Six and 12 Weeks of Caloric Restriction Increases β Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes1–3

Sathananthan, Matheni; Shah, Meera; Edens, Kim; Grothe, Karen; Piccinini, Francesca; Farrugia, Luca P.; Micheletto, Francesco; Man, Chiara Dalla; Cobelli, Claudio; Rizza, Robert A.; Camilleri, Michael; Vella, Adrian

doi:10.3945/jn.115.210617

Cited by 42 publications

(54 citation statements)

References 28 publications

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“…Interestingly, as in humans2022232426, this occurred even though there was only a modest reduction in body weight and fat pad mass. Moreover, despite the rapid improvement in glucose homeostasis in the diet reversal mice, liver lipids were not completely normalised and remained ~2-fold higher than those in the CHOW group.…”

Section: Discussionmentioning

confidence: 82%

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Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

Kowalski

Hamley

Selathurai

et al. 2016

Sci Rep

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In humans, low-energy diets rapidly reduce hepatic fat and improve/normalise glycemic control. Due to difficulties in obtaining human liver, little is known about changes to the lipid species and pathway fluxes that occur under these conditions. Using a combination of stable isotope, and targeted metabolomic approaches we investigated the acute (7–9 days) hepatic effects of switching high-fat high-sucrose diet (HFD) fed obese mice back to a chow diet. Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic triacyl- and diacylglycerol. However, these parameters were still elevated compared to chow fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized. The diet reversal resulted in marked reductions in hepatic de novo lipogenesis when compared to the chow and HFD groups. Compared with HFD, glycerolipid synthesis was reduced in the reversal animals, however it remained elevated above that of chow controls, indicating that despite experiencing a net loss in lipid stores, the liver was still actively esterifying available fatty acids at rates higher than that in chow control mice. This effect likely promotes the re-esterification of excess free fatty acids released from the breakdown of adipose depots during the weight loss period.

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Section: Discussionmentioning

confidence: 82%

“…In humans with T2D, it is clear that glycemic control can be rapidly normalized by either bariatric surgery2021 or very-low energy diets2223242526 with much of this being liver mediated2022232426. The underlying mechanisms responsible, however, are unclear.…”

mentioning

confidence: 99%

Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

Kowalski

Hamley

Selathurai

et al. 2016

Sci Rep

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show abstract

“…We performed a relatively mild low-calorie diet as compared with most other studies in literature. For example, 16 wk of ;1000 kcal/d led to 13.5-kg weight loss (27), 12 wk of ,900 kcal/d led to 14.8-kg loss (28), and 800 kcal/d for 8 wk led to 11.1-kg (63.5) weight loss (29).…”

Section: Discussionmentioning

confidence: 99%

Measuring phenotypic flexibility by transcriptome time‐course analyses during challenge tests before and after energy restriction

et al. 2019

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Metabolic challenge tests may be a valuable tool to magnify the effects of diet on health. The use of transcriptomics enables a more extensive characterization of the effects of diet. The question remains whether transcriptome time‐course analyses during challenge tests will deliver more information on the effect of diet than a static fasting measurement. A dietary intervention known to improve health is energy restriction (ER). Seventy‐two healthy, overweight men and women aged 50–65 were subjected to an oral glucose tolerance test (OGTT) and a mixed‐meal test (MMT) before and after 12 wk of a 20% ER diet or control diet. Whole‐genome gene expression of peripheral blood mononuclear cells was performed before and after the intervention. This was done during fasting, during the OGTT at 30, 60, and 120 min, and during the MMT at 60, 120, 240, and 360 min. Upon ER, the OGTT resulted in a faster and more pronounced down‐regulation in gene expression of oxidative phosphorylation, cell adhesion, and DNA replication compared with the control. The MMT showed less‐consistent effects. The OGTT combined with transcriptomics can be used to measure dynamic cellular adaptation upon an intervention that cannot be determined with a static fasting measurement.—Van Bussel, I. P. G., Fazelzadeh, P., Frost, G. S., Rundle, M., Afman, L. A. Measuring phenotypic flexibility by transcriptome time‐course analyses during challenge tests before and after energy restriction. FASEB J. 33, 10280–10290 (2019). http://www.fasebj.org

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“…The concept of the fasting and caloric restriction response as a therapeutic to be leveraged in longevity, healthspan, and metabolism from rodents to early primates to humans (1,(35)(36)(37)(38)(39)(40) is gaining traction. Already in the clinical realm, caloric restriction improved multiple indices related to aging, cardiovascular disease and diabetes mellitus (2,(41)(42)(43). However, strict and prolonged adherence to caloric restriction, intermittent fasting or any intensive dietary restriction directed toward weight loss carries with it several practical barriers.…”

Section: Discussionmentioning

confidence: 99%

ALOXE3 is a hepatic fasting-responsive lipoxygenase that enhances insulin sensitivity via hepatic PPARγ

Higgins

Zhang

et al. 2018

Preprint

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The hepatic glucose fasting response is gaining traction as a therapeutic pathway to enhance hepatic and wholehost metabolism. However, the mechanisms underlying these metabolic effects remain unclear. Here, we demonstrate the lipoxygenase, ALOXE3, is a novel effector of the therapeutic fasting response. We show that ALOXE3 is activated during fasting, glucose withdrawal, or trehalose/trehalose analogue treatment. Hepatocytespecific ALOXE3 expression reduced weight gain and hepatic steatosis in diet-induced and genetically obese (db/db) models. ALOXE3 expression moreover enhanced basal thermogenesis and abrogated insulin resistance in db/db diabetic mice. Targeted metabolomics demonstrated accumulation of the PPARg ligand, 12-KETE in hepatocytes overexpressing ALOXE3. Strikingly, PPARg inhibition reversed hepatic ALOXE3-mediated insulin sensitization, suppression of hepatocellular ATP production and oxygen consumption, and gene induction of PPARg coactivator-1a (PGC1a) expression. Moreover, hepatocyte-specific PPARg deletion reversed the therapeutic effect of hepatic ALOXE3 expression on diet-induced insulin intolerance. ALOXE3 is therefore a novel effector of the hepatocellular fasting response that leverages both PPARg-mediated and pleiotropic effects to augment hepatic and whole-host metabolism, and is thus a promising target to ameliorate metabolic disease.

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Six and 12 Weeks of Caloric Restriction Increases β Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes1–3

Cited by 42 publications

References 28 publications

Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis

Measuring phenotypic flexibility by transcriptome time‐course analyses during challenge tests before and after energy restriction

ALOXE3 is a hepatic fasting-responsive lipoxygenase that enhances insulin sensitivity via hepatic PPARγ

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