Glucose Intolerance Low Carb Diet

high-fat, low-carbohydrate ketogenic diets (KD) are used in weight loss programs and are associated with improvement of the glycemic status in obese subjects (30, 35) and patients with type 2 diabetes (11, 19). KD are also used as an effective treatment for refractory epilepsy (7, 27, 33).

Blood glucose levels are tightly controlled by the hormones insulin and glucagon produced by pancreatic β- and α-cells, respectively. When the consumption of carbohydrates is limited, the body switches from a glucose-based energy metabolism to a fat-based metabolism in which β-oxidation of free fatty acids (FFA) serves as the primary source of energy. This leads to a permanent state of ketosis. Insulin counteracts ketogenesis by stimulating the use of glucose as primary energy source and by decreasing the release of FFA in the circulation (21). In contrast, glucagon stimulates ketogenesis, hepatic glucose production, and lipolysis (1, 40). Changes in glucose metabolism are associated with adaptation of the number and/or function of β-cells to produce and secrete an adequate amount of insulin (6, 34). Also α-cell mass can be modulated by dietary changes (14). Inadequate adaptation leads to glucose intolerance and eventually results in diabetes mellitus (9, 21).

Despite their beneficial effects on weight loss and epileptic seizures, KD may have adverse side effects such as kidney stones, impaired growth, osteoporosis, and hyperlipidemia (3, 23) on the long term. Furthermore, several short-term studies in rodents have shown that KD leads to hepatic steatosis, insulin resistance, and glucose intolerance (4, 16, 20).

It is unknown whether the metabolic effects induced by long-term KD also affect the endocrine pancreas. In addition, the effect of KD on glucose metabolism has only been studied in mice after short-term diets (2, 16, 20). Therefore, we investigated the effects of a long-term KD on glucose tolerance and pancreatic β- and α-cell mass.

MATERIALS AND METHODS

Animals.

Male C57BL/6J mice, 10 wk old (Charles River Laboratories, Wilmington, MA), were fed a KD (Research Diets, New Brunswick, NJ) or regular chow (control; Special Diets Services, Essex, UK) for 22 wk. The proportion of calories derived from nutrients for the KD, which is similar to other studies (2, 12, 16, 18), and control diet is described in Table 1. In addition, 8-wk-old male C57BL/6J mice were fed a KD or a normal diet (D12450B; Research Diets) for 1 wk. Before euthanization, mice were anesthetized by isoflurane inhalation. Animal experiments were approved by the ethical committee on animal care and experimentation of the Leiden University Medical Center.

**Table 1. Diet composition**
	Control		KD
	kcal/100 kcal	g/100 g	kcal/100 kcal	g/100 g
Protein	27.2	22.5	5.9	10.0
Carbohydrate	61.2	50.4	1.0	2.0
Fat	11.5	4.2	93.1	72.0
Dietary fiber		16.2		8.5
Methionine		0.37		0.29
Choline		0.14		0.34
Saturated fatty acids	1.9	0.7	29.6	22.8
Monounsaturated fatty acids	3.0	1.1	33.7	25.9
Polyunsaturated fatty acids	4.2	1.6	24.6	18.9
ω-3 fatty acids	0.5	0.2	2.0	1.5
Energy density, kcal/g	3.3		6.9

Glucose and insulin tolerance test.

Glucose tolerance was assessed after 1, 5, 12, and 20 wk of diet. An intraperitoneal glucose tolerance test (GTT) was performed in overnight-fasted mice. Blood samples were drawn from the tail vein before injecting 2 g/kg glucose and after 15, 30, 60, and 120 min. Insulin tolerance was assessed after 22 wk of diet. An intraperitoneal insulin tolerance test (ITT) was performed in animals that had been fasted for 6 h. After measuring basal blood glucose concentration from the tail vein, 1.0 U/kg insulin was injected followed by monitoring of the blood glucose concentrations after 15, 30, 60, and 90 min. Blood glucose concentrations were measured using a glucose meter (Accu Chek, Roche, Basel, Switzerland) and β-hydroxybutyrate concentrations using a ketone meter (Precision Xtra System; Abbot Diabetes Care, Alameda, CA). Insulin concentrations were measured by ELISA (Ultra Sensitive Mouse Insulin ELISA kit; Chrystal Chem, Downers Grove, IL).

