scholarly journals Cell Autonomous Dysfunction and Insulin Resistance in Pancreatic α Cells

2019 ◽  
Vol 20 (15) ◽  
pp. 3699 ◽  
Author(s):  
Norikiyo Honzawa ◽  
Kei Fujimoto ◽  
Tadahiro Kitamura
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Current Knowledge ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Hepatic Glucose

To date, type 2 diabetes is considered to be a “bi-hormonal disorder” rather than an “insulin-centric disorder,” suggesting that glucagon is as important as insulin. Although glucagon increases hepatic glucose production and blood glucose levels, paradoxical glucagon hypersecretion is observed in diabetes. Recently, insulin resistance in pancreatic α cells has been proposed to be associated with glucagon dysregulation. Moreover, cell autonomous dysfunction of α cells is involved in the etiology of diabetes. In this review, we summarize the current knowledge about the physiological and pathological roles of glucagon.

Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice

2003 ◽  
Vol 285 (4) ◽  
pp. E718-E728 ◽  
Author(s):  
Jennifer Altomonte ◽  
Anja Richter ◽  
Sonal Harbaran ◽  
Jenny Suriawinata ◽  
Jun Nakae ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Cultured Cells ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Diabetic Mice ◽  
Hepatic Expression ◽  
Glucose Levels ◽  
Fasting Glycemia ◽  
Blood Glucose Levels ◽  
Hepatic Glucose

Excessive hepatic glucose production is a contributing factor to fasting hyperglycemia in diabetes. Insulin suppresses hepatic glucose production by inhibiting the expression of two gluconeogenic enzymes, phospho enolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase). The forkhead transcription factor Foxo1 has been implicated as a mediator of insulin action in regulating hepatic gluconeogenesis, and a Foxo1 mutant (Foxo1-Δ256), devoid of its carboxyl domain, has been shown to interfere with Foxo1 function and inhibit gluconeogenic gene expression in cultured cells. To study the effect of Foxo1-Δ256 on glucose metabolism in animals, the Foxo1-Δ256 cDNA was delivered to the livers of mice by adenovirus-mediated gene transfer. Hepatic Foxo1-Δ256 production resulted in inhibition of gluconeogenic activity, as evidenced by reduced PEPCK and G-6-Pase expression in the liver. Mice treated with the Foxo1-Δ256 vector exhibited significantly reduced blood glucose levels. In contrast, blood glucose levels in control vector-treated animals remained unchanged, which coincided with the lack of alterations in the expression levels of PEPCK and G-6-Pase. When tested in diabetic db/db mice, hepatic production of Foxo1-Δ256 was shown to reduce fasting hyperglycemia. Furthermore, we showed that hepatic Foxo1 expression was deregulated as a result of insulin resistance in diabetic mice and that Foxo1-Δ256 interfered with Foxo1 function via competitive binding to target promoters. These results demonstrated that functional inhibition of Foxo1, caused by hepatic expression of its mutant, is associated with reduced hepatic gluconeogenic activity and improved fasting glycemia in diabetic mice.

scholarly journals Berberine Attenuates Hyperglycemia by Inhibiting the Hepatic Glucagon Pathway in Diabetic Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-8 ◽  
Author(s):  
Ying Zhong ◽  
Jing Jin ◽  
Peiyu Liu ◽  
Yu Song ◽  
Hui Zhang ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Intracellular Camp ◽  
Diabetic Mice ◽  
Hepatic Gluconeogenesis ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Hepatic Glucose ◽  
Glucose Output

Dysregulated glucagon drives hyperfunction in hepatic glucose output, which is the main cause of persistent hyperglycemia in type 2 diabetes. Berberine (Zhang et al., 2010) has been used as a hypoglycemic agent, yet the mechanism by which BBR inhibits hepatic gluconeogenesis remains incompletely understood. In this study, we treated diabetic mice with BBR, tested blood glucose levels, and then performed insulin, glucose lactate, and glucagon tolerance tests. Intracellular cAMP levels in hepatocytes were determined by ELISA, hepatic gluconeogenetic genes were assayed by RT-qPCR, and the phosphorylation of CREB, which is the transcriptional factor controlling the expression of gluconeogenetic genes, was detected by western blot. BBR reduced blood glucose levels, improved insulin and glucose tolerance, and suppressed lactate- and glucagon-induced hepatic gluconeogenesis in ob/ob and STZ-induced diabetic mice. Importantly, BBR blunted glucagon-induced glucose production and gluconeogenic gene expression in hepatocytes, presumably through reducing cAMP, which resulted in the phosphorylation of CREB. By utilizing a cAMP analogue, adenylate cyclase (AC), to activate cAMP synthetase, and an inhibitor of the cAMP degradative enzyme, phosphodiesterase (PDE), we revealed that BBR accelerates intracellular cAMP degradation. BBR reduces the intracellular cAMP level by activating PDE, thus blocking activation of downstream CREB and eventually downregulating gluconeogenic genes to restrain hepatic glucose production.

