A new degree of complexi(n)ty in the regulation of GLUT4 trafficking

2021 ◽  
Vol 478 (7) ◽  
pp. 1315-1319
Author(s):  
Luc Bertrand ◽  
Marine De Loof ◽  
Christophe Beauloye ◽  
Sandrine Horman ◽  
Laurent Bultot
Keyword(s):  
Glucose Transporter ◽  
Whole Body ◽  
Glucose Transporter 4 ◽  
Insulin Stimulation ◽  
Cell Plasma Membrane ◽  
Cell Plasma ◽  
Challenges And Opportunities ◽  
Future Challenges ◽  
Whole Body Metabolism

Loss of the insulin-stimulated glucose uptake in muscle is a crucial event participating in the defect of whole-body metabolism in type 2 diabetes. Therefore, identification by Pavarotti et al. (Biochem. J (2021) 478 (2): 407–422) of complexin-2 as an important contributor to glucose transporter 4 (GLUT4) translocation to muscle cell plasma membrane upon insulin stimulation is essential. The present commentary discusses the biological importance of the findings and proposes future challenges and opportunities.

scholarly journals SEC16A is a RAB10 effector required for insulin-stimulated GLUT4 trafficking in adipocytes

2016 ◽  
Vol 214 (1) ◽  
pp. 61-76 ◽  
Author(s):  
Joanne Bruno ◽  
Alexandria Brumfield ◽  
Natasha Chaudhary ◽  
David Iaea ◽  
Timothy E. McGraw
Keyword(s):  
Glucose Transporter ◽  
Whole Body ◽  
Site Formation ◽  
Coated Vesicle ◽  
Coat Proteins ◽  
Insulin Stimulation ◽  
Exit Site ◽  
Recycling Endosome ◽  
Transport Vesicles ◽  
Intracellular Compartments

RAB10 is a regulator of insulin-stimulated translocation of the GLUT4 glucose transporter to the plasma membrane (PM) of adipocytes, which is essential for whole-body glucose homeostasis. We establish SEC16A as a novel RAB10 effector in this process. Colocalization of SEC16A with RAB10 is augmented by insulin stimulation, and SEC16A knockdown attenuates insulin-induced GLUT4 translocation, phenocopying RAB10 knockdown. We show that SEC16A and RAB10 promote insulin-stimulated mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment. We propose RAB10–SEC16A functions to accelerate formation of the vesicles that ferry GLUT4 to the PM during insulin stimulation. Because GLUT4 continually cycles between the PM and intracellular compartments, the maintenance of elevated cell-surface GLUT4 in the presence of insulin requires accelerated biogenesis of the specialized GLUT4 transport vesicles. The function of SEC16A in GLUT4 trafficking is independent of its previously characterized activity in ER exit site formation and therefore independent of canonical COPII-coated vesicle function. However, our data support a role for SEC23A, but not the other COPII components SEC13, SEC23B, and SEC31, in the insulin stimulation of GLUT4 trafficking, suggesting that vesicles derived from subcomplexes of COPII coat proteins have a role in the specialized trafficking of GLUT4.

scholarly journals Insulin Stimulation of GLUT4 Exocytosis, but Not Its Inhibition of Endocytosis, Is Dependent on RabGAP AS160

2004 ◽  
Vol 15 (10) ◽  
pp. 4406-4415 ◽  
Author(s):  
Anja Zeigerer ◽  
Mary Kate McBrayer ◽  
Timothy E. McGraw
Keyword(s):  
Plasma Membrane ◽  
Blood Glucose ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Whole Body ◽  
Insulin Stimulation ◽  
Molecular Events ◽  
Intracellular Compartments ◽  
Blood Glucose Homeostasis ◽  
Stimulation Of