Plasma analysis.

Plasma leptin, IL-6, IL-1β, and monocyte chemotactic protein (MCP)-1 were detected using a custom Cytokine/Metabolic multiplex assay (Mesoscale Discovery, Gaithersburg, MD). Plasma cholesterol, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured on a Roche Modular P800 analyzer (Roche).

Liver triglyceride analysis.

Following euthanization, the liver was dissected, weighed, and stored at −80°C. Lipid extraction was performed using a modified protocol of Bligh and Dyer (5). Briefly, liver tissue was homogenized in ice-cold methanol. Lipids were extracted by addition of ice-cold chloroform. After centrifugation, the supernatant was dried with nitrogen gas. Lipids were dissolved in chloroform with 2% Triton X-100 (Sigma-Aldrich) and dried. Finally, lipids were dissolved in 100 μl H₂0. Triglyceride content was measured using an enzymatic kit (Roche), and protein content was measured using the BCA protein assay kit (Pierce, Rockford, IL). Liver triglyceride content was defined as total triglyceride content per milligram of protein.

Islet morphometry.

The pancreas was dissected and weighed after euthanization. To obtain representative samples of the entire organ, pancreata from each mouse (6/group) were cut in three pieces (duodenal, gastric, and splenic region) (13) that were fixed by immersion in a 4% paraformaldehyde solution, embedded in paraffin blocks, and sliced into 4-μm sections. From each block four sections, with an interval of at least 200 μm between sections, were immunostained and analyzed. The average of the three regions was taken as a measure for the entire organ.

For the identification of β-cells, sections were immunostained with guinea pig anti-insulin IgG (Millipore, Billerica, MA) or rabbit anti-insulin IgG (Santa Cruz Biotechnology, Santa Cruz, CA) for 1 h followed by horseradish peroxidase (HRP)-conjugated secondary antibody for 1 h. α-Cells were identified by immunostaining by rabbit anti-glucagon IgG (Vector Laboratories, Burlingame, CA) for 1 h followed by HRP-conjugated secondary antibody for 1 h. Sections were developed with 3,3′-diaminobenzidine tetrahydrochloride or liquid permanent red (LPR, Dako, Denmark) and counterstained with hematoxylin. Stained sections were digitally imaged (Panoramic MIDI; 3DHISTECH).

β-Cell area and pancreas area were determined using an image analysis program (Stacks 2.1; LUMC), excluding large blood vessels, larger ducts, adipose tissue, and lymph nodes as previously described (11). β-Cell mass was determined by the ratio of β-cell area to pancreas area multiplied by the pancreas weight. β-Cell cluster size was determined as the median size of β-cell clusters (defined as ≥4 β-cells per cluster) per mice. α-Cell mass was determined as previously described (14) by calculating the ratio of α-cell area to β-cell area, using Image J software (Image J; National Institutes of Health, Bethesda, MD) multiplied by the β-cell mass.

Statistical analysis.

Data are presented as means ± SE. Statistical calculations were carried out using GraphPad Prism 5 (GraphPad Software, San Diego, CA). The statistical significance of differences was determined by an unpaired Student's t-test, Mann-Whitney test, or two-way ANOVA, followed by Bonferroni's multiple-comparisons test, as appropriate. P < 0.05 was considered statistically significant.

RESULTS

No weight loss after 22 wk of KD.

The KD was not associated with weight loss after 22 wk of diet, despite an initial weight loss during the first weeks of diet (Fig. 1A). After 22 wk, body weight in the KD-fed mice was 34.8 ± 1.2 vs. 32.2 ± 0.4 g in the control mice (P < 0.05). After 5 wk, increased concentrations of circulating β-hydroxybutyrate were measured and remained elevated after 20 wk of diet, which indicates a ketotic state in KD-fed mice (Fig. 1B).

KD leads to dyslipidemia, a proinflammatory state, and hepatic steatosis.

