̽��ֱ�� of Cambridge - insulin

DNA discovery highlights how we maintain healthy blood sugar levels after meals

cjb250 — Thu, 08 Jun 2023 15:00:48 +0000

̽��ֱ��findings, published today in Nature Genetics, could help inform future treatments of type 2 diabetes, which affects around 4 million people in the UK and over 460 million people worldwide.

Several factors contribute to an increased risk of type 2 diabetes, such as older age, being overweight or having obesity, physical inactivity, and genetic predisposition. If untreated, type 2 diabetes can lead to complications, including eye and foot problems, nerve damage, and increased risk of heart attack and stroke.

A key player in the development of the condition is insulin, a hormone that regulates blood sugar – glucose – levels. People who have type 2 diabetes are unable to correctly regulate their glucose levels, either because they don’t secrete enough insulin when glucose levels increase, for example after eating a meal, or because their cells are less sensitive to insulin, a phenomenon known as ‘insulin resistance’.

Most studies to date of insulin resistance have focused on the fasting state – that is, several hours after a meal – when insulin is largely acting on the liver. But we spend most of our time in the fed state, when insulin acts on our muscle and fat tissues.

It’s thought that the molecular mechanisms underlying insulin resistance after a so-called ‘glucose challenge’ – a sugary drink, or a meal, for example – play a key role in the development of type 2 diabetes. Yet these mechanisms are poorly-understood.

Professor Sir Stephen O’Rahilly, Co-Director of the Wellcome-MRC Institute of Metabolic Science at the ̽��ֱ�� of Cambridge, said: “We know there are some people with specific rare genetic disorders in whom insulin works completely normally in the fasting state, where it’s acting mostly on the liver, but very poorly after a meal, when it’s acting mostly on muscle and fat. What has not been clear is whether this sort of problem occurs more commonly in the wider population, and whether it’s relevant to the risk of getting type 2 diabetes.”

To examine these mechanisms, an international team of scientists used genetic data from 28 studies, encompassing more than 55,000 participants (none of whom had type 2 diabetes), to look for key genetic variants that influenced insulin levels measured two hours after a sugary drink.

̽��ֱ��team identified new 10 loci – regions of the genome – associated with insulin resistance after the sugary drink. Eight of these regions were also shared with a higher risk of type 2 diabetes, highlighting their importance.

One of these newly-identified loci was located within the gene that codes for GLUT4, the critical protein responsible for taking up glucose from the blood into cells after eating. This locus was associated with a reduced amount of GLUT4 in muscle tissue.

To look for additional genes that may play a role in glucose regulation, the researchers turned to cell lines taken from mice to study specific genes in and around these loci. This led to the discovery of 14 genes that played a significant role in GLUT 4 trafficking and glucose uptake – with nine of these never previously linked to insulin regulation.

Further experiments showed that these genes influenced how much GLUT4 was found on the surface of the cells, likely by altering the ability of the protein to move from inside the cell to its surface. ̽��ֱ��less GLUT4 that makes its way to the surface of the cell, the poorer the cell’s ability to remove glucose from the blood.

Dr Alice Williamson, who carried out the work while a PhD student at the Wellcome-MRC Institute of Metabolic Science, said: “What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work – and in particular how, when these mechanisms go wrong, they can lead to common diseases such as type 2 diabetes.”

Given that problems regulating blood glucose after a meal can be an early sign of increased type 2 diabetes risk, the researchers are hopeful that the discovery of the mechanisms involved could lead to new treatments in future.

Professor Claudia Langenberg, Director of the Precision Healthcare ̽��ֱ�� Research Institute (PHURI) at Queen Mary ̽��ֱ�� of London and Professor of Computational Medicine at the Berlin Institute of Health, Germany, said: “Our findings open up a potential new avenue for the development of treatments to stop the development of type 2 diabetes. It also shows how genetic studies of dynamic challenge tests can provide important insights that would otherwise remain hidden.”

̽��ֱ��research was supported by Wellcome, the Medical Research Council and the National Institute for Health and Care Research.

