scholarly journals SAT-653 Exploring the Role of Brown Adipokines on Hepatic Insulin Resistance Using a Microfluidic Organ-On-Chip

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nida Tanataweethum ◽  
Chaeeun Lee ◽  
Allyson Trang ◽  
Franklin Zhong ◽  
Kihwan Kim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Production ◽  
Conditioned Media ◽  
Hepatic Insulin Resistance ◽  
Brown Adipocyte ◽  
On Chip

Abstract The development of insulin resistance (IR) in liver is a key of pathophysiologic response in type 2 diabetes. Although insulin resistance impairs its ability to suppress hepatic glucose production, insulin regulation of lipogenesis is maintained (1). Currently available insulin sensitizers are effective at lowering glucose levels, but have significant adverse effect on weight gain due to triglyceride accumulation, which highlights a need to develop new therapeutic treatment options for type 2 diabetes. Brown adipose tissue (BAT) has been studied as a new target for anti-obesity and type 2 diabetes as BAT stimulation increases energy expenditure, reduces adiposity, and improves insulin sensitivity (2). However, the underlying mechanisms are not completely understood. To identify the role of BAT adipokines on hepatic insulin resistance, we developed an insulin resistant liver organ-on-chip model and then perfused primary mouse brown adipocyte conditioned media through the hepatocytes. Our results demonstrate that IR hepatocytes treated with brown adipocyte - conditioned media restores insulin sensitivity and improves glucose metabolism. This was verified by significantly increased expression of Phospho-Akt (Ser473) and glucose production gene markers (G6pc and PEPCK), lowered glucose production, increased glucose uptake, and increased glycogen synthesis in treated hepatocytes over IR group (p < 0.05). Our results also indicate that brown adipocyte - conditioned media treatment has the potential to suppress lipogenesis in hepatic insulin resistance. This was confirmed by significantly reduced expression of a lipogenesis gene marker (SREPB1) and fatty acid uptake in treated hepatocytes over IR group (p < 0.05). Current efforts are focused towards identifying the BAT adipokine via mass spectrometry. We conclude that BAT-derived endocrine factors could be a potential target for new drug discovery for obesity and type 2 diabetes treatment. Reference: (1) Langlet et al. Cell. 2017 Nov;171(4):824-835. (2) Subhadraw et al. Am J Physiol Endocrinol Metlab. 2015 Jun;308(12):E1043-E1055. Nothing to Disclose: NT, CL, AT, FZ, KK, JM, RC, AB

scholarly journals Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Denise E. Lackey ◽  
Felipe C. G. Reis ◽  
Roi Isaac ◽  
Rizaldy C. Zapata ◽  
Dalila El Ouarrat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Target Genes ◽  
Obese Mice ◽  
Tissue Macrophage

Abstract Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity.

scholarly journals Increased hypothalamic-pituitary-adrenal axis activity and hepatic insulin resistance in low-birth-weight rats

2007 ◽  
Vol 293 (5) ◽  
pp. E1451-E1458 ◽  
Author(s):  
Esben S. Buhl ◽  
Susanne Neschen ◽  
Shin Yonemitsu ◽  
Joerg Rossbacher ◽  
Dongyan Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Birth Weight ◽  
Insulin Sensitivity ◽  
Low Birth Weight ◽  
Hepatic Insulin Resistance ◽  
Hypothalamic Pituitary Adrenal ◽  
Adrenal Axis ◽  
Pituitary Adrenal Axis

Individuals born with a low birth weight (LBW) have an increased prevalence of type 2 diabetes, but the mechanisms responsible for this association are unknown. Given the important role of insulin resistance in the pathogenesis of type 2 diabetes, we examined insulin sensitivity in a rat model of LBW due to intrauterine fetal stress. During the last 7 days of gestation, rat dams were treated with dexamethasone and insulin sensitivity was assessed in the LBW offspring by a hyperinsulinemic euglycemic clamp. The LBW group had liver-specific insulin resistance associated with increased levels of PEPCK expression. These changes were associated with pituitary hyperplasia of the ACTH-secreting cells, increased morning plasma ACTH concentrations, elevated corticosterone secretion during restraint stress, and an ∼70% increase in 24-h urine corticosterone excretion. These data support the hypothesis that prenatal stress can result in chronic hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in increased plasma corticosterone concentrations, upregulation of hepatic gluconeogenesis, and hepatic insulin resistance.

scholarly journals The Role of Diet on Insulin Sensitivity

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3042
Author(s):  
Maria Mirabelli ◽  
Diego Russo ◽  
Antonio Brunetti
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cardiovascular Disease ◽  
Insulin Sensitivity ◽  
Dietary Composition ◽  
Reproductive Disorders

Growing evidence shows that dietary composition has a marked impact on the risk of developing obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), certain types of endocrine cancer and many other intertwined metabolic and reproductive disorders, all featured by insulin resistance (IR) [...]

