Snapin Mediates Incretin Action and Augments Glucose-Dependent Insulin Secretion

Song, Wonkyong; Seshadri, Madhav; Ashraf, Uzair; Mdluli, Thembi; Mondal, Prosenjit; Keil, Meg; Azevedo, Monalisa F.; Kirschner, Lawrence S.; Stratakis, Constantine A.; Hussain, Mehboob A.

doi:10.1016/j.cmet.2011.02.002

Cited by 106 publications

(106 citation statements)

References 49 publications

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“…2a, bottom panel), and then tested metformin efficacy in vivo. In agreement with a previous report (29), PKAR1a knock-out led to a significant elevation in fasting blood glucose levels (Fig. 2a).…”

Section: Resultssupporting

confidence: 82%

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Chang

Peng

et al. 2016

Journal of Biological Chemistry

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Metformin is the most commonly prescribed oral anti-diabetic agent worldwide. Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment, and many patients become less responsive to metformin over time. It remains unknown how metformin resistance or insensitivity occurs. Recently, we found that therapeutic metformin concentrations suppressed glucose production in primary hepatocytes through AMPK; activation of the cAMP-PKA pathway negatively regulates AMPK activity by phosphorylating AMPK␣ subunit at Ser-485, which in turn reduces AMPK activity. In this study, we find that metformin failed to suppress glucose production in primary hepatocytes with constitutively activated PKA and did not improve hyperglycemia in mice with hyperglucagonemia. Expression of the AMPK␣1(S485A) mutant, which is unable to be phosphorylated by PKA, increased both AMPK␣ activation and the suppression of glucose production in primary hepatocytes treated with metformin. Intriguingly, salicylate/ aspirin prevents the phosphorylation of AMPK␣ at Ser-485, blocks cAMP-PKA negative regulation of AMPK, and improves metformin resistance. We propose that aspirin/salicylate may augment metformin's hepatic action to suppress glucose production.Diabetes is the fastest-growing chronic disease worldwide, and type 2 diabetes (T2D) 2 accounts for more than 90% of diabetes cases. Metformin has been used to treat T2D since the 1950s and works primarily by controlling fasting hyperglycemia (1). Now, over 150 million people worldwide take this medication; guidelines for the treatment of T2D published by the American Diabetes Association and the European Association for the Study of Diabetes in 2012 jointly recommended metformin as the initial drug for T2D treatment (2).Surprisingly, about 35% of diabetic patients either lack or have a delayed response to metformin treatment (3-6), and many patients become less responsive to metformin over time (4). It remains unknown how metformin resistance/ insensitivity occurs. Several genes have been reported to be associated with glycemic control by metformin. In particular, variants of the organic cation transporter and the metformin transporter, have been linked to a reduction in metformin action (7-9). Because of the high occurrence of metformin resistance in diabetic patients, genetic variants in known genes alone cannot explain this phenomenon; therefore, nongenetic factors may also contribute to the response to metformin.Recently, we found that treatment with metformin prior to the addition of cAMP led to greater suppression of glucose production and AMPK activation when compared with simultaneous treatment with metformin and cAMP (10), suggesting that the cAMP-PKA pathway exerts a negative effect on AMPK activation. In both diabetic animal models and human subjects, serum glucagon levels and the ratios of glucagon to insulin are often elevated (11)(12)(13)(14) and are responsible for increased hepatic glucose output and hyperglycemia in T2D (15). Elevated glucagon l...

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Section: Resultssupporting

confidence: 82%

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Chang

Peng

et al. 2016

Journal of Biological Chemistry

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“…Selective ablation of RIα in β cells leads to disinhibition of PKA and increased phosphorylation of the transcription factor cAMP-response element-binding protein (CREB) (Song et al 2011). Mice with RIα ablation in β cells show greatly enhanced glucose-stimulated insulin secretion and increased glucose tolerance (Song et al 2011, Hussain et al 2012). More importantly, human patients with heterozygous RIα-inactivating mutation (Carney's complex) also showed increased insulin release during oral glucose tolerance test (Song et al 2011).…”

