scholarly journals Impact of Probiotic Combination in InR[E19]/TM2 Drosophila melanogaster on Longevity, Related Gene Expression, and Intestinal Microbiota: A Preliminary Study

2020 ◽  
Vol 8 (7) ◽  
pp. 1027
Author(s):  
Shuang Ma ◽  
Hao Sun ◽  
Weichao Yang ◽  
Mingfu Gao ◽  
Hui Xu
Keyword(s):  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
High Throughput Sequencing ◽  
Metabolic Diseases ◽  
Standard Diet ◽  
Median Lifespan ◽  
Treatment Of Diabetes ◽  
Receptor Family

The insulin receptor (InR) pertains to the insulin receptor family, which plays a key role in the insulin/insulin-like growth factor (IGF)-like signaling (IIS) pathway. Insulin signaling defects may result in the development of metabolic diseases, such as type 2 diabetes, and the InR mutant has been suggested to bear insulin signaling deficiency. Numerous studies have reported that probiotics are beneficial for the treatment of diabetes; however, the effect of probiotics on patients with InR deficiency has seldom been reported. Therefore, we chose the InR[E19]/TM2 Drosophila melanogaster to investigate. The results indicated that probiotics significantly reduce the mean and median lifespan of InR[E19]/TM2 Drosophila (by 15.56% and 23.82%, respectively), but promote that of wild-type files (by 9.31% and 16.67%, respectively). Significant differences were obtained in the expression of lifespan- and metabolism-related genes, such as Imp-L2, Tor, and GstD2, between the standard diet groups and the probiotics groups. Furthermore, analysis of 16S rDNA via high throughput sequencing revealed that the gut bacterial diversity of Drosophila fed with a probiotic combination also differs from that of Drosophila fed with a standard diet. In summary, these findings indicate that a probiotic combination indeed affects InR[E19]/TM2 Drosophila, but not all of its impacts are positive.

scholarly journals Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

2021 ◽  
Author(s):  
Qian Zhou ◽  
Wan-Wan Sun ◽  
Jia-Cong Chen ◽  
Huilu Zhang ◽  
Jie Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Trna Synthetase ◽  
Blood Samples ◽  
Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

Genistein and Momordica charantia L. prevents oxidative stress and upregulate proglucagon and insulin receptor mRNA in diabetic rats.

2021 ◽  
Author(s):  
Wusa Makena ◽  
Abdullahi Ibrahim Iliya ◽  
Joseph Olajide Hambolu ◽  
James Abrak Timbuak ◽  
Uduak Emmanuel Umana ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Type 2 Diabetes ◽  
Insulin Receptor ◽  
Mrna Expression ◽  
Insulin Signaling ◽  
Diabetic Rats ◽  
Momordica Charantia ◽  
Receptor Mrna ◽  
Group I

Type 2 diabetes (T2D) occur as a result of insulin resistance and malfunction in insulin signaling. Controlling hyperglycemia and activation of insulin signaling are important in the management of T2D. The study aimed to evaluate the effect of Genistein and Momordica charantia L. fruit on oxidative stress, markers of inflammation, and their role on proglucagon and insulin receptor mRNA expression by RT-PCR in diabetic rats. Thirty-five albino rats were divided into seven groups (n=5). Group I (non-diabetic) and group II (diabetic control) were treated with distilled water, groups III and IV received 250mg/kg and 500mg/kg lyophilized MCF respectively. Groups V and VI received 10mg/kg and 20mg/kg Genistein respectively while group VII received 500mg/kg Metformin. The administration lasted for 28 days. MCF and Genistein significantly reduced IL-1β and TNFα levels that was elevated in serum of diabetic rats. Treatment with MCF and Genistein significant increased the expression of proglucagon mRNA in the small intestine and insulin receptor mRNA in the liver of diabetic rats. In conclusion, MCF and Genistein ameliorate type 2 diabetes complications by preventing the loss of insulin-positive cells, inhibiting IL-1β and TNFα and up-regulating proglucagon and insulin receptor mRNA expression. Novelty: • MCF and Genistein has an inhibitory effect on diabetic induced IL-1β and TNFα production. • MCF and Genistein up-regulates proglucagon and insulin receptor mRNA expression.

scholarly journals Defective liver glycogen autophagy related to hyperinsulinemia in intrauterine growth-restricted newborn wistar rats

