Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet - PubMed (original) (raw)

Comparative Study

. 2018 Oct;596(19):4597-4609.

doi: 10.1113/JP275173. Epub 2018 Aug 8.

Affiliations

Comparative Study

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

Gerald Grandl et al. J Physiol. 2018 Oct.

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.

Keywords: high fat diet; insulin resistance; ketogenic diet.

© 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

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Figures

Figure 1

Figure 1. Short‐term obesogenic HFD feeding but not KD causes increases in fasting insulin and HOMA‐IR

Plasma metabolic parameters of chow vs. 3 days of KD or HFD‐fed mice after a 6 h fast. A, glucose levels. B, plasma insulin. C, calculated homeostatic model assessment of insulin resistance HOMA‐IR. D, plasma TG. E, plasma FFA. F, plasma cholesterol. G, plasma total ketones. H, body weight change after 3 days of diet. I, average energy intake (n = 4–16). Data are plotted as the mean ± SEM. * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 by ANOVA.

Figure 2

Figure 2. Short‐term KD or HFD feeding causes impaired glucose clearance and insulin tolerance

A,

i.p.

GTT of mice fed chow, KD or HFD for 3 days, after a 6 h fast. B, AUC of GTT. C,

i.p.

ITT of mice fed chow, KD or HFD for 3 days, after a 6 h fast. D, AUC of ITT (n = 7–8). Data are plotted as the mean ± SEM. * P < 0.05, ** P < 0.01, **** P < 0.0001 by ANOVA.

Figure 3

Figure 3. Steady‐state RER inversely correlates with glucose tolerance, although all groups respond to an i.p. glucose challenge with an increase in RER

A, V˙O2 used during the first 24 h after switching animals from chow to KD or HFD. B, V˙CO2 produced during the first 24 h after switching animals from chow to KD or HFD. C, average V˙O2 and V˙CO2 during light and dark phase in the first 24 h after diet switch. D, RER of mice fed KD, HFD or chow during the first 24 h. E, RER during GTT on day 3; arrow indicates the time of glucose injection after a 6 h fast. F, change in RER directly after

i.p.

injection of glucose (n = 4–8). Data are plotted as the mean ± SEM. * P < 0.05 by ANOVA.

Figure 4

Figure 4. Hyperinsulinaemic–euglycaemic clamps reveal differences in insulin‐suppressed endogenous glucose production but not tissue glucose uptake

A, scheme of glucose clamp procedure. B, blood glucose levels during clamp. C, glucose infusion rates during clamp. D, glucose infusion rates at steady‐state. E, rates of basal and insulin‐inhibited endogenous glucose production. F, rates of basal and insulin‐stimulated glucose disappearance (Rd). G, glucose uptake during hyperinsulinaemic–euglycaemic clamps into epididymal WAT and skeletal muscle (quadriceps) (n = 4–5). Data are plotted as the mean ± SEM. * P < 0.05, ** P < 0.01 by ANOVA.

Figure 5

Figure 5. Repeating hyperinsulinaemic–euglycaemic clamps with lower insulin and glucose targets confirms an effect via insulin‐suppressed endogenous glucose production

A, scheme of glucose clamp procedure. B, blood glucose levels during clamp. C, glucose infusion rates during clamp. D, glucose infusion rates at steady state. E, rates of basal and insulin‐inhibited endogenous glucose production. F, rates of basal and insulin‐stimulated glucose disappearance (R d). G, glucose uptake during hyperinsulinaemic–euglycaemic clamps into epididymal WAT and skeletal muscle (quadriceps) (n = 3–4). Data are plotted as the mean ± SEM. * P < 0.05, ** P < 0.01 by ANOVA.

Comment in

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