DIABETES III: A CAUSE OF ALZHEIMER’S DISEASE

INTRODUCTION

Type III diabetes also known as hybrid or double diabetes is a new and dangerous phenomenon. It is found that type III Diabetes affects brain insulin levels, and appears to be one of the major causes of Alzheimer's disease . Insulin receptors in the brain are sensitive to particles known as ADDL's.

When someone has Alzheimer's there are accumulations of ADDL's which appear to be responsible for deteriorating synapses in the brain. ADDL's also cause disruption of the insulin receptors in the brain, which makes them insulin resistant.Scientists feel that this is a "brain-specific" form of diabetes. . It is confirmed by various new studies that insulin production in the brain declines as Alzheimer's disease advances resulting in cell death and tangles in the brain and abnormalities in insulin signaling. Brain levels of insulin and its related cellular receptors fall precipitously during the early stages of Alzheimer's. Insulin levels continue to drop progressively as the disease becomes more severe.

WHAT IS TYPE III DIABETES ? 

Type III diabetes may be described as the lowering newly discovered brain insulin than its normal levels, which appears to be associated with Alzheimer's disease in some way.  

WHAT IS ALZHEIMERS DISEASE ? 

Alzheimers disease is most likely a neuroendocrine disorder, or another type of diabetes or it can also be described as the commonest form of dementia.It is of unknown aetiology although genetic factors may be involved.There is progressive atrophy of the cerebral cortex accompanied by deteriorating mental functioning.Females are affected twice as often as males and it usually affects those over 60 years,the incidence increasing with age.Death usually occurs between 2 and 8 years after onset.    

RELATION BETWEEN TYPE III DIABETES AND ALZHEIMERS DISEASE 

Levels of insulin and of its receptors diminish significantly in the brain in early Alzheimer's, and continue to fall as the disease progresses Insulin disappears early and dramatically in Alzheimer's disease," many of the unexplained features of Alzheimer's, such as cell death and tangles in the brain, appear to be linked to abnormalities in insulin signalling. This demonstrates that the disease is most likely a neuroendocrine disorder, or another type of diabetes.“ Is alzheimer's really just type III diabetes? A lack of insulin may cause AD, but statins could keep it in check.. Low levels of acetylcholine a hallmark of Alzheimer's are directly linked to this loss of insulin and insulin-like growth factor function in the brain. This demonstrates that the disease is most likely a neuroendocrinal disorder. One task of insulin in the brain is to stimulate the expression of choline acetyltransferase (ChAT), the enzyme responsible for making acetylcholine, the researchers discovered. This provides them with a causal link between their own findings and acetylcholine deficiency, a known marker of Alzheimer's disease.  

ASSOSIATION TYPE III DIABETES AND CNS INSULIN RESISTANCE 

Recent studies have indicated an association between Alzheimer’s disease (AD) and central nervous system (CNS) insulin resistance. However, the cellular mechanisms underlying the link between these two pathologies have not been elucidated. Here we show that signal transduction by neuronal insulin receptors (IR) is strikingly sensitive to disruption by soluble A{beta} oligomers (also known as ADDLs). ADDLs are known to accumulate in AD brain and have recently been implicated as primary candidates for initiating deterioration of synapse function, composition, and structure. Using mature cultures of hippocampal neurons, a preferred model for studies of synaptic cell biology, we found that ADDLs caused a rapid and substantial loss of neuronal surface IRs specifically on dendrites bound by ADDLs. Removal of dendritic IRs was associated with increased receptor immunoreactivity in the cell body, indicating redistribution of the receptors. The neuronal response to insulin, measured by evoked IR tyrosine autophosphorylation, was greatly inhibited by ADDLs. Inhibition also was seen with added glutamate or potassium-induced depolarization. The effects on IR function were completely blocked by NMDA receptor antagonists, tetrodotoxin, and calcium chelator BAPTA-AM. Downstream from the IR, ADDLs induced a phosphorylation of Akt at serine473, a modification associated with neurodegenerative and insulin resistance diseases. These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses. Gestational Diabetes: Cause of type III diabetes Gestational Diabetes occurs during pregnancy. A combination of inadequate insulin secretion and responsiveness accounts for the major cause of Type 3 Diabetes. The insulin resistance happens mainly due to the secretion of additional hormones, namely progesterone, prolactin, estrogen, cortisol and human placental lactogen, in the placenta, which partially blocks the effect of insulin. Diabetes during pregnancy is transient. After the delivery gestational diabetes usually disappears.Though gestational diabetes is temporary, it can be dangerous to both mother and the fetus. Baby may be born with more than normal weight (Macrosomia). Mothers with Gestational diabetes have increased tendency of developing Type 2 Diabetes later in life.Around 2%-5% of pregnancies may have Gestational diabetes mellitus. Careful medical supervision during the pregnancy can wash out all the problems that may occur due to Type 3 Diabetes. Symptoms of Type Three Diabetes Generally gestational diabetes does not develop any symptoms though rarely the following may appear in the pregnant woman.Polyuria - Frequent urinationPolydipsia - Increased  ThirstPolyphagia - Increased AppetiteWeight loss in spite of increased appetiteFatigueNausea and vomitingFrequent infections including those of the bladder, vagina, and skinBlurred vision   