To assess the metabolic profile of KD-fed mice, several markers that are also associated with the metabolic syndrome in humans were measured. After 22 wk, there was a significant increase of plasma cholesterol, triglyceride, leptin, MCP-1, IL-1β, and IL-6 concentrations in plasma of KD-fed mice (Table 2). To assess whether these systemic markers were related to metabolic changes in the liver, the intrahepatic triglyceride levels were determined as a measure of hepatic steatosis. Liver triglyceride content was increased twofold after 22 wk of KD [379 ± 41 nmol/mg protein (KD) vs. 159 ± 19 nmol/mg protein (control), P < 0.01]. In addition, plasma ALT and AST were significantly increased.

**Table 2. Plasma markers of the metabolic syndrome in control mice and mice fed a ketogenic diet for 22 wk**
	Control	KD
Total cholesterol, mg/dl	92.7 ± 3.1	141.3 ± 9.5^b
Triglyceride, mg/dl	42.0 ± 1.5	64.9 ± 6.8^b
Leptin, ng/ml	0.63 ± 0.37	2.35 ± 0.99^a
MCP-1, pg/ml	6.20 ± 0.73	12.65 ± 1.40^c
IL-1β, pg/ml	1.19 ± 0.31	3.86 ± 1.17^a
IL-6, pg/ml	3.20 ± 2.11	19.84 ± 8.02^a
ALT, U/l	31.3 ± 0.9	80.6 ± 15.8^b
AST, U/l	89.0 ± 10.7	155.2 ± 31.4^a

Long-term KD leads to glucose intolerance.

Glucose tolerance tended to be decreased after 5 wk, but KD-fed mice became markedly glucose intolerant after 12 wk of diet (Fig. 2, A–D). After 1 wk KD, insulin concentrations were increased during the GTT (Fig. 2, E and I). However, continuation of the diet for 5 wk or longer resulted in insufficient insulin secretion from β-cells to maintain glucose tolerance (Fig. 2, F–H and J–L). After 20 wk diet, glucose-induced insulin concentrations were significantly decreased in KD-fed mice (Fig. 2L). Insulin-dependent glucose uptake assessed by an ITT was also reduced in KD-fed mice compared with control mice after 22 wk (Fig. 3, A and B). Also, the fasting insulin-to-glucose ratio was significantly increased in KD-fed mice (Fig. 3C).

**Fig. 3.**Insulin tolerance in control and KD-fed mice. A: blood glucose concentrations during the insulin tolerance test (n = 7–8 mice) after 22 wk of diet. B: inverse AUC below baseline glucose concentrations during the insulin tolerance test (n = 7–8 mice). C: fasting insulin-to-glucose ratio after 20 wk of diet (n = 8–9 mice). **P < 0.01 and ***P < 0.001 vs. control.

KD leads to decreased β- and α-cell mass.

After 22 wk, β-cell mass in KD-fed mice, determined by analyzing 175.1 ± 7.1 mm² pancreatic tissue/mouse, was decreased (Fig. 4, A–C). The density of islets was unchanged (Fig. 4D), but the median β-cell cluster size was significantly decreased (Fig. 4E). This was because of a relatively increased number of islets with a size smaller than 2,500 μm² in KD-fed mice (Fig. 4F). The α-cell mass was reduced by 50% in KD-fed mice after 22 wk, which resulted in a decreased α-cell/β-cell ratio in KD-fed mice (Fig. 5, A–D).

**Fig. 5.**α-Cell mass in control and KD-fed mice after 22 wk. A: representative image of α-cells (brown) in control mice. Scale bar = 50 μm. B: representative image of α-cells (brown) in KD-fed mice. Scale bar = 50 μm. C: α-cell mass (n = 7–10 mice). D: α-cell/β-cell ratio (n = 7–10 mice). **P < 0.01 vs. control.

DISCUSSION

High-fat, low-carbohydrate KD have been associated with beneficial effects on body weight and epileptic seizures. However, their effects on pancreatic endocrine cells and glucose metabolism on the long term are less clear. The main results of our study show that long-term KD in mice causes glucose intolerance and a reduction in both β- and α-cell mass, but no weight loss. This indicates that long-term KD leads to features that are also associated with the metabolic syndrome in humans and an increased risk for type 2 diabetes.

