Jill K. Morris

Insulin resistance impairs nigrostriatal dopamine function

Clinical studies have indicated a link between Parkinsons disease (PD) and Type 2 Diabetes. Although preclinical studies have examined the effect of high-fat feeding on dopamine function in brain reward pathways, the effect of diet on neurotransmission in the nigrostriatal pathway, which is affected in PD and parkinsonism, is less clear. We hypothesized that a high-fat diet, which models early-stage Type 2 Diabetes, would disrupt nigrostriatal dopamine function in young adult Fischer 344 rats. Rats were fed a high fat diet (60% calories from fat) or a normal chow diet for 12 weeks. High fat-fed animals were insulin resistant compared to chow-fed controls. Potassium-evoked dopamine release and dopamine clearance were measured in the striatum using in vivo electrochemistry. Dopamine release was attenuated and dopamine clearance was diminished in the high-fat diet group compared to chow-fed rats. Magnetic resonance imaging indicated increased iron deposition in the substantia nigra of the high fat group. This finding was supported by alterations in the expression of several proteins involved in iron metabolism in the substantia nigra in this group compared to chow-fed animals. The diet-induced systemic and basal ganglia-specific changes may play a role in the observed impairment of nigrostriatal dopamine function.

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinsons disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IκBα in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure.

Impaired glycemia increases disease progression in mild cognitive impairment

Insulin resistance and type 2 diabetes are associated with cognitive decline and increased risk for Alzheimers disease (AD). Relatively few studies have assessed the impact of metabolic dysfunction on conversion to AD in mild cognitive impairment (MCI), and it is unclear whether glycemic status is associated with clinically relevant measures of cognitive decline and brain structure in MCI. This study used the Alzheimers Disease Neuroimaging Initiative database to examine the relationship of baseline glycemia with conversion to AD and longitudinal clinical, cognitive, and imaging measures of decline. Subjects with MCI (n = 264) with baseline and 2-year Clinical Dementia Rating data available were classified according to American Diabetes Association criteria for fasting glucose at baseline. The groups were normoglycemic (fasting glucose, <100 mg/dL; n = 167) or impaired glycemia (fasting glucose, ≥ 100 mg/dL, n = 97). The impaired glycemia group included individuals with fasting glucose that either reached the American Diabetes Association cut point for impaired fasting glucose or individuals with diagnosed diabetes. Two-year change in Clinical Dementia Rating-Sum of Boxes, cognitive performance testing (global cognition), brain volume (whole-brain and hippocampal volume), fluorodeoxyglucose-positron emission tomography, and conversion to AD were assessed. Subjects with normoglycemia at baseline had less functional (Clinical Dementia Rating-Sum of Boxes) and global cognitive decline over 2 years than subjects with impaired glycemia. Subjects with normoglycemia also lost less whole-brain volume and exhibited lower conversion from MCI to AD. There was no difference in hippocampal volume change or fluorodeoxyglucose-positron emission tomography between groups. These results suggest that baseline glycemia is related to cognitive decline and progression to AD.

Is Alzheimer's disease a systemic disease?

Although Alzheimers disease (AD) is the most common neurodegenerative disease, the etiology of AD is not well understood. In some cases, genetic factors explain AD risk, but a high percentage of late-onset AD is unexplained. The fact that AD is associated with a number of physical and systemic manifestations suggests that AD is a multifactorial disease that affects both the CNS and periphery. Interestingly, a common feature of many systemic processes linked to AD is involvement in energy metabolism. The goals of this review are to 1) explore the evidence that peripheral processes contribute to AD risk, 2) explore ways that AD modulates whole-body changes, and 3) discuss the role of genetics, mitochondria, and vascular mechanisms as underlying factors that could mediate both central and peripheral manifestations of AD. Despite efforts to strictly define AD as a homogeneous CNS disease, there may be no single etiologic pathway leading to the syndrome of AD dementia. Rather, the neurodegenerative process may involve some degree of baseline genetic risk that is modified by external risk factors. Continued research into the diverse but related processes linked to AD risk is necessary for successful development of disease-modifying therapies.

Lipoic acid increases heat shock protein expression and inhibits stress kinase activation to improve insulin signaling in skeletal muscle from high-fat-fed rats.

The antioxidant alpha-lipoic acid (LA) has been shown to improve insulin action in high-fat (HF)-fed animal models, yet little is known about its underlying mechanisms of action. We hypothesize that LA acts by inducing heat shock proteins (HSPs), which then inhibit stress kinases known to interfere with insulin signaling intermediates. Male Wistar rats were fed a HF diet (60% calories from fat) for 6 wk, while controls received a chow diet (10% calories from fat). One-half of the rats in each group received daily LA injections (30 mg/kg body wt). In rats fed a HF diet, LA increased expression of HSP72 and activation of HSP25 in soleus muscle, but it had no effect on HSPs in muscle from chow-fed rats. LA treatment reduced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and inhibitor of kappaB kinase-beta (IKKbeta) activity (IkappaBalpha protein levels) in rats fed a HF diet and effectively restored insulin responsiveness, as seen by insulin-stimulated phosphorylated Akt/Akt and 2-deoxyglucose uptake in soleus muscle. LA also induced activation of p38 MAPK and AMP-activated protein kinase, proteins previously implicated in insulin-independent glucose uptake. In addition, acute LA treatment induced HSPs in vitro in L6 muscle cells and prevented the activation of JNK and IKKbeta with stimulants such as anisomycin and TNF-alpha, respectively. In conclusion, our results suggest chronic LA treatment results in stress kinase inhibition and improved insulin signaling through a HSP-mediated mechanism.