ROLE OF INSULIN IN TREATMENT OF DIABETES III; CAUSE OF ALZHEIMERS DISEASE

An emerging body of evidence suggests that an increased prevalence of insulin abnormalities and insulin resistance in Alzheimer's disease may contribute to the disease pathophysiology and clinical symptoms. It has long been known that insulin is essential for energy metabolism in the periphery. In the past 2 decades, convergent findings have begun to demonstrate that insulin also plays a role in energy metabolism and other aspects of CNS function. Investigators reported 20 years ago that insulin and insulin receptors were densely but selectively expressed in the brain, including the medial temporal regions that support the formation of memory. It has recently been demonstrated that insulin-sensitive glucose transporters are localised to the same regions supporting memory and that insulin plays a role in memory functions. Collectively, these findings suggest that insulin may contribute to normal cognitive functioning and that insulin abnormalities may exacerbate cognitive impairments, such as those associated with Alzheimer's disease. Insulin may also play a role in regulating the amyloid precursor protein and its derivative β-amyloid (Aβ), which is associated with senile plaques, a neuropathological hallmark of Alzheimer's disease. It has been proposed that insulin can accelerate the intracellular trafficking of Aβ and interfere with its degradation. These findings are consistent with the notion that insulin abnormalities may potentially influence levels of Aβ in the brains of patients with Alzheimer's disease. The increased occurrence of insulin resistance in Alzheimer's disease and the numerous mechanisms through which insulin may affect clinical and pathological aspects of the disease suggest that improving insulin effectiveness may have therapeutic benefit for patients with Alzheimer's disease. The thiazolidinedione rosiglitazone has been shown to have a potent insulin-sensitising action that appears to be mediated through the peroxisome proliferator-activated receptor-y (PPAR-γ). PPAR-y agonists, such as rosiglitazone, also have anti-inflammatory effects that may be of therapeutic benefit in patients with Alzheimer's disease. This review presents evidence suggesting that insulin resistance plays a role in the pathophysiology and clinical symptoms of Alzheimer's disease. Based on this evidence, we propose that treatment of insulin resistance may reduce the risk or retard the development of Alzheimer's disease.

Insulin Receptor Stops Progression Of Alzheimer's Disease: MECHANISM 

Stimulation of a receptor in the brain that controls insulin responses has been shown to halt or diminish the neurodegeneration of Alzheimer's disease, providing evidence that the disease can be treated in its early stages, according to a study.It has been found that peroxisome-proliferator activated receptor (PPAR) agonists prevent several components of neurodegeneration and preserve learning and memory in rats with induced Alzheimer's disease (AD). They found that an agonist for PPAR delta, a receptor that is abundant in the brain, had the most overall benefit.

"This raises the possibility that you can treat patients with mild cognitive impairment who have possible or probable Alzheimer's disease. This is really amazing because right now, there's just no treatment that works,".

