Insulin Resistance in Tetracycline-Repressible Munc18c Transgenic Mice

Spurlin, Beth A.; R, Thomas; Nevins, Angela K.; Kim, Hyo Jeong; Kim, Yoonjung; Noh, Hye Lim; Shulman, Gerald I.; Kim, Jason K.; Thurmond, Debbie C.

doi:10.2337/diabetes.52.8.1910

Cited by 40 publications

(55 citation statements)

References 52 publications

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“…When stimulated by insulin this clamp is removed by an unknown mechanism and the GLUT4 vesicle docks with the plasma membrane. Displaced munc18c may also be involved in fusing the GLUT4 vesicle to the plasma membrane [7,15]. It remains to be seen whether any component of the insulin signalling cascade regulates munc18c.…”

Section: Introductionmentioning

confidence: 99%

Protein kinase-ζ interacts with munc18c: role in GLUT4 trafficking

2005

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Aims/hypothesis: Insulin-stimulated glucose transport requires a signalling cascade through kinases protein kinase (PK) Cζ/λ and PKB that leads to movement of GLUT4 vesicles to the plasma membrane. The aim of this study was to identify missing links between the upstream insulin-regulated kinases and the GLUT4 vesicle trafficking system. Materials and methods: A yeast twohybrid screen was conducted, using as bait full-length mouse munc18c, a protein known to be part of the GLUT4 vesicle trafficking machinery. Results: The yeast twohybrid screen identified PKCζ as a novel interactor with munc18c. Glutathione S transferase (GST) pull-downs with GST-tagged munc18c constructs confirmed the interaction, mapped a key region of munc18c that binds PKCζ to residues 295-338 and showed that the N-terminal region of PKCζ was required for the interaction. Endogenous munc18c was shown to associate with endogenous PKCζ in vivo in various cell types. Importantly, insulin stimulation increased the association by approximately three-fold. Moreover, disruption of PKCζ binding to munc18c by deletion of residues 295-338 of munc18c or deletion of the N-terminal region of PKCζ markedly inhibited the ability of insulin to stimulate glucose uptake or GLUT4 translocation. Conclusions/interpretation: We have identified a physiological interaction between munc18c and PKCζ that is insulin-regulated. This establishes a link between a kinase (PKCζ) involved in the insulin signalling cascade and a known component of the GLUT4 vesicle trafficking pathway (munc18c). The results indicate that PKCζ regulates munc18c and suggest a model whereby insulin triggers the docking of PKCζ to munc18c, resulting in enhanced GLUT4 translocation to the plasma membrane.

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Section: Introductionmentioning

confidence: 99%

Protein kinase-ζ interacts with munc18c: role in GLUT4 trafficking

2005

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“…Ϫ/Ϫ KO and wild-type (WT) mice (age 4 -6 months) were fasted for 18 h prior to the intraperitoneal glucose tolerance test (IPGTT), as described previously (23). One week following the same mice were assessed for insulin sensitivity using the insulin tolerance test (ITT), wherein mice were fasted for 6 h prior to intraperitoneal injection with Humulin R (0.75 units/kg body weight).…”

Section: Intraperitoneal Glucose Tolerance and Insulin Tolerance Testmentioning

confidence: 99%

“…Human Islet Perifusion-Pancreatic human islets (obtained through the Integrated Islet Distribution Program, IIDP, donor information listed in supplemental Table S3) were used for perifusion in a strategy similar to that used for mouse islet perifusion, as previously described (11,23). Criteria for human donor islet acceptance: receipt within 36 h of isolation, and of at least 80% purity and 75% viability.…”

Section: S3mentioning

confidence: 99%

“…All mice for studies here were obtained by heterozygous crossing and paired littermates used as controls. Mouse pancreatic islets were isolated and used for perifusion, as previously described (11,23). Briefly, pancreata pooled from five ϳ12-week-old male mice were batch-digested with collagenase, purified using a Ficoll density gradient, and incubated overnight in RPMI 1640 at 37°C, 5% CO 2 .…”

Section: S3mentioning

confidence: 99%

“…The plasmid-based siRNA construct pSilencer1.0-Cdc42 (siCdc42) was generated as previously described (11,23); targeting sequence encoding 19 nucleotides (nt) of human Cdc42 is 5Ј-CTAACCACTGTC-CAAAGAC-3Ј. Adenoviruses were packaged with green fluorescent protein (GFP) to facilitate identification of transduced cells.…”

Section: S3mentioning

confidence: 99%

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Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Wang¹,

Oh²,

Clapp³

et al. 2011

Journal of Biological Chemistry

Self Cite

119

166

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Background: P21-activated kinase (PAK1) is a downstream effector of the GTPase Cdc42. Results: Inhibition of Cdc42-PAK1 signaling in human islets inhibited insulin secretion. PAK1 knock-out mice showed defects in insulin release and skeletal muscle insulin action, underlying impaired whole body glucose homeostasis. Conclusion: Attenuated PAK1 abundance/activation may contribute to type 2 diabetes susceptibility. Significance: Cdc42-PAK1 signaling is crucial for regulating glucose homeostasis in vivo.

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Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake

Merz

Thurmond

2020

Comprehensive Physiology

310

187

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The skeletal muscle is the largest organ in the body, by mass. It is also the regulator of glucose homeostasis, responsible for 80% of postprandial glucose uptake from the circulation. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in exercise and metabolic disease. In this article, we give an overview of the importance of skeletal muscle in metabolism, describing its role in glucose uptake and the diseases that are associated with skeletal muscle metabolic dysregulation. We focus on the role of skeletal muscle in peripheral insulin resistance and the potential for skeletal muscle-targeted therapeutics to combat insulin resistance and diabetes, as well as other metabolic diseases like aging and obesity. In particular, we outline the possibilities and pitfalls of the quest for exercise mimetics, which are intended to target the molecular mechanisms underlying the beneficial effects of exercise on metabolic disease. We also provide a description of the molecular mechanisms that regulate skeletal muscle glucose uptake, including a focus on the SNARE proteins, which are essential regulators of glucose transport into the skeletal muscle.

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Insulin Resistance in Tetracycline-Repressible Munc18c Transgenic Mice

Cited by 40 publications

References 52 publications

Protein kinase-ζ interacts with munc18c: role in GLUT4 trafficking

Protein kinase-ζ interacts with munc18c: role in GLUT4 trafficking

Inhibition or Ablation of p21-activated Kinase (PAK1) Disrupts Glucose Homeostatic Mechanisms in Vivo

Role of Skeletal Muscle in Insulin Resistance and Glucose Uptake

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