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Liu H, Li T, Chen XL, Yu HL, Yu YR. Impact of setting distinct target blood glucose levels on endogenous insulin suppression and pharmacodynamics of insulin preparations. World J Diabetes 2025; 16:101779. [PMID: 39959272 PMCID: PMC11718471 DOI: 10.4239/wjd.v16.i2.101779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/15/2024] [Accepted: 12/05/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND Insulin therapy plays a crucial role in managing diabetes. Regulatory guidelines mandate assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of new insulin formulations with euglycemic clamp techniques before entry into the market. Typically, blood glucose (BG) levels are maintained at 5% below baseline to suppress endogenous insulin secretion in healthy volunteers. However, in scenarios where BG baseline is relatively low, maintaining it at 5% below baseline can increase hypoglycemic risk. Consequently, we adjusted to maintain it at 2.5% below a baseline of < 4.00 mmol/L. It remains uncertain whether this adjustment impacts endogenous insulin inhibition or the PD of study insulin. AIM To evaluate and compare the PD and C-peptide status using two different target BG setting methods. METHODS Data came from euglycemic clamp trials assessing the PK/PD of insulin aspart (IAsp) in healthy participants. Target BG was set at 2.5% below baseline for those with a basal BG of < 4.00 mmol/L (group A), and at 5% below baseline for others (group B). The area under the curve (AUC) of IAsp (AUCIAsp, 0-8 h) and GIR from 0 to 8 hours (AUCGIR, 0-8 h) was used to characterize the PK and PD of IAsp, respectively. The C-peptide reduction and PK/PD of IAsp were compared between the two groups. RESULTS Out of 135 subjects, 15 were assigned to group A and 120 to group B; however, group B exhibited higher basal C-peptide (1.59 ± 0.36 vs 1.32 ± 0.42 ng/mL, P = 0.006). Following propensity score matching to adjust for basal C-peptide differences, 71 subjects (15 in group A and 56 in group B) were analyzed. No significant differences were observed in demographics, IAsp dosage, or clamp quality. Group B showed significantly higher baseline (4.35 ± 0.21 vs 3.91 ± 0.09 mmol/L, P < 0.001), target (4.13 ± 0.20 vs 3.81 ± 0.08 mmol/L, P < 0.001), and clamped (4.10 ± 0.17 vs 3.80 ± 0.06 mmol/L, P < 0.001) BG levels. Both groups exhibited comparable C-peptide suppression (32.5% ± 10.0% vs 35.6% ± 12.1%, P = 0.370) and similar IAsp activity (AUCGIR, 0-8 h: 1433 ± 400 vs 1440 ± 397 mg/kg, P = 0.952) under nearly equivalent IAsp exposure (AUCIAsp, 0-8 h: 566 ± 51 vs 571 ± 85 ng/mL × h, P = 0.840). CONCLUSION Maintaining BG at 2.5% below a baseline of < 4.00 mmol/L did not compromise the endogenous insulin suppression nor alter the observed pharmacodynamic effects of the study insulin.
