited Notch2 signalling underlying the increased lens fibre cells differentiation in high myopia
Yunqian Yao, Ling Wei, Zhenhua Chen, Hao Li, Jiao Qi, Qingfeng Wu, Xingtao Zhou, Yi Lu, Xiangjia Zhu
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Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus
Yu‐Huan Peng, Ping Wang, Xiao‐Qun He, Ming‐Zhao Hong, Feng Liu
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Soluble T-cadherin promotes pancreatic β-cell proliferation by upregulating Notch signaling
Tomonori Okita, Shunbun Kita, Shiro Fukuda, Keita Fukuoka, Emi Kawada-Horitani, Masahito Iioka, Yuto Nakamura, Yuya Fujishima, Hitoshi Nishizawa, Dan Kawamori, Taka-aki Matsuoka, Maeda Norikazu, Iichiro Shimomura
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Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas
Adem Y. Dawed, Sook Wah Yee, Kaixin Zhou, Nienke van Leeuwen, Yanfei Zhang, Moneeza K. Siddiqui, Amy Etheridge, Federico Innocenti, Fei Xu, Josephine H. Li, Joline W. Beulens, Amber A. van der Heijden, Roderick C. Slieker, Yu-Chuan Chang, Josep M. Mercade
Diabetes Care.2021; 44(12): 2673. CrossRef

Clinical Diabetes & Therapeutics
Early Assessment of the Risk for Gestational Diabetes Mellitus: Can Fasting Parameters of Glucose Metabolism Contribute to Risk Prediction?: Veronica Falcone, Grammata Kotzaeridi, Melanie Hanne Breil, Ingo Rosicky, Tina Stopp, Gülen Yerlikaya-Schatten, Michael Feichtinger, Wolfgang Eppel, Peter Husslein, Andrea Tura, Christian S. Göbl; Diabetes Metab J. 2019;43(6):785-793. Published online March 12, 2019; DOI: https://doi.org/10.4093/dmj.2018.0218

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Abstract PDF PubReader

Background

An early identification of the risk groups might be beneficial in reducing morbidities in patients with gestational diabetes mellitus (GDM). Therefore, this study aimed to assess the biochemical predictors of glycemic conditions, in addition to fasting indices of glucose disposal, to predict the development of GDM in later stage and the need of glucose-lowering medication.

Methods

A total of 574 pregnant females (103 with GDM and 471 with normal glucose tolerance [NGT]) were included. A metabolic characterization was performed before 15⁺⁶ weeks of gestation by assessing fasting plasma glucose (FPG), fasting insulin (FI), fasting C-peptide (FCP), and glycosylated hemoglobin (HbA1c). Thereafter, the patients were followed-up until the delivery.

Results

Females with NGT had lower levels of FPG, FI, FCP, or HbA1c at the early stage of pregnancy, and therefore, showed an improved insulin action as compared to that in females who developed GDM. Higher fasting levels of FPG and FCP were associated with a higher risk of developing GDM. Moreover, the predictive accuracy of this metabolic profiling was also good to distinguish the patients who required glucose-lowering medications. Indices of glucose disposal based on C-peptide improved the predictive accuracy compared to that based on insulin. A modified quantitative insulin sensitivity check index (QUICKIc) showed the best differentiation in terms of predicting GDM (area under the receiver operating characteristics curve [ROC-AUC], 72.1%) or need for pharmacotherapy (ROC-AUC, 83.7%).

Conclusion

Fasting measurements of glucose and C-peptide as well as the surrogate indices of glycemic condition could be used for stratifying pregnant females with higher risk of GDM at the beginning of pregnancy.

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Epidemiology
Clinical Characteristics of People with Newly Diagnosed Type 2 Diabetes between 2015 and 2016: Difference by Age and Body Mass Index: Kyoung Hwa Ha, Cheol Young Park, In Kyung Jeong, Hyun Jin Kim, Sang-Yong Kim, Won Jun Kim, Ji Sung Yoon, In Joo Kim, Dae Jung Kim, Sungrae Kim; Diabetes Metab J. 2018;42(2):137-146. Published online February 14, 2018; DOI: https://doi.org/10.4093/dmj.2018.42.2.137

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Background

We evaluated the clinical characteristics of insulin resistance and β-cell dysfunction in newly diagnosed, drug-naive people with type 2 diabetes by analyzing nationwide cross-sectional data.