KD resulted in weight loss in the first weeks of the diet, which is in line with previous reports in rodents (2, 20, 22). Also in patients with refractory epilepsy, short-term (3–4 mo) KD treatment resulted in decreased body weight (25, 28). However, we now show that a prolonged KD is not associated with weight loss. After 12 wk, weight gain is similar in both groups of mice. Long-term use of KD in children with epilepsy resulted in slowed growth but did not change the body mass index (17, 28, 39). In rats it has been shown that 4–6 wk KD leads to visceral fat accumulation (32) and increased leptin concentrations (10). We did not assess the effect of long-term KD on body composition. However, the elevated plasma leptin concentrations observed in our study suggest that prolonged KD eventually leads to regaining weight because of an increase of body fat.

Long-term KD leads to increased plasma cholesterol and triglyceride levels indicative of dyslipidemia. In previous short-term studies, increased plasma cholesterol levels were observed after 9 wk of diet (2), whereas at that time point plasma triglyceride levels were lower. Also, in both adults and children with refractory epilepsy, KD was associated with increased plasma cholesterol and triglyceride levels (24, 38). Furthermore, the increased plasma cytokine concentrations in our study suggest a systemic proinflammatory state in long-term KD-fed mice. This is in line with the observation that short-term KD in mice is associated with increased inflammatory markers in liver and adipose tissue (2) and macrophage infiltration in the liver (16). Also, we show that KD-fed mice had increased plasma levels of the chemokine MCP-1, which is associated with increased macrophage recruitment to the liver (26). In patients with the metabolic syndrome, increased MCP-1 is associated with macrophage infiltration in fat tissue and a proinflammatory state (8). Recently, a short-term very-low-carbohydrate diet in overweight and obese humans resulted in increased concentrations of the inflammatory marker C-reactive protein (12), which is associated with an increased risk for the metabolic syndrome (18).

Dyslipidemia and the proinflammatory state induced by KD may be the consequence of the high content of saturated fatty acids. It was shown that a short-term polyunsaturated fat-enriched KD did not adversely alter lipid metabolism in adults (15). Also, supplementation of a high-fat diet with ω-3 polyunsaturated fatty acids has been shown to prevent high-fat diet-induced insulin resistance by reducing inflammasome-dependent inflammation in rodents (41). However, in our study, the higher content of ω-3 fatty acids in the KD could not prevent proinflammatory effects on the long term. Whether further modification of the fatty acid content of KDs can attenuate dyslipidemia and the proinflammatory effects on the long term needs further study.

Furthermore, KD-fed mice showed signs of steatohepatitis as indicated by the increased hepatic triglyceride content and elevated AST and ALT levels. This is in line with metabolic changes observed in previous studies in mice (2, 16, 20, 22) and may indicate an early stage of nonalcoholic fatty liver disease (16, 36). Recent short-term studies have shown that supplementation of KD with choline or methionine could limit hepatic steatosis and the proinflammatory state of the liver, respectively (31, 37). However, the similar methionine and higher choline content of KD in our study did not prevent signs of steatohepatitis in the long term. Altogether these data indicate that a prolonged KD leads to dyslipidemia, a proinflammatory state, and signs of hepatic steatosis.

In this study we show that long-term KD is associated with pronounced glucose intolerance and reduced insulin-stimulated glucose uptake. This was also observed in a recent study by Bielohuby et al. after 4 wk of KD in mice (4). We now show that insulin concentrations were increased to maintain normoglycemia after 1 wk of KD, but continuation of the KD resulted in insufficient insulin secretion to maintain glucose tolerance.