Reference
Williamson, A et al. Genome-wide association study and functional characterisation identifies candidate genes for insulin-stimulated glucose uptake. Nat Gen; 8 June 2023; DOI: 10.1038/s41588-023-01408-9

A study of the DNA of more than 55,000 people worldwide has shed light on how we maintain healthy blood sugar levels after we have eaten, with implications for our understanding of how the process goes wrong in type 2 diabetes.

What’s exciting about this is that it shows how we can go from large scale genetic studies to understanding fundamental mechanisms of how our bodies work

Alice Williamson

eak_kkk (Pixabay)

Cola

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Greater understanding of polycystic ovary syndrome

jeh98 — Tue, 29 Sep 2015 10:44:08 +0000

In the largest genome wide association study (GWAS) into polycystic ovary syndrome (PCOS) to date, new research conducted by scientists at the ̽��ֱ�� of Cambridge and ten other institutions, including 23andMe, has identified genetic variants and causal links associated with PCOS, some of which might be relevant to informing positive lifestyle and treatment choices for women.

Published this week in the journal Nature Communications, this study looked at genetic information from more than 200,000 women.

”We estimate that one in every five women in the UK have polycystic ovaries and therefore research such as this is critical to advance our understanding and help us to better tackle the disease.” said Dr John Perry, of the Medical Research Council (MRC) Epidemiology Unit at the ̽��ֱ�� of Cambridge, and study co-lead. “Not only did we find new genetic markers for PCOS, and confirm some linkages seen in previous studies, but our analyses also help us to understand the underlying biology of the disease in more detail.”

̽��ֱ��study found that the risk of PCOS was increased by genetic variants that are known to act by increasing body mass index (BMI) and insulin resistance. ̽��ֱ��findings indicate that therapies that counteract these mechanisms could be beneficial in women with PCOS.

“Previous studies had suggested that weight loss has only partial benefits for women with PCOS,” said Dr Ken Ong, of the MRC Epidemiology Unit and study co-lead. “We recommend that new studies should be done to test whether more intensive efforts to reduce body weight and improve insulin resistance are effective in treating women with PCOS.”

In additional to these causal links, the study also identified new genetic variants that implicate three of the four epidermal growth factor receptors, which are known targets of some modern cancer therapies. This opens up new avenues of research into future treatments in PCOS. Another new variant identified in the FSHB gene (which encodes the beta subunit of ‘follicle stimulating hormone’ FSH), indicates that low levels of FSH may also contribute to the development of PCOS.

PCOS is a condition that impacts how a woman’s ovaries work. It is very common, affecting millions of women in the UK. It is a leading cause of fertility problems and is also associated with an increased risk of developing health problems in later life, such as Type 2 diabetes and high cholesterol.

̽��ֱ��researchers used genetic information from more than 5,000 women of European ancestry who are 23andMe customers, reported having PCOS and consented to research. ̽��ֱ��study also included another 82,000 women customers of 23andMe who also consented to research but do not have the condition. Those women were used as controls for the study.

Researchers also did follow up in 2,000 other women, whose PCOS had been clinically validated, and another 100,000 women without the condition. Those women were studied by the Icelandic company deCODE, by researchers at the Erasmus Medical Center in the Netherlands, and also at the Center for Human Genetic Research at Massachusetts General Hospital in Boston, USA.

Reference:

Felix R Day, et al. "Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome" Nature Communications 6 (29 September 2015).

A new genetic study of over 200,000 women reveals the underlying mechanisms of polycystic ovary syndrome, as well as potential interventions.

We estimate that one in every five women in the UK have polycystic ovaries and therefore research such as this is critical to help us to better tackle the disease

John Perry

Ed Uthman

Ovum in Cumulus Oophorus, Human Ovary

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Breastfeeding may reduce Alzheimer’s risk

tdk25 — Mon, 05 Aug 2013 08:04:23 +0000

Mothers who breastfeed their children may have a lower risk of developing Alzheimer’s Disease, with longer periods of breastfeeding also lowering the overall risk, a new study suggests.