Methods

We collected the clinical data of 912 participants with newly diagnosed diabetes from 83 primary care clinics and hospitals nationwide from 2015 to 2016. The presence of insulin resistance and β-cell dysfunction was defined as a homeostatic model assessment of insulin resistance (HOMA-IR) value ≥2.5 and fasting C-peptide levels <1.70 ng/mL, respectively.

Results

A total of 75.1% and 22.6% of participants had insulin resistance and β-cell dysfunction, respectively. The proportion of participants with insulin resistance but no β-cell dysfunction increased, and the proportion of participants with β-cell dysfunction but no insulin resistance decreased as body mass index (BMI) increased. People diagnosed with diabetes before 40 years of age had significantly higher HOMA-IR and BMI than those diagnosed over 65 years of age (HOMA-IR, 5.0 vs. 3.0; BMI, 28.7 kg/m² vs. 25.1 kg/m²). However, the β-cell function indices were lower in people diagnosed before 40 years of age than in those diagnosed after 65 years of age (homeostatic model assessment of β-cell function, 39.3 vs. 64.9; insulinogenic index, 10.3 vs. 18.7; disposition index, 0.15 vs. 0.25).

Conclusion

We observed that the main pathogenic mechanism of type 2 diabetes is insulin resistance in participants with newly diagnosed type 2 diabetes. In addition, young adults with diabetes are more likely to have higher insulin resistance with obesity and have higher insulin secretory defect with severe hyperglycemia in the early period of diabetes than older populations.

Citations

Citations to this article as recorded by

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Response: Clinical Characteristics of People with Newly Diagnosed Type 2 Diabetes between 2015 and 2016: Difference by Age and Body Mass Index (Diabetes Metab J2018;42:137-46)
Kyoung Hwa Ha, Dae Jung Kim, Sungrae Kim
Diabetes & Metabolism Journal.2018; 42(3): 251. CrossRef
Letter: Clinical Characteristics of People with Newly Diagnosed Type 2 Diabetes between 2015 and 2016: Difference by Age and Body Mass Index (Diabetes Metab J 2018;42:137-46)
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Diabetes & Metabolism Journal.2018; 42(3): 249. CrossRef

Others
Comparison of the Usefulness of the Updated Homeostasis Model Assessment (HOMA2) with the Original HOMA1 in the Prediction of Type 2 Diabetes Mellitus in Koreans: Young Seok Song, You-Cheol Hwang, Hong-Yup Ahn, Cheol-Young Park; Diabetes Metab J. 2016;40(4):318-325. Published online May 27, 2016; DOI: https://doi.org/10.4093/dmj.2016.40.4.318

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Background

The original homeostasis model assessment (HOMA1) and the updated HOMA model (HOMA2) have been used to evaluate insulin resistance (IR) and β-cell function, but little is known about the usefulness of HOMA2 for the prediction of diabetes in Koreans. The aim of this study was to demonstrate the usefulness of HOMA2 as a predictor of type 2 diabetes mellitus in Koreans without diabetes.

Methods

The study population consisted of 104,694 Koreans enrolled at a health checkup program and followed up from 2001 to 2012. Participants were divided into a normal glucose tolerance (NGT) group and a pre-diabetes group according to fasting glucose and glycosylated hemoglobin levels. Anthropometric and laboratory data were measured at the baseline checkup, and HOMA values were calculated at the baseline and follow-up checkups. The hazard ratios (HRs) of the HOMA1 and HOMA2 values and the prevalence of diabetes at follow-up were evaluated using a multivariable Cox proportional hazards model and Kaplan-Meier analysis.

