Tag Archives: #prediabetes

Prediabetes May be Linked to Worse Brain Health (Medicine)

People with prediabetes, whose blood sugar levels are higher than normal, may have an increased risk of cognitive decline and vascular dementia, according to a new study led by UCL researchers.

For the study, published in the journal Diabetes, Obesity and Metabolism, researchers analysed data from the UK Biobank of 500,000 people aged 58 years on average, and found that people with higher than normal blood sugar levels were 42% more likely to experience cognitive decline over an average of four years, and were 54% more likely to develop vascular dementia over an average of eight years (although absolute rates of both cognitive decline and dementia were low).

The associations remained true after other influential factors had been taken into account – including age, deprivation, smoking, BMI and whether or not participants had cardiovascular disease.

People with prediabetes have blood sugar levels that are higher than usual, but not high enough to be diagnosed with type 2 diabetes. It means they are more at risk of developing diabetes. There are an estimated five to seven million people* with prediabetes in the UK.

Lead author Dr Victoria Garfield (UCL Institute of Cardiovascular Science and the UCL MRC Unit for Lifelong Health & Ageing) said: “Our research shows a possible link between higher blood sugar levels – a state often described as ‘prediabetes’ – and higher risks of cognitive decline and vascular dementia. As an observational study, it cannot prove higher blood sugar levels cause worsening brain health. However, we believe there is a potential connection that needs to be investigated further.

“Previous research has found a link between poorer cognitive outcomes and diabetes but our study is the first to investigate how having blood sugar levels that are relatively high – but do not yet constitute diabetes – may affect our brain health.”

In the study, researchers investigated how different blood sugar levels, or glycaemic states, were associated with performance in cognitive tests over time, dementia diagnoses, and brain structure measured by MRI scans of the brain. Each of these measures were limited to smaller subsets of the Biobank sample (for instance, only 18,809 participants had follow-up cognitive tests).

At recruitment all of the UK Biobank participants underwent an HbA1c test, which determines average blood sugar levels over the past two to three months. Participants were divided into five groups on the basis of the results – “low-normal” level of blood sugar, normoglycaemia (having a normal concentration of sugar in the blood), prediabetes, undiagnosed diabetes and diabetes. A result between 42-48 mmol/mol (6.0-6.5%) was classified as prediabetes.

The researchers used data from repeated assessments of visual memory to determine whether participants had cognitive decline or not. Though absolute rates of cognitive decline were low, people with prediabetes and diabetes had a similarly higher likelihood of cognitive decline – 42% and 39% respectively.

Looking at dementia diagnoses, researchers found that prediabetes was associated with a higher likelihood of vascular dementia, a common form of dementia caused by reduced blood flow to the brain, but not Alzheimer’s disease. People with diabetes, meanwhile, were three times more likely to develop vascular dementia than people whose blood sugar levels were classified as normal, and more likely to develop Alzheimer’s disease.

Senior author Professor Nishi Chaturvedi (UCL MRC Unit for Lifelong Health & Ageing) said: “In this relatively young age group, the risks of cognitive decline and of dementia are very low; the excess risks we observe in relation to elevated blood sugar only modestly increase the absolute rates of ill health. Seeing whether these effects persist as people get older, and where absolute rates of disease get higher, will be important.

“Our findings also need to be replicated using other datasets. If they are confirmed, they open up questions about the potential benefits of screening for diabetes in the general population and whether we should be intervening earlier.”

Among 35,418 participants of the UK Biobank study who underwent MRI brain scans, researchers found that prediabetes was associated somewhat with a smaller hippocampus and more strongly associated with having lesions on the brain (white matter hyperintensities, WMHs) – both associated with age-related cognitive impairment.

The researchers said that some of these differences could be explained by elevated blood pressure, as those participants taking antihypertensive medication were likely to have more WMHs and smaller hippocampal volume. Rather than the treatment having an adverse effect on the brain, the researchers said use of such medication might be an indicator of earlier untreated high blood pressure.

People with prediabetes can reduce their risk of developing type 2 diabetes by eating a healthy, balanced diet, being more active, and staying at a healthy weight.