̽��ֱ��report, newly published in the Journal of Alzheimer’s Disease, suggests that the link may be to do with certain biological effects of breastfeeding. For example, breastfeeding restores insulin tolerance which is significantly reduced during pregnancy, and Alzheimer’s is characterised by insulin resistance in the brain.

Although they used data gathered from a very small group of just 81 British women, the researchers observed a highly significant and consistent correlation between breastfeeding and Alzheimer’s risk. They argue that this was so strong that any potential sampling error was unlikely.

At the same time, however, the connection was much less pronounced in women who already had a history of dementia in their family. ̽��ֱ��research team hope that the study – which was intended merely as a pilot – will stimulate further research looking at the relationship between female reproductive history and disease risk.

̽��ֱ��findings may point towards new directions for fighting the global Alzheimer’s epidemic – especially in developing countries where cheap, preventative measures are desperately needed.

More broadly, the study opens up new lines of enquiry in understanding what makes someone susceptible to Alzheimer’s in the first place. It may also act as an incentive for women to breastfeed, rather than bottle-feed – something which is already known to have wider health benefits for both mother and child.

Dr Molly Fox, from the Department of Biological Anthropology at the ̽��ֱ�� of Cambridge, who led the study, said: “Alzheimer’s is the world’s most common cognitive disorder and it already affects 35.6 million people. In the future, we expect it to spread most in low and middle-income countries. So it is vital that we develop low-cost, large-scale strategies to protect people against this devastating disease.”

Previous studies have already established that breastfeeding can reduce a mother’s risk of certain other diseases, and research has also shown that there may be a link between breastfeeding and a woman’s general cognitive decline later in life. Until now, however, little has been done to examine the impact of breastfeeding duration on Alzheimer’s risk.

Fox and her colleagues – Professor Carlo Berzuini and Professor Leslie Knapp – interviewed 81 British women aged between 70 and 100. These included both women with, and without, Alzheimer’s. In addition, the team also spoke to relatives, spouses and carers.

Through these interviews, the researchers collected information about the women’s reproductive history, their breastfeeding history, and their dementia status. They also gathered information about other factors that might account for their dementia, for example, a past stroke, or brain tumour.

Dementia status itself was measured using a standard rating scale called the Clinical Dementia Rating (CDR). ̽��ֱ��researchers also developed a method for estimating the age of Alzheimer’s sufferers at the onset of their disease, using the CDR as a basis and taking into account their age and existing, known patterns of Alzheimer’s progression. All of this information was then compared with the participants’ breastfeeding history.

Despite the small number of participants, the study revealed a number of clear links between breastfeeding and Alzheimer’s. These were not affected when the researchers took into account other potential variables such as age, education history, the age when the woman first gave birth, her age at menopause, or her smoking and drinking history.

̽��ֱ��researchers observed three main trends:

• Women who breastfed exhibited a reduced Alzheimer’s Disease risk compared with women who did not.

• Longer breastfeeding history was significantly associated with a lower Alzheimer’s Risk.

• Women who had a higher ratio of total months pregnant during their life to total months breastfeeding had a higher Alzheimer’s risk.

̽��ֱ��trends were, however, far less pronounced for women who had a parent or sibling with dementia. In these cases, the impact of breastfeeding on Alzheimer’s risk appeared to be significantly lower, compared with women whose families had no history of dementia.

̽��ֱ��study argues that there may be a number of biological reasons for the connection between Alzheimer’s and breastfeeding, all of which require further investigation.

One theory is that breastfeeding deprives the body of the hormone progesterone, compensating for high levels of progesterone which are produced during pregnancy. Progesterone is known to desensitize the brain’s oestrogen receptors, and oestrogen may play a role in protecting the brain against Alzheimer’s.

