TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

Blagosklonny, Mikhail V.

doi:10.1038/cddis.2013.506

Cited by 109 publications

(115 citation statements)

References 171 publications

(213 reference statements)

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“…tion of the insulin receptor (IR), protein kinase B (Akt), and mTOR ( Fig. 3F) (9). These data show that KO adipose demonstrates a phenotype of dampened insulin signaling.…”

Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationmentioning

confidence: 72%

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Troche

Aydemir

Cousins

2016

American Journal of Physiology-Endocrinology and Metabolism

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Troche C, Beker Aydemir T, Cousins RJ. Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity. Am J Physiol Endocrinol Metab 310: E258 -E268, 2016. First published December 8, 2015 doi:10.1152/ajpendo.00421.2015.-Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 (Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPAR␥), and activation of NF-B and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-B). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism.

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“…tion of the insulin receptor (IR), protein kinase B (Akt), and mTOR ( Fig. 3F) (9). These data show that KO adipose demonstrates a phenotype of dampened insulin signaling.…”

Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationmentioning

confidence: 72%

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Troche

Aydemir

Cousins

2016

American Journal of Physiology-Endocrinology and Metabolism

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“…100,114 Paracrine geroconversion also takes place. 115,116 Gradually geroconversion involves most cells in diverse tissues.…”

Section: From Gerontology To Medicinementioning

confidence: 99%

Geroconversion: irreversible step to cellular senescence

2014

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“…Third, age-related changes in postreceptor insulin signaling proteins such as insulin receptor substrate-1 have been associated with the development of insulin resistance (Carvalho et al, 1996;Nagasaki et al, 2000). These proteins are influenced by nutrients such as glucose, AA, and fatty acids (Blagosklonny, 2013). Nevertheless, further research is required to determine whether a combination of these factors (i.e., insulin receptor, GLUT-4, insulin signaling proteins), or possibly other factors are responsible for the strong age-related decrease in whole body insulin sensitivity in young calves.…”

Section: Decrease In Insulin Sensitivitymentioning

confidence: 99%

Insulin sensitivity in calves decreases substantially during the first 3 months of life and is unaffected by weaning or fructo-oligosaccharide supplementation

Pantophlet

Gilbert

Borne

et al. 2016

Journal of Dairy Science

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Veal calves at the age of 4 to 6 mo often experience problems with glucose homeostasis, as indicated by postprandial hyperglycemia, hyperinsulinemia, and insulin resistance. It is not clear to what extent the ontogenetic development of calves or the feeding strategy [e.g., prolonged milk replacer (MR) feeding] contribute to this pathology. The objective of this study was therefore to analyze effects of MR feeding, weaning, and supplementation of short-chain fructo-oligosaccharides (FOS) on the development of glucose homeostasis and insulin sensitivity in calves during the first 3 mo of life. Thirty male Holstein-Friesian calves (18±0.7 d of age) were assigned to 1 of 3 dietary treatments: the control (CON) group received MR only, the FOS group received MR with the addition of short-chain FOS, and the solid feed (SF) group was progressively weaned to SF. The CON and FOS calves received an amount of MR, which gradually increased (from 400 to 1,400 g/d) during the 71-d trial period. For the SF calves, the amount of MR increased from 400 to 850 g/d at d 30, and then gradually decreased, until completely weaned to only SF at d 63. The change in whole body insulin sensitivity was assessed by intravenous glucose tolerance tests. Milk tolerance tests were performed twice to assess changes in postprandial blood glucose, insulin, and nonesterified fatty acid responses. Whole-body insulin sensitivity was high at the start (16.7±1.6×10(-4) [μU/mL](-1)), but decreased with age to 4.2±0.6×10(-4) [μU/mL](-1) at the end of the trial. The decrease in insulin sensitivity was most pronounced (~70%) between d 8 and 29 of the trial. Dietary treatments did not affect the decrease in insulin sensitivity. For CON and FOS calves, the postprandial insulin response was 3-fold higher at the end of the trial than at the start, whereas the glucose response remained similar. The SF calves, however, showed pronounced hyperglycemia and hyperinsulinemia at the end of the trial, although weaning did not affect insulin sensitivity. We conclude that whole body insulin sensitivity decreases by 75% in calves during the first 3 mo of life. Weaning or supplementation of short-chain FOS does not affect this age-related decline in insulin sensitivity. Glucose homeostasis is not affected by supplementation of short-chain FOS in young calves, whereas postprandial responses of glucose and insulin to a MR meal strongly increase after weaning.

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TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists

Cited by 109 publications

References 171 publications

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Geroconversion: irreversible step to cellular senescence

Insulin sensitivity in calves decreases substantially during the first 3 months of life and is unaffected by weaning or fructo-oligosaccharide supplementation

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