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Fast cure for diabetes

Kulbhushan Tikoo.

Fasting is a well established way of dietary restriction. It involves limiting food and calorie intake below normal levels without reaching malnutrition and can extend the lifespan in most, if not all species, including humans.

Based on this assumption, dietary restriction should prolong not only life span, but also youthfulness and keep at bay diseases associated with lifestyle disorders. In fact, in both rodents and humans, limiting the caloric intake delays many age-associated traits and diseases, including cognitive deterioration and cancer. In addition, dietary restriction can reduce body weight and normalise blood glucose, insulin, and leptin levels in obese animals and humans.

Research 1 carried out at the National Institute of Pharmaceutical Education and Research, Mohali explored the role of intermittent fasting in the progression of diabetic nephropathy and the different underlying mechanisms involved. The observations suggest that alternate day fasting in diabetic animals prevents progression of renal disease. Dietary restrictions also helped reduce tumor formation and increased resistance of neurons to dysfunction and degeneration in experimental models of Alzheimer's, Parkinson's disease and stroke.

Molecular mechanism

The merits of fasting to cure diabetes find mention in ancient Indian Ayurvedic texts such as the Caraka Samhita Sutra. Several ayurvedic practitioners in the country still use fasting as one of the treatment protocols in diabetes. As one starves, digestive enzymes inactivate different toxin as well as all patho-physiological factors responsible for progression of the disease. This is how Ayurveda explains the mechanism. However, the different molecular and cellular mechanisms involved in fasting are not completely known.

More recently, several possible molecular mechanisms have been proposed that might explain the beneficial effects of intermittent fasting on aging and disease including reduction in mitochondrial oxyradical production, induction of a cytoprotective cellular stress response, and stimulation of the production of growth factors.

In addition, to these mechanisms, the NIPER study demonstrated that alternate day fasting prevents the decrease in sirtuins (Sir 2) expression in the kidney of diabetic animals during the nephropathy progression. Several reports have shown involvement of sirtuins (a longevity protein) in extending the life span of wide variety of organisms2.

Two different paradigms to extend life span are widely employed in rat and mice — calorie restriction (CR), in which 30 to 40% less than normal food is allowed for consumption; and intermittent fasting (IF), in which food is given every other day. Out of several possible molecular mechanisms that might explain the beneficial effect of CR or IF, one is increase in expression of sirtuins. Several reports also show involvement of sirtuins in inflammation, which is involved in number of pathological conditions, including diabetes, cancer, arthritis, asthma, heart disease and neuro-degeneratation.

Sirtuins target many proteins that are not histones, they have been demonstrated to bind and deacetylate p53 in vitro and in vivo. The expression of p53 protein in the kidneys of diabetic animals increased as compared to their respective controls. However, the expression of proapoptotic p53 reduced significantly in the kidneys of diabetic rats on IF regimen.

The expression as well as activation of p53 is thought to be mediated by Sir2 dependent deacetylation. They both share an inverse relationship as is evident from the results where the Sir2 expression is decreased and at the same time p53 is upregulated. Further IF decreases the level of caspases-3 and p38 which are involved in apoptosis as compared to diabetic animal kidney and shows its antiapoptotic effect. Although the mechanism by which IF exerts its anti apoptotic effects is yet to be understood in detail but these results suggest a cross talk between Sir2, p53, p38 and caspase-3.

These and other findings may have unique clinical efficacy in preventing the development and progression of diabetic complications in diabetes. In the present scenario in India, there has been a marked change in lifestyle and eating habits of people rendering them more prone to develop different lifestyle disorders like diabetes and metabolic syndrome. Fasting could be a useful intervention for enhancing life span as well as minimising the risk of metabolic disorders.

Past work

A clinical study aimed at increasing exercise combined with diet is able to decrease the incidence of type 2 diabetes3. The Indian Diabetes Prevention Programme demonstrated the lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance4.

As per World Health Organization (WHO), across the world the total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. The maximum absolute increase in the number of people with diabetes will be in India. In 2000, the number of diabetic patients was 31 million and is predicted to go up to 79 million till 20305. India is the capital of the lifestyle disease diabetes.

Of all the abnormalities associated with diabetes, nephropathy or renal failure has became the world's leading cause of chronic and end-stage renal disease6. It is associated with structural changes in the glomerulus such as thickening of the glomerular basement membrane and eventually causes progressive hyperfiltration and albuminuria. As the disease progresses, glomerular filtration rate (GFR) declines and leads to end-stage renal disease.

To treat diabetic nephropathy, a variety of therapeutic approaches or treatment are available. While they can slow down the development of the disease, they do not stop the progression of end stage renal failure.

The author is an associate professor in the department of pharmacology and toxicology at the National Institute of Pharmaceutical Education and Research, Punjab, India.



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