Kidney damage 'reversed' in diabetic mice

BBC News has reported that “diet can ‘reverse kidney failure’ in mice”. It said that a diet high in fat and low in carbohydrate can repair kidney damage in diabetic mice.

The research looked at the effect on kidney function of a “ketogenic diet”, consisting of 87% fat, 5% carbohydrate and 8% protein, compared to a standard carbohydrate-rich diet in mouse models of type 1 and type 2 diabetes.

The diabetic mice, which had abnormal amounts of protein in their urine, indicating poor kidney function, showed improvement in kidney function over eight weeks of being on the ketogenic diet.

This was a small animal study and further research is needed to see what aspect of the diet underlies the effects seen. The implications for humans are limited and, as the researchers point out, it is unfeasible for humans to adopt such a high-fat diet in the long term owing to the health risks of consuming so much fat. Follow-up studies are more likely to look at the proteins involved in fat metabolism and their effect on kidney cells, to try to produce drugs that mimic the effect of the diet. As the BBC points out, the diet “mimics the effect of starvation and should not be used without medical advice”.

Where did the story come from?

The study was carried out by researchers from Mount Sinai School of Medicine, New York. Funding was provided by The Juvenile Diabetes Research Foundation. The study was published in the peer-reviewed medical journal PLoS One.

The research was covered very well by the BBC, which highlighted the preliminary nature of the animal study and that the diet was unlikely to be recommended for people with diabetes.

What kind of research was this?

This animal study investigated the effect of a “ketogenic” diet on mouse models of type 1 or type 2 diabetes, in which the mice had damage to their kidneys. Kidney damage is a common complication of diabetes and is known as diabetic nephropathy. The high levels of blood sugar associated with diabetes gradually cause damage to the tiny blood vessels and microstructures of the kidney, affecting their ability to filter correctly. Leakage of blood proteins (albumin) into the urine is the key sign of diabetic nephropathy.

A ketogenic diet is high in fat, low in carbohydrate and contains an average amount of protein. It mimics starvation and encourages the body to burn fats rather than carbohydrates. Burning fats replaces glucose as the energy source.

In both type 1 and type 2 diabetes, the body is less able to regulate blood glucose levels. Insulin is the hormone that regulates blood sugar levels. Type 1 diabetes results from the body’s failure to produce insulin. Type 2 results from insulin resistance, or a lack of sensitivity of the body’s cells to the actions of insulin.

What did the research involve?

The researchers used two mouse models of diabetes: a type of mouse called the Akita mouse, which produces less insulin (mimicking type 1 diabetes), and db/db mice, which are less responsive to insulin (mimicking type 2 diabetes). The researchers set up two experiments, one comparing 28 Akita and 28 normal mice, and the other comparing 20 db/db and 20 normal mice.

The mice were all 10 weeks old at the start of the study. The researchers collected urine samples when the mice were 20 weeks of age. At that time in the Akita versus control study, half of the mice from each group were placed on a ketogenic diet (5% carbohydrate, 8% protein, 87% fat). The other half of the animals were kept on a standard high-carbohydrate control diet (64% carbohydrate, 23% protein, 11% fat).

In the db/db versus control study, the ketogenic diet was started in half the mice from each group when the mice were 12 weeks old. The mice were kept on the ketogenic diets for eight weeks and urine samples were collected. The researchers measured levels of albumin in the mouse urine samples to assess how well their kidneys were functioning.

The Akita mice had a shorter life expectancy than the normal mice. The researchers expected that the Akita mice would not survive on the standard diet for eight weeks. They found that after 2 weeks on the standard diet (when the mice were 22 weeks old) two of the Akita mice had died. The researchers therefore decided to cull all of the Akita mice and also the normal mice that had received the standard diet so that they could compare the gene activity of Akita versus the control mice on the standard diet when they were the same age. The Akita and normal mice that were given the ketogenic diet all survived for the full eight weeks of the study, therefore the researchers compared the gene activity of the akita mice verses the control mice on the ketogenic diet when they were 28 weeks old. In the db/db versus normal mice study all of the mice that had received either the standard or the ketogenic mice were followed for the full eight weeks.

What were the basic results?

The Akita mice developed high blood sugar at four weeks of age and by the time they were 20 weeks their urine samples showed that they had developed kidney damage. Within one week of switching to the ketogenic diet when they were 20 weeks old, their blood sugar levels were in the normal range. Although the researchers sacrificed all of the non-diabetic mice and Akita mice who had received the control diet 2 weeks after they started the diet, they continued to monitor the non-diabetic mice versus the Akita mice on the ketogenic diet. They found, based on urine measurements, that the kidney damage seen in the Akita mice was reversed within two months on the ketogenic diet.

In the db/db type 2 diabetes mouse model, the mice developed high blood sugar by 12 weeks of age. At this time, half of the db/db mice and the non-diabetic mice were placed on the ketogenic diet. The ketogenic diet reduced blood sugar levels by around 50%, but they were still outside normal levels. Within eight weeks of being on the diet, the abnormalities in the urine samples indicating kidney damage were almost completely corrected. The db/db mice, compared with the non-diabetic mice, gained weight while on the ketogenic diet.

When the researchers examined the activity of genes in the kidney, they found there were nine genes that were more active in the Akita mice and db/db mice compared with the non-diabetic mice. However, the increased activity of these genes completely reversed in the Akita mice and largely or completely reversed in the db/db mice given the ketogenic diet.

In the laboratory, the researchers then examined the structure of the kidneys themselves in the db/db mice. They found that the abnormal structure indicating kidney damage was less common in the db/db mice on the ketogenic diet compared with mice on the standard diet, but their kidneys still showed damage compared with non-diabetic mice.

How did the researchers interpret the results?

The researchers say that previous studies of models of type 1 diabetes have found that good glucose control could prevent, but not reverse, kidney damage. This present study showed that the ketogenic diet could actually reverse the damage.

The researchers say that their research proves that manipulating a diet can prevent some of the damage caused by diabetes. However, they say that the “ketogenic diet is probably too extreme for chronic use in adult patients” and may produce side effects. They say that if they can refine what aspects of the diet caused the effects then this may lead to the development of drugs that act in a more targeted way.

Conclusion

This preliminary animal research shows that a high-fat, low-carbohydrate diet was associated with some benefit in mouse models of type 1 and type 2 diabetes, in terms of reducing the kidney damage usually seen in these animals.

Though this animal model is meant to be representative of the kidney damage that can occur in people with diabetes, it is not clear whether a similar effect would be seen in humans. This research is unlikely to lead to a similar diet-based therapy for people with diabetes, as the side effects of eating such a high-fat diet are likely to outweigh any benefits. It is more likely that this study may form the basis for further studies looking at the proteins involved in fat metabolism and how they can affect kidney function and damage.

The researchers demonstrated that kidney function was restored over time by measuring albumin in the urine before and after the diet. However, as they only looked at the structure of the kidney at the end of the study it is not clear whether damage to the structure of the kidney was reversed by the diet, or whether the diet had prevented subsequent damage. To see if damage to the kidney structure was reversed the researchers would need to compare the structure of the kidney in age-matched mice before and after the diet. This small study would need further follow-up in animals to see the precise effect of this diet on the kidneys.

This study has no current implications for the prevention or treatment of diabetic nephropathy in humans.