This inadequate insulin secretory response could be the result of β-cell dysfunction, an insufficient β-cell number, or a combination of these two mechanisms. The results in this study strongly indicate that long-term KD leads to an insulin secretory defect. Furthermore, not only after short-term diet (4) but also after long-term KD, β-cell mass is reduced. An inadequate function and/or number of β-cells leads to insufficient insulin secretion that results in glucose intolerance and ultimately type 2 diabetes in humans (21, 29). Interestingly, also the α-cell mass was decreased considerably, which is in line with decreased glucagon levels that have been observed after 5 wk of KD in mice (20). In relative terms, this decreased α-cell mass was even more pronounced than the reduction in β-cell mass, resulting in a major decrease of the α-cell/β-cell ratio. Decreased glucagon levels lead to less gluconeogenesis from the liver, which may prevent hyperglycemia in KD-fed mice. Whether this change in α-cell mass is a direct consequence of KD or a response to counteract glucose intolerance remains to be elucidated.

Altogether, the results of this study indicate that a long-term high-fat, low-carbohydrate KD in mice does not cause weight loss and leads to glucose intolerance and a reduction in both β- and α-cell mass. In addition, dyslipidemia, a proinflammatory state, and signs of hepatic steatosis are observed. Effects of short-term diets cannot be automatically translated to metabolic effects after long-term diet use.

GRANTS

This work was supported by the Diabetes Cell Therapy Initiative consortium, including the Dutch Diabetes Research Foundation.

DISCLOSURES

The authors declare that there is no conflict of interest associated with this article.

AUTHOR CONTRIBUTIONS

J.H.E., L.v.D., T.J.R., F.C., B.E.B., and E.J.d.K. contributed to the conception and design of the research; J.H.E., L.v.D., and H.A.T. performed the experiments; J.H.E. and L.v.D. analyzed the data; J.H.E., L.v.D., T.J.R., F.C., B.E.B., and E.J.d.K. interpreted the results of the experiments; J.H.E. and L.v.D. prepared the figures; J.H.E., L.v.D., F.C., B.E.B., and E.J.d.K. drafted the manuscript; J.H.E., L.v.D., H.A.T., T.J.R., F.C., B.E.B., and E.J.d.K. edited and revised the manuscript; J.H.E., L.v.D., H.A.T., T.J.R., F.C., B.E.B., and E.J.d.K. approved the final version of the manuscript.

ACKNOWLEDGMENTS

We thank Dr. Bruno Guigas and Dr. Janna van Diepen for expert advice.