Results

After adjusting for several diabetes risk factors, all of the HOMA values except 1/HOMA1-β and 1/HOMA2-β in the NGT group were significant predictors of the progression to diabetes. In the NGT group, there was no significant difference in HOMA1-IR (HR, 1.09; 95% confidence interval [CI], 1.04 to 1.14) and HOMA2-IR (HR, 1.11; 95% CI, 1.04 to 1.19). However, in the pre-diabetes group, 1/HOMA2-β was a more powerful marker (HR, 1.29; 95% CI, 1.26 to 1.31) than HOMA1-IR (HR, 1.23; 95% CI, 1.19 to 1.28) or 1/HOMA1-β (HR, 1.14; 95% CI, 1.12 to 1.16). In the non-diabetic group (NGT+pre-diabetes), 1/HOMA2-β was also a stronger predictor of diabetes (HR, 1.27; 95% CI, 1.25 to 1.29) than HOMA1-IR (HR, 1.14; 95% CI, 1.12 to 1.15) or 1/HOMA1-β (HR, 1.13; 95% CI, 1.11 to 1.14).

Conclusion

HOMA2 is more predictive than HOMA1 for the progression to diabetes in pre-diabetes or non-diabetic Koreans.

Citations

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The Insulin Resistance but Not the Insulin Secretion Parameters Have Changed in the Korean Population during the Last Decade: Hae Kyung Yang, Jin Hee Lee, In-Young Choi, Hyuk Sang Kwon, Jeong Ah Shin, Seung Hee Jeong, Seung-Hwan Lee, Jae Hyoung Cho, Ho Young Son, Kun Ho Yoon; Diabetes Metab J. 2015;39(2):117-125. Published online April 20, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.2.117

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Abstract PDF PubReader

Background

This study aimed to compare the patterns of insulin secretion and resistance between Korean subjects in the 1990s and 2000s.

Methods

Insulin secretion and resistance indices were calculated from subjects who underwent 75-g oral glucose tolerance tests in the year 1997 to 1999 and 2007 to 2011 at the Seoul St. Mary's Hospital, Korea.

Results

A total of 578 subjects from the 1990s (mean age, 48.5 years) and 504 subjects from the 2000s (mean age, 50.2 years) were enrolled. Compared with the subjects from the 1990s, those from the 2000s exhibited increased insulin resistance (increased homeostatic model assessment for insulin resistance), and reduced insulin sensitivity (reduced Matsuda index and quantitative insulin sensitivity check index), regardless of their glucose tolerance status. However, insulinogenic index did not reveal significant differences between the 2 decades in subjects with or without diabetes. A distinct relationship was confirmed between Matsuda index and total area under the curve (insulin/glucose) in each glucose tolerance group. The mean product of the Matsuda index and the total area under the curve (insulin/glucose) as well as the oral disposition index, was lower in subjects with normal glucose tolerance from the 2000s than in those from the 1990s.

Conclusion

After rapid economic growth and changes in lifestyle patterns, insulin resistance has worsened across the glucose tolerance status; however, the insulin secretory function remained unchanged, which resulted in an increase in the susceptibility to the development of type 2 diabetes mellitus among Korean subjects without diabetes. We could not rule out the potential selection bias and therefore, further studies in general Korean population are needed.