Alzheimer's is a brain-specific neuroendocrine disorder, or a Type 3 diabetes, distinct from other types of diabetes. They showed that insulin and IGF-I receptors are produced separately in the brain, and begin to disappear early in Alzheimer's and continue to decline as the disease progresses. As insulin signaling breaks down, it leads to increased oxidative stress, impaired metabolism and cell death -- all causing neurodegeneration.

It was found that Alzheimer's in rats  can be replicated with Streptozotocin (STZ), a compound that is known to destroy insulin producing cells in the pancreas and cause diabetes. When injected into the brains of rats, the compound mimicked the neurodegeneration of Alzheimer's disease -- plaque deposits, neurofibrillary tangles, diminished brain size, impaired cognitive function, cell loss and overall brain deterioration.

Having created an animal model for Alzheimer's, researchers in this study induced Alzheimer's with STZ and then administered treatment with three classes of PPAR agonists -- alpha, gamma and delta. All are found in various tissues and organs in the body, including the brain, and PPAR gamma is already FDA approved as a treatment for Type 2 diabetes, or adult-onset diabetes. The two other classes of PPAR agonists have not yet been approved for clinical use.

Following treatment, many of the abnormalities associated with Alzheimer's were reduced or nearly disappeared. The agonists affected different regions of the brain, with PPAR delta producing the most striking effect in preserving the hypothalamus and temporal lobes, areas of the brain responsible for memory, learning, and behavior. In these brain regions, PPAR alpha and PPAR gamma were effective in reducing amyloid gene expression. PPAR delta had the most benefit for reducing oxidative stress and improving learning and memory.

"That was the most spectacular, because everybody wants something for cognitive impairment, and that was the most improved with the PPAR delta agonist."

Researchers were not able to stop the deterioration of insulin and its receptors. However, by administering PPAR, they were able to bypass the defects in insulin signaling and preserve the cells that need insulin to thrive. PPAR molecules go directly to the nucleus of cells and tell DNA to turn on or off genes that are normally regulated by insulin, thus preventing them from dying and allowing them to communicate with each other. The major effects of the PPAR treatments were to increase brain size, preserve insulin and IGF-II receptor bearing neurons, and preserve learning and memory.

"The trigger for dementia is the loss of insulin and IGF producing cells. The cells that need those growth factors subsequently die. This study shows you can block the second phase, which is responsible for dementia. This is great news for patients since you treat early stages of disease,".

Another promising result for Alzheimer's patients is that these drugs could be given in the form of a pill,. In the study, the drugs were injected to control the amounts administered.

"One of the most exciting findings was that peripheral (intraperitoneal) injection of the PPAR agonists either partially or completely rescued the brains from neurodegeneration,".

Alzheimer's appears to be caused by parallel abnormalities -- impaired insulin signaling and oxidative stress, which is regulated by the genes NOS and NOX. The PPAR agonists treatments target both problems. They preserve the cells regulated by insulin and IGF, and they decrease oxidative stress, resulting in fewer lesions in the brain.

"If the diagnosis is suspected or patients are in the early phases of AD, there's a good possibility they could get treatment that will help them. It's possible that in the moderate phase, treatment will also help, but more work needs to be done to show that,".

Treatment is not likely to work in the late stages of the disease, because the cells have already died.

 Picture caption: ADDLs (green dots), which bind to specific nerve cells, induce a striking loss of insulin receptors (red dots) from the surface of these cells. Neurons with bound ADDLs show a virtual absence of insulin receptors. Reciprocally, neurons with no ADDL binding show abundant insulin receptors.  ROLE OF APOE4 GENE: 

The study also found the association between diabetes and risk of Alzheimer's disease was strongest in people who did not have the APOE4 gene, which is known to increase the risk of Alzheimer's disease.This shows that insulin problems are an important risk factor for Alzheimer's disease when the high risk gene is missing.

All patients in the present study underwent APO-E genotyping. The APO-E gene has three allelic variants and five common genotypes. Of these, the APO-E4 allele has been associated with an increased risk for Alzheimer's disease. The type 2 allele appears to provide substantial protection against Alzheimer's disease. Another genetic abnormality, a mutation on the amyloid precursor protein gene on chromosome 21, has been linked to a more rare form of early onset Alzheimer's disease.