Section: Camp/pka In Pancreatic Isletsmentioning

confidence: 99%

“…More important, PKA can directly enhance insulin exocytosis through phosphorylating secretory granuleassociated proteins such as snapin and synaptotagmin ( Fig. 3A) (Seino & Shibasaki 2005, Song et al 2011 to increase Ca 2+ responsiveness, and this mechanism may account for the majority of PKA's effect on insulin release (Ammala et al 1993).…”

Section: Camp/pka In Pancreatic Isletsmentioning

confidence: 99%

“…Mice with RIα ablation in β cells show greatly enhanced glucose-stimulated insulin secretion and increased glucose tolerance (Song et al 2011, Hussain et al 2012). More importantly, human patients with heterozygous RIα-inactivating mutation (Carney's complex) also showed increased insulin release during oral glucose tolerance test (Song et al 2011). Another strategy to increase β cell PKA activity is the selective expression of a constitutively active PKA Cα subunit in Figure 2 Glucose homeostasis is regulated by the coordinated actions of various organs.…”

Section: Camp/pka In Pancreatic Isletsmentioning

confidence: 99%

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Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Yang

2016

Journal of Molecular Endocrinology

145

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In mammals, cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that is usually elicited by binding of hormones and neurotransmitters to G protein-coupled receptors (GPCRs). cAMP exerts many of its physiological effects by activating cAMPdependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis, and neural control of glucose homeostasis. This review summarizes recent genetic and pharmacological studies concerning the regulation of glucose homeostasis by cAMP/PKA in pancreas, liver, skeletal muscle, adipose tissues, and brain. We also discuss the strategies for targeting cAMP/PKA pathway for research and potential therapeutic treatment of type 2 diabetes mellitus (T2D).

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“…Further studies have extended the fusogenic function of Snapin in a wide array of membrane fusion events in non-neuronal cells such as endosome-mediated cytokinesis, phagosome maturation, and insulin exocytosis (Ilardi et al, 1999;Buxton et al, 2003;Gromley et al, 2005;Song et al, 2011;Tiwari et al, 2009). Snapin executes the fusogenic function in part by associating with proteins in vesicle SNARE (v-SNARE) complexes on donor membranes and drives the fusion with trans SNARE (t-SNARE) complexes on target membranes such as lysosomal membranes (Buxton et al, 2003;Lu et al, 2009;Pan et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Beclin 1-interacting autophagy protein Atg14L targets SNARE-associated protein Snapin to coordinate endocytic trafficking

Kim

Zhong

Sheng

et al. 2012

Journal of Cell Science

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SummaryAutophagy is a highly regulated membrane remodeling process that allows the lysosome-mediated degradation of cytoplasmic entities by sequestrating them in double-membrane autophagosomes. Autophagy is hence highly intertwined with the endocytic trafficking pathway, sharing similar molecular machinery. Atg14L, also known as Beclin 1-associated autophagy-related key regulator (Barkor), directly interacts with Beclin 1 through its coiled-coil domain and enhances phosphatidylinositol 3-phosphate kinase class III (PI3KC3) activity to induce autophagosome membrane nucleation, highlighting its essential role in the early stage of mammalian autophagy. Here, we report a novel function of Atg14L in the endocytic trafficking pathway wherein Atg14L binds to and colocalizes with the fusogenic SNARE effector protein Snapin to facilitate endosome maturation. Atg14L specifically binds to Snapin and this interaction effectively facilitates endosomal maturation without affecting autophagic cargo degradation. Consequently, atg14l knockdown significantly delayed the late stage of endocytic trafficking, as evidenced by the retarded kinetics of internalized surface receptor degradation. This phenotype was effectively complemented by wild-type Atg14L or Beclin 1-binding mutant, but not by its Snapin-binding mutant. Taken together, our study demonstrates that Atg14L functions as a multivalent trafficking effector that regulates endosome maturation as well as autophagosome formation, reflecting the complexity of the crosstalk between autophagic and endocytic vesicle trafficking in higher eukaryotes.

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Snapin Mediates Incretin Action and Augments Glucose-Dependent Insulin Secretion

Cited by 106 publications

References 49 publications

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Activation of the cAMP-PKA pathway Antagonizes Metformin Suppression of Hepatic Glucose Production

Targeting cAMP/PKA pathway for glycemic control and type 2 diabetes therapy

Beclin 1-interacting autophagy protein Atg14L targets SNARE-associated protein Snapin to coordinate endocytic trafficking

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