Citations

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Chul-Hee Kim, Hong-Kyu Kim, Eun-Hee Kim, Sung-Jin Bae, Jaewon Choe, Joong-Yeol Park
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Association of serum 25-hydroxyvitamin D and diabetes-related factors in Korean adults without diabetes: The Fifth Korea National Health and Nutrition Examination Survey 2010–2012
Hyunah Kim, Hyunyong Lee, Hyeon Woo Yim, Hun-Sung Kim
Primary Care Diabetes.2018; 12(1): 59. CrossRef
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Suk Chon, Sang Youl Rhee, Kyu Jeung Ahn, Sei Hyun Baik, Yongsoo Park, Moon Suk Nam, Kwan Woo Lee, Soon Jib Yoo, Gwanpyo Koh, Dae Ho Lee, Young Seol Kim, Jeong‐Taek Woo
Diabetes, Obesity and Metabolism.2018; 20(5): 1121. CrossRef
Four Plasma Glucose and Insulin Responses to a 75 g OGTT in Healthy Young Japanese Women
Kei Takahashi, Hidetaka Nakamura, Hiroshi Sato, Hideto Matsuda, Kazuo Takada, Tomiko Tsuji
Journal of Diabetes Research.2018; 2018: 1. CrossRef
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In‐Kyung Jeong, Choon Hee Chung, Zhiguang Zhou, Jeong Hee Han, Ran Duan, Diana M. Edralin, Angel Rodriguez
Journal of Diabetes.2017; 9(4): 396. CrossRef
Insulin Secretory Capacity and Insulin Resistance in Korean Type 2 Diabetes Mellitus Patients
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Antisenescence activity of G9a inhibitor BIX01294 on human bone marrow mesenchymal stromal cells
Min-Ji AHN, Sin-Gu JEONG, Goang-Won CHO
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Urinary N-acetyl-β-D-glucosaminidase, an early marker of diabetic kidney disease, might reflect glucose excursion in patients with type 2 diabetes
So Ra Kim, Yong-ho Lee, Sang-Guk Lee, Eun Seok Kang, Bong-Soo Cha, Jeong-Ho Kim, Byung-Wan Lee
Medicine.2016; 95(27): e4114. CrossRef

Hexane Extract of Orthosiphon stamineus Induces Insulin Expression and Prevents Glucotoxicity in INS-1 Cells: Hae-Jung Lee, Yoon-Jung Choi, So-Young Park, Jong-Yeon Kim, Kyu-Chang Won, Jong-Keun Son, Yong-Woon Kim; Diabetes Metab J. 2015;39(1):51-58. Published online February 16, 2015; DOI: https://doi.org/10.4093/dmj.2015.39.1.51

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Background

Hyperglycemia, a characteristic feature of diabetes, induces glucotoxicity in pancreatic β-cells, resulting in further impairment of insulin secretion and worsening glycemic control. Thus, preservation of insulin secretory capacity is essential for the management of type 2 diabetes. In this study, we evaluated the ability of an Orthosiphon stamineus (OS) extract to prevent glucotoxicity in insulin-producing cells.

Methods

We measured insulin mRNA expression and glucose-stimulated insulin secretion (GSIS) in OS-treated INS-1 cells after exposure to a high glucose (HG; 30 mM) concentration.

Results

The hexane extract of OS elevated mRNA expression of insulin as well as pancreatic and duodenal homeobox-1 of INS-1 cells in a dose-dependent manner. The hexane OS extract also increased the levels of phosphorylated phosphatidylinositol 3-kinase (PI3K) in a concentration-dependent manner. Additionally, Akt phosphorylation was elevated by treatment with 100 and 200 µmol of the hexane OS extract. Three days of HG exposure suppressed insulin mRNA expression and GSIS; these expressions were restored by treatment with the hexane OS extract. HG elevated peroxide levels in the INS-1 cells. These levels were unaffected by OS treatment under both normal and hyperglycemic conditions.

Conclusion

Our results suggested that the hexane extract of OS elevates insulin mRNA expression and prevents glucotoxicity induced by a 3-day treatment with HG. This was associated with the activation of PI-3K and Akt.