ADDLS:IN ALZHEIMERS DISEASE: 

 It has been discovered  brain insulin signaling -- crucial for memory formation -- would stop working in Alzheimer’s disease.A toxic protein found in the brains of individuals with Alzheimer’s removes insulin receptors from nerve cells, rendering those neurons insulin resistant. (The protein, known to attack memory-forming synapses, is called an ADDL for “amyloid ß-derived diffusible ligand.”)

 The levels of brain insulin and its related receptors are lower in individuals with Alzheimer’s disease, the recent study sheds light on the emerging idea of Alzheimer’s being a “type 3” diabetes.

Many of the existing drugs now used to treat diabetic patients may protect neurons from ADDLs and improve insulin signaling in individuals with Alzheimer’s.

In the brain, insulin and insulin receptors are vital to learning and memory. When insulin binds to a receptor at a synapse, it turns on a mechanism necessary for nerve cells to survive and memories to form.Alzheimer’s disease may in part be caused by insulin resistance in the brain .

“We found the binding of ADDLs to synapses somehow prevents insulin receptors from accumulating at the synapses where they are needed,instead, they are piling up where they are made, in the cell body, near the nucleus. Insulin cannot reach receptors there. This finding is the first molecular evidence as to why nerve cells should become insulin resistant in Alzheimer’s disease.”

ADDLS are small, soluble aggregated proteins. The clinical data strongly support a theory in which ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function by a process predicted to be reversible.

It was found that ADDLs bind very specifically at synapses, initiating deterioration of synapse function and causing changes in synapse composition and shape. It has been shown that the molecules that make memories at synapses -- insulin receptors -- are being removed by ADDLs from the surface membrane of nerve cells.

OVER ACTIVITY OF ENZYME GSK3beta: 

In the present study,behavioral and memory testing, high-tech imaging, as well as a variety of biochemical tests are used to study metabolic processes within the brains of NIRKO mice and compare them with those of normal mice. Compared with normal mice, NIRKO mice had markedly reduced activity of insulin signaling proteins in the brain. This was found to lead to overactivity of an enzyme called GSK3 beta, which in turn, led to excessive phosphorylation (or hyperphosphorylation) of a protein called tau. Hyperphosphorylation of tau is a hallmark of brain lesions seen in Alzheimer's disease and has been suggested to be an early marker of this disease. On the other hand, the NIRKO mice showed no changes in the proliferation or survival of neurons, memory, or basal brain glucose metabolism, suggesting that insulin resistance may interact with other risk factors to promote full-blown Alzheimer's disease.

DIAGNOSIS OF ALZHEIMERS DISEASE:    DRUGS  USED IN TREATMENT OF TYPE III DIABETES: 

1.     Namenda

2.     Rosiglitazone    

 

CONCLUSION

It is found that type III Diabetes affects brain insulin levels, and appears to be one of the major causes of Alzheimer's disease. Type III diabetes may be described as the lowering newly discovered braininsulin than its normal levels, which appears to be associated with Alzheimer's disease in some way. It is confirmed by various new studies that insulin production in the brain declines as Alzheimer's disease advances resulting in cell death and tangles in the brain and abnormalities in insulin signaling. Brain levels of insulin and its related cellular receptors fall precipitously during the early stages of Alzheimer's. Insulin levels continue to drop progressively as the disease becomes more severe. Low levels of acetylcholine a hallmark of Alzheimer's are directly linked to this loss of insulin and insulin-like growth factor function in the brain. This demonstrates that the disease is most likely a neuroendocrinal disorder. Persons with Alzheimer disease shows the accumulations of ADDL's which appear to be responsible for deteriorating synapses in the brain. ADDL's also causes disruption of the insulin receptors in the brain, which makes them insulin resistant. Thus it can be describe as a "brain-specific" form of diabetes.    

ANSHUL MISHRA*ADINA INSTITUTE OF PHARMACEUTICAL SCIENCES SAGAR (M.P.)

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