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Affiliation(s)
- Hui Liu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Clinical Trial Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ting Li
- Health Management Center, General Practice Medical Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin-Lei Chen
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hong-Ling Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ye-Rong Yu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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Tao YF, Pan YF, Zhong CY, Wang QC, Hua JX, Lu SQ, Li Y, Dong YL, Xu P, Jiang BJ, Qiang J. Silencing the fatty acid elongase gene elovl6 induces reprogramming of nutrient metabolism in male Oreochromis niloticus. Int J Biol Macromol 2024; 271:132666. [PMID: 38806081 DOI: 10.1016/j.ijbiomac.2024.132666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 05/05/2024] [Accepted: 05/23/2024] [Indexed: 05/30/2024]
Abstract
Elongation of very long-chain fatty acids protein 6 (ELOVL6) plays a pivotal role in the synthesis of endogenous fatty acids, influencing energy balance and metabolic diseases. The primary objective of this study was to discover the molecular attributes and regulatory roles of ELOVL6 in male Nile tilapia, Oreochromis niloticus. The full-length cDNA of elovl6 was cloned from male Nile tilapia, and was determined to be 2255-bp long, including a 5'-untranslated region of 193 bp, a 3'-untranslated region of 1252 bp, and an open reading frame of 810 bp encoding 269 amino acids. The putative protein had typical features of ELOVL proteins. The transcript levels of elovl6 differed among various tissues and among fish fed with different dietary lipid sources. Knockdown of elovl6 in Nile tilapia using antisense RNA technology resulted in significant alterations in hepatic morphology, long-chain fatty acid synthesis, and fatty acid oxidation, and led to increased fat deposition in the liver and disrupted glucose/lipid metabolism. A comparative transcriptomic analysis (elovl6 knockdown vs. the negative control) identified 5877 differentially expressed genes with significant involvement in key signaling pathways including the peroxisome proliferator-activated receptor signaling pathway, fatty acid degradation, glycolysis/gluconeogenesis, and the insulin signaling pathway, all of which are crucial for lipid and glucose metabolism. qRT-PCR analyses verified the transcript levels of 13 differentially expressed genes within these pathways. Our findings indicate that elovl6 knockdown in male tilapia impedes oleic acid synthesis, culminating in aberrant nutrient metabolism.
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Affiliation(s)
- Yi-Fan Tao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Yi-Fan Pan
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Chun-Yi Zhong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Qing-Chun Wang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Ji-Xiang Hua
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Si-Qi Lu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Yan Li
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Ya-Lun Dong
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
| | - Bing-Jie Jiang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China.
| | - Jun Qiang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi 214081, China; Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.
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Tao YF, Qiang J, Bao JW, Chen DJ, Yin GJ, Xu P, Zhu HJ. Changes in Physiological Parameters, Lipid Metabolism, and Expression of MicroRNAs in Genetically Improved Farmed Tilapia ( Oreochromis niloticus) With Fatty Liver Induced by a High-Fat Diet. Front Physiol 2018; 9:1521. [PMID: 30425654 PMCID: PMC6218568 DOI: 10.3389/fphys.2018.01521] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Accepted: 10/09/2018] [Indexed: 01/17/2023] Open
Abstract
Tilapia is susceptible to hepatic steatosis when grown in intensive farming systems. The aim of this study was to explore the mechanism of fatty liver induced by a high-fat diet (HFD) in genetically improved farmed tilapia (GIFT, Oreochromis niloticus). Juvenile GIFT were fed with HFD or a normal-fat diet (NFD) for 60 days. Substantial fat deposition in the liver of HFD-fed GIFT on days 20, 40, and 60 was observed using hematoxylin – eosin staining and oil red O staining. The increased fat deposition was consistent with increased triglyceride (TG) and total cholesterol (TC) levels in the liver of HFD-fed GIFT. There were significant differences (P < 0.05) in serum biochemical indexes (TG, TC, low density lipoprotein-cholesterol, and insulin contents, and alanine aminotransferase activity) between GIFT fed a HFD and GIFT fed a NFD on days 20, 40, and 60. Furthermore, 60 days of a HFD significantly changed (P < 0.05) the hepatic fatty acid composition, and led to increased polyunsaturated fatty acid levels and decreased saturated fatty acid and monounsaturated fatty acid levels. Hepatic antioxidant enzyme activities increased by day 20 and then declined, which led to an increase in malondialdehyde contents in the liver of HFD-fed GIFT. Molecular analyses revealed that the microRNAs miR-122, miR-29a, and miR-145-5p were upregulated, whereas miR-34a was downregulated in HFD-fed GIFT. SCD, ELOVL6, and SRD5A2 encode three important enzymes in lipid metabolism, and were identified as potential targets of miRNAs. The transcript levels of hepatic SCD and ELOVL6 were decreased and that of hepatic SRD5A2 was increased in GIFT fed a HFD. Overall, the results of this study revealed a potential link between miRNAs and fatty liver induced by HFD, and suggest that a HFD could lead to excess fat deposition in the GIFT liver, which may disrupt hepatic lipid metabolism and reduce the antioxidant defense capacity.