Citations

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An Updated Review of Ethnobotany, Ethnopharmacology, Phytochemistry and Pharmacological Activities of Orthosiphon stamineus Benth
Anandarajagopal Kalusalingam, Dania Najiha Hasnu, Abdullah Khan, Ching Siang Tan, Bama Menon, Venkateshan Narayanan, Khang Wen Goh, Asmuni Mohd Ikmal, Noraini Talip, Poonguzhali Subramanian, Long Chiau Ming
Malaysian Applied Biology.2024; 53(1): 1. CrossRef
Scopoletin protects INS-1 pancreatic β cells from glucotoxicity by reducing oxidative stress and apoptosis
Jae Eun Park, Ji Sook Han
Toxicology in Vitro.2023; 93: 105665. CrossRef
A Systematic Review of Orthosiphon stamineus Benth. in the Treatment of Diabetes and Its Complications
Qirou Wang, Jia Wang, Nannan Li, Junyu Liu, Jingna Zhou, Pengwei Zhuang, Haixia Chen
Molecules.2022; 27(2): 444. CrossRef
Comprehensive chemical and metabolic profiling of anti‐hyperglycemic active fraction from Clerodendranthi Spicati Herba
Yun Luo, Yue Liu, Quan Wen, Yulin Feng, Ting Tan
Journal of Separation Science.2021; 44(9): 1805. CrossRef
Short-Term Protocols to Obtain Insulin-Producing Cells from Rat Adipose Tissue: Signaling Pathways and In Vivo Effect
Krista Minéia Wartchow, Letícia Rodrigues, Lucas Zingano Suardi, Barbara Carolina Federhen, Nicholas Guerini Selistre, Carlos-Alberto Gonçalves, Patrícia Sesterheim
International Journal of Molecular Sciences.2019; 20(10): 2458. CrossRef
Understanding glycaemic control and current approaches for screening antidiabetic natural products from evidence-based medicinal plants
Chintha Lankatillake, Tien Huynh, Daniel A. Dias
Plant Methods.2019;[Epub] CrossRef
50% Ethanol extract of Orthosiphon stamineus modulates genotoxicity and clastogenicity induced by mitomycin C
Dhamraa Waleed Al-dualimi, Aman Shah Abdul Majid, Sarah Furqan Faisal Al-Shimary, Amal Aziz Al-Saadi, Raghdaa Al Zarzour, Muhammad Asif, Chern Ein Oon, Amin Malik Shah Abdul Majid
Drug and Chemical Toxicology.2018; 41(1): 82. CrossRef
Can Tea Extracts Exert a Protective Effect Against Diabetes by Reducing Oxidative Stress and Decreasing Glucotoxicity in Pancreatic β-Cells?
Heeyoung Chae, Patrick Gilon
Diabetes & Metabolism Journal.2015; 39(1): 27. CrossRef

Impact of Serum Triglyceride and High Density Lipoprotein Cholesterol Levels on Early-Phase Insulin Secretion in Normoglycemic and Prediabetic Subjects: Masanori Shimodaira, Tomohiro Niwa, Koji Nakajima, Mutsuhiro Kobayashi, Norinao Hanyu, Tomohiro Nakayama; Diabetes Metab J. 2014;38(4):294-301. Published online August 20, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.4.294

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Background

Increased triglycerides (TGs) and decreased high density lipoprotein cholesterol (HDL-C) levels are established as diabetic risks for nondiabetic subjects. The aim of this study was to investigate the relationship among TG, HDL-C, TG/HDL-C ratio, and early-phase insulin secretion in normoglycemic and prediabetic subjects.

Methods

We evaluated 663 Japanese subjects who underwent the 75-g oral glucose tolerance test. On the basis of these results, the subjects were divided into four groups: those with normal glucose tolerance (NGT; n=341), isolated impaired fasting glucose (i-IFG; n=211), isolated impaired glucose tolerance (i-IGT; n=71), and combined IFG and IGT (IFG+IGT; n=40). Insulin secretion was estimated by the insulinogenic index (IGI) (Δinsulin/Δglucose [30 to 0 minutes]) and disposition index (DI) (IGI/homeostasis model assessment of insulin resistance).

Results

In prediabetic subjects (i-IFG, i-IGT, and IFG+IGT), linear regression analyses revealed that IGI and DI were positively correlated with HDL-C levels. Moreover, in subjects with i-IGT and (IFG+IGT), but not with i-IFG, the indices of insulin secretion were negatively correlated with the log-transformed TG and TG/HDL-C ratio. In both the subjects with i-IGT, multivariate linear regression analyses revealed that DI was positively correlated with HDL-C and negatively with log-transformed TG and TG/HDL-C ratio. On the other hand, in subjects with NGT, there was no association between insulin secretion and lipid profiles.

Conclusion

These results revealed that serum TG and HDL-C levels have different impacts on early-phase insulin secretion on the basis of their glucose tolerance status.

