Corinne G. Jolivalt

Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin.

We have evaluated the effect of peripheral insulin deficiency on brain insulin pathway activity in a mouse model of type 1 diabetes, the parallels with Alzheimers disease (AD), and the effect of treatment with insulin. Nine weeks of insulin‐deficient diabetes significantly impaired the learning capacity of mice, significantly reduced insulin‐degrading enzyme protein expression, and significantly reduced phosphorylation of the insulin‐receptor and AKT. Phosphorylation of glycogen synthase kinase‐3 (GSK3) was also significantly decreased, indicating increased GSK3 activity. This evidence of reduced insulin signaling was associated with a concomitant increase in tau phosphorylation and amyloid β protein levels. Changes in phosphorylation levels of insulin receptor, GSK3, and tau were not observed in the brain of db/db mice, a model of type 2 diabetes, after a similar duration (8 weeks) of diabetes. Treatment with insulin from onset of diabetes partially restored the phosphorylation of insulin receptor and of GSK3, partially reduced the level of phosphorylated tau in the brain, and partially improved learning ability in insulin‐deficient diabetic mice. Our data indicate that mice with systemic insulin deficiency display evidence of reduced insulin signaling pathway activity in the brain that is associated with biochemical and behavioral features of AD and that it can be corrected by insulin treatment.

Type-1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice

A number of studies suggest an association between Alzheimers disease (AD) and diabetes: AD patients show impaired insulin function, whereas cognitive deficits and increased risk of developing AD occur in diabetic patients. The reasons for the increased risk are not known. Recent studies of disturbances in the insulin-signaling pathway have revealed new perspectives on the links between AD and Type 1 diabetes with a particular focus on glycogen synthase-kinase-3 (GSK3). We have therefore characterized a mouse model of combined insulin-deficient diabetes and AD and find that diabetes exaggerated defects in the brain of APP transgenic mice. Mice with combined APP overexpression and diabetes showed a decreased insulin receptor activity and an increased GSK3beta activity. Concomitantly, tau phosphorylation and number of Abeta plaques, the two pathologic hallmarks of AD, were increased in the brain of diabetic-APP transgenic mice. Our results indicate that the pathologic features of AD are exaggerated in the brain of APP transgenic mice that have concurrent insulin-deficient diabetes, and underscore a possible mechanism of brain dysfunction common to AD and diabetes.

Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters

Abstract Diabetic rats show behavioral indices of painful neuropathy that may model the human condition. Hyperalgesia during the formalin test in diabetic rats is accompanied by the apparently paradoxical decrease in spinal release of excitatory neurotransmitters and increase in the inhibitory neurotransmitter GABA. Decreased expression of the potassium‐chloride co‐transporter, KCC2, in the spinal cord promotes excitatory properties of GABA. We therefore measured spinal KCC2 expression and explored the role of the GABAA receptor in rats with painful diabetic neuropathy. KCC2 protein levels were significantly reduced in the spinal cord of diabetic rats, while levels of NKCC1 and the GABAA receptor were unchanged. Spinal delivery of the GABAA receptor antagonist bicuculline reduced formalin‐evoked flinching in diabetic rats and also dose‐dependently alleviated tactile allodynia. GABAA receptor‐mediated rate‐dependent depression of the spinal H reflex was absent in the spinal cord of diabetic rats. Control rats treated with the KCC2 blocker DIOA, mimicked diabetes by showing increased formalin‐evoked flinching and diminished rate‐ dependent depression. The ability of bicuculline to alleviate allodynia and formalin‐evoked hyperalgesia in diabetic rats is consistent with a reversal of the properties of GABA predicted by reduced spinal KCC2 and suggests that reduced KCC2 expression and increased GABA release contribute to spinally mediated hyperalgesia in diabetes.

Mitochondrial respiratory chain dysfunction in dorsal root ganglia of streptozotocin-induced diabetic rats and its correction by insulin treatment.

OBJECTIVE Impairments in mitochondrial physiology may play a role in diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in sensory neurons is due to abnormal mitochondrial respiratory function. RESEARCH DESIGN AND METHODS Rates of oxygen consumption were measured in mitochondria from dorsal root ganglia (DRG) of 12- to- 22-week streptozotocin (STZ)-induced diabetic rats, diabetic rats treated with insulin, and age-matched controls. Activities and expression of components of mitochondrial complexes and reactive oxygen species (ROS) were analyzed. RESULTS Rates of coupled respiration with pyruvate + malate (P + M) and with ascorbate + TMPD (Asc + TMPD) in DRG were unchanged after 12 weeks of diabetes. By 22 weeks of diabetes, respiration with P + M was significantly decreased by 31–44% and with Asc + TMPD by 29–39% compared with control. Attenuated mitochondrial respiratory activity of STZ-diabetic rats was significantly improved by insulin that did not correct other indices of diabetes. Activities of mitochondrial complexes I and IV and the Krebs cycle enzyme, citrate synthase, were decreased in mitochondria from DRG of 22-week STZ-diabetic rats compared with control. ROS levels in perikarya of DRG neurons were not altered by diabetes, but ROS generation from mitochondria treated with antimycin A was diminished compared with control. Reduced mitochondrial respiratory function was associated with downregulation of expression of mitochondrial proteins. CONCLUSIONS Mitochondrial dysfunction in sensory neurons from type 1 diabetic rats is associated with impaired rates of respiratory activity and occurs without a significant rise in perikaryal ROS.

