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Insulin Effects Weigh Heavy on the Brain

Insulin Effects Weigh Heavy on the Brain Boston—Known best for its role in the body as a regulator of blood glucose levels and fatty acid storage, insulin also acts in the brain to aid memory and thinking. Thus, when insulin regulation is disrupted, as it is in many common medical conditions including obesity and diabetes, the risk for cognitive impairment rises. Insulin dysregulation sets the stage for certain neurodegenerative disorders, particularly Alzheimer disease (AD), said Suzanne Craft, PhD, professor of psychiatry, University of Washington, Seattle. Craft and colleagues have been studying the link between insulin and memory for the past decade, and their research is suggesting potential approaches to treat, delay, or even prevent AD. She recently presented some of their findings at the annual meeting of the Endocrine Society. Insulin acts in certain areas of the brain to enhance memory and cognition. (Photo credit: Molecule source: PDB ID 1ZNJ) In normal physiology—and also when insulin is administered peripherally at optimal doses—insulin can enhance memory, noted Craft. But when insulin levels are poorly controlled, as is the case in millions of older adults with type 2 diabetes who have insulin resistance accompanied by persistently high levels of insulin, problems in the brain can ensue. For example, in a study of 16 healthy individuals, Craft's team found evidence that hyperinsulinemia is associated with inflammation in the brain and also triggers an accumulation of the 42-peptide form of β-amyloid, the precursor of amyloid plaques that are found in certain brain regions and are a hallmark of AD (Fishel MA et al. Arch Neurol. 2005;62:1539-1544). Evidence implicating insulin resistance, type 2 diabetes, and inflammation as risk factors for AD has been building for some time. The hormone appears to boost β-amyloid levels by competing with the peptide for insulin-degrading enzyme, which degrades and clears both insulin and β-amyloid. But insulin-degrading enzyme seems to prefer insulin to β-amyloid, so when high levels of insulin are present, β-amyloid peptides aggregate into plaques. Increases in β-amyloid are known to raise the risk of neurodegenerative disease and impair memory. Craft hypothesizes that treating insulin resistance might improve memory and even avert cognitive decline in people with mild cognitive impairment. To this end, her team has been investigating insulin-sensitizing agents called PPAR-gama agonists that lower insulin levels in the body and have potent anti-inflammatory effects. She described unpublished preliminary findings from a randomized, placebo-controlled trial which compares the effects of the PPAR-gama agonist pioglitazone with nateglinide, a drug from a different class of antidiabetic agents. Both drugs produce comparable levels of hyperglycemic therapy, noted Craft, but they work through two different mechanisms—nateglinide increases insulin levels, whereas pioglitazone reduces them. In the study, 71 adults older than 55 years who were newly diagnosed as having impaired glucose tolerance or type 2 diabetes were randomized to receive pioglitazone, nateglinide, or placebo for 4 months. All participants underwent cognitive testing at baseline, 2 months, and 4 months; 21 patients with insulin resistance and 9 healthy controls also had positron emission tomography (PET) scans at the beginning and end of the study. Performance on memory tasks improved in participants who received pioglitazone but not in those who took nateglinide or placebo. The degree of improvement with pioglitazone was proportional to patients' metabolic responses to treatment (measured by a 2-hour oral glucose tolerance test); the higher the response to treatment, the more improvement in memory. Craft said that a resting PET scan revealed significant differences between those with insulin resistance compared with controls. Those with insulin resistance showed a reduction in glucose metabolism in areas known to be affected in the earliest stages of AD—the left temporal cortex and the right parietal region—as well as in an unanticipated area of hypometabolism, the frontal cortex. Controls who performed a word memory task while in the PET scanner showed increased glucose metabolism in the frontal cortex. Participants with increased glucose tolerance showed diminished activity in glucose metabolism; those with frank diabetes showed an even greater reduction in activity in that area, said Craft. In other unpublished work, Craft's team has been studying the effects of intranasal insulin, which has been demonstrated to produce a quick boost in memory in healthy adults who receive insulin through this route (Benedict C et al. Neuropsychopharmacology. doi:10.1038/sj.npp.1301193 [published online ahead of print August 16, 2006]. (The advantage of delivering insulin intranasally rather than intravenously is that it avoids causing undesirable systemic adverse effects such as hypoglycemia.) In a small trial, 46 older adults with memory impairment and 22 healthy controls received either a nasal dose of saline or nothing or one of 4 different insulin doses; all participants underwent cognitive testing before and after the intervention. While all individuals who received insulin showed improved performance when retested 15 minutes after receiving the hormone, its effects on memory in those with memory impairment were “dramatic,” said Craft. Further investigation is under way to better understand the links between insulin and cognition as well as to examine whether the potential treatment methods arising from the research are effective for AD or age-related memory impairment. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Insulin Effects Weigh Heavy on the Brain