Reference: Garfield, V., Farmaki, A.‐E., Eastwood, S.V., Mathur, R., Rentsch, C.T., Bhaskaran, K., Smeeth, L. and Chaturvedi, N. (2021), Brain health across the entire glycaemic spectrum: the UK Biobank. Diabetes Obes Metab. Accepted Author Manuscript. https://doi.org/10.1111/dom.14321


Provided by University College London

Prediabetes Subtypes Identified (Medicine)

All prediabetes is not the same: in people in the preliminary stages of type 2 diabetes, there are six clearly distinguishable subtypes, which differ in the development of the disease, diabetes risk, and the development of secondary diseases. This is shown in a study by the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, Tübingen University Hospital and the German Center for Diabetes Research (DZD). The results have now been published in Nature Medicine. The new classification can help in the future to prevent the manifestation of diabetes or the development of diabetes complications through targeted prevention.

Diabetes is a worldwide pandemic. Since 1980, the number of people with diabetes has quadrupled worldwide. In Germany alone, 7 million people suffer from it. And the trend is still rising. By 2040, the number of people with type 2 diabetes could increase to as many as 12 million. But type 2 diabetes does not develop from one day to the next. People often go through a longer preliminary stage of diabetes, in which blood glucose levels are already elevated but people are not yet ill. “For people with prediabetes it has not been possible until now to predict whether they would develop diabetes and be at risk for serious complications such as kidney failure, or whether they would only have a harmless form with slightly higher blood glucose levels but without significant risk,” said Professor Hans-Ulrich Häring, who initiated the study 25 years ago. However, such a distinction is important for the targeted prevention of the metabolic disease and thus for counteracting the diabetes pandemic. Researchers from Tübingen have now achieved an important breakthrough. Using cluster analysis* in people with prediabetes, they have discovered six distinct subtypes with different diabetes risk. A differentiated classification of prediabetes and diabetes makes it possible to carry out individual and early prevention and therapy of diabetes and its secondary diseases in a way that is adapted to the development of the disease.

Prediabetes: Six different clusters identified

The research group led by Professor Häring and Professor Fritsche at the University Hospital in Tübingen has conducted detailed studies of the metabolism of people with prediabetes who are still considered healthy. The test persons (n=899) are from the Tübingen Family Study and the study of the Tübingen Lifestyle Program. They have repeatedly undergone intensive clinical, laboratory chemical, magnetic resonance imaging and genetic examinations in Tübingen over the past 25 years. Based on key metabolic parameters such as blood glucose levels, liver fat, body fat distribution, blood lipid levels and genetic risk, the researchers were able to identify six subtypes of prediabetes. “As in manifest diabetes, there are also different disease types in the preliminary stage of diabetes, which differ in blood glucose levels, insulin action and insulin secretion, body fat distribution, liver fat and genetic risk,” said first author Professor Robert Wagner from the DZD Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, summarizing the results of the study.

In people with prediabetes, there are six clearly distinguishable subtypes (clusters), which differ in development of the diseases, risk for diabetes, and development of complications. Image source: IDM, DZD

Three of these groups (clusters 1, 2 and 4) are characterized by a low diabetes risk. The study participants in clusters 1 and 2 were healthy. Slim people are the main members of cluster 2. They have a particularly low risk of developing complications. Cluster 4 consists of overweight people, whose metabolism is still relatively healthy. The three remaining subtypes (clusters 3, 5 and 6) are associated with an increased risk of diabetes and/or secondary diseases. People who belong to subtype 3 produce too little insulin and have a high risk of developing diabetes. People in cluster 5 have a pronounced fatty liver and a very high risk of diabetes because their bodies are resistant to the blood glucose lowering effect of insulin. In subtype 6, damage to the kidneys occurs even before diabetes is diagnosed. Here, mortality is also particularly high.

But can the classification into six prediabetes subtypes also be confirmed in other cohorts? To investigate this, the researchers extended the analysis to include almost 7000 subjects in the Whitehall II Cohort in London and there, too, identified the six prediabetes subtypes.

More targeted prevention measures

The researchers are already making further plans. “Next, in prospective studies, we will first seek to determine to what extent the new findings are applicable for the classification of individual persons into risk groups,” said Professor Andreas Fritsche of Tübingen University Hospital. If this is the case, people with a high risk profile could be identified early on and receive specific treatment.

These results are based on research conducted by the Diabetes Research Department at Tübingen University Hospital over the past 25 years to characterize people with an increased risk of diabetes. The study was funded by the German Research Foundation, the Federal Ministry of Education and Research and the State of Baden-Württemberg.

“One of the DZD’s goals is to develop precise prevention and therapy measures, i.e. the appropriate prevention or treatment for the right group of people at the right time. The combination of in-depth clinical and molecular research with state-of-the-art bioinformatics has made this internationally important result possible. The identification of subtypes in the preliminary stages of type 2 diabetes is an important step towards precision medicine in the prevention of diabetes and its complications,” says DZD Executive Director Prof. Martin Hrab? de Angelis.

Note:

  • Cluster analysis:

Cluster analysis is a method through which the objects of investigation (e.g. persons) can be grouped on the basis of given criteria and characteristics. The groups found in this way – also called clusters – then contain cases that are similar to each other. A formed cluster should be maximally homogeneous in itself, but at the same time it should differ as much as possible from the other clusters. Here, six different clusters could be identified in test persons with pre-diabetes on the basis of eight core parameters important for metabolism (including blood glucose levels, liver fat, body fat distribution, blood lipid levels and genetic risk).

Reference: Robert Wagner et al: Pathophysiology-based subphenotyping of individuals at elevated risk for type 2 diabetes. Nature Medicine. DOI: https://doi.org/10.1101/2020.10.12.20210062

Provided by German Center for Diabetes Research

The Gut Microbiota Forms A Molecule That Can Contribute To Diabetes Progression (Medicine)

It is the bacterial changes in the gut that increase the levels of imidazole propionate, the molecule that makes the body’s cells resistant to insulin in type 2 diabetes. This result emerges from a European study, MetaCardis.

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The gut and its bacteria are considered important in many diseases and several studies have shown that the gut microbiota affects the breakdown of several different parts of our diet. In previous research on gut microbiota and type 2 diabetes, the focus has often been on butyric acid-producing dietary fibers and their possible effects on blood sugar regulation and insulin resistance.

In previous research led by Fredrik Bäckhed, Professor of molecular medicine at the University of Gothenburg, demonstrated that diabetes can be linked to a changes in the composition of intestinal bacteria, which increases the production of molecules that may contribute to the disease.

His group has shown that the altered intestinal microbiota leads to altered metabolism of the amino acid histidine, which in turn leads to increased production of imidazole propionate, the molecule that prevents the blood sugar lowering effects of insulin.

An article published in the journal Nature Communications now confirms the initial findings in a large European study with 1,990 subjects, which shows that patients with type 2 diabetes from Denmark, France and Germany also had increased levels of imidazole propionate in their blood.

“Our study clearly shows that imidazole propionate is elevated in type 2 diabetes in other populations as well” says Fredrik Bäckhed, and continues:

“The study also shows that the levels of imidazole propionate are elevated even before the diabetes diagnosis is established, in so-called prediabetes. This may indicate that imidazole propionate may contribute to disease progression.”

The altered gut microbiota observed in people with type 2 diabetes has fewer species than normal glucose tolerant individuals, which is also linked to other diseases. The researchers speculate that this leads to an altered metabolism of the amino acid histidine.

The EU-funded research collaboration MetaCardis has been led by Karine Clément, Professor of Nutrition at Sorbonne University and Assistance Publique Hôpitaux de Paris, a direction of an INSERM group in Paris.

“Interestingly enough, our findings suggest that it is the altered intestinal microbiota rather than the histidine intake in the diet that affects the levels of imidazole propionate”. She continuous:

“An unhealthy diet also associates with increased imidazole propionate in individuals with type 2 diabetes”.

One problem with research on microbiota and various diseases has been limited reproducibility. By studying the products that the bacteria produce, the metabolites, one focuses on the function of the bacteria rather than on the exact species in the intestine. Fredrik Bäckhed:

“The collaboration gave us unique opportunities to confirm preliminary findings that imidazole propionate can be linked to type 2 diabetes. Here we had the opportunity to analyze almost 2,000 samples and can thus determine that elevated levels of imidazole propionate can be linked to type 2 diabetes. As the levels are elevated even in prediabetes, imidazole propionate may also cause the disease in some cases, he says.

References: http://dx.doi.org/10.1038/s41467-020-19589-w

Provided by University of Gotherburg