Reversal of Diabetic Nephropathy by a Ketogenic Diet

Poplawski, Michal; Mastaitis, Jason; Isoda, Fumiko; Grosjean, Fabrizio; Zhao, Feng; Mobbs, Charles V.

doi:10.1371/journal.pone.0018604

Cited by 96 publications

(100 citation statements)

References 31 publications

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“…Recently, feeding mice a strictly ketogenic diet (5% carbohydrate, 8% protein, 87% fat) reversed a mild form of nephropathy. 4 Although implementing such an extreme diet …”

mentioning

confidence: 99%

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mohamed

Jayakumar

Chen

et al. 2016

Journal of the American Society of Nephrology

106

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Diabetes is the leading cause of kidney failure, accounting for .45% of new cases of dialysis. Diabetic nephropathy is characterized by inflammation, fibrosis, and oxidant stress, pathologic features that are shared by many other chronic inflammatory diseases. The cytokine IL-17A was initially implicated as a mediator of chronic inflammatory diseases, but recent studies dispute these findings and suggest that IL-17A can favorably modulate inflammation. Here, we examined the role of IL-17A in diabetic nephropathy. We observed that IL-17A levels in plasma and urine were reduced in patients with advanced diabetic nephropathy. Type 1 diabetic mice that are genetically deficient in IL-17A developed more severe nephropathy, whereas administration of low-dose IL-17A prevented diabetic nephropathy in models of type 1 and type 2 diabetes. Moreover, IL-17A administration effectively treated, prevented, and reversed established nephropathy in genetic models of diabetes. Protective effects were also observed after administration of IL-17F but not IL-17C or IL-17E. Notably, tubular epithelial cell-specific overexpression of IL-17A was sufficient to suppress diabetic nephropathy. Mechanistically, IL-17A administration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophage WAP domain protein in an AMP-activated protein kinasedependent manner and favorably modulated renal oxidative stress and AMP-activated protein kinase activation. Administration of recombinant microglia/macrophage WAP domain protein suppressed diabetes-induced albuminuria and enhanced M2 marker expression. These observations suggest that the beneficial effects of IL-17 are isoform-specific and identify low-dose IL-17A administration as a promising therapeutic approach in diabetic kidney disease. CKDs such as diabetic nephropathy are a serious public health problem. In the United States, .20 million adults have CKD, and 20%-40% of patients with diabetes develop nephropathy. The financial burden of diabetes is estimated to be $245 billion per year in the United States alone, and the cost for diabetic nephropathy is estimated to be .$20 billion per year. While intensive insulin therapy and control of hypertension can delay the onset of diabetic nephropathy, 1-3 these therapies cannot reverse CKD once it has developed. Recently, feeding mice a strictly ketogenic diet (5% carbohydrate, 8% protein, 87% fat) reversed a mild form of nephropathy. 4 Although implementing such an extreme diet

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“…Recently, feeding mice a strictly ketogenic diet (5% carbohydrate, 8% protein, 87% fat) reversed a mild form of nephropathy. 4 Although implementing such an extreme diet …”

mentioning

confidence: 99%

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mohamed

Jayakumar

Chen

et al. 2016

Journal of the American Society of Nephrology

106

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“…We developed a novel panel of genes that were induced in association with diabetic nephropathy, and they were all at least partially reversed (in most cases completely reversed) by the ketogenic diet. We carried out a similar study in Type II (db/db) diabetic mice with similar results: functionally (albumin/ creatinine ratios) diabetic nephropathy was completely reversed, and at the molecular level the gene profile associated with diabetic nephropathy was largely reversed as well [40], although blood glucose was only partially normalized. Taken together these data suggest that a plausible treatment for diabetic complications would be for patients to be placed on a low-carbohydrate, highprotein diet Aktkins-type diet [18][19][20][21], which entails relatively high compliance compared to the classic ketogenic diet.…”

Section: Low-carbohydrate Diets In Animal Models Of Obesity and Diabetesmentioning

confidence: 76%

“…Thus the classic ketogenic diet is remarkable effective in normalizing blood glucose even in highly hyperglycemia Type 1 diabetic mice. We next assessed if the ketogenic diet would be effective in reversing diabetic complications [40], which are not reversed even by normalization of blood glucose [28][29][30][31][32][33][34]. We chose to focus initially on nephropathy because this complication is relatively easy to measure non-invasively by frequent assessment of urinary albumin/creatinine ratios.…”

