PLoS One. 2014 Aug 29;9(8):e104948. doi: 10.1371/journal.pone.0104948.

Long-term low carbohydrate diet leads to deleterious metabolic manifestations in diabetic mice

Handa K, Inukai K, Onuma H, Kudo A, Nakagawa F, Tsugawa K, Kitahara A, Moriya R, Takahashi K, Sumitani Y, Hosaka T, Kawakami H, Oyadomari S, Ishida H

Third Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.



We investigated long-term effects of low carbohydrate diets on wild type mice, streptozotocin-injected and KKAy obese diabetic mice. These mice were pair-fed three different types of diets, standard chow (SC, C∶P∶F = 63∶15∶22), a low carbohydrate (LC, C∶P∶F = 38∶25∶37) diet and a severely carbohydrate restricted (SR, C∶P∶F = 18∶45∶37) diet for 16 weeks. Despite comparable body weights and serum lipid profiles, wild type and diabetic mice fed the low carbohydrate diets exhibited lower insulin sensitivity and this reduction was dependent on the amount of carbohydrate in the diet. When serum fatty acid compositions were investigated, monounsaturation capacity, i.e. C16:1/C16:0 and C18:1/C18:0, was impaired in all murine models fed the low carbohydrate diets, consistent with the decreased expression of hepatic stearoyl-CoA desaturase-1 (SCD1). Interestingly, both the hepatic expressions and serum levels of fibroblast growth factor 21 (FGF21), which might be related to longevity, were markedly decreased in both wild type and KKAy mice fed the SR diet. Taking into consideration that fat compositions did not differ between the LC and SR diets, we conclude that low carbohydrate diets have deleterious metabolic effects in both wild type and diabetic mice, which may explain the association between diets relatively low in carbohydrate and the elevated risk of cardiovascular events observed in clinical studies.




In the original article, we focused on the altered expressions of SCD1 and FGF21 in mice fed a low carbohydrate diet versus the control chow diet.  In a preliminary experiment, we assessed hepatic gene expressions using cDNA microarray analysis for screening the hepatic genes expressed differently in the two groups.  We screened ~10,000 transcripts in liver tissues and found 386 up-regulated (by more than 2.5 fold) genes and 685 down-regulated (by less than 0.5 fold) genes in mice fed the low carbohydrate diet as compared with those given the control chow diet.  Among these genes, we selected those significantly related to biomedical metabolism or arteriosclerosis, and these are presented in Figure 1.  As shown in Figure 1, SCD1 and FGF21 are widely recognized as genes showing markedly decreased expression in mice fed a low carbohydrate diets. We are particularly interested in the lipocalin 2 gene, which is highly increased in mice on a low carbohydrate diet, though we did not mention this in the original article.  As lipocalin 2 was recently shown to be a tumor marker for breast cancer, we speculate that this gene likely accounts for the vulnerability of patients on low carbohydrate diets to the development of malignancies.


Up-regulated genes (≧2.0 fold) fold Down-regulated genes (<0.5 fold) fold
lipocalin 2 115.1 glutathione peroxidase 5 0.06
metallothionein 2 111.1 defensin b 48 0.11
sarcolipin 98.1 stearoyl CoA desaturase 1 (SCD1) 0.11
serum amyloid A1 85.1 cysteine sulfinic acid decarboxylase 0.12
PI-4P 5kinase type 1a 61.5 fatty acid synthase 0.16
orosomucoid 3 48.2 cystatin 11 0.15
cytochrome p450 family 2 subfamily b 46.8 somatostatin receptor 2 0.16
organic cation transporter 33.1 lipocalin 8 0.17
fibrinogen-like protein 1 13.2 collagen type4 a4 0.18
centrosome protein 55 11.8 FGF21 0.21
protease 3 11.6 resistin 0.23
adenosine monophosphate deaminase 10.3 formin 2 0.26
chemokine ligand 1 9.6 espin 0.26
apolipoprotein L 10b 9.3 syncytin a 0.28
MIS18 binding protein 9.1 protocadherin 0.28
late cornified envelope 1C 8.9 follstatin 0.29
scavenger receptor class A 7.9 arylsulfatase G 0.31
cation transporter regulator-like 1 7.7 glutathione S-transferase 0.31
exonuclease 1 7.6 fructose bisphosphatase 2 0.31
runt related transcription factor 2 7.4 GABA receptor 0.31
centromere protein M 6.9 spondin 2 0.32
ninein 6.8 GPR110 0.33
oxidized LDL protein receptor 1 6.4 ICAM4 0.33
guanylate binding protein 6.3 acetyl CoA carboxylase a 0.34
claudin 8 5.8 GM2 ganglioside activator protein 0.34
S100 calcium binding protein A8 5.6 cholin kinase a 0.35
histone cluster 1, H1b 5.5 CD83 antigen 0.36
PDZ binding kinase 5.3 cyclin dependent kinase inhibitor 2B 0.36
FBJ osteosarcoma oncogene 5.2 leptin receptor 0.36
proteoglycan 4 5.2 galanin receptor 2 0.37
IL-1 receptor type 1 5.1 CD9 antigen 0.37
suppressor of cytokine signalling 3 5.1 Gmeb1 0.37
perilirin 4 4.8 phospholipase A2 0.38
lipopolysaccharide binding protein 4.8 dopa decarboxylase 0.39
interleukin 27 4.7 tight junction protein 0.39
calpain 8 4.5 RAB GTPase activating protein 1 0.39
IGFBP1 4.4 prostaglandin E receptor 3 0.41
nicotinamide N-methyltransferase 4.3 fatty acid binding protein 0.41
CD180 antigen 4.3 cytochrome C 0.41
CD200 receptor 1 3.5 cystatin 13 0.41
cyclin A2 3.5 G6pase catalytic 0.41
titin 3.3 spectrin a 0.41
zinc finger protein 3.2 crystallin C 0.42
phospholipase C delta 4 3.1 syntaxin binding protein 5 0.42
oxysterol binding protein-like 3 3.1 plexin A3 0.42
heat shock protein 3 3.1 aquaporin 8 0.44
lipin 1 2.9 CD19 antigen 0.45
guanine deaminase 2.9 neuregulin 1 0.46
neuregulin 4 2.8 TGF b2 0.46
hexokinase 3 2.8 glycine decarboxylase 0.46
IL6-receptor a 2.7 supervillin 0.46
monoacylglycerol O-acyltransferase 1 2.7 sortilin 1 0.47
phospholipase B1 2.6 IRS-1 0.47
CD36 antigen 2.6 guanine monophosphate synthetase 0.48
STAT3 2.5 tau tubulin kinase 1 0.48
estrogen receptor 1a 2.5 ephrin B3 0.49
hypoxia inducible factor 3a 2.5 SUMO 0.49
IL1a 2.5 MAPKKK 9 0.49
phospholipase C ε1 2.5 sideroflexin 5 0.49


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