Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets

Bielohuby, Maximilian; Sisley, Stephanie; Sandoval, Darleen A.; Herbach, Nadja; Zengin, Ayse; Fischereder, Michael; Menhofer, Dominik; Stoehr, Barbara J. M.; Stemmer, Kerstin; Wanke, Rüdiger; Tschöp, Matthias H.; Seeley, Randy J.; Bidlingmaier, Martin

doi:10.1152/ajpendo.00208.2013

Cited by 63 publications

(71 citation statements)

References 56 publications

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“…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.…”

Section: Discussionsupporting

confidence: 89%

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Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

124

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Ellenbroek JH, van Dijck L, Töns HA, Rabelink TJ, Carlotti F, Ballieux BE, de Koning EJ. Long-term ketogenic diet causes glucose intolerance and reduced ␤-and ␣-cell mass but no weight loss in mice. Am J Physiol Endocrinol Metab 306: E552-E558, 2014. First published January 7, 2014 doi:10.1152/ajpendo.00453.2013.-High-fat, low-carbohydrate ketogenic diets (KD) are used for weight loss and for treatment of refractory epilepsy. Recently, short-time studies in rodents have shown that, besides their beneficial effect on body weight, KD lead to glucose intolerance and insulin resistance. However, the long-term effects on pancreatic endocrine cells are unknown. In this study we investigate the effects of long-term KD on glucose tolerance and ␤-and ␣-cell mass in mice. Despite an initial weight loss, KD did not result in weight loss after 22 wk. Plasma markers associated with dyslipidemia and inflammation (cholesterol, triglycerides, leptin, monocyte chemotactic protein-1, IL-1␤, and IL-6) were increased, and KD-fed mice showed signs of hepatic steatosis after 22 wk of diet. Long-term KD resulted in glucose intolerance that was associated with insufficient insulin secretion from ␤-cells. After 22 wk, insulin-stimulated glucose uptake was reduced. A reduction in ␤-cell mass was observed in KD-fed mice together with an increased number of smaller islets. Also ␣-cell mass was markedly decreased, resulting in a lower ␣-to ␤-cell ratio. Our data show that long-term KD causes dyslipidemia, a proinflammatory state, signs of hepatic steatosis, glucose intolerance, and a reduction in ␤-and ␣-cell mass, but no weight loss. This indicates that long-term high-fat, lowcarbohydrate KD lead to features that are also associated with the metabolic syndrome and an increased risk for type 2 diabetes in humans. pancreatic islet; ketogenic diet; glucose intolerance; ␤-cell; ␣-cell

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Section: Discussionsupporting

confidence: 89%

“…Furthermore, several short-term studies in rodents have shown that KD leads to hepatic steatosis, insulin resistance, and glucose intolerance (4,16,20).…”

mentioning

confidence: 99%

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Ellenbroek

Dijck

Töns

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

124

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“…Studies which directly examined the impact of high-fat, high-protein, low-carbohydrate diets on insulin sensitivity have reported conflicting findings, with some showing that such diets lead to glucose intolerance and insulin resistance (2)(3)(4)19), and others reporting it prevents insulin resistance (22), or causes no change in insulin resistance (5,8). While we found a steady progression of insulin-dependent Akt phosphorylation (taken as a measure of insulin effect) in hearts of animals fed CONT diet, there was an unusual response to insulin in the HFLCD-fed heart, with an initially high baseline amount of p-Akt at very low insulin levels and a blunted response as the dose was increased.…”

Section: Discussionmentioning

confidence: 99%

“…In the 13 C NMR spectrum on the right, K represents isotopomer peaks derived from ketone (3-HB); C represents those derived from carbohydrate (glucose, lactate, and pyruvate). Note that ␤-oxidation of [1][2][3][4][5][6][7][8][9][10][11][12][13] C]palmitate results in seven unlabeled acetyl-CoA fragments and one [1-ketone buffer, high insulin led to decreased FFA oxidation and upregulated ketone oxidation (P Ͻ 0.05 for high insulin compared with low insulin with the same ketone level, perfusion condition, and diet); this effect was not seen with low ketone buffer. At the low level insulin buffer, high ketone upregulated FFA oxidation and decreased ketone oxidation (P Ͻ 0.05 in the HFLCD group for high ketone compared with low ketone with the same insulin level, perfusion condition).…”