REFERENCES

1. Arafat AM, Kaczmarek P, Skrzypski M, Pruszyśka-Oszmalek E, Kołodziejski P, Szczepankiewicz D, Sassek M, Wojciechowicz T, Wiedenmann B, Pfeiffer AFH, Nowak KW, Strowski MZ. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis? Diabetologia 56: 588–597, 2013.
Crossref | PubMed | ISI | Google Scholar
2. Badman MK, Kennedy AR, Adams AC, Pissios P, Maratos-Flier E. A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 297: E1197–E1204, 2009.
Link | ISI | Google Scholar
3. Bergqvist AGC. Long-term monitoring of the ketogenic diet: Do's and Don'ts. Epilepsy Res 100: 261–266, 2012.
Crossref | PubMed | ISI | Google Scholar
4. Bielohuby M, Sisley S, Sandoval a D, Herbach N, Zengin A, Fischereder M, Menhofer D, Stoehr BJM, Stemmer K, Wanke R, Tschöp MH, Seeley RJ, Bidlingmaier M. Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets. Am J Physiol Endocrinol Metab 305: E1059–E1070, 2013.
Link | ISI | Google Scholar
5. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917, 1959.
Crossref | PubMed | Google Scholar
6. Bonner-Weir S. Perspective: postnatal pancreatic beta cell growth. Endocrinology 141: 1926–1929, 2000.
Crossref | PubMed | ISI | Google Scholar
7. Bough KJ, Eagles DA. A ketogenic diet increases the resistance to pentylenetetrazole-induced seizures in the rat. Epilepsia 40: 138–143, 1999.
Crossref | PubMed | ISI | Google Scholar
8. Bremer AA, Devaraj S, Afify A, Jialal I. Adipose tissue dysregulation in patients with metabolic syndrome. J Clin Endocrinol Metab 96: E1782–E1788, 2011.
Crossref | PubMed | ISI | Google Scholar
9. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–110, 2003.
Crossref | PubMed | ISI | Google Scholar
10. Caton SJ, Bielohuby M, Bai Y, Spangler LJ, Burget L, Pfluger P, Reinel C, Czisch M, Reincke M, Obici S, Kienzle E, Tschöp MH, Bidlingmaier M. Low-carbohydrate high-fat diets in combination with daily exercise in rats: Effects on body weight regulation, body composition and exercise capacity. Physiol Behav 106: 185–192, 2012.
Crossref | PubMed | ISI | Google Scholar
11. Dashti HM, Mathew TC, Khadada M, Al-Mousawi M, Talib H, Asfar SK, Behbahani AI, Al-Zaid NS. Beneficial effects of ketogenic diet in obese diabetic subjects. Mol Cell Biochem 302: 249–256, 2007.
Crossref | PubMed | ISI | Google Scholar
12. Ebbeling CB, Swain JF, Feldman HA, Wong WW, Hachey DL, Garcia-Lago E, Ludwig DS. Effects of dietary composition on energy expenditure during weight-loss maintenance. J Am Med Assoc 307: 2627–2634, 2012.
Crossref | ISI | Google Scholar
13. Ellenbroek JH, Töns HA, de Graaf N, Loomans CJ, Engelse MA, Vrolijk H, Voshol PJ, Rabelink TJ, Carlotti F, de Koning EJ. Topologically heterogeneous beta cell adaptation in response to high-fat diet in mice. PLoS One 8: e56922, 2013.
Crossref | PubMed | ISI | Google Scholar
14. Ellenbroek JH, Töns HA, Westerouen van Meeteren MJ, de Graaf N, Hanegraaf MA, Rabelink TJ, Carlotti F, de Koning EJ. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia 56: 1980–1986, 2013.
Crossref | PubMed | ISI | Google Scholar
15. Fuehrlein BS, Rutenberg MS, Silver JN, Warren MW, Theriaque DW, Duncan GE, Stacpoole PW, Brantly ML. Differential metabolic effects of saturated versus polyunsaturated fats in ketogenic diets. J Clin Endocrinol Metab 89: 1641–1645, 2004.
Crossref | PubMed | ISI | Google Scholar
16. Garbow JR, Doherty JM, Schugar RC, Travers S, Weber ML, Wentz AE, Ezenwajiaku N, Cotter DG, Brunt EM, Crawford PA. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 300: G956–G967, 2011.
Link | ISI | Google Scholar
17. Groesbeck DK, Bluml RM, Kossoff EH. Long-term use of the ketogenic diet in the treatment of epilepsy. Dev Med Child Neurol 48: 978–981, 2006.
Crossref | PubMed | ISI | Google Scholar
18. Haffner SM. The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97: 3A–11A, 2006.
Crossref | PubMed | ISI | Google Scholar
19. Hussain TA, Mathew TC, Dashti AA, Asfar S, Al-Zaid N, Dashti HM. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28: 1016–1021, 2012.
Crossref | PubMed | ISI | Google Scholar
20. Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, Zhang XM, Samuel VT, Shulman GI. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 299: E808–E815, 2010.
Link | ISI | Google Scholar
21. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444: 840–846, 2006.
Crossref | PubMed | ISI | Google Scholar