Growth Factors as Therapeutics for Diabetic Neuropathy

There has been a rapid growth in appreciation of the diverse array of neurotrophic factors, growth factors and other biological molecules that have the capacity to support adult neurons and direct reparative processes after injury to the nervous system. Understanding the mechanisms by which these factors operate offers the opportunity to use either the factors themselves or other agents that manipulate relevant signal transduction pathways as therapeutics for a wide range of neurodegenerative diseases, including diabetic neuropathy. In this review, we aim to summarize current knowledge of the extent to which loss of neurotrophic support contributes to the pathogenesis of diabetic neuropathy, present pre-clinical evidence that supports the potential efficacy of growth factors or their mimetics against indices of diabetic neuropathy and highlight the emerging approaches to manipulating neuronal support mechanisms that show potential for translation to clinical use. Recent advances in directly assessing the progression of nerve damage in diabetic patients will hopefully facilitate renewed clinical evaluation of treatments for degenerative diabetic neuropathy and provide the framework for advancing the potential of growth factors as a therapy for this widespread and currently untreatable condition.

GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice.

Aim: Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that induces glucose‐dependent insulin secretion and may have neurotrophic properties. Our aim was to identify the presence and activity of GLP‐1 receptors (GLP‐1Rs) in peripheral nerve and to assess the impact of GLP‐1R agonists on diabetes‐induced nerve disorders.

B vitamins alleviate indices of neuropathic pain in diabetic rats.

There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

FOOD FOR THOUGHT: THE ROLE OF APPETITIVE PEPTIDES IN AGE-RELATED COGNITIVE DECLINE

Through their well described actions in the hypothalamus, appetitive peptides such as insulin, orexin and leptin are recognized as important regulators of food intake, body weight and body composition. Beyond these metabolic activities, these peptides also are critically involved in a wide variety of activities ranging from modulation of immune and neuroendocrine function to addictive behaviors and reproduction. The neurological activities of insulin, orexin and leptin also include facilitation of hippocampal synaptic plasticity and enhancement of cognitive performance. While patients with metabolic disorders such as obesity and diabetes have greater risk of developing cognitive deficits, dementia and Alzheimers disease (AD), the underlying mechanisms that are responsible for, or contribute to, age-related cognitive decline are poorly understood. In view of the importance of these peptides in metabolic disorders, it is not surprising that there is a greater focus on their potential role in cognitive deficits associated with aging. The goal of this review is to describe the evidence from clinical and pre-clinical studies implicating insulin, orexin and leptin in the etiology and progression of age-related cognitive decline. Collectively, these studies support the hypothesis that leptin and insulin resistance, concepts normally associated with the hypothalamus, are also applicable to the hippocampus.

Diabetes exacerbates amyloid and neurovascular pathology in aging-accelerated mice.

Mounting evidence supports a link between diabetes, cognitive dysfunction, and aging. However, the physiological mechanisms by which diabetes impacts brain function and cognition are not fully understood. To determine how diabetes contributes to cognitive dysfunction and age‐associated pathology, we used streptozotocin to induce type 1 diabetes (T1D) in senescence‐accelerated prone 8 (SAMP8) and senescence‐resistant 1 (SAMR1) mice. Contextual fear conditioning demonstrated that T1D resulted in the development of cognitive deficits in SAMR1 mice similar to those seen in age‐matched, nondiabetic SAMP8 mice. No further cognitive deficits were observed when the SAMP8 mice were made diabetic. T1D dramatically increased Aβ and glial fibrillary acidic protein immunoreactivity in the hippocampus of SAMP8 mice and to a lesser extent in age‐matched SAMR1 mice. Further analysis revealed aggregated Aβ within astrocyte processes surrounding vessels. Western blot analyses from T1D SAMP8 mice showed elevated amyloid precursor protein processing and protein glycation along with increased inflammation. T1D elevated tau phosphorylation in the SAMR1 mice but did not further increase it in the SAMP8 mice where it was already significantly higher. These data suggest that aberrant glucose metabolism potentiates the aging phenotype in old mice and contributes to early stage central nervous system pathology in younger animals.

Glycogen synthase kinase‐3 inhibition prevents learning deficits in diabetic mice

There is an increasing awareness that diabetes has an impact on the central nervous system, with reports of impaired learning, memory, and mental flexibility being more common in diabetic subjects than in the general population. Insulin‐deficient diabetic mice also display learning deficits associated with defective insulin‐signaling in the brain and increased activity of GSK3. In the present study, AR‐A014418, a GSK3β inhibitor, and TX14(A), a neurotrophic factor with GSK3 inhibitory properties, were tested against the development of learning deficits in mice with insulin‐deficient diabetes. Treatments were started at onset of diabetes and continued for 10 weeks. Treatment with AR‐A014418 or TX14(A) prevented the development of learning deficits, assessed by the Barnes maze, but only AR‐A014418 prevented memory deficits, as assessed by the object recognition test. Diabetes‐induced increased levels of amyloid β protein and phosphorylated tau were not significantly affected by the treatments. However, the diabetes‐induced decrease in synaptophysin, a presynaptic protein marker of hippocampal plasticity, was partially prevented by both treatments. These results suggest a role for GSK3 and/or reduced neurotrophic support in the development of cognitive deficits in diabetic mice that are associated with synaptic damage.