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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identification of genes and pathways that alter lifespan has allowed for new insights into factors that control the aging process as well as disease. While strong molecular links exist between aging and metabolism, we hypothesize that targeting the mechanisms involved in aging will also give rise to therapeutics that treat other devastating age-related diseases, such as neurodegeneration, cancer, inflammation and cardiovascular disease. Insulin sensitivity, glycemic control and adiposity are not only hallmarks of the major metabolic diseases, type 2 diabetes and obesity, but they also represent significant risk factors for the development of Alzheimer's Disease and cognitive impairment. Insulin/IGF-1 signaling is an important pathway regulating aging and disease in a variety of species, including mammals. Here we describe an important role for the gut-derived peptide ghrelin in upstream signaling through the insulin/IGF-1 pathway and exemplify modulation of ghrelin signaling as an approach to mechanistic treatment of multiple age-related diseases by virtue of its ability to regulate key metabolic functions.
Curr Alzheimer Res 2007 Apr
PMID:Insulin resistance, glycemic control and adiposity: key determinants of healthy lifespan. 1743 Feb 40

In mammals, glucocorticoid actions appear to have evolved to maintain and enhance energy stores to be used for life-saving gluconeogenesis. They act on the brain to stimulate search behaviors, palatable feeding and emotionally relevant memories, and they act on the body to mobilize stored peripheral energy and direct it to central depots that serve the substrate needs of the liver. Our work in rats shows that searching and intake of palatable foods (sucrose, saccharin and lard) are stimulated by corticosterone in a dose-related fashion. Adrenalectomized rats gain weight poorly, have low fat content, increased sympathetic neural and hypothalamo-pituitary-adrenal outflow, and altered behaviors. Replacement with corticosterone reverses these effects. Surprisingly, when such rats are provided with 30% sucrose to drink, in addition to saline, all of the usual effects of adrenalectomy are corrected without corticosterone. We hypothesize that there is a metabolic feedback system that decreases stress-responsiveness. Although we have not yet identified the signal associated with sucrose drinking, the weight of mesenteric fat correlates inversely with hypothalamic corticotropin-releasing factor (CRF). When rats eat lard and sucrose ad libitum, fat stores increase and CRF, ACTH and corticosterone responses are reduced. During stress, chow intake decreases but intake of lard and sucrose does not. Our current working model suggests that palatability signals and neural signals from fat stores act on brain to reduce activity in the central stress response system. Correlative results from a clinical study support the powerful role of small changes in glucocorticoids in type 2 diabetes.
Curr Alzheimer Res 2007 Apr
PMID:Glucocorticoids, the etiology of obesity and the metabolic syndrome. 1743 Feb 47

Epidemiological evidence supports the existence of a possible link between type II diabetes mellitus (T2DM) and late-onset Alzheimer's disease (LOAD). Polymorphisms from candidate genes for T2DM were genotyped in a two-stage approach to identify novel risk factors for LOAD. One hundred fifty-two polymorphisms were initially genotyped in a case:control cohort: nine SNPs showed individual association with disease status under at least one genetic model, while an additional two SNPs showed a haplotype association. In a replication study, we confirmed significant association of SNPs within three genes--PPARgamma, SOS2, and PCK1--with Alzheimer's disease. In particular, our data suggest that the effect of variants within these genes might be influenced by gender.
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PMID:Candidate gene association study of insulin signaling genes and Alzheimer's disease: evidence for SOS2, PCK1, and PPARgamma as susceptibility loci. 1744 Sep 48

It has been known for some time that diabetes may be associated with impaired cognitive function. During the last decade, epidemiological data have emerged suggesting a linkage between diabetes, particularly type 2 diabetes, and Alzheimer's disease (AD). There is evidence to suggest that impaired activities of neurotrophic factors such as insulin, IGF-1 and NGF, which occur in both diabetes and AD, may provide a mechanistic link between the two disorders. An additional probable factor that has been less evaluated to date is hypercholesterolemia, a common accompaniment to type 2 diabetes. Increased cholesterol availability is believed to play a crucial role in the abnormal metabolism of amyloid precursor protein leading to accumulation of amyloid-beta. Impaired insulin signaling in particular appears to be involved in hyperphosphorylation of the tau protein, which constitutes neurofibrillary tangles in AD. The linkage between abnormal amyloid metabolism and phosphor-tau is likely to be provided by the activation of caspases both by increased amyloid-beta and by impaired insulin signaling. Although the details of many of these components still await evaluation, it appears clear that commonalities exist in the underlying pathogenesis of diabetes and Alzheimer's disease. In this review we provide a brief update on linkages between these two diverse but common disorders.
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PMID:Diabetes and Alzheimer's disease - is there a connection? 1748 40

