Posts Tagged ‘Flemming Pociot’

Mutation in gene SIRT1 which protects against cancer and heart disease may cause Diabetes type 1

March 15, 2013

I was diagnosed with Diabetes Type 2 a few years ago but a number of friends have children and grandchildren suffering from Diabetes Type 1.  This is a life-long condition and with modern drugs is manageable but not apparently curable. But treatment starts as babies and the children have a tough time in handling all the injections. The causes are not very clear but a genetic origin has long been suspected since the highest prevalence of Diabetes Type 1 is in Northern Europe, particularly in Scandinavia. Incidence varies from 8 to 17 per 100,000 in Northern Europe and the US, with a high of about 35 per 100,000 in Scandinavia to a low of 1 per 100,000 in Japan and China.

Now Danish researchers have found that a mutation in a particular gene  – SIRT1 – may be a prerequisite for the development of Diabetes Type 1.

Identification of a SIRT1 Mutation in a Family with Type 1 Diabetes

Anna Biason-Lauber, Flemming Pociot et al, Cell Metabolism, Volume 17, Issue 3, 448-455, 5 March 2013, 10.1016/j.cmet.2013.02.001

  • Individuals carrying mutation in SIRT1 are susceptible to type 1 diabetes
  • Human SIRT1 regulates the production of nitric oxide and cytokines
  • SIRT1 regulates immune and metabolic function in humans


Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P ininsulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.

ScienceNordic reports:

“Scientists have known for years that type 1 diabetes has a strong genetic component. But this is probably the first time that a mutation has been discovered in a single gene that causes type 1 diabetes,” says Professor Flemming Pociot, MD, a research group leader at Glostrup Hospital, Denmark, who took part in the international study. .. 

It is normally very difficult to locate the right places in the genome as there are some 20,000 different genes in the human body to go through. ”For this reason, scientists often search for defective genes in families where many members are affected by the same disease. That way we can see whether the affected family members share any specific gene mutations,” explains Pociot.

In the new study, the researchers examined an Israeli family in which four members suffered from T1D. Having searched through the family’s genome, they located a mutation in a gene known as SIRT1. ”This gene is incredibly interesting because other studies indicate that it could play a part in prolonging life, and that it can for instance prevent cancer and cardiovascular disease.”

In most T1D patients, the disease is autoimmune, i.e. the patient’s immune defence attacks the body’s own cells. This was also the case with the Israeli patients, and it soon became clear that the defective sirtuin protein was partly responsible for these faults in the immune system. “We compared the cell behaviour in the patients to that of the healthy family members. It turned out that the patients were far more sensitive to some of the factors we know are central in autoimmune diseases,” says the researcher.

They also carried out a series of experiments on mice to see if they could identify the detailed mechanisms behind the defective sirtuin protein.

They noted that the sirtuin proteins appeared to affect the so-called cytokines – a type of protein that plays a key role in the regulation of the immune system.

The researchers’ theory is, simply stated, that the mutated sirtuin proteins cause the cytokines in the immune system to kill the wrong cells, including those that produce the body’s vital hormone insulin.

The lack of insulin, which helps regulate the blood sugar, is one of the hallmarks of T1D.

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