Insulin maintains whole body blood glucose homeostasis, in part, by regulating the amount of the GLUT4 glucose transporter on the cell surface of fat and muscle cells. Insulin induces the redistribution of GLUT4 from intracellular compartments to the plasma membrane, by stimulating a large increase in exocytosis and a smaller inhibition of endocytosis. A considerable amount is known about the molecular events of insulin signaling and the complex itinerary of GLUT4 trafficking, but less is known about how insulin signaling is transmitted to GLUT4 trafficking. Here, we show that the AS160 RabGAP, a substrate of Akt, is required for insulin stimulation of GLUT4 exocytosis. A dominant-inhibitory mutant of AS160 blocks insulin stimulation of exocytosis at a step before the fusion of GLUT4-containing vesicles with the plasma membrane. This mutant, however, does not block insulin-induced inhibition of GLUT4 endocytosis. These data support a model in which insulin signaling to the exocytosis machinery (AS160 dependent) is distinct from its signaling to the internalization machinery (AS160 independent).

scholarly journals PPARs-Orchestrated Metabolic Homeostasis in the Adipose Tissue

2021 ◽  
Vol 22 (16) ◽  
pp. 8974
Author(s):  
Chen Sun ◽  
Shuyu Mao ◽  
Siyu Chen ◽  
Wenxiang Zhang ◽  
Chang Liu
Keyword(s):  
Adipose Tissue ◽  
Drug Targets ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Unique Role ◽  
Molecular Events ◽  
Peroxisome Proliferator Activated Receptors ◽  
Whole Body Metabolism ◽  
Metabolic Syndromes

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to “safely” store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology.

scholarly journals Spatial and temporal studies of metabolic activity: contrasting biochemical kinetics in tissues and pathways during fasted and fed states

2019 ◽  
Vol 316 (6) ◽  
pp. E1105-E1117 ◽  
Author(s):  
Natalie A. Daurio ◽  
Yichen Wang ◽  
Ying Chen ◽  
Haihong Zhou ◽  
Ester Carballo-Jane ◽  
...  
Keyword(s):  
Metabolic Activity ◽  
Whole Body ◽  
Spatial And Temporal Patterns ◽  
Disease Phenotypes ◽  
Biochemical Kinetics ◽  
Dietary Components ◽  
Whole Body Metabolism ◽  
Nutrient Homeostasis

The regulation of nutrient homeostasis, i.e., the ability to transition between fasted and fed states, is fundamental in maintaining health. Since food is typically consumed over limited (anabolic) periods, dietary components must be processed and stored to counterbalance the catabolic stress that occurs between meals. Herein, we contrast tissue- and pathway-specific metabolic activity in fasted and fed states. We demonstrate that knowledge of biochemical kinetics that is obtained from opposite ends of the energetic spectrum can allow mechanism-based differentiation of healthy and disease phenotypes. Rat models of type 1 and type 2 diabetes serve as case studies for probing spatial and temporal patterns of metabolic activity via [2H]water labeling. Experimental designs that capture integrative whole body metabolism, including meal-induced substrate partitioning, can support an array of research surrounding metabolic disease; the relative simplicity of the approach that is discussed here should enable routine applications in preclinical models.

Evidence for physiological coupling of insulin-mediated glucose metabolism and limb blood flow

2000 ◽  
Vol 279 (6) ◽  
pp. E1264-E1270 ◽  
Author(s):  
Kieren Mather ◽  
Markku Laakso ◽  
Steven Edelman ◽  
Ginger Hook ◽  
Alain Baron
Keyword(s):  
Blood Flow ◽  
Glucose Metabolism ◽  
Whole Body ◽  
Glucose Disposal ◽  
Insulin Stimulation ◽  
Insulin Resistant ◽  
Type 2 Dm ◽  
Glucose Disposal Rate ◽  
Type 2 Diabetic