Recent evidence suggests that the molecular defects associated with the development of diabetes also contribute to an increased risk of all types of dementia, including Alzheimer's disease, vascular dementia and Pick's disease. Indeed, the presence of type II diabetes mellitus results in a two to three fold higher risk of developing dementia [Fontbonne et al., 2001. Changes in cognitive abilities over a 4-year period are unfavourably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care 24, 366-370; Gregg et al., 2000. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Archives of Internal Medicine 160, 174-180; Peila et al., 2002. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256-1262]. There are currently 250 million people worldwide (>2 million in the UK) diagnosed with diabetes, and this number is predicted to double within the next 20 years, therefore the associated risk translates into a potential explosion in the appearance of dementia in the population. This review primarily focuses on the proposed molecular links between insulin action, Diabetes and Alzheimer's disease, while discussing the potential for therapeutic intervention to alleviate these disorders. In particular, we will review the regulation of glycogen synthase kinase-3 (GSK-3) and its neuronal substrates.
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PMID:Molecular connexions between dementia and diabetes. 1754 31

We examined the relation of type 2 diabetes mellitus to parkinsonian signs in older persons. Participants were 1030 women and men (mean age 80.3 y, education 14.5 y, Mini-Mental State Examination 27.9) without dementia or Parkinson disease, enrolled in the Rush Memory and Aging Project, an epidemiologic study of aging. We used separate linear and logistic regression models, adjusted for age, sex, and education, to examine the relation of diabetes, identified by history and medication inspection, to each of the scores of global parkinsonian signs and 4 separate parkinsonian signs. Diabetes was present in 140 (14%) participants. Most participants had mild parkinsonian signs. Diabetes was associated with a more severe global parkinsonian signs score (beta=0.20, SE=0.10, P=0.05) and postural reflex impairment-gait disturbance (beta=0.40, SE=0.17, P=0.02), but not with bradykinesia, rigidity, or tremor. Associations were no longer significant after controlling for vascular risk factors or conditions, particularly body mass index and congestive heart failure. Overall, there was no evidence that vascular variables modified the relation of diabetes to parkinsonian signs. In summary, we found that diabetes was associated with parkinsonian signs, especially postural reflex impairment-gait disturbance, and that vascular factors may play a role in this association.
Alzheimer Dis Assoc Disord
PMID:Diabetes and parkinsonian signs in older persons. 1754 40

Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and lipid peroxides are elevated and concentrations of endothelial nitric oxide (eNO) decreased in type 2 diabetes mellitus and Alzheimer's disease. This suggests that both these diseases are low-grade systemic inflammatory conditions and are closely associated with each other. Recent studies revealed that plasma and tissue concentrations of enzymes butyrylcholinesterase and acetylcholinesterase are elevated in type 2 diabetes and Alzheimer's disease. Acetylcholine has anti-inflammatory actions. Hence, elevated butyrylcholinesterase and acetylcholinesterase concentrations will lead to a decrease in the levels of acetylcholine that could trigger the onset of low-grade systemic inflammation seen in type 2 diabetes and Alzheimer's disease. In view of this, we propose that butyrylcholinesterase and acetylcholinesterase will not only serve as therapeutic targets but also may serve as markers to predict the development of type 2 diabetes mellitus and Alzheimer's disease.
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PMID:Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer's disease. 1755 29

Glucagon-like peptide-1 (GLP-1) has been endorsed as a promising and attractive agent in the treatment of type 2 diabetes mellitus (T2DM). Both Alzheimer's disease (AD) and T2DM share some common pathophysiologic hallmarks, such as amyloid beta (Abeta), phosphoralation of tau protein, and glycogen synthase kinase-3. GLP-1 possesses neurotropic properties and can reduce amyloid protein levels in the brain. Based on extensive studies during the past decades, the understanding on AD leads us to believe that the primary targets in AD are the Abeta and tau protein. Combine these findings, GLP-1 is probably a promising agent in the therapy of AD. This review was focused on the biochemistry and physiology of GLP-1, communities between T2DM and AD, new progresses of GLP-1 in treating T2MD and improving some pathologic hallmarks of AD.
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PMID:Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer's disease? 1759 27

Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged > or = 60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy.
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PMID:The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods. 1759 21

The hepatic clearance of amyloid beta-peptide (1-40) [Abeta(1-40)] from plasma, which is largely mediated by low-density lipoprotein receptor-related protein (LRP-1), is suggested to play a role in preventing Abeta(1-40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral Abeta deposition in insulin-resistant type II diabetes mellitus. The purpose of this study was to clarify the effect of insulin on the hepatic clearance of Abeta(1-40). LRP-1 expression on the hepatic plasma membrane was increased in a time-dependent manner by portal infusion of insulin and was 2.2-fold greater than that in nontreated controls after a 10-min infusion, whereas the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [(125)I]Abeta(1-40) was also induced by insulin in a time-dependent manner. The increase in [(125)I]Abeta(1-40) uptake by insulin was concentration-dependent (EC(50) = 230 pM) and was completely abolished by receptor-associated protein (2 muM), an LRP-1 inhibitor. In conclusion, plasma insulin facilitates LRP-1 translocation to the hepatic plasma membrane from the intracellular pool, resulting in significant enhancement of hepatic Abeta(1-40) uptake from the circulating blood. The presently proposed mechanism would explain the epidemiological results demonstrating that type II diabetes mellitus is a risk factor of Alzheimer's disease.
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PMID:Insulin facilitates the hepatic clearance of plasma amyloid beta-peptide (1 40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes. 1760 17


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