Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

Blagosklonny, Mikhail V.

doi:10.4161/cc.10.24.18595

Cited by 55 publications

(56 citation statements)

References 93 publications

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“…Indeed, these 2 extremes of response are even displayed by the same organ, i.e., increased hepatic production of glucose, 12,25 and parenchymal deposition of lipid, 32-36 associated with insulin resistance, 37,38 suggesting that this principle could be applied to organs and tissues separately, as well as involving the body as a whole.…”

Section: Coexistent Insulin Deficiency and Insulin Excess In Organs Andmentioning

confidence: 97%

“…52 The O 2 partial pressure regulates the expression of genes encoding glucosemetabolizing enzymes, (for example: pyruvate carboxykinase, glucokinase and pyruvate kinase), through O 2 -responsive transcription factors, such as hypoxiainducible factor (HIF). 53,54 Moreover, liver metabolism is controlled among others by nuclear receptors, 36 mammalian target of rapamycin (mTOR) pathway, 37 and sirtuin family of proteins. 38 The model of metabolic zonation assumes a functional specialization by each hepatic zone (Fig.…”

Section: Metabolic Compartmentalization Of Glucose Production and Lipmentioning

confidence: 99%

“…However, in the acini area, the hepatocytes are exposed to a spatial biochemical gradient that influences metabolism and gene expression, so cell specialization does exist to some degree, depending on locale. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52] Parenchymal acini of the liver are divisible into 2 circulatory zones, based on proximity to afferent vessels. 36 Periportal hepatocytes are supplied by blood rich in oxygen and nutrients, whereas the blood reaching perivenous hepatocytes (at the periphery of acini) is oxygen-poor and nutrient-depleted.…”

Section: Metabolic Compartmentalization Of Glucose Production and Lipmentioning

confidence: 99%

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Insulin resistance in the liver: Deficiency or excess of insulin?

2014

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In insulin-resistant states (obesity, pre-diabetes, and type 2 diabetes), hepatic production of glucose and lipid synthesis are heightened in concert, implying that insulin deficiency and insulin excess coexists in this setting. The fact that insulin may be inadequate or excessive at any one point in differing organs and tissues has many biologic ramifications. In this context the concept of metabolic compartmentalization in the liver is offered herein as one perspective of this paradox. In particular, we focus on the hypothesis that insulin resistance accentuates differences in periportal and perivenous hepatocytes, namely periportal glucose production and perivenous lipid synthesis. Subsequently, excessive production of glucose and accumulation of lipids could be expected in the livers of patients with obesity and insulin resistance. Overall, in this review, we provide our integrative perspective regarding how excessive production of glucose in periportal hepatocytes and accumulation of lipids in perivenous hepatocytes interact in insulin resistant states.

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Section: Coexistent Insulin Deficiency and Insulin Excess In Organs Andmentioning

confidence: 97%

Section: Metabolic Compartmentalization Of Glucose Production and Lipmentioning

confidence: 99%

Section: Metabolic Compartmentalization Of Glucose Production and Lipmentioning

confidence: 99%

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Insulin resistance in the liver: Deficiency or excess of insulin?

2014

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“…In addition, as insulin signaling itself is a regulator of mTOR1, extensive insulin inhibition with consequently downregulates mTOR, reduces the protective mTOR signaling and insulin resistance featured in T2D [149]. Ultimately, the response to mTOR1 is biphasic: initially mTOR1 increases β-cell production and reduces insulin resistance while over time, chronic mTOR1 activation induces insulin resistance and hyperglycemia ultimately proving toxic to pancreatic β-cells [148].…”

Section: Mtormentioning

confidence: 99%

“…This is attributed to the long-term effects of mTOR1 signaling and its effects on β-cell integrity. Chronic mTOR1 activation by glucose impairs IRS signaling which over time induces β-cell insulin resistance ultimately leading to β-cell failure [147,148]. In addition, as insulin signaling itself is a regulator of mTOR1, extensive insulin inhibition with consequently downregulates mTOR, reduces the protective mTOR signaling and insulin resistance featured in T2D [149].…”

Section: Mtormentioning

confidence: 99%

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Lomis¹

2015

J Diabetes Metab

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The gut microflora is a community of trillions of bacterial cells synergistically inhabiting the human gastrointestinal tract. These microbes contact everything that is consumed and release regulatory factors that affect host energy homeostasis, lipid and carbohydrate metabolism, activation of immune cells, oxidative state, epithelial cell wall integrity and even neurological signals. The gut microflora is essentially an independent organ supporting human health where imbalances in the gut community populations (dysbiosis) manifest in disease. Diabetes and neurodegenerative disorders such as Alzheimer's and Parkinson's disease share a similar molecular pathology rooted in gut microflora activity. Both of these conditions are associated with a dysbiosis characterized by low species diversity, a higher proportion of pathobionts at the expense of symbionts, an abundance of proinflammatory microbes and fewer butyrate-producing strains. Many of these factors can be ameliorated with Lactobacillus spp. and Bifidobacterium spp. probiotic treatment aimed to reestablish healthy gut microflora diversity. Indeed, certain commensal and pathogenic strains promote chronic low-grade inflammation that stresses cellular infrastructure eventually leading to apoptosis in both the pancreas and the brain. Also, lack of some beneficial fermentation products such as butyrate and ferulic acid initiates a cascade of events disrupting metabolic homeostasis. Finally, signaling initiated by the microflora and its metabolites has been shown to disrupt the delicate intracellular balance of PI3K/Akt/mTOR signaling, which fundamentally regulates events leading up to diabetes and neurodegenerative disease pathogenesis. The following review investigates the relationship between the manifestation and molecular signaling of diabetes and neurodegenerative disorders and how the balance of gut microflora populations is critical to both prevent and possibly treat these diseases.

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Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease

Johnson¹

2018

Subcellular Biochemistry

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Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

Cited by 55 publications

References 93 publications

Insulin resistance in the liver: Deficiency or excess of insulin?

Insulin resistance in the liver: Deficiency or excess of insulin?

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease

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