Citations

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The protective effects of lipoxin A4 on type 2 diabetes mellitus: A Chinese prospective cohort study
Sudan Wang, Xiaoyan Qian, Chao Shen, Qian Sun, Yang Jing, Bingyue Liu, Kexin Zhang, Mengyuan Li, Junrong Wang, Hui Zhou, Chen Dong
Frontiers in Endocrinology.2023;[Epub] CrossRef
Interaction between the GCKR rs1260326 variant and serum HDL cholesterol contributes to HOMA-β and ISIMatusda in the middle-aged T2D individuals
Min Shen, Liying Jiang, Hechun Liu, Hao Dai, Hemin Jiang, Yu Qian, Zhixiao Wang, Shuai Zheng, Heng Chen, Tao Yang, Qi Fu, Kuanfeng Xu
Journal of Human Genetics.2023; 68(12): 835. CrossRef
Elevated triglyceride/high-density lipoprotein-cholesterol ratio as a risk factor for progression to prediabetes: a 5-year retrospective cohort study in Japan
Masanori Shimodaira, Yu Minemura, Tomohiro Nakayama
Journal of Diabetes & Metabolic Disorders.2023;[Epub] CrossRef
Association ofTG/HDLCratio trajectory and risk of type 2 diabetes: A retrospective cohort study inChina
Yanyan Zhang, Pei Qin, Yanmei Lou, Ping Zhao, Xue Li, Ranran Qie, Xiaoyan Wu, Minghui Han, Shengbing Huang, Yang Zhao, Dechen Liu, Yuying Wu, Yang Li, Xingjin Yang, Yang Zhao, Yifei Feng, Changyi Wang, Jianping Ma, Xiaolin Peng, Hongen Chen, Dan Zhao, Sha
Journal of Diabetes.2021; 13(5): 402. CrossRef
Triglycerides/high-density lipoprotein cholesterol is a predictor similar to the triglyceride–glucose index for the diagnosis of metabolic syndrome using International Diabetes Federation criteria of insulin resistance in obese adolescents: a cross-sectio
Nazlı Nur Aslan Çin, Hülya Yardımcı, Nevra Koç, Seyit Ahmet Uçaktürk, Mehtap Akçil Ok
Journal of Pediatric Endocrinology and Metabolism.2020; 33(6): 777. CrossRef
Comparison of Serum PCSK9 Levels in Subjects with Normoglycemia, Impaired Fasting Glucose, and Impaired Glucose Tolerance
Eugene Han, Nan Hee Cho, Seong-Su Moon, Hochan Cho
Endocrinology and Metabolism.2020; 35(2): 480. CrossRef
Triglycerides/glucose index is a useful surrogate marker of insulin resistance among adolescents
B Kang, Y Yang, E Y Lee, H K Yang, H-S Kim, S-Y Lim, J-H Lee, S-S Lee, B-K Suh, K-H Yoon
International Journal of Obesity.2017; 41(5): 789. CrossRef
The TyG index may predict the development of cardiovascular events
Laura Sánchez‐Íñigo, David Navarro‐González, Alejandro Fernández‐Montero, Juan Pastrana‐Delgado, Jose Alfredo Martínez
European Journal of Clinical Investigation.2016; 46(2): 189. CrossRef
TyG Index Change Is More Determinant for Forecasting Type 2 Diabetes Onset Than Weight Gain
David Navarro-González, Laura Sánchez-Íñigo, Alejandro Fernández-Montero, Juan Pastrana-Delgado, Jose Alfredo Martinez
Medicine.2016; 95(19): e3646. CrossRef
Comparative analysis of the efficacy of omega-3 fatty acids for hypertriglyceridaemia management in Korea
H.-S. Kim, H. Kim, Y. J. Jeong, S. J. Yang, S. J. Baik, H. Lee, S.-H. Lee, J. H. Cho, I.-Y. Choi, H. W. Yim, K.-H. Yoon
Journal of Clinical Pharmacy and Therapeutics.2016; 41(5): 508. CrossRef
Relationship between insulin sensitivity and insulin secretion rate: not necessarily hyperbolic
S. H. Kim, A. Silvers, J. Viren, G. M. Reaven
Diabetic Medicine.2016; 33(7): 961. CrossRef
The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance but not of β cell function in a Chinese population with different glucose tolerance status
Meicen Zhou, Lixin Zhu, Xiangli Cui, Linbo Feng, Xuefeng Zhao, Shuli He, Fan Ping, Wei Li, Yuxiu Li
Lipids in Health and Disease.2016;[Epub] CrossRef
Interactive effects of C-reactive protein levels on the association between APOE variants and triglyceride levels in a Taiwanese population
Semon Wu, Lung-An Hsu, Ming-Sheng Teng, Jeng-Feng Lin, Hsin-Hua Chou, Ming-Cheng Lee, Yi-Ming Wu, Cheng-Wen Su, Yu-Lin Ko
Lipids in Health and Disease.2016;[Epub] CrossRef
Lipoproteins and β-Cell Functions: From Basic to Clinical Data
Dae Ho Lee
Diabetes & Metabolism Journal.2014; 38(4): 274. CrossRef