Section: Impact Of Perfusion Buffer Composition (Insulin and Ketone Lmentioning

confidence: 99%

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Liu

Wang

Douglas

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Liu J, Wang P, Douglas SL, Tate JM, Sham S, Lloyd SG. Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion. Am J Physiol Heart Circ Physiol 311: H1-H10, 2016. First published May 6, 2016; doi:10.1152/ajpheart.00809.2015.-High-fat, low-carbohydrate Diet (HFLCD) impairs the myocardial response to ischemia-reperfusion, but the underlying mechanisms remain elusive. We sought to determine the magnitude of diet-induced alterations in intrinsic properties of the myocardium (including insulin sensitivity and substrate oxidation) and circulating substrate and insulin differences resulting from diet, leading to this impaired response. Rats were fed HFLCD (60% kcal from fat/30% protein/10% carbohydrate) or control diet (CONT) (16%/19%/65%) for 2 wk. Isolated hearts underwent global low-flow ischemia followed by reperfusion (I/R). Carbon-13 NMR spectroscopy was used to determine myocardial substrate TCA cycle entry. Myocardial insulin sensitivity was assessed as dose-response of Akt phosphorylation. There was a significant effect of HFLCD and I/R with both these factors leading to an increase in free fatty acid (FFA) oxidation and a decrease in carbohydrate or ketone oxidation. Following I/R, HFLCD led to decreased ketone and increased FFA oxidation; the recovery of left ventricular (LV) function was decreased in HFLCD and was negatively correlated with FFA oxidation and positively associated with ketone oxidation. HFLCD also resulted in reduced insulin sensitivity. Under physiologic ranges, there were no direct effects of buffer insulin and ketone levels on oxidation of any substrate and recovery of cardiac function after I/R. An insulinketone interaction exists for myocardial substrate oxidation characteristics. We conclude that the impaired recovery of function after ischemia-reperfusion with HFLCD is largely due to intrinsic diet effects on myocardial properties, rather than to diet effect on circulating insulin or substrate levels. diet; myocardial ischemia-reperfusion injury; insulin; metabolism NEW & NOTEWORTHYThe substrate oxidation and response to I/R are more dependent on diet than on physiologic range changes in circulating substrate and insulin. This was associated with altered insulin sensitivity. After I/R, there was a positive (with ketone) and negative (with FFA) correlation between recovery of function and substrate oxidation.HIGH-FAT, LOW-CARBOHYDRATE DIETS (HFLCD S ) are used by many people in an effort to lose weight. The effect of such diets on cardiovascular health has been the subject of intense investigation. Population studies evaluating the impact of HFLCD on cardiovascular clinical outcomes have provided a range of results, with some finding favorable changes in cardiovascular disease risk factors (9, 35, 37), and others showing an increased risk of adverse outcomes in both animal (29) and human studies, including in the setting of myocardial infarction (23). Consistent with this latter finding, we have p...

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“…Most of the food items available are categorically rich in fat and simple carbohydrates. Food influences hormones such as insulin [1,2] and leptin [3,4]. Insulin and leptin, both anorexic hormones, are known to suppress appetite [5].…”

Section: Introductionmentioning

confidence: 99%

Insulinooporność poprzedza nietolerancję glukozy i hiperleptynemię u myszy C57BL/6J otrzymujących karmę wysokotłuszczową i zawierającą cukry proste

Bn¹,

D’Souza

Abraham³

2016

Endokrynologia Polska

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Introduction: Very few systematic studies are done during the onset and progression of metabolic syndrome in suitable animal models. In this paper we present the effect of High-Fat Simple Carbohydrate (HFSC) feed on the metabolic hormones in C57BL/6J mice to understand the sequence of events leading to impairment of glucose homeostasis. Material and methods: One-month-old male C57BL/6J mice were fed with control (C group) and HFSC (T group) feed (n = 30 each) respectively for five months. The glucose tolerance was studied by Oral Glucose Tolerance Test (OGTT) whereas serum insulin and leptin were quantified using ELISA kits, and serum cortisol was quantified using CLIA kits. Results: Insulin resistance index and HOMA-IR levels were higher in the mice of group T as compared to age-matched mice of group C within one month and significantly higher after and five months of feeding. The total area under the glucose tolerance test curve (AUC) and the insulin curve (AUC ins) was found to significantly increase in the mice of T group as compared to the mice of C group as early as two months of feeding and was elevated after 5 months post feeding. Comparison of the Matsuda index revealed that pancreatic beta cell function was significantly lower in mice of T group as compared to mice of C group by five months of feeding. Leptin levels fluctuated during the 1 st -4 th month and by the 5 th month significant hyperleptinaemia was detected. There was no significant change in cortisol levels in mice of group T as compared to mice of group C after five months of feeding. Conclusions: HFSC feed induces insulin resistance by the first month and progressively impairs glucose tolerance, resulting in hyperleptinaemia by the fifth month in male C57BL/6J mice. (Endokrynol Pol 2016; 67 (6): 592-598)

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Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets

Cited by 63 publications

References 56 publications

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Long-term ketogenic diet causes glucose intolerance and reduced β- and α-cell mass but no weight loss in mice

Impact of high-fat, low-carbohydrate diet on myocardial substrate oxidation, insulin sensitivity, and cardiac function after ischemia-reperfusion

Insulinooporność poprzedza nietolerancję glukozy i hiperleptynemię u myszy C57BL/6J otrzymujących karmę wysokotłuszczową i zawierającą cukry proste

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