Another possibility is that breastfeeding increases a woman’s glucose tolerance by restoring her insulin sensitivity after pregnancy. Pregnancy itself induces a natural state of insulin resistance. This is significant because Alzheimer’s is characterised by a resistance to insulin in the brain (and therefore glucose intolerance) to the extent that it is even sometimes referred to as “Type 3 diabetes”.

“Women who spent more time pregnant without a compensatory phase of breastfeeding therefore may have more impaired glucose tolerance, which is consistent with our observation that those women have an increased risk of Alzheimer’s disease,” Fox added.

̽��ֱ��full paper: Maternal Breastfeeding History and Alzheimer’s Disease Risk can be found here.

For more information about this story, please contact Tom Kirk, Tel: 01223 332300, thomas.kirk@admin.cam.ac.uk

A new study suggests that mothers who breastfeed run a lower risk of developing Alzheimer’s, with longer periods of breastfeeding further reducing the risk.

In the future, we expect Alzheimer's to spread most in low and middle-income countries, so it is vital that we develop low-cost, large-scale strategies to protect people against it.

Molly Fox

Anton Nossik via Wikimedia Commons

Breastfeeding.

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Artificial pancreas promise for common diabetes complication

gm349 — Fri, 15 Apr 2011 11:26:10 +0000

Hypoglycaemia (or a ‘hypo’) occurs when the level of glucose in the blood falls too low. If left untreated the person having a hypo can eventually become unconscious after experiencing warning signs as the body tries to raise the blood glucose level. These unpleasant signs often include feeling shaky, sweating, tingling in the lips, heart pounding, and irritability. In extreme cases hypoglycaemia can lead to coma and brain damage, and can sometimes prove fatal.

̽��ֱ��‘artificial pancreas’ or closed-loop insulin delivery system automatically manages a person’s diabetes. ̽��ֱ��device regulates blood glucose levels by releasing insulin when alerted to high levels of glucose, and withholding it when levels are low. Currently people with Type 1 diabetes have to either inject insulin several times a day or wear an insulin pump² which releases the hormone via a cannula inserted under the skin.

̽��ֱ�� of Cambridge researcher Dr Roman Hovorka led two studies to evaluate the performance of the artificial pancreas in 10 men and 14 women, aged 18 to 65, who had used an insulin pump for at least three months.

̽��ֱ��first study monitored 12 participants overnight after consuming a medium-sized meal (60 g carbohydrate) at 7pm. In the second study, the other 12 participants were monitored overnight after consuming a larger meal (100 g carbohydrate) accompanied by alcohol at 8.30pm.

̽��ֱ��studies showed a 22 per cent improvement in the time participants kept their blood glucose levels in a safe range, halving the time they spent with low blood glucose levels and reducing the risk of both short term and long term complications.

Dr Hovorka said: “Hypoglycaemia remains a major challenge, especially during the night, so it’s encouraging to see such promising results from our trial using commercially available devices.

“ ̽��ֱ��study is a stepping stone to testing the artificial pancreas at home and suggests that the artificial pancreas may be suitable in adults as well as in children and adolescents we found previously.”

Diabetes UK Director of Research Dr Iain Frame said: “Although early days, this exciting area of research is a fantastic example of how existing technologies, in this case, insulin pumps and continuous glucose monitors, can be adapted and developed. ̽��ֱ��improvements in glucose control overnight using this new technology are impressive and it is good to see this work develop with the addition of testing the effects following a meal with some wine.

“We now need to see an extension of this study, one which tests larger numbers of people, and then take it out of the hospital and in to the home setting.”

̽��ֱ��research was published in the British Medical Journal today, 15 April.

Cambridge research funded by the health charity Diabetes UK has for the first time successfully demonstrated the potential of an ‘artificial pancreas’ in preventing night-time hypoglycaemia in adults with Type 1 diabetes.

Hypoglycaemia remains a major challenge, especially during the night, so it’s encouraging to see such promising results from our trial using commercially available devices.

Dr Roman Hovorka

Diabetes UK

Artificial pancreas: 1. Glucose levels monitored continuously 2. Required insulin dose calculated 3. Insulin does delivered automatically

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