Reviews

Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor: Peter Proks; Diabetes Metab J. 2013;37(3):157-164. Published online June 14, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.3.157

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Abstract PDF PubReader

Adenosine triphosphate (ATP)-sensitive potassium (K_ATP) channels in pancreatic β-cells play a crucial role in insulin secretion and glucose homeostasis. These channels are composed of two subunits: a pore-forming subunit (Kir6.2) and a regulatory subunit (sulphonylurea receptor-1). Recent studies identified large number of gain of function mutations in the regulatory subunit of the channel which cause neonatal diabetes. Majority of mutations cause neonatal diabetes alone, however some lead to a severe form of neonatal diabetes with associated neurological complications. This review focuses on the functional effects of these mutations as well as the implications for treatment.

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Long-term Follow-up of Glycemic and Neurological Outcomes in an International Series of Patients With Sulfonylurea-Treated ABCC8 Permanent Neonatal Diabetes
Pamela Bowman, Frances Mathews, Fabrizio Barbetti, Maggie H. Shepherd, Janine Sanchez, Barbara Piccini, Jacques Beltrand, Lisa R. Letourneau-Freiberg, Michel Polak, Siri Atma W. Greeley, Eamon Rawlins, Tarig Babiker, Nicholas J. Thomas, Elisa De Franco, S
Diabetes Care.2021; 44(1): 35. CrossRef
Structure based analysis of KATP channel with a DEND syndrome mutation in murine skeletal muscle
Shoichiro Horita, Tomoyuki Ono, Saul Gonzalez-Resines, Yuko Ono, Megumi Yamachi, Songji Zhao, Carmen Domene, Yuko Maejima, Kenju Shimomura
Scientific Reports.2021;[Epub] CrossRef
Clinical and Genetic Characteristics of ABCC8 Nonneonatal Diabetes Mellitus: A Systematic Review
Meng Li, Xueyao Han, Linong Ji, Karim Gariani
Journal of Diabetes Research.2021; 2021: 1. CrossRef
Spacial models of malfunctioned protein complexes help to elucidate signal transduction critical for insulin release
Katarzyna Walczewska-Szewc, Wieslaw Nowak
Biosystems.2019; 177: 48. CrossRef
Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms
Conor McClenaghan, Alex Hanson, Monica Sala-Rabanal, Helen I. Roessler, Dragana Josifova, Dorothy K. Grange, Gijs van Haaften, Colin G. Nichols
Journal of Biological Chemistry.2018; 293(6): 2041. CrossRef
Hyperinsulinism-Causing Mutations Cause Multiple Molecular Defects in SUR1 NBD1
Claudia P. Alvarez, Marijana Stagljar, D. Ranjith Muhandiram, Voula Kanelis
Biochemistry.2017; 56(18): 2400. CrossRef
K_ATP Channel Mutations and Neonatal Diabetes
Kenju Shimomura, Yuko Maejima
Internal Medicine.2017; 56(18): 2387. CrossRef
Molecular action of sulphonylureas on KATP channels: a real partnership between drugs and nucleotides
Heidi de Wet, Peter Proks
Biochemical Society Transactions.2015; 43(5): 901. CrossRef
Successful development and use of a thermodynamic stability screen for optimizing the yield of nucleotide binding domains
Elvin D. de Araujo, Voula Kanelis
Protein Expression and Purification.2014; 103: 38. CrossRef
Reclasificación y transferencia de insulina a sulfonilureas en un paciente con mutación en KCNJ11 tras 15 años de tratamiento con insulina
Magdalena Capponi, Carmen Quirós, Ignacio Conget, Enric Esmatjes, Marga Giménez
Avances en Diabetología.2014; 30(4): 115. CrossRef

A Systematic Review of Oxidative Stress and Safety of Antioxidants in Diabetes: Focus on Islets and Their Defense: Udayakumar Karunakaran, Keun-Gyu Park; Diabetes Metab J. 2013;37(2):106-112. Published online April 16, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.2.106

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A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in diabetic complications, especially β-cell dysfunction and failure. Under physiological conditions, reactive oxygen species serve as second messengers that facilitate signal transduction and gene expression in pancreatic β-cells. However, under pathological conditions, an imbalance in redox homeostasis leads to aberrant tissue damage and β-cell death due to a lack of antioxidant defense systems. Taking into account the vulnerability of islets to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed as a way to protect β-cells against diabetic insults. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions, as well as the therapeutic benefits of antioxidants, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with β-cell failure.

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Baccharis trimera (Carqueja) Improves Metabolic and Redox Status in an Experimental Model of Type 1 Diabetes
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The Potential of South African Herbal Tisanes, Rooibos and Honeybush in the Management of Type 2 Diabetes Mellitus
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Fuel-Stimulated Insulin Secretion Depends upon Mitochondria Activation and the Integration of Mitochondrial and Cytosolic Substrate Cycles: Gary W. Cline; Diabetes Metab J. 2011;35(5):458-465. Published online October 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.5.458

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The pancreatic islet β-cell is uniquely specialized to couple its metabolism and rates of insulin secretion with the levels of circulating nutrient fuels, with the mitochondrial playing a central regulatory role in this process. In the β-cell, mitochondrial activation generates an integrated signal reflecting rates of oxidativephosphorylation, Kreb's cycle flux, and anaplerosis that ultimately determines the rate of insulin exocytosis. Mitochondrial activation can be regulated by proton leak and mediated by UCP2, and by alkalinization to utilize the pH gradient to drive substrate and ion transport. Converging lines of evidence support the hypothesis that substrate cycles driven by rates of Kreb's cycle flux and by anaplerosis play an integral role in coupling responsive changes in mitochondrial metabolism with insulin secretion. The components and mechanisms that account for the integrated signal of ATP production, substrate cycling, the regulation of cellular redox state, and the production of other secondary signaling intermediates are operative in both rodent and human islet β-cells.

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The Causes and Consequences of Low Levels of High Density Lipoproteins in Patients with Diabetes: Philip J. Barter; Diabetes Metab J. 2011;35(2):101-106. Published online April 30, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.2.101

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Type 2 diabetes is commonly accompanied by a low level of high density lipoprotein cholesterol (HDL-C) that contributes to the increased cardiovascular risk associated with this condition. Given that HDLs have the ability to improve increase the uptake of glucose by skeletal muscle and to stimulate the secretion of insulin from pancreatic beta cells the possibility arises that a low HDL concentration in type 2 diabetes may also contribute to a worsening of diabetic control. Thus, there is a double case for raising the level of HDL-C in patients with type 2 diabetes: to reduce cardiovascular risk and to improve glycemic control. Approaches to raising HDL-C include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. Of currently available drugs, the most effective is niacin. Newer formulations of niacin are reasonably well tolerated and have the ability to increase HDL-C by up to 30%. The effect of niacin on cardiovascular events in type 2 diabetes is currently being tested in a large-scale clinical outcome trial.

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