黑料不打烊

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We know about Type 1 and Type 2 diabetes, but what is 鈥楾ype 3 diabetes鈥?

Alzheimer鈥檚 Disease is increasingly being referred to as 鈥楾ype 3 diabetes.鈥 Here we look at the evidence.

The incidence of diabetes mellitus has reached epidemic levels in recent years, affecting one in every 10 adults globally in 2021. Ninety percent of these individuals have Type 2 Diabetes (T2D) which is characterized by two defects, namely resistance to the metabolic actions of insulin in combination with an inability of the pancreatic islet beta-cells to secrete enough insulin to overcome this resistance. T2D is also often associated with overweight or obesity, which plays a role in the development of the insulin resistance.

Over the past few years, it has become apparent that not every person with T2D is the same. For example, that involved over 400,000 individuals with T2D, identified 8 distinct sub-groups or clusters based on the expression of specific sets of genes. of over one-million individuals identified 12 different clusters of genes associated with T2D. As expected, many of these genes relate to beta cell and adipose cell function, as well as body weight overall.

T1D, in contrast, is caused by an autoimmune process that destroys the beta cells, thus mandating insulin administration for survival. Rare forms of diabetes also include Pancreatic Diabetes, usually caused by surgical removal of the pancreas and, hence the beta cells. Furthermore, some individuals have been reported to have what is now-called Type 1.5 Diabetes, which has features of both T1D and T2D. However, what is common to all of these forms of diabetes is high blood sugar (or glucose) levels. Hence, they are more accurately described as聽Diabetes Mellitus, which is derived from the Greek word for聽siphon聽and the Latin word for聽honey, respectively, because the some of that sugar in the blood is passed through the kidneys into the urine, making it 鈥榮weet鈥.

In contrast to these well-established types of diabetes, some researchers have suggested the existence of another form of diabetes, T3D. This new term is being used by some to describe Alzheimer鈥檚 Disease (AD), which is also reaching epidemic levels, affecting one-in nine people over the age of 65. However, in contrast to T1D and T2D, AD is characterized by deposition of abnormal proteins in the brain, causing neurodegeneration and resulting in dementia. There are a number of similarities between AD and T2D that have led to the belief that there is a relationship between these diseases. For example, some studies have shown that individuals with poorly-controlled T2D (i.e. higher levels of blood glucose) have a 2-to-3-fold increased risk of cognitive impairment that progresses to dementia, and a majority of those with AD have either T2D or elevated fasting blood glucose levels. Furthermore, one of the abnormal proteins that is deposited in the brains of individuals with AD, amyloid, has been found at unusually high levels in the pancreatic islets of those with T2D, although not in their brains. However, whether these correlative studies indicate a causal relationship between these diseases has not been demonstrated, nor has the relationship with elevated blood sugar levels.

There are also a number of distinctions between AD and T2D that decrease enthusiasm for the T3D hypothesis. Hence, disease-associated changes in neural activity and blood flow in different parts of the brain are not identical in those with AD as compared with T2D. Additionally, there are differences in some of the blood markers of the two diseases.

While the findings to date indicate that there may be some-sort of association between the two diseases, insight into an actual mechanism has also remained elusive. However, the available data does support the existence of one mechanism that is common to both AD and T2D, that being the presence of insulin resistance. Insulin is the main hormone that increases the uptake of glucose from the blood into tissues such as skeletal muscle. Hence, insulin resistance is associated with increased levels of blood glucose in T2D. However, the brain also uses glucose as an energy source, and insulin resistance in the brain may therefore contribute to decreased neural function in T2D. Furthermore, insulin resistance has been clearly demonstrated in the brains from individuals with AD, even in the absence of T2D. Most notably, one key brain region that was found to be affected was the hippocampus, which is required for memory consolidation and has also been directly implicated in the cognitive decline associated with AD.

One additional possible mechanism that may link AD to T2D relates to the increased progression to dementia seen in those with higher blood glucose levels. Again, while not understood at the molecular level, this relationship may help to explain pre-clinical (i.e. animal) studies suggesting that treatment of individuals with AD using glucagon-like peptide-1 receptor agonists (i.e. Ozempic) may slow or delay cognitive decline in association with their known effects to reduce blood glucose levels or, perhaps, neuroinflammation responses. However, of note, these findings have not been confirmed in the very few studies on humans with AD.

Although there are some similarities between AD and T2D, whether AD should be considered to be a novel form of diabetes, T3D, remains an unproven hypothesis. Notably, such hypotheses are incredibly difficult to prove, with confirmation requiring brain samples from affected individuals, while animal models of both diseases suffer from notable limitations. Furthermore, these hypotheses do not take into account the rare, but known genetic causes of these diseases. However, despite the names that are used, focusing on the prevention and treatment of both AD and T2D should remain a high priority, given their high global prevalence.


@PatriciaBrubaker

Patricia Brubaker, Ph.D., F.R.S.C., F.C.A.H.S. is a Professor Emerita, Departments of Physiology and Medicine and a Banting & Best Distinguished Scholar at the University of Toronto, Toronto, ON, Canada. Dr. Brubaker completed both her undergrad and PhD at 黑料不打烊 University.

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