22. Kennedy AR, Pissios P, Otu H, Roberson R, Xue B, Asakura K, Furukawa N, Marino FE, Liu FF, Kahn BB, Libermann TA, Maratos-Flier E. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 292: E1724–E1739, 2007.
Link | ISI | Google Scholar
23. Kossoff EH, Wang HS. Dietary therapies for epilepsy. Biomed J 36: 2–8, 2013.
Crossref | PubMed | Google Scholar
24. Kwiterovich PO, Vining EP, Pyzik P, Skolasky R, Freeman JM. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. J Am Med Assoc 290: 912–920, 2003.
Crossref | PubMed | ISI | Google Scholar
25. Liu YMC, Williams S, Basualdo-Hammond C, Stephens D, Curtis R. A prospective study: growth and nutritional status of children treated with the ketogenic diet . 103: 707–712, 2003.
Google Scholar
26. Mitchell C, Couton D, Couty JP, Anson M, Crain AM, Bizet V, Rénia L, Pol S, Mallet V, Gilgenkrantz H. Dual role of CCR2 in the constitution and the resolution of liver fibrosis in mice. Am J Pathol 174: 1766–1775, 2009.
Crossref | PubMed | ISI | Google Scholar
27. Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. Lancet Neurol 7: 500–506, 2008.
Crossref | PubMed | ISI | Google Scholar
28. Neal EG, Chaffe HM, Edwards N, Lawson MS, Schwartz RH, Cross JH. Growth of children on classical and medium-chain triglyceride ketogenic diets. Pediatrics 122: e334–e340, 2008.
Crossref | PubMed | ISI | Google Scholar
29. Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 378: 169–181, 2011.
Crossref | PubMed | ISI | Google Scholar
30. Partsalaki I, Karvela A, Spiliotis BE. Metabolic impact of a ketogenic diet compared to a hypocaloric diet in obese children and adolescents. J Pediatr Endocrinol Metab 25: 697–704, 2012.
Crossref | PubMed | ISI | Google Scholar
31. Pissios P, Hong S, Kennedy AR, Prasad D, Liu FF, Maratos-Flier E. Methionine and choline regulate the metabolic phenotype of a ketogenic diet. Mol Metab 2: 306–313, 2013.
Crossref | PubMed | ISI | Google Scholar
32. Ribeiro LC, Chittó AL, Müller AP, Rocha JK, Castro da Silva M., Quincozes-Santos A, Nardin P, Rotta LN, Ziegler DR, Gonçalves CA, Da Silva RS, Perry MLS, Gottfried C. Ketogenic diet-fed rats have increased fat mass and phosphoenolpyruvate carboxykinase activity. Mol Nutr Food Res 52: 1365–1371, 2008.
Crossref | PubMed | ISI | Google Scholar
33. Ruskin DN, Masino SA. The nervous system and metabolic dysregulation: emerging evidence converges on ketogenic diet therapy (Abstract). Front Neurosci 6: 33, 2012.
Crossref | PubMed | ISI | Google Scholar
34. Saisho Y, Butler AE, Manesso E, Elashoff D, Rizza RA, Butler PC. B-Cell mass and turnover in humans: effects of obesity and aging. Diabetes Care 36: 111–117, 2013.
Crossref | PubMed | ISI | Google Scholar
35. Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, Williams T, Williams M, Gracely EJ, Stern L. A low-carbohydrate as compared with a low-fat diet in severe obesity. N Engl J Med 348: 2074–2081, 2003.
Crossref | PubMed | ISI | Google Scholar
36. Schugar RC, Crawford PA. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr Opin Clin Nutr Metab Care 15: 374–380, 2012.
Crossref | PubMed | ISI | Google Scholar
37. Schugar RC, Huang X, Moll AR, Brunt EM, Crawford P. Role of choline deficiency in the Fatty liver phenotype of mice fed a low protein, very low carbohydrate ketogenic diet. PLoS One 8: e74806, 2013.
Crossref | PubMed | ISI | Google Scholar
38. Sirven J, Whedon B, Caplan D, Liporace J, Glosser D, O'Dwyer J, Sperling MR. The ketogenic diet for intractable epilepsy in adults: preliminary results. Epilepsia 40: 1721–1726, 1999.
Crossref | PubMed | ISI | Google Scholar
39. Tagliabue A, Bertoli S, Trentani C, Borrelli P, Veggiotti P. Effects of the ketogenic diet on nutritional status, resting energy expenditure, and substrate oxidation in patients with medically refractory epilepsy: a 6-month prospective observational study. Clin Nutr 31: 246–249, 2012.
Crossref | PubMed | ISI | Google Scholar
40. Unger RH, Cherrington AD. Science in medicine glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122: 4–12, 2012.
Crossref | PubMed | ISI | Google Scholar
41. Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J, Zhou R. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38: 1154–1163, 2013.
Crossref | PubMed | ISI | Google Scholar

Glucose Intolerance Low Carb Diet

Source: https://journals.physiology.org/doi/abs/10.1152/ajpendo.00453.2013

Header Ads Widget

Glucose Intolerance Low Carb Diet