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Short‐term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high‐fat diet

Published on Oct 1, 2018in The Journal of Physiology
· DOI :10.1113/JP275173
Gerald Grandl4
Estimated H-index: 4
,
Leon G. Straub5
Estimated H-index: 5
+ 4 AuthorsChristian Wolfrum29
Estimated H-index: 29
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Abstract
KEY POINTS A ketogenic diet is known to lead to weight loss and is considered metabolically healthy; however there are conflicting reports on its effect on hepatic insulin sensitivity. KD fed animals appear metabolically healthy in the fasted state after 3 days of dietary challenge, whereas obesogenic high-fat diet (HFD) fed animals show elevated insulin levels. A glucose challenge reveals that both KD and HFD fed animals are glucose intolerant. Glucose intolerance correlates with increased lipid oxidation and lower respiratory exchange ratio (RER); however, all animals respond to glucose injection with an increase in RER. Hyperinsulinaemic-euglycaemic clamps with double tracer show that the effect of KD is a result of hepatic insulin resistance and increased glucose output but not impaired glucose clearance or tissue glucose uptake in other tissues. ABSTRACT Despite being a relevant healthcare issue and heavily investigated, the aetiology of type 2 diabetes (T2D) is still incompletely understood. It is well established that increased endogenous glucose production (EGP) leads to a progressive increase in glucose levels, causing insulin resistance and eventual loss of glucose homeostasis. The consumption of high carbohydrate, high-fat, western style diet (HFD) is linked to the development of T2D and obesity, whereas the consumption of a low carbohydrate, high-fat, ketogenic diet (KD) is considered healthy. However, several days of carbohydrate restriction are known to cause selective hepatic insulin resistance. In the present study, we compare the effects of short-term HFD and KD feeding on glucose homeostasis in mice. We show that, even though KD fed animals appear to be healthy in the fasted state, they exhibit decreased glucose tolerance to a greater extent than HFD fed animals. Furthermore, we show that this effect originates from blunted suppression of hepatic glucose production by insulin, rather than impaired glucose clearance and tissue glucose uptake. These data suggest that the early effects of HFD consumption on EGP may be part of a normal physiological response to increased lipid intake and oxidation, and that systemic insulin resistance results from the addition of dietary glucose to EGP-derived glucose.
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Published in Cell Cycle 3.26
Mikhail V. Blagosklonny58
Estimated H-index: 58
(Roswell Park Cancer Institute)
ABSTRACTDesigned a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly cau...
Published in Cell Death and Disease 5.96
Mikhail V. Blagosklonny58
Estimated H-index: 58
(Roswell Park Cancer Institute)
Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. T...
Published on Jul 15, 2019in Diabetologia 7.11
Leon G. Straub5
Estimated H-index: 5
(EPFL: École Polytechnique Fédérale de Lausanne),
Vissarion Efthymiou (EPFL: École Polytechnique Fédérale de Lausanne)+ 10 AuthorsMyrtha Arnold7
Estimated H-index: 7
(EPFL: École Polytechnique Fédérale de Lausanne)
Aims/hypothesis In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.
Published on Mar 1, 2019in The Journal of Physiology
Kyle D. Medak1
Estimated H-index: 1
(U of G: University of Guelph),
Logan K. Townsend4
Estimated H-index: 4
(U of G: University of Guelph)
Published on Feb 22, 2019in bioRxiv
Jelle R. Dalenberg8
Estimated H-index: 8
(Yale University),
Barkha P. Patel2
Estimated H-index: 2
+ 5 AuthorsDana M. Small38
Estimated H-index: 38
(Yale University)
There is a general consensus that overconsumption of sugar sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no, or low-calorie 9diet9 drinks is a subject of intensive debate and controversy. Here, we show that metabolic dysfunction, coupled with reduced central sensitivity to sweet, but not sour, salty or bitter taste, occurs when sucralose is repeatedly consumed with, but not without, ...
Published on Oct 1, 2018in The Journal of Physiology
Mark L. Evans33
Estimated H-index: 33