Ketogenic diet and STZ-induced diabetes

High fat diets cause diabetes. At least this is what we are told. Researchers frequently use streptozotocin (STZ) to induce diabetes in experimental animals. So, following the logic, a low carbohydrate ketogenic diet (LCKD) plus STZ would make rats extremely diabetic, with a very reduced chance to survive in the long term. 

So let's see what happens when STZ-treated rats are fed a normal chow diet (ND), a LCKD and a high carbohydrate diet (HCHO) (1). The macronutrient ratios for the latter were (C/F/P): LCKD 10/60/30 and HCHO 70/10/20.

Bodyweight remained constant in the LCKD group, while it was reduced significantly in the HCHO and ND groups. In the latter, after the administration of STZ, blood glucose (BG) increased from 105mg/dL at baseline to 650mg/dL at the end of the experimental period. In contrast, the LCKD group maintained BG levels around 100mg/dL. Food intake also was drastically increased in HCHO and ND groups, showing polyphagia. The LCKD rats showed a little increased in food intake, then decreased and remained constant during the whole study. Water intake was also constant in the LCKD compared to HCHO and ND. Urine output was also increased in the latter groups. (Remember the "three P's" of diabetes: polydipsia, polyphagia and polyurea). Glucosuria after STZ injection reached 1000mg/dL. However, LCKD showed negative glucosuria. Summing up: LCKD rats didnt show any marker of diabetes comared to HCHO and ND rats. They maintained calorie intake, weight and BG levels normal. No polydipsia, polyphagia or polyurea. 

One recent study warned about the mechanism by which high fat diets could cause diabetes and beta-cell dysfunction. Yes, this is the famous study by Ohtsubo et al (2). For a more comprehensive review of this study please refer to the one written by Denise Minger. In a nutshell, what the authors found was that elevated concentration of free fatty acids (FFA) caused nuclear exclusion and reduced expression of FOXA2 and HNF1A transcription factors in beta cells. This resulted in depletion of GnT-4a glycosylation and glucose transporter expression, leading to beta-cell dysfunction. This is one mechanism by which lipotoxicity contributes to diabetes onset. However, STZ causes cell death in pancreatic beta-cells through methylation, the release of free radicals or by the formation of nitric oxide. The mechanism found by Ohtsubo might be reversible. Beta-cell destruction might not. This is one of the most important problems with advanced diabetes, and might be involved in the evolution of type 2 into type 1 diabetes (3). Thus, studies using models of beta-cell destruction might be more relevant for understanding the basis of autoimmune or chronic uncontrolled diabetes.

This leads us to the most interesting part of the resent study. The authors assessed the histology of the Langerhans islets in the different rats by H&E staining. 

Copyright © 2010 Elsevier GmbH. All rights reserved.

(a) and (b) show the sections of the pancreas from control HCHO and ND rats. Circles show islets of Langerhans and arrows show vacuoles. (d) and (e) are from diabetic HCHO and ND rats, respectively. As can be seen, there is almost no islet left after STZ administration. On the other hand, diabetic LCKD rats showed no reduction of islets compared to LCKD controls ((c) and (f)). 

To further assess the efect of the different diets on beta-cell destruction, the authors used Gomori's Chrome Alum Haematoxylin-Phloxine stain. 

Copyright © 2010 Elsevier GmbH. All rights reserved.

Beta-cells are stained blue, alfa-cells are stained red and delta-cells are stained pink. (a), (b) and (c) are control ND, HCHO and LCKD; (d), (e) and (f) are diabetic ND, HCHO and LCKD, respectively. 

Overall, there was a clear protection against beta-cell destruction in the diabetic LCKD rats, compared to diabetic HCHO and ND rats. However, the number of beta-cells in control rats was not different between groups. 

How can a ketogenic diet can prevent the onset of diabetes induced by STZ and a high-fat diet cause diabetes? Isnt a ketogenic diet a high-fat diet? First, a high-fat diet is not necessarily a ketogenic diet. The term "high-fat diet" is used without a consensus in the literature, so a high sugar-high fat diet might be promoted as a high-fat diet (this is why is EXTREMELY important to read the methods). Second, lipotoxicity is a major cause of metabolic dysfunction. However, lipotoxicity doesnt implies a high-fat diet. It implies dysregulation of lipid metabolism. If anything, a ketogenic diet should restore a normal lipid metabolism. Third, there is a difference in comparing in vitro results with in vivo results. I have highlighted the importance of this distinction before. Finally, diabetes is a highly complex disease. I believe that the most serious cases have definitely an immune component, so there is targeted destruction of beta-cells. The authors speculated that the ketogenic diet prevented diabetes by the antioxidant effect of ketone bodies (because one of the cytotoxic effects of STZ in beta-cells is mediated by the increase in free radicals).

In conclusion, saying that high-fat ketogenic diets cause diabetes is as silly as saying that high carbohydrate diets cause diabetes. There is an extreme metabolic flexibility present in healthy humans, which can adapt to a wide range of macronutrient ratios. Food toxins, as stressed by other authors are another source of problems, which can confound the effect of different diets. 


People with diabetes might benefit from low carbohydrate diets not only by the proximate effect of the diet (less dietary glucose, which treats the symptom, not the cause), but because of calorie restriction, which alleviates lipotoxicity. This can also be achieved with an hypocaloric high-carbohydrate diet. But with people in with autoimmune type I diabetes, LADA, or severe cases of type 2 diabetes, a ketogenic diet could prevent progression of the disease more efficiently, preventing oxidative stress-mediated cell death. 

Al-Khalifa A, Mathew TC, Al-Zaid NS, Mathew E, & Dashti H (2011). Low carbohydrate ketogenic diet prevents the induction of diabetes using streptozotocin in rats. Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie, 63 (7-8), 663-9 PMID: 21943927