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan de Toro-Martín ◽  
Tamara Fernández-Marcelo ◽  
Águeda González-Rodríguez ◽  
Fernando Escrivá ◽  
Ángela M. Valverde ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Metabolic Diseases ◽  
Critical Role ◽  
Liver Glycogen ◽  
Hormonal Control ◽  
Standard Diet ◽  
Major Organ ◽  
Mtorc1 Pathway

Abstract Maternal malnutrition plays a critical role in the developmental programming of later metabolic diseases susceptibility in the offspring, such as obesity and type 2 diabetes. Because the liver is the major organ that produces and supplies blood glucose, we aimed at defining the potential role of liver glycogen autophagy in the programming of glucose metabolism disturbances. To this end, newborns were obtained from pregnant Wistar rats fed ad libitum with a standard diet or 65% food-restricted during the last week of gestation. We found that newborns from undernourished mothers showed markedly high basal insulin levels whereas those of glucagon were decreased. This unbalance led to activation of the mTORC1 pathway and inhibition of hepatic autophagy compromising the adequate handling of glycogen in the very early hours of extrauterine life. Restoration of autophagy with rapamycin but not with glucagon, indicated no defect in autophagy machinery per se, but in signals triggered by glucagon. Taken together, these results support the notion that hyperinsulinemia is an important mechanism by which mobilization of liver glycogen by autophagy is defective in food-restricted animals. This early alteration in the hormonal control of liver glycogen autophagy may influence the risk of developing metabolic diseases later in life.

scholarly journals MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

PLoS ONE ◽  
2011 ◽  
Vol 6 (8) ◽  
pp. e22839 ◽  
Author(s):  
Dwi Setyowati Karolina ◽  
Arunmozhiarasi Armugam ◽  
Subramaniam Tavintharan ◽  
Michael T. K. Wong ◽  
Su Chi Lim ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Receptor Substrate ◽  
Insulin Receptor Substrate 1

scholarly journals Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats

2021 ◽  
Vol 22 (5) ◽  
pp. 2469
Author(s):  
Katarzyna Szkudelska ◽  
Marzanna Deniziak ◽  
Maciej Sassek ◽  
Ignacy Szkudelski ◽  
Wojciech Noskowiak ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Binding Capacity ◽  
Receptor Expression ◽  
Biologically Active ◽  
Blood Levels ◽  
Gk Rats

Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue.

scholarly journals High-Fat Diet Alters the Intestinal Microbiota in Streptozotocin-Induced Type 2 Diabetic Mice

2019 ◽  
Vol 7 (6) ◽  
pp. 176 ◽  
Author(s):  
Sheng Liu ◽  
Panpan Qin ◽  
Jing Wang
Keyword(s):  
Intestinal Microbiota ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
16S Rrna Gene Sequencing ◽  
Chow Diet ◽  
Rrna Gene ◽  
Standard Diet ◽  
High Fat ◽  
Diabetes Status

Intestinal microbiota is closely associated with various metabolic diseases such as type 2 diabetes (T2D), and microbiota is definitely affected by diet. However, more work is required to gain detailed information about gut metagenome and their associated impact with diet in T2D patients. We used a streptozotocin-high-fat diet (HFD) to induce a T2D mouse model and investigated the effect of standard chow diet and HFD on the composition and function of gut microbiota. We found that a HFD could worsen the diabetes status compared with a standard diet. 16S rRNA gene sequencing revealed that a HFD caused a large disturbance to the microbial structure and was linked to an increased ratio of Firmicutes to Bacteroidetes. A HFD increased the bacteria of the Ruminococcaceae and Erysipelotrichaceae family and decreased the bacteria of S24-7 and Rikenellaceae. Meanwhile, a HFD decreased the abundance of Parabacteroides distasonis and Eubacterium dolichum, both of which have previously been reported to alleviate obesity and metabolic dysfunctions. Moreover, PICRUSt-predicted KEGG pathways related to membrane transport, lipid metabolism, and xenobiotics biodegradation and metabolism were significantly elevated in HFD-fed T2D mice. Our results provide insights into dietary and nutritional approaches for improving host metabolism and ameliorating T2D.

scholarly journals Variants of Insulin-Signaling Inhibitor Genes in Type 2 Diabetes and Related Metabolic Abnormalities

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Carlo de Lorenzo ◽  
Annalisa Greco ◽  
Teresa Vanessa Fiorentino ◽  
Gaia Chiara Mannino ◽  
Marta Letizia Hribal
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Signaling ◽  
Metabolic Diseases ◽  
Receptor Activation ◽  
Serine Threonine Kinase ◽  
Downstream Signaling ◽  
Genes Encoding ◽  
Inhibitor Genes

Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of theENPP1gene and for rs2295490 of theTRIB3gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis.

Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes

2004 ◽  
Vol 287 (3) ◽  
pp. E537-E546 ◽  
Author(s):  
Sangeeta R. Kashyap ◽  
Renata Belfort ◽  
Rachele Berria ◽  
Swangjit Suraamornkul ◽  
Thongchai Pratipranawatr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Family History ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Insulin Action ◽  
Low Dose ◽  
History Of ◽  
Plasma Ffa

Muscle insulin resistance develops when plasma free fatty acids (FFAs) are acutely increased to supraphysiological levels (∼1,500–4,000 μmol/l). However, plasma FFA levels >1,000 μmol/l are rarely observed in humans under usual living conditions, and it is unknown whether insulin action may be impaired during a sustained but physiological FFA increase to levels seen in obesity and type 2 diabetes mellitus (T2DM) (∼600–800 μmol/l). It is also unclear whether normal glucose-tolerant subjects with a strong family history of T2DM (FH+) would respond to a low-dose lipid infusion as individuals without any family history of T2DM (CON). To examine these questions, we studied 7 FH+ and 10 CON subjects in whom we infused saline (SAL) or low-dose Liposyn (LIP) for 4 days. On day 4, a euglycemic insulin clamp with [3-3H]glucose and indirect calorimetry was performed to assess glucose turnover, combined with vastus lateralis muscle biopsies to examine insulin signaling. LIP increased plasma FFA ∼1.5-fold, to levels seen in T2DM. Compared with CON, FH+ were markedly insulin resistant and had severely impaired insulin signaling in response to insulin stimulation. LIP in CON reduced insulin-stimulated glucose disposal (Rd) by 25%, insulin-stimulated insulin receptor tyrosine phosphorylation by 17%, phosphatidylinositol 3-kinase activity associated with insulin receptor substrate-1 by 20%, and insulin-stimulated glycogen synthase fractional velocity over baseline (44 vs. 15%; all P < 0.05). In contrast to CON, a physiological elevation in plasma FFA in FH+ led to no further deterioration in Rd or to any additional impairment of insulin signaling. In conclusion, a 4-day physiological increase in plasma FFA to levels seen in obesity and T2DM impairs insulin action/insulin signaling in CON but does not worsen insulin resistance in FH+. Whether this lack of additional deterioration in insulin signaling in FH+ is due to already well-established lipotoxicity, or to other molecular mechanisms related to insulin resistance that are nearly maximally expressed early in life, remains to be determined.

scholarly journals IRS posttranslational modifications in regulating insulin signaling

2018 ◽  
Vol 60 (1) ◽  
pp. R1-R8 ◽  
Author(s):  
Jinghua Peng ◽  
Ling He
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Posttranslational Modifications ◽  
Insulin Signaling ◽  
Critical Role ◽  
Transferase Activity ◽  
Obese Mice ◽  
Promising Therapeutic Target ◽  
Treatment Of Diabetes

Insulin resistance is the hallmark of type 2 diabetes; however, the mechanism underlying the development of insulin resistance is still not completely understood. Previous reports showed that posttranslational modifications of IRS play a critical role in insulin signaling, especially the phosphorylation of IRS by distinct kinases. While it is known that increasing Sirtuin1 deacetylase activity improves insulin sensitivity in the liver, the identity of its counterpart, an acetyl-transferase, remains unknown. Our recent study shows that elevated endotoxin (LPS) levels in the liver of obese mice lead to the induction of the acetyl-transferase P300 through the IRE1-XBP1s pathway. Subsequently, induced P300 impairs insulin signaling by acetylating IRS1 and IRS2 in the insulin signaling pathway. Therefore, the P300 acetyl-transferase activity appears to be a promising therapeutic target for the treatment of diabetes.

scholarly journals Brain Insulin Resistance: Focus on Insulin Receptor-Mitochondria Interactions

2021 ◽  
Author(s):  
Igor Pomytkin ◽  
Vsevolod Pinelis
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Signaling ◽  
Metabolic Stress ◽  
Glutamate Excitotoxicity ◽  
Receptor Signal ◽  
Brain Insulin Resistance ◽  
Substrate Proteins ◽  
The Brain

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer&rsquo;s disease and other dementias, Parkinson&rsquo;s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

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