Section: Low-carbohydrate Diets In Animal Models Of Obesity and Diabetesmentioning

confidence: 99%

Mechanisms by Which the Ketogenic Diet Reverses Obesity and Diabetes

Moreno¹

2017

EMIJ

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Since the beginning of the 20th century, when low-carbohydrate diets were first implemented to treat Type 1 diabetes, the role of dietary composition in regulating glucose homeostasis and, increasingly, energy balance, has been the subject of great interest to both biomedical researchers and, increasingly, to the public. In fairly extreme circumstances (e.g., Type 1 diabetes untreated with insulin) low-carbohydrate diets (which are generally high-fat diets) can be useful to reduce blood glucose, but since the advent of insulin therapy, and increasing appreciation of the cardiovascular consequences of hyperlipidemia, clinical practice has dramatically favored highcarbohydrate, low-fat diets for diabetes (especially Type 2 diabetes, largely associated with obesity). This clinical advice, at the time, seemed fairly radical. In a famous treatise, "The Physiology of Taste" published in 1825, Brillat-Savarin, argue that consumption of "natural" diets (e.g., meat and vegetables) promote health, whereas "cultivated" diet (e.g., derived from rice and wheat) increasingly led to deterioration of health associated with affluence.Similarly, in 1837 Sylvester Graham published "A treatise on bread and breadmaking", essentially a tirade against food with grains (as well as meat), which were not suited to the assumption that gluttony was among the greatest sins (clearly a theme in subsequent American diet fads). Similarly throughout the 20th century popular diets (including those promotes by Adelle Davis in the 1950s, Robert Atkins in the 1970s, the paleo diet, and increasingly many more) have emphasized lowcarbohydrate, high-fat diets especially for weight loss (viewed by the public as a more compelling concern than glucose homeostasis). While these diets have little if any clinical evidence for efficacy, low-calorie, low-protein diets that produce ketogenesis are extremely effective to reverse obesity, hyperglycemia, and diabetic complications. The mini-review examines possible mechanisms mediating these remarkable effects, particularly focusing on epigenetic effects on hypothalamic neurons.

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“…Another study involving diabetic mice with induced renal disease reversed their diabetic nephropathy with a low carbohydrate ketogenic diet. The ketone 3-beta-hydroxybutyric acid (3-OHB) was thought to protect the kidneys from the oxidative stress of glucose [9].…”

Section: Discussionmentioning

confidence: 99%

A Low Carbohydrate Diet Effective in the Treatment of Obese or Diabetic Patients with Chronic Kidney Disease

Gann¹

2015

JDMDC

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Aim: Diet of Hope Institute specializes in the treatment of obesity, diabetes, hypertension, and metabolic syndrome. In 2011, a patient being treated at our clinic improved estimated glomerular filtration rate (eGFR) from 46 to 80. The patient was obese, hypertensive and diabetic. She lost 10% of her body weight and was able to stop her diabetic and blood pressure medications. This finding prompted the Institute to collect data regarding the frequency of kidney disease in the clinic's patient population and evaluate its response to our disease management program which emphasizes a low carbohydrate and normal protein diet. Methods:Of five hundred consecutive patients referred to the program, thirty-three patients (6.6%) carried the diagnosis of chronic kidney disease as established by their nephrologist. These patients were supervised for an average of 6.3 months during 2013 and 2014 and data were collected at that time. Statistical analysis was subsequently performed in January 2015. Carbohydrates were restricted to berries and non-starchy vegetables. Daily protein intake was calculated at 0.5gm per pound of body weight up to a maximum of 120gm. Results:In a population of thirty-three patients diagnosed with chronic kidney disease, eGFR increased by an average of 25.5%, serum creatinine decreased by an average of 13.7% and blood urea nitrogen (BUN) decreased by an average of 9.1%.Average weight loss was 23.8 pounds or 10.2% of body weight. Conclusion:A low carbohydrate and normal protein diet can be effective in improving renal function in obese, hypertensive, and diabetic patients.

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Reversal of Diabetic Nephropathy by a Ketogenic Diet

Cited by 96 publications

References 31 publications

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mechanisms by Which the Ketogenic Diet Reverses Obesity and Diabetes

A Low Carbohydrate Diet Effective in the Treatment of Obese or Diabetic Patients with Chronic Kidney Disease

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