We hypothesized that the vasodilation observed during insulin stimulation is closely coupled to the rate of glucose metabolism. Lean (L, n = 13), obese nondiabetic (OB, n = 13), and obese type 2 diabetic subjects (Type 2 DM, n = 16) were studied. Leg blood flow (LBF) was examined under conditions of euglycemic hyperinsulinemia (EH) and hyperglycemic hyperinsulinemia (HH), which produced a steady-state whole body glucose disposal rate (GDR) of ∼2,000 μmol · m−2 · min−1. At this GDR, under both conditions, subjects across the range of insulin sensitivity exhibited equivalent LBF (l/min EH: L, 0.42 ± 0.03; OB, 0.43 ± 0.03; Type 2 DM, 0.38 ± 0.07; P= 0.72 by ANOVA. HH: L, 0.44 ± 0.04; OB, 0.39 ± 0.05; Type 2 DM, 0.41 ± 0.04; P = 0.71). The continuous relationship between LBF and GDR did not differ across subject groups [slope × 10−5l/(μmol · m−2 · min−1) by ANOVA. EH: L, 8.6; OB, 9.2; Type 2 DM, 7.9; P = 0.91. HH: L, 4.2; OB, 2.5; Type 2 DM, 4.1; P = 0.77], although this relationship did differ between the EH and HH conditions ( P = 0.001). These findings support a physiological coupling of LBF and insulin-mediated glucose metabolism. The mechanism(s) linking substrate delivery and metabolism appears to be intact in insulin-resistant states.

scholarly journals Adipocytes Exhibit Abnormal Subcellular Distribution and Translocation of Vesicles Containing Glucose Transporter 4 and Insulin-Regulated Aminopeptidase in Type 2 Diabetes Mellitus: Implications Regarding Defects in Vesicle Trafficking

2001 ◽  
Vol 86 (11) ◽  
pp. 5450-5456 ◽  
Author(s):  
Lidia Maianu ◽  
Susanna R. Keller ◽  
W. Timothy Garvey
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Mass Index ◽  
Body Mass ◽  
Glucose Transporter ◽  
Diabetic Patients ◽  
Low Density ◽  
Glucose Transporter 4 ◽  
Glut 4

Insulin resistance in type 2 diabetes is due to impaired stimulation of the glucose transport system in muscle and fat. Different defects are operative in these two target tissues because glucose transporter 4 (GLUT 4) expression is normal in muscle but markedly reduced in fat. In muscle, GLUT 4 is redistributed to a dense membrane compartment, and insulin-mediated translocation to plasma membrane (PM) is impaired. Whether similar trafficking defects are operative in human fat is unknown. Therefore, we studied subcellular localization of GLUT4 and insulin-regulated aminopeptidase (IRAP; also referred to as vp165 or gp160), which is a constituent of GLUT4 vesicles and also translocates to PM in response to insulin. Subcutaneous fat was obtained from eight normoglycemic control subjects (body mass index, 29 ± 2 kg/m2) and eight type 2 diabetic patients (body mass index, 30 ± 1 kg/m2; fasting glucose, 14 ± 1 mm). In adipocytes isolated from diabetics, the basal 3-O-methylglucose transport rate was decreased by 50% compared with controls (7.1 ± 2.9 vs. 14.1 ± 3.7 mmol/mm2 surface area/min), and there was no increase in response to maximal insulin (7.9 ± 2.7 vs. 44.5 ± 9.2 in controls). In membrane subfractions from controls, insulin led to a marked increase of IRAP in the PM from 0.103 ± 0.04 to 1.00± 0.33 relative units/mg protein, concomitant with an 18% decrease in low-density microsomes and no change in high-density microsomes (HDM). In type 2 diabetes, IRAP overall expression in adipocytes was similar to that in controls; however, two abnormalities were observed. First, in basal cells, IRAP was redistributed away from low-density microsomes, and more IRAP was recovered in HDM (1.2-fold) and PM (4.4-fold) from diabetics compared with controls. Second, IRAP recruitment to PM by maximal insulin was markedly impaired. GLUT4 was depleted in all membrane subfractions (43–67%) in diabetes, and there was no increase in PM GLUT4 in response to insulin. Type 2 diabetes did not affect the fractionation of marker enzymes. We conclude that in human adipocytes: 1) IRAP is expressed and translocates to PM in response to insulin; 2) GLUT4 depletion involves all membrane subfractions in type 2 diabetes, although cellular levels of IRAP are normal; and 3) in type 2 diabetes, IRAP accumulates in membrane vesicles cofractionating with HDM and PM under basal conditions, and insulin-mediated recruitment to PM is impaired. Therefore, in type 2 diabetes, adipocytes express defects in trafficking of GLUT4/IRAP-containing vesicles similar to those causing insulin resistance in skeletal muscle.

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