Friedrich, M. J.
JAMA , Volume 296 (14) – Oct 11, 2006
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Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.296.14.1717
Publisher site
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Abstract

Boston—Known best for its role in the body as a regulator of blood glucose levels and fatty acid storage, insulin also acts in the brain to aid memory and thinking. Thus, when insulin regulation is disrupted, as it is in many common medical conditions including obesity and diabetes, the risk for cognitive impairment rises. Insulin dysregulation sets the stage for certain neurodegenerative disorders, particularly Alzheimer disease (AD), said Suzanne Craft, PhD, professor of psychiatry, University of Washington, Seattle. Craft and colleagues have been studying the link between insulin and memory for the past decade, and their research is suggesting potential approaches to treat, delay, or even prevent AD. She recently presented some of their findings at the annual meeting of the Endocrine Society. Insulin acts in certain areas of the brain to enhance memory and cognition. (Photo credit: Molecule source: PDB ID 1ZNJ) In normal physiology—and also when insulin is administered peripherally at optimal doses—insulin can enhance memory, noted Craft. But when insulin levels are poorly controlled, as is the case in millions of older adults with type 2 diabetes who have insulin resistance accompanied by persistently high levels of insulin, problems in the brain can ensue. For example, in a study of 16 healthy individuals, Craft's team found evidence that hyperinsulinemia is associated with inflammation in the brain and also triggers an accumulation of the 42-peptide form of β-amyloid, the precursor of amyloid plaques that are found in certain brain regions and are a hallmark of AD (Fishel MA et al. Arch Neurol. 2005;62:1539-1544). Evidence implicating insulin resistance, type 2 diabetes, and inflammation as risk factors for AD has been building for some time. The hormone appears to boost β-amyloid levels by competing with the peptide for insulin-degrading enzyme, which degrades and clears both insulin and β-amyloid. But insulin-degrading enzyme seems to prefer insulin to β-amyloid, so when high levels of insulin are present, β-amyloid peptides aggregate into plaques. Increases in β-amyloid are known to raise the risk of neurodegenerative disease and impair memory. Craft hypothesizes that treating insulin resistance might improve memory and even avert cognitive decline in people with mild cognitive impairment. To this end, her team has been investigating insulin-sensitizing agents called PPAR-gama agonists that lower insulin levels in the body and have potent anti-inflammatory effects. She described unpublished preliminary findings from a randomized, placebo-controlled trial which compares the effects of the PPAR-gama agonist pioglitazone with nateglinide, a drug from a different class of antidiabetic agents. Both drugs produce comparable levels of hyperglycemic therapy, noted Craft, but they work through two different mechanisms—nateglinide increases insulin levels, whereas pioglitazone reduces them. In the study, 71 adults older than 55 years who were newly diagnosed as having impaired glucose tolerance or type 2 diabetes were randomized to receive pioglitazone, nateglinide, or placebo for 4 months. All participants underwent cognitive testing at baseline, 2 months, and 4 months; 21 patients with insulin resistance and 9 healthy controls also had positron emission tomography (PET) scans at the beginning and end of the study. Performance on memory tasks improved in participants who received pioglitazone but not in those who took nateglinide or placebo. The degree of improvement with pioglitazone was proportional to patients' metabolic responses to treatment (measured by a 2-hour oral glucose tolerance test); the higher the response to treatment, the more improvement in memory. Craft said that a resting PET scan revealed significant differences between those with insulin resistance compared with controls. Those with insulin resistance showed a reduction in glucose metabolism in areas known to be affected in the earliest stages of AD—the left temporal cortex and the right parietal region—as well as in an unanticipated area of hypometabolism, the frontal cortex. Controls who performed a word memory task while in the PET scanner showed increased glucose metabolism in the frontal cortex. Participants with increased glucose tolerance showed diminished activity in glucose metabolism; those with frank diabetes showed an even greater reduction in activity in that area, said Craft. In other unpublished work, Craft's team has been studying the effects of intranasal insulin, which has been demonstrated to produce a quick boost in memory in healthy adults who receive insulin through this route (Benedict C et al. Neuropsychopharmacology. doi:10.1038/sj.npp.1301193 [published online ahead of print August 16, 2006]. (The advantage of delivering insulin intranasally rather than intravenously is that it avoids causing undesirable systemic adverse effects such as hypoglycemia.) In a small trial, 46 older adults with memory impairment and 22 healthy controls received either a nasal dose of saline or nothing or one of 4 different insulin doses; all participants underwent cognitive testing before and after the intervention. While all individuals who received insulin showed improved performance when retested 15 minutes after receiving the hormone, its effects on memory in those with memory impairment were “dramatic,” said Craft. Further investigation is under way to better understand the links between insulin and cognition as well as to examine whether the potential treatment methods arising from the research are effective for AD or age-related memory impairment.

Journal

JAMA – American Medical Association

Published: Oct 11, 2006

Keywords: brain,insulin

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