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Affiliation(s)
- Yi-Fan Tao
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Jun Qiang
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Jing-Wen Bao
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - De-Ju Chen
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Guo-Jun Yin
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Pao Xu
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China.,Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Hao-Jun Zhu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
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Muscelli E, Pereira JA, Lazarin MA, da Silva CA, Pareja JC, Saad MJ. Lack of insulin inhibition on insulin secretion in non-diabetic morbidly obese patients. Int J Obes (Lond) 2001; 25:798-804. [PMID: 11439292 DOI: 10.1038/sj.ijo.0801607] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2000] [Revised: 12/07/2000] [Accepted: 01/03/2001] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS Twelve obese patients, normotolerant to glucose (8 F/4 M, body mass index (BMI)=54.8+/-2.5 kg/m(2), 39 y) and 16 lean control subjects (10 F/6 M, BMI=22.0+/-0.5 kg/m(2), 31 y). DESIGN AND MEASUREMENTS An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280 pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS The obese subjects were insulin resistant (M=19.8+/-1.6 vs 48.7+/-2.6 micromol/min kg FFM, P<0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425+/-131 pmol/l vs lean 550+/-63 pmol/l; P<0.0001) decreased less during the clamp in the obese groups (-16.9+/-6.9% vs -43.0+/-5.6% relative to fasting values; P=0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r=0.56, P=0.03), even after adjustment for the clamp glucose variation. CONCLUSION We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.
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Affiliation(s)
- E Muscelli
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas (UNICAMP), 13081-970, Campinas, São Paulo, Brazil.
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Lee PD, Jensen MD, Divertie GD, Heiling VJ, Katz HH, Conover CA. Insulin-like growth factor-binding protein-1 response to insulin during suppression of endogenous insulin secretion. Metabolism 1993; 42:409-14. [PMID: 7683739 DOI: 10.1016/0026-0495(93)90095-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Insulin-like growth factor-binding protein-1 (IGFBP-1) is one of several related proteins that bind and modulate the actions of IGFs. The liver is the primary source of IGFBP-1, and insulin is a major regulator of hepatic IGFBP-1 production. We report five sets of investigations that further define the characteristics of hepatic IGFBP-1 response to insulin. In normal subjects, a continuous high-dose insulin infusion caused a rapid decrease in plasma IGFBP-1 concentrations, with a rate of 0.24 +/- 0.04 microgram/L.min-1 and a t1/2 of 89 +/- 4 minutes. Conversely, a 3-hour somatostatin (SRIF) infusion caused a 4.5-fold increase in plasma IGFBP-1 levels. SRIF plus low-dose insulin infusion (to inhibit break-through insulin secretion) resulted in a plateau in IGFBP-1 concentrations at 5 to 8 hours, with a t1/2 to achieve steady state of 60 to 75 minutes. Under similar conditions, a stepped increase in plasma glucose level from 5 to 9 mmol/L had no effect on the rate of IGFBP-1 increase in plasma, indicating that an acute increase in glucose concentration within a physiologic range has no independent inhibitory effect on IGFBP-1 production in the presence of a nonsuppressive insulin level. Using SRIF plus sequential graded insulin infusions, the threshold peripheral (= portal) plasma insulin concentration for IGFBP-1 suppression was between 65 and 172 pmol/L. Subjects with insulin-dependent diabetes mellitus (IDDM) showed a similar dose-response pattern, suggesting that insulin regulation of IGFBP-1 may be normal in IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- P D Lee
- Department of Pediatrics, Baylor College of Medicine, Houston, TX
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