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.

scholarly journals Recombinant Human Insulin-Like Growth Factor I Treatment for 1 Week Improves Metabolic Control in Type 2 Diabetes by Ameliorating Hepatic and Muscle Insulin Resistance*

2000 ◽  
Vol 85 (9) ◽  
pp. 3077-3084
Author(s):  
Kenneth Cusi ◽  
Ralph DeFronzo
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Growth Factor ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Recombinant Human Insulin ◽  
Factor I ◽  
Endogenous Glucose

Abstract The administration of recombinant human insulin-like growth factor I (rhIGF-I) reduces hyperglycemia and insulin requirements in subjects with severe insulin resistance syndromes and in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms responsible for the improved metabolic control are incompletely understood. One proposed mechanism is that rhIGF-I therapy in T2DM may bypass early defects in insulin action (i.e. signal transduction), leading to improved hepatic and/or peripheral insulin sensitivity. To test this hypothesis, we used the euglycemic insulin clamp to measure the response to 7 days of rhIGF-I therapy (80 μg/kg, sc, twice daily) in eight poorly controlled T2DM subjects. rhIGF-I significantly improved fasting (203 ± 12 vs. 134 ± 14 mg/dL; P < 0.01) and day-long (0800–1700 h; 234 ± 11 vs. 153 ± 10 mg/dL; P < 0.01) plasma glucose levels. Basal endogenous glucose production decreased from 3.2 ± 0.2 to 2.7 ± 0.2 mg/kg lean body mass· min (P < 0.03) despite a concomitant decline in the fasting plasma insulin concentration from 13 ± 5 to 5 ± 1 μU/mL (P < 0.01). The decrement in basal endogenous glucose production was closely correlated with the decrement in fasting plasma glucose concentration (r = 0.78; P < 0.01). Whole body insulin-stimulated glucose disposal increased by 27% (from 5.6 ± 0.8 to 7.1 ± 0.8 mg/kg lean body mass·min; P < 0.01), but remained well below that observed in age- and weight-matched healthy subjects. The effects of rhIGF-I on endogenous glucose production and peripheral insulin sensitivity resemble those observed with intensified insulin regimens in T2DM. We conclude that 7 days of sc rhIGF-I improves glucose control by improving hepatic and muscle insulin sensitivity, but it remains markedly abnormal. This indicates that an intrinsic defect(s) responsible for insulin resistance in T2DM cannot be overcome by rhIGF-I treatment.

scholarly journals The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

Nature ◽  
2014 ◽  
Vol 510 (7503) ◽  
pp. 84-91 ◽  
Author(s):  
Rachel J. Perry ◽  
Varman T. Samuel ◽  
Kitt F. Petersen ◽  
Gerald I. Shulman
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Insulin Resistance ◽  
Hepatic Lipids

1758-P: Type 2 Diabetes–Associated Mood Disorders: Role of Insulin Resistance in Serotonergic Neurons

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1758-P
Author(s):  
HUGO MARTIN ◽  
SÉBASTIEN BULLICH ◽  
FABIEN DUCROCQ ◽  
MARION GRALAND ◽  
CLARA OLIVRY ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mood Disorders ◽  
Serotonergic Neurons ◽  
P Type

1746-P: Obese Youth with Type 1 Diabetes (T1D) Have Worse Hepatic Insulin Resistance (IR) Than Youth with Type 2 Diabetes (T2D)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1746-P
Author(s):  
PATTARA WIROMRAT ◽  
MELANIE CREE-GREEN ◽  
BRYAN C. BERGMAN ◽  
KALIE L. TOMMERDAHL ◽  
AMY BAUMGARTNER ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Hepatic Insulin Resistance ◽  
Obese Youth

scholarly journals Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1617
Author(s):  
Pierluigi Scalia ◽  
Antonio Giordano ◽  
Caroline Martini ◽  
Stephen J. Williams
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Growth Factor ◽  
Solid Tumors ◽  
Common Finding ◽  
Absolute Increase ◽  
Preferential Expression ◽  
Exon 11

Insulin receptor (IR) and IR-related signaling defects have been shown to trigger insulin-resistance in insulin-dependent cells and ultimately to give rise to type 2 diabetes in mammalian organisms. IR expression is ubiquitous in mammalian tissues, and its over-expression is also a common finding in cancerous cells. This latter finding has been shown to associate with both a relative and absolute increase in IR isoform-A (IR-A) expression, missing 12 aa in its EC subunit corresponding to exon 11. Since IR-A is a high-affinity transducer of Insulin-like Growth Factor-II (IGF-II) signals, a growth factor is often secreted by cancer cells; such event offers a direct molecular link between IR-A/IR-B increased ratio in insulin resistance states (obesity and type 2 diabetes) and the malignant advantage provided by IGF-II to solid tumors. Nonetheless, recent findings on the biological role of isoforms for cellular signaling components suggest that the preferential expression of IR isoform-A may be part of a wider contextual isoform-expression switch in downstream regulatory factors, potentially enhancing IR-dependent oncogenic effects. The present review focuses on the role of isoform- and paralog-dependent variability in the IR and downstream cellular components playing a potential role in the modulation of the IR-A signaling related to the changes induced by insulin-resistance-linked conditions as well as to their relationship with the benign versus malignant transition in underlying solid tumors.

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