Molecular Approaches to Study Control of Glucose Homeostasis

Neubauer, Nicole; Kulkarni, Rohit

doi:10.1093/ilar.47.3.199

Cited by 27 publications

(29 citation statements)

References 148 publications

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“…1D). Defects of glucose regulation typically exhibit increasing severity with age (25), so it is notable that Bmal1 Ϫ/Ϫ mice at only 8-12 weeks exhibit glucose intolerance comparable to that of mice lacking AKT2, a major integrator of insulin signaling (26). After an overnight fast or after an overnight fast followed by refeeding, Bmal1 Ϫ/Ϫ mice had significantly reduced serum insulin (Fig.…”

Section: Resultsmentioning

confidence: 96%

Physiological significance of a peripheral tissue circadian clock

Lamia

Storch²,

Weitz³

2008

Proc. Natl. Acad. Sci. U.S.A.

918

837

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Mammals have circadian clocks in peripheral tissues, but there is no direct evidence of their physiological importance. Unlike the suprachiasmatic nucleus clock that is set by light and drives restactivity and fasting-feeding cycles, peripheral clocks are set by daily feeding, suggesting that at least some contribute metabolic regulation. The liver plays a well known role in glucose homeostasis, and we report here that mice with a liver-specific deletion of Bmal1, an essential clock component, exhibited hypoglycemia restricted to the fasting phase of the daily feeding cycle, exaggerated glucose clearance, and loss of rhythmic expression of hepatic glucose regulatory genes. We conclude that the liver clock is important for buffering circulating glucose in a time-of-daydependent manner. Our findings suggest that the liver clock contributes to homeostasis by driving a daily rhythm of hepatic glucose export that counterbalances the daily cycle of glucose ingestion resulting from the fasting-feeding cycle.glucose homeostasis ͉ liver

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Section: Resultsmentioning

confidence: 96%

Physiological significance of a peripheral tissue circadian clock

Lamia

Storch²,

Weitz³

2008

Proc. Natl. Acad. Sci. U.S.A.

918

837

View full text Add to dashboard Cite

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“…Animal models have provided major molecular insights into the role of different cellular pathways involved in the modulation of glucose homeostasis. How and to what extent these genes contribute to the human disease requires further investigation (Neubauer and Kulkarni, 2006). …”

Section: Discussionmentioning

confidence: 99%

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Díaz-Castroverde

Gómez-Hernández

Fernández

et al. 2016

Disease Models &Amp; Mechanisms

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Type 2 diabetes mellitus is a complex metabolic disease and its pathogenesis involves abnormalities in both peripheral insulin action and insulin secretion. Previous in vitro data showed that insulin receptor isoform A, but not B, favours basal glucose uptake through its specific association with endogenous GLUT1/2 in murine hepatocytes and beta cells. With this background, we hypothesized that hepatic expression of insulin receptor isoform A in a mouse model of type 2 diabetes could potentially increase the glucose uptake of these cells, decreasing the hyperglycaemia and therefore ameliorating the diabetic phenotype. To assure this hypothesis, we have developed recombinant adeno-associated viral vectors expressing insulin receptor isoform A (IRA) or isoform B (IRB) under the control of a hepatocyte-specific promoter. Our results demonstrate that in the long term, hepatic expression of IRA in diabetic mice is more efficient than IRB in ameliorating glucose intolerance. Consequently, it impairs the induction of compensatory mechanisms through beta cell hyperplasia and/or hypertrophy that finally lead to beta cell failure, reverting the diabetic phenotype in about 8 weeks. Our data suggest that long-term hepatic expression of IRA could be a promising therapeutic approach for the treatment of type 2 diabetes mellitus.

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“…While it is not certain if delivery was less efficient in the anesthetized state using a single session treatment or if the accentuated increase in phosphorylation observed for the awake delivery was due to repeated treatment, a week long treatment is better representative of the biochemical changes likely induced following chronic use of insulin IND. The activation of IR kinase supported by the 4x increase in autophosphorylation of the receptor would be anticipated to phosphorylate many downstream signaling cascades in OB neurons that are typically activated to achieve the well-known pleiotropic effects of insulin signaling in other cells (Neubauer and Kulkarni, 2006; McNay, 2007). Kv1.3 channel is only one of those known downstream substrates, however, even when only considering ion channels as substrates, many voltage- and ligand-gated channels are known to be modulated by insulin signaling pathways (i.e.…”

Section: Discussionmentioning

confidence: 99%

Awake Intranasal Insulin Delivery Modifies Protein Complexes and Alters Memory, Anxiety, and Olfactory Behaviors

Marks¹,

Tucker²,

Cavallin³

et al. 2009

J. Neurosci.

213

218

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The role of insulin pathways in olfaction is of significant interest with the widespread pathology of diabetes mellitus and its associated metabolic and neuronal comorbidities. The insulin receptor (IR) kinase is expressed at high levels in the olfactory bulb, in which it suppresses a dominant Shaker ion channel (Kv1.3) via tyrosine phosphorylation of critical N-and C-terminal residues. We optimized a 7 d intranasal insulin delivery (IND) in awake mice to ascertain the biochemical and behavioral effects of insulin to this brain region, given that nasal sprays for insulin have been marketed notwithstanding our knowledge of the role of Kv1.3 in olfaction, metabolism, and axon targeting. IND evoked robust phosphorylation of Kv1.3, as well as increased channel protein-protein interactions with IR and postsynaptic density 95. IND-treated mice had an increased short-and long-term object memory recognition, increased anxiolytic behavior, and an increased odor discrimination using an odor habituation protocol but only moderate change in odor threshold using a two-choice paradigm. Unlike Kv1.3 gene-targeted deletion that alters metabolism, adiposity, and axonal targeting to defined olfactory glomeruli, suppression of Kv1.3 via IND had no effect on body weight nor the size and number of M72 glomeruli or the route of its sensory axon projections. There was no evidence of altered expression of sensory neurons in the epithelium. In mice made prediabetic via diet-induced obesity, IND was no longer effective in increasing long-term object memory recognition nor increasing anxiolytic behavior, suggesting state dependency or a degree of insulin resistance related to these behaviors.

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Molecular Approaches to Study Control of Glucose Homeostasis

Cited by 27 publications

References 148 publications

Physiological significance of a peripheral tissue circadian clock

Physiological significance of a peripheral tissue circadian clock

Insulin receptor isoform A ameliorates long-term glucose intolerance in diabetic mice

Awake Intranasal Insulin Delivery Modifies Protein Complexes and Alters Memory, Anxiety, and Olfactory Behaviors

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