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

2002 ◽  
Vol 282 (1) ◽  
pp. E38-E45 ◽  
Author(s):  
Chaodong Wu ◽  
David A. Okar ◽  
Christopher B. Newgard ◽  
Alex J. Lange
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Kk Mice ◽  
Hepatic Glucose

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

Effect of a selective rise in sinusoidal norepinephrine on HGP is due to an increase in glycogenolysis

1998 ◽  
Vol 274 (1) ◽  
pp. E162-E171 ◽  
Author(s):  
Chang An Chu ◽  
Dana K. Sindelar ◽  
Doss W. Neal ◽  
Eric J. Allen ◽  
E. Patrick Donahue ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Control Group ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Molar Basis ◽  
Hepatic Glucose ◽  
The Difference ◽  
Over Time

To determine the effect of a selective rise in liver sinusoidal norepinephrine (NE) on hepatic glucose production (HGP), norepinephrine (50 ng ⋅ kg−1 ⋅ min−1) was infused intraportally (Po-NE) for 3 h into five 18-h-fasted conscious dogs with a pancreatic clamp. In the control protocol, NE (0.2 ng ⋅ kg−1 ⋅ min−1) and glucose were infused peripherally to match the arterial NE and blood glucose levels in the Po-NE group. Hepatic sinusoidal NE levels rose ∼30-fold in the Po-NE group but did not change in the control group. The arterial NE levels did not change significantly in either group. During the portal NE infusion, HGP increased from 1.9 ± 0.2 to 3.5 ± 0.4 mg ⋅ kg−1 ⋅ min−1(15 min; P < 0.05) and then gradually fell to 2.4 ± 0.4 mg ⋅ kg−1 ⋅ min−1by 3 h. HGP in the control group did not change (2.0 ± 0.2 to 2.0 ± 0.2 mg ⋅ kg−1 ⋅ min−1) for 15 min but then gradually fell to 1.1 ± 0.2 mg ⋅ kg−1 ⋅ min−1by the end of the study. Because the fall in HGP from 15 min on was parallel in the two groups, the effect of NE on HGP (the difference between HGP in the two groups) did not decline over time. Gluconeogenesis did not change significantly in either group. In conclusion, elevation in hepatic sinusoidal NE significantly increases HGP by selectively stimulating glycogenolysis. Compared with the previously determined effects of epinephrine or glucagon on HGP, the effect of NE is, on a molar basis, less potent but nore sustained over time.

scholarly journals Adropin reduces blood glucose levels in mice by limiting hepatic glucose production

2019 ◽  
Vol 7 (8) ◽  
pp. e14043 ◽  
Author(s):  
Dharendra Thapa ◽  
Bingxian Xie ◽  
Janet R. Manning ◽  
Manling Zhang ◽  
Michael W. Stoner ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Hepatic Glucose

scholarly journals Considerations for Maximizing the Exercise “Drug” to Combat Insulin Resistance: Role of Nutrition, Sleep, and Alcohol

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1708
Author(s):  
Mary-Margaret E. Remchak ◽  
Kelsey L. Piersol ◽  
Sabha Bhatti ◽  
Andrea M. Spaeth ◽  
Jennifer F. Buckman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Nutrient Timing ◽  
First Line Therapy ◽  
Hepatic Glucose ◽  
Skeletal Muscle Glucose Uptake

Insulin resistance is a key etiological factor in promoting not only type 2 diabetes mellitus but also cardiovascular disease (CVD). Exercise is a first-line therapy for combating chronic disease by improving insulin action through, in part, reducing hepatic glucose production and lipolysis as well as increasing skeletal muscle glucose uptake and vasodilation. Just like a pharmaceutical agent, exercise can be viewed as a “drug” such that identifying an optimal prescription requires a determination of mode, intensity, and timing as well as consideration of how much exercise is done relative to sitting for prolonged periods (e.g., desk job at work). Furthermore, proximal nutrition (nutrient timing, carbohydrate intake, etc.), sleep (or lack thereof), as well as alcohol consumption are likely important considerations for enhancing adaptations to exercise. Thus, identifying the maximal exercise “drug” for reducing insulin resistance will require a multi-health behavior approach to optimize type 2 diabetes and CVD care.

Efeitos dos Programas de Treinamento Aeróbio, de Força e Combinado na Glicose Sanguínea em Diabéticos do Tipo 2: uma Revisão Sistemática/ Effects of Aerobic, Strength and Combined Programs Training on Blood Glucose in Type 2 Diabetic: a Systematic Review.

1970 ◽  
Vol 5 (1) ◽  
pp. 61-74 ◽  
Author(s):  
Alexandre de Souza E Silva ◽  
Maria Paula Gonçalves Mota
Keyword(s):  
Diabetes Mellitus ◽  
Systematic Review ◽  
Type 2 Diabetes ◽  
Blood Glucose ◽  
Training Program ◽  
Aerobic Training ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Pubmed Database

O trabalho tem como objetivo analisar os estudos que avaliaram os efeitos dos programas de treinamento aeróbio, força e combinado nos níveis de glicose sanguínea em indivíduos com diabetes do tipo 2. Foi utilizado o método de revisão sistemática, sendo utilizada a base de dados PubMed. As palavras chaves utilizadas para pesquisa foram training and diabetes. Foram identificados 484 artigos originais. Apenas 17 estudos respeitaram os critérios de inclusão. Os resultados evidenciam que os programas de treinamento aeróbio diminuíram os níveis de glicose. O programa de treinamento de força também foi favorável à diminuição dos níveis de glicose sanguínea. Já o programa de treinamento combinado não demonstrou efeitos favoráveis no controle da glicose sanguínea. Conclui-se que o programa de treinamento aeróbio e de força ajudam a controlar os níveis de glicose sanguínea em indivíduos com diabetes do tipo 2. Palavras-chave: diabetes mellitus, treinamento, glicose.ABSTRACTThe study aims to analyze the studies that evaluated the effects of aerobic, strength and combined programs training in blood glucose levels in people with type 2 diabetes. We used a systematic review method and is used to PubMed database. The key words used for searching were training and diabetes. We identified 484 original articles. Only 17 studies complied with the inclusion criteria. The results show that aerobic training programs decreased glucose levels. The strength training program was also favorable to decrease in blood glucose levels. But the combined training program has not shown favorable effects on blood glucose control. We conclude that the aerobic training and strength helps control blood glucose levels in individuals with type 2 diabetes. Keywords: diabetes mellitus, training, glucose.

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