scholarly journals Regulation of Insulin Secretion and Proinsulin Biosynthesis by Succinate

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5110-5118 ◽  
Author(s):  
Veronique Attali ◽  
Marcela Parnes ◽  
Yafa Ariav ◽  
Erol Cerasi ◽  
Nurit Kaiser ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Phenylacetic Acid ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Negative Regulator ◽  
Biosynthetic Activity ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Proinsulin Biosynthesis ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Oxide Synthase

Succinate stimulates insulin secretion and proinsulin biosynthesis. We studied the effects of reduced nicotinamide adenine dinucleotide phosphate (NADPH)-modulating pathways on glucose- and succinate-stimulated insulin secretion and proinsulin biosynthesis in the rat and the insulin-resistant Psammomys obesus. Disruption of the anaplerotic pyruvate/malate shuttle by phenylacetic acid inhibited glucose- and succinate-stimulated insulin secretion and succinate-stimulated proinsulin biosynthesis in both species. In contrast, phenylacetic acid failed to inhibit glucose-stimulated proinsulin biosynthesis in P. obesus islets. Inhibition of the NADPH-consuming enzyme neuronal nitric oxide synthase (nNOS) with l-NG-nitro-l-arginine methyl ester or with NG-monomethyl-l-arginineG doubled succinate-stimulated insulin secretion in rat islets, suggesting that succinate- and nNOS-derived signals interact to regulate insulin secretion. In contrast, nNOS inhibition had no effect on succinate-stimulated proinsulin biosynthesis in both species. In P. obesus islets, insulin secretion was not stimulated by succinate in the absence of glucose, whereas proinsulin biosynthesis was increased 5-fold. Conversely, under stimulating glucose levels, succinate doubled insulin secretion, indicating glucose-dependence. Pyruvate ester and inhibition of nNOS partially mimicked the permissive effect of glucose on succinate-stimulated insulin secretion, suggesting that anaplerosis-derived signals render the β-cells responsive to succinate. We conclude that β-cell anaplerosis via pyruvate carboxylase is important for glucose- and succinate-stimulated insulin secretion and for succinate-stimulated proinsulin biosynthesis. In P. obesus, pyruvate/malate shuttle dependent and independent pathways that regulate proinsulin biosynthesis coexist; the latter can maintain fuel stimulated biosynthetic activity when the succinate-dependent pathway is inhibited. nNOS signaling is a negative regulator of insulin secretion, but not of proinsulin biosynthesis.

scholarly journals The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice

2008 ◽  
Vol 197 (1) ◽  
pp. 181-187 ◽  
Author(s):  
Bo Ahrén ◽  
Maria Sörhede Winzell ◽  
Giovanni Pacini
Keyword(s):  
Insulin Secretion ◽  
High Fat Diet ◽  
Insulin Response ◽  
Area Under The Curve ◽  
Oral Glucose ◽  
Incretin Effect ◽  
High Fat ◽  
Intravenous Glucose ◽  
Insulin Resistant ◽  
Glucose Levels

To study whether the incretin effect is involved in adaptively increased insulin secretion in insulin resistance, glucose was infused at a variable rate to match glucose levels after oral glucose (25 mg) in normal anesthetized C57BL/6J female mice or in mice rendered insulin resistant by 8 weeks of high-fat feeding. Insulin response was markedly higher after oral than i.v. glucose in both groups, and this augmentation was even higher in high-fat fed than normal mice. In normal mice, the area under the curve (AUCinsulin) was augmented from 4.0±0.8 to 8.0±1.8 nmol/l×60 min by the oral glucose, i.e. by a factor of 2 (P=0.023), whereas in the high-fat fed mice, AUCinsulin was augmented from 0.70±0.4 to 12.4±2.5 nmol/l×60 min, i.e. by a factor of 17 (P<0.001). To examine whether the incretin hormone glucagon-like peptide-1 (GLP-1) is responsible for this difference, the effect of i.v. GLP-1 was compared in normal and high-fat fed mice. The sensitivity to i.v. GLP-1 in stimulating insulin secretion was increased in the high-fat diet fed mice: the lowest effective dose of GLP-1 was 650 pmol/kg in normal mice and 13 pmol/kg in the high-fat diet fed mice. We conclude that 1) the incretin effect contributes by ∼50% to insulin secretion by the oral glucose in normal mice, 2) this effect is markedly exaggerated in insulin-resistant mice fed a high-fat diet, and 3) this augmented incretin contribution in the high-fat fed mice may partially be explained by GLP-1.

scholarly journals The Mechanism of Jian-Gan-Xiao-Zhi Decoction in Insulin Resistant Adipocytes and Its Component Analysis

2021 ◽  
Vol 16 (3) ◽  
pp. 1934578X2199767
Author(s):  
Fang Fang ◽  
Wei-Bo Wen ◽  
Xue-Hua Xie ◽  
Ling Yang ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Lipid Synthesis ◽  
Glucose Consumption ◽  
Astragaloside Iv ◽  
Serum Samples ◽  
Rat Serum ◽  
Jnk Pathway ◽  
Alcoholic Fatty Liver ◽  
Insulin Resistant ◽  
Glucose Levels ◽  
Main Components

Background: Jian-Gan-Xiao-Zhi decoction (JGXZ) is a traditional Chinese medicine formula to treat patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to analyze the mechanism of JGXZ in adipocytes and detect the main components of the drug in rat serum. Methods: 3T3-L1 preadipocytes were used to establish an insulin resistant (IR) adipocyte model. Lipid accumulation in adipocytes was detected by oil red O staining. After JGXZ treatment, glucose consumption, total cholesterol (TC), and triglyceride (TG) were analyzed using the corresponding kits. ROS levels were measured by flow cytometry. In addition, Western blot was used to assess LKB1/AMPK and JNK/IRS/PI3k/AKT expressions. The main components of JGXZ in rat serum samples were detected by LC-MS/MS using a Phenomenex Luna C18 column, a mobile phase of methanol and 0.1% formic acid solution, and ESI detection. Results: JGXZ significantly decreased glucose levels and adipogenesis, accompanied by decreased IR ( P < 0.01). Besides, JGXZ markedly affected ROS, LKB1/AMPK, and JNK/IRS/PI3k/AKT levels ( P < 0.01). R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone could be significantly quantified. Conclusions: JGXZ decreased glucose and lipid synthesis, possibly via the ROS/AMPK/JNK pathway. R1, Rg1, paeoniflorin, Rb1, astragaloside IV, and tanshinone in JGXZ could play major roles in treating NAFLD, which could assist in the study of the mechanism of JGXZ in treating NAFLD.

scholarly journals Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Miwa Nahata ◽  
Sachiko Mogami ◽  
Hitomi Sekine ◽  
Seiichi Iizuka ◽  
Naoto Okubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Aged Mice ◽  
Glucose Levels ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Daily Food ◽  
Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

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