In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake

Non‐technical summary  Previous studies show that oestrogen is beneficial for maintaining blood glucose levels and helping the body respond to insulin. Despite these previous findings, the mechanism by which oestrogen acts is unknown. We show that specific activation of oestrogen receptor α (ERα) increases glucose uptake into skeletal muscle when insulin is present. Activation of oestrogen receptor β (ERβ) alone or activation of both ERα and ERβ together did not increase glucose uptake into skeletal muscle. This suggests that oestrogens beneficial effect occurs by activating ERα. These results have important implications for understanding the mechanisms of glucose homeostasis, particularly in postmenopausal women with low oestrogen levels.

Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's disease.

Clinical evidence has shown a correlation between Parkinsons disease (PD) and Type 2 Diabetes (T2D), as abnormal glucose tolerance has been reported in >50% of PD patients. The development of insulin resistance and the degeneration of nigrostriatal dopamine (DA) neurons are both mediated by oxidative mechanisms, and oxidative stress is likely a mechanistic link between these pathologies. Although glucose uptake in neuronal tissues is primarily non-insulin dependent, proteins involved in insulin signaling, such as insulin receptor substrate 2 (IRS2) and glucose transporter 4 (GLUT4), are present in the basal ganglia. The purpose of this study was to determine whether nigrostriatal DA depletion affects measures of insulin resistance in the striatum. Six weeks after 6-hydroxydopamine (6-OHDA) infusion into the medial forebrain bundle, rats were classified as having either partial (20-65%) or severe (90-99%) striatal DA depletion. Increased IRS2 serine phosphorylation, a marker of insulin resistance, was observed in the DA-depleted striatum. Additionally, severe depletion resulted in decreased total IRS2, indicating possible degradation of the protein. Decreased phosphorylation of AKT and expression of the kinase glycogen synthase kinase-3 alpha (GSK3-alpha) was also measured in the striatum of severely DA-depleted animals. Finally, expression of heat shock protein 25 (Hsp25), which is protective against oxidative damage and can decrease stress kinase activity, was decreased in the striatum of lesioned rats. Together, these results support the hypothesis that nigrostriatal DA depletion impairs insulin signaling in the basal ganglia.

Dose-Response of Aerobic Exercise on Cognition: A Community-Based, Pilot Randomized Controlled Trial

Epidemiological studies suggest a dose-response relationship exists between physical activity and cognitive outcomes. However, no direct data from randomized trials exists to support these indirect observations. The purpose of this study was to explore the possible relationship of aerobic exercise dose on cognition. Underactive or sedentary participants without cognitive impairment were randomized to one of four groups: no-change control, 75, 150, and 225 minutes per week of moderate-intensity semi-supervised aerobic exercise for 26-weeks in a community setting. Cognitive outcomes were latent residual scores derived from a battery of 16 cognitive tests: Verbal Memory, Visuospatial Processing, Simple Attention, Set Maintenance and Shifting, and Reasoning. Other outcome measures were cardiorespiratory fitness (peak oxygen consumption) and measures of function functional health. In intent-to-treat (ITT) analyses (n = 101), cardiorespiratory fitness increased and perceived disability decreased in a dose-dependent manner across the 4 groups. No other exercise-related effects were observed in ITT analyses. Analyses restricted to individuals who exercised per-protocol (n = 77) demonstrated that Simple Attention improved equivalently across all exercise groups compared to controls and a dose-response relationship was present for Visuospatial Processing. A clear dose-response relationship exists between exercise and cardiorespiratory fitness. Cognitive benefits were apparent at low doses with possible increased benefits in visuospatial function at higher doses but only in those who adhered to the exercise protocol. An individual’s cardiorespiratory fitness response was a better predictor of cognitive gains than exercise dose (i.e., duration) and thus maximizing an individual’s cardiorespiratory fitness may be an important therapeutic target for achieving cognitive benefits. Trial Registration ClinicalTrials.gov NCT01129115

Insulin Receptor Substrate 2 Expression and Involvement in Neuronal Insulin Resistance in Diabetic Neuropathy

Insulin signaling depends on tyrosine phosphorylation of insulin receptor substrates (IRSs) to mediate downstream effects; however, elevated serine phosphorylation of IRS impairs insulin signaling. Here, we investigated IRS protein expression patterns in dorsal root ganglia (DRG) of mice and whether their signaling was affected by diabetes. Both IRS1 and IRS2 are expressed in DRG; however, IRS2 appears to be the prevalent isoform and is expressed by many DRG neuronal subtypes. Phosphorylation of Ser(731)IRS2 was significantly elevated in DRG neurons from type 1 and type 2 diabetic mice. Additionally, Akt activation and neurite outgrowth in response to insulin were significantly decreased in DRG cultures from diabetic ob/ob mice. These results suggest that DRG neurons express IRS proteins that are altered by diabetes similar to other peripheral tissues, and insulin signaling downstream of the insulin receptor may be impaired in sensory neurons and contribute to the pathogenesis of diabetic neuropathy.

Oxaloacetate Activates Brain Mitochondrial Biogenesis, Enhances the Insulin Pathway, Reduces Inflammation, and Stimulates Neurogenesis

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis.