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1.  Identification of Factors Associated With Sural Nerve Regeneration and Degeneration in Diabetic Neuropathy 
Diabetes Care  2013;36(12):4043-4049.
Patients with diabetic neuropathy (DN) demonstrate variable degrees of nerve regeneration and degeneration. Our aim was to identify risk factors associated with sural nerve degeneration in patients with DN.
Demographic, anthropometric, biochemical, and anatomical data of subjects with DN from a 52-week trial of acetyl-L-carnitine were retrospectively examined. Based on the change in sural nerve myelinated fiber density (ΔMFD%), subjects were divided into three groups: regenerator (top 16 percentiles, n = 67), degenerator (bottom 16 percentiles, n = 67), and intermediate (n = 290), with dramatically increased, decreased, and steady ΔMFD%, respectively. ANOVA, Fisher exact test, and multifactorial logistic regression were used to evaluate statistical significance.
ΔMFD%s were 35.6 ± 17.4 (regenerator), −4.8 ± 12.1 (intermediate), and −39.8 ± 11.0 (degenerator). HbA1c at baseline was the only factor significantly different across the three groups (P = 0.01). In multifactorial logistic regression, HbA1c at baseline was also the only risk factor significantly different between regenerator (8.3 ± 1.6%) and degenerator (9.2 ± 1.8%) (odds ratio 0.68 [95% CI 0.54–0.85]; P < 0.01). Support Vector Machine classifier using HbA1c demonstrated 62.4% accuracy of classifying subjects into regenerator or degenerator. A preliminary microarray experiment revealed that upregulated genes in the regenerator group are enriched with cell cycle and myelin sheath functions, while downregulated genes are enriched in immune/inflammatory responses.
These data, based on the largest cohort with ΔMFD% information, suggest that HbA1c levels predict myelinated nerve fiber regeneration and degeneration in patients with DN. Therefore, maintaining optimal blood glucose control is likely essential in patients with DN to prevent continued nerve injury.
PMCID: PMC3836098  PMID: 24101696
2.  Criteria for Creating and Assessing Mouse Models of Diabetic Neuropathy 
Current drug targets  2008;9(1):3-13.
Diabetic neuropathy (DN) is a serious and debilitating complication of both type 1 and type 2 diabetes. Despite intense research efforts into multiple aspects of this complication, including both vascular and neuronal metabolic derangements, the only treatment remains maintenance of euglycemia. Basic research into the mechanisms responsible for DN relies on using the most appropriate animal model. The advent of genetic manipulation has moved mouse models of human disease to the forefront. The ability to insert or delete genes affected in human patients offers unique insight into disease processes; however, mice are still not humans and difficulties remain in interpreting data derived from these animals. A number of studies have investigated and described DN in mice but it is difficult to compare these studies with each other or with human DN due to experimental differences including background strain, type of diabetes, method of induction and duration of diabetes, animal age and gender. This review describes currently used DN animal models. We followed a standardized diabetes induction protocol and designed and implemented a set of phenotyping parameters to classify the development and severity of DN. By applying standard protocols, we hope to facilitate the comparison and characterization of DN across different background strains in the hope of discovering the most human like model in which to test potential therapies.
PMCID: PMC4026946  PMID: 18220709
NOD; Akita; ob/ob; db/db; outbred mice; nerve conduction velocity; intraepidermal nerve fiber density
3.  Treating symptomatic hyperprolactinemia in women with schizophrenia: presentation of the ongoing DAAMSEL clinical trial (Dopamine partial Agonist, Aripiprazole, for the Management of Symptomatic ELevated prolactin) 
BMC Psychiatry  2013;13:214.
Prolactin elevations occur in people treated with antipsychotic medications and are often much higher in women than in men. Hyperprolactinemia is known to cause amenorrhea, oligomenorrhea, galactorrhea and gynecomastia in females and is also associated with sexual dysfunction and bone loss. These side effects increase risk of antipsychotic nonadherence and suicide and pose significant problems in the long term management of women with schizophrenia. In this manuscript, we review the literature on prolactin; its physiology, plasma levels, side effects and strategies for treatment. We also present the rationale and protocol for an ongoing clinical trial to treat symptomatic hyperprolactinemia in premenopausal women with schizophrenia. More attention and focus are needed to address these significant side effects and help the field better personalize the treatment of women with schizophrenia.
PMCID: PMC3766216  PMID: 23968123
Women; Prolactin; Amenorrhea; Galactorrhea; Clinical trial; Sexual dysfunction; Osteoporosis; Aripiprazole
4.  Mouse Models of Diabetic Neuropathy 
Neurobiology of disease  2007;28(3):276-285.
Diabetic neuropathy (DN) is a debilitating complication of type 1 and type 2 diabetes. Rodent models of DN do not fully replicate the pathology observed in human patients. We examined DN in streptozotocin (STZ)-induced [B6] and spontaneous type 1 diabetes [B6Ins2Akita] and spontaneous type 2 diabetes [B6-db/db, BKS-db/db]. DN was defined using the criteria of the Animal Models of Diabetic Complications Consortium ( Despite persistent hyperglycemia, the STZ-treated B6 and B6Ins2Akita mice were resistant to the development of DN. In contrast, DN developed in both type 2 diabetes models: the B6-db/db and BKS-db/db mice. The persistence of hyperglycemia and development of DN in the B6-db/db mice required an increased fat diet while the BKS-db/db mice developed severe DN and remained hyperglycemic on standard mouse chow. Our data support the hypothesis that genetic background and diet influence the development of DN and should be considered when developing new models of DN.
PMCID: PMC3730836  PMID: 17804249
BKS; streptozotocin; B6Ins2Akita; sciatic nerve; dorsal root ganglia
5.  Neurodegeneration and early lethality in SOD2-deficient mice: a comprehensive analysis of the central and peripheral nervous systems 
Neuroscience  2012;212:201-213.
The contribution of oxidative stress to diabetic complications including neuropathy is widely known. Mitochondrial and cellular damage are associated with the overproduction of reactive oxygen species and decreased levels or function of the cellular antioxidant mitochondrial manganese superoxide dismutase (SOD2). We hypothesized that targeted SOD2 deletion in the peripheral nervous system using cre-lox technology under control of the nestin promoter would accelerate neuropathy in a type 2 model of diabetes, the BKS.db/db mouse. SOD2-deficient mice, however, demonstrated severe gait deformities and seizures and died by 20 days of age. Examination of SOD2 expression levels revealed that SOD2 was lost in brain and reduced in the spinal cord, but appeared normal in dorsal root ganglia and peripheral nerves in SOD2-deficient mice. These findings indicate incomplete targeted knockout of SOD2. Morphological examination revealed cortical lesions similar to spongiform encephalopathy in the brain of SOD2-deficient mice. No lesions were evident in the spinal cord, but changes in myelin within the sciatic and sural nerves including a lack of cohesion between layers of compact myelin was observed. Together, these results indicate that targeted neuronal SOD2 knockout using the nestin promoter results in severe central nervous system degeneration and perinatal lethality in mice. A specific peripheral nervous system-targeting construct is required to examine the consequences of SOD2 knockout in diabetic neuropathy.
PMCID: PMC3367053  PMID: 22516022
ROS; SOD2; oxidative stress; diabetic neuropathy; BKS.db/db mice
6.  The identification of gene expression profiles associated with progression of human diabetic neuropathy 
Brain  2011;134(11):3222-3235.
Diabetic neuropathy is a common complication of diabetes. While multiple pathways are implicated in the pathophysiology of diabetic neuropathy, there are no specific treatments and no means to predict diabetic neuropathy onset or progression. Here, we identify gene expression signatures related to diabetic neuropathy and develop computational classification models of diabetic neuropathy progression. Microarray experiments were performed on 50 samples of human sural nerves collected during a 52-week clinical trial. A series of bioinformatics analyses identified differentially expressed genes and their networks and biological pathways potentially responsible for the progression of diabetic neuropathy. We identified 532 differentially expressed genes between patient samples with progressing or non-progressing diabetic neuropathy, and found these were functionally enriched in pathways involving inflammatory responses and lipid metabolism. A literature-derived co-citation network of the differentially expressed genes revealed gene subnetworks centred on apolipoprotein E, jun, leptin, serpin peptidase inhibitor E type 1 and peroxisome proliferator-activated receptor gamma. The differentially expressed genes were used to classify a test set of patients with regard to diabetic neuropathy progression. Ridge regression models containing 14 differentially expressed genes correctly classified the progression status of 92% of patients (P < 0.001). To our knowledge, this is the first study to identify transcriptional changes associated with diabetic neuropathy progression in human sural nerve biopsies and describe their potential utility in classifying diabetic neuropathy. Our results identifying the unique gene signature of patients with progressive diabetic neuropathy will facilitate the development of new mechanism-based diagnostics and therapies.
PMCID: PMC3212712  PMID: 21926103
biomarkers; diabetic neuropathy; classification model; sural nerve; gene expression
7.  Cortical Neurons Develop Insulin Resistance and Blunted Akt Signaling: A Potential Mechanism Contributing to Enhanced Ischemic Injury in Diabetes 
Antioxidants & Redox Signaling  2011;14(10):1829-1839.
Patients with diabetes are at higher risk of stroke and experience increased morbidity and mortality after stroke. We hypothesized that cortical neurons develop insulin resistance, which decreases neuroprotection via circulating insulin and insulin-like growth factor-I (IGF-I). Acute insulin treatment of primary embryonic cortical neurons activated insulin signaling including phosphorylation of the insulin receptor, extracellular signal-regulated kinase (ERK), Akt, p70S6K, and glycogen synthase kinase-3β (GSK-3β). To mimic insulin resistance, cortical neurons were chronically treated with 25 mM glucose, 0.2 mM palmitic acid (PA), or 20 nM insulin before acute exposure to 20 nM insulin. Cortical neurons pretreated with insulin, but not glucose or PA, exhibited blunted phosphorylation of Akt, p70S6K, and GSK-3β with no change detected in ERK. Inhibition of the phosphatidylinositol 3-kinase (PI3-K) pathway during insulin pretreatment restored acute insulin-mediated Akt phosphorylation. Cortical neurons in adult BKS-db/db mice exhibited higher basal Akt phosphorylation than BKS-db+ mice and did not respond to insulin. Our results indicate that prolonged hyperinsulinemia leads to insulin resistance in cortical neurons. Decreased sensitivity to neuroprotective ligands may explain the increased neuronal damage reported in both experimental models of diabetes and diabetic patients after ischemia-reperfusion injury. Antioxid. Redox Signal. 14, 1829–1839.
PMCID: PMC3078499  PMID: 21194385
8.  The effects of anesthesia on measures of nerve conduction velocity in male C57Bl6/J mice 
Neuroscience letters  2010;483(2):127-131.
PMCID: PMC2941214  PMID: 20691755
sciatic nerve; sural nerve; isoflurane; 2-2-2 tribromoethanol; surface temperature
9.  Literature-based discovery of diabetes- and ROS-related targets 
BMC Medical Genomics  2010;3:49.
Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS.
We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy.
SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers ( Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG.
Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.
PMCID: PMC2988702  PMID: 20979611
10.  Elevated Triglycerides Correlate With Progression of Diabetic Neuropathy 
Diabetes  2009;58(7):1634-1640.
To evaluate mechanisms underlying diabetic neuropathy progression using indexes of sural nerve morphometry obtained from two identical randomized, placebo-controlled clinical trials.
Sural nerve myelinated fiber density (MFD), nerve conduction velocities (NCVs), vibration perception thresholds, clinical symptom scores, and a visual analog scale for pain were analyzed in participants with diabetic neuropathy. A loss of ≥500 fibers/mm2 in sural nerve MFD over 52 weeks was defined as progressing diabetic neuropathy, and a MFD loss of ≤100 fibers/mm2 during the same time interval as nonprogressing diabetic neuropathy. The progressing and nonprogressing cohorts were matched for baseline characteristics using an O'Brien rank-sum and baseline MFD.
At 52 weeks, the progressing cohort demonstrated a 25% decrease (P < 0.0001) from baseline in MFD, while the nonprogressing cohort remained unchanged. MFD was not affected by active drug treatment (P = 0.87), diabetes duration (P = 0.48), age (P = 0.11), or BMI (P = 0.30). Among all variables tested, elevated triglycerides and decreased peroneal motor NCV at baseline significantly correlated with loss of MFD at 52 weeks (P = 0.04).
In this cohort of participants with mild to moderate diabetic neuropathy, elevated triglycerides correlated with MFD loss independent of disease duration, age, diabetes control, or other variables. These data support the evolving concept that hyperlipidemia is instrumental in the progression of diabetic neuropathy.
PMCID: PMC2699859  PMID: 19411614
11.  Oxidative Injury and Neuropathy in Diabetes and Impaired Glucose Tolerance 
Neurobiology of disease  2008;30(3):420-429.
Clinical studies suggest that impaired glucose tolerance (IGT) is associated with the development of neuropathy. The aim of the current study was to determine if neuropathy developed in the female Zucker Diabetic Fatty (ZDF) rat, an animal model of IGT and type 2 diabetes. The ZDF rat develops impaired glucose tolerance (IGT) when fed a control diet, and frank diabetes when fed a high fat diet. Following 10 weeks of hyperglycemia, sensory nerve action potentials (SNAP) and compound motor action potentials (CMAP) were reduced and sensory conduction velocities were slowed (distal > proximal) in the tail and hind limb in ZDF animals with IGT and frank diabetes (p<0.01). Neuropathy was coupled with evidence of increased reactive oxygen species (ROS) and cellular injury in dorsal root ganglion (DRG) neurons from IGT animals. Our study supports the hypothesis that neuropathy develops in an animal model of IGT and is associated with evidence of oxidative injury in DRG and peripheral nerves.
PMCID: PMC2453225  PMID: 18424057
neuropathy; diabetes; impaired glucose tolerance; oxidative stress; axons; dorsal root ganglia; Schwann cells
12.  SOD2 Protects Neurons from Injury in Cell Culture and Animal Models of Diabetic Neuropathy 
Experimental neurology  2007;208(2):216-227.
Hyperglycemia-induced oxidative stress is an inciting event in the development of diabetic complications including diabetic neuropathy. Our observations of significant oxidative stress and morphological abnormalities in mitochondria led us to examine manganese superoxide dismutase (SOD2), the enzyme responsible for mitochondrial detoxification of oxygen radicals. We demonstrate that over expression of SOD2 decreases superoxide (O2•−) in cultured primary dorsal root ganglion (DRG) neurons and subsequently blocks caspase-3 activation and cellular injury. Under expression of SOD2 in dissociated DRG cultures from adult SOD2+/− mice results in increased levels of O2•−, activation of caspase-3 cleavage and decreased neurite outgrowth under basal conditions that are exacerbated by hyperglycemia. These profound changes in sensory neurons led us to explore the effects of decreased SOD2 on the development of diabetic neuropathy (DN) in mice. DN was assessed in SOD2+/− C57BL/6J mice and their SOD2+/+ litter mates following streptozotocin (STZ) treatment. These animals, while hyperglycemic, do not display any signs of DN. DN was observed in the C57BL/6Jdb/db mouse, and decreased expression of SOD2 in these animals increased DN. Our data suggest that SOD2 activity is an important cellular modifier of neuronal oxidative defense against hyperglycemic injury.
PMCID: PMC2190625  PMID: 17927981
neuropathy; oxidative stress; SOD2
13.  Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: Prevention by lipoic acid treatment 
BMC Nephrology  2006;7:6.
A reduction in the number of podocytes and podocyte density has been documented in the kidneys of patients with diabetes mellitus. Additional studies have shown that podocyte injury and loss occurs in both diabetic animals and humans. However, most studies in animals have examined relatively long-term changes in podocyte number and density and have not examined effects early after initiation of diabetes. We hypothesized that streptozotocin diabetes in rats and mice would result in an early reduction in podocyte density and that this reduction would be prevented by antioxidants.
The number of podocytes per glomerular section and the podocyte density in glomeruli from rats and mice with streptozotocin (STZ)-diabetes mellitus was determined at several time points based on detection of the glomerular podocyte specific antigens, WT-1 and GLEPP1. The effect of insulin administration or treatment with the antioxidant, α-lipoic acid, on podocyte number was assessed.
Experimental diabetes resulted in a rapid decline in apparent podocyte number and podocyte density. A significant reduction in podocytes/glomerular cross-section was found in STZ diabetes in rats at 2 weeks (14%), 6 weeks (18%) and 8 weeks (34%) following STZ injection. Similar declines in apparent podocyte number were found in STZ diabetes in C57BL/6 mice at 2 weeks, but not at 3 days after injection. Treatment with α-lipoic acid substantially prevented podocyte loss in diabetic rats but treatment with insulin had only a modest effect.
STZ diabetes results in reduction in apparent podocyte number and in podocyte density within 2 weeks after onset of hyperglycemia. Prevention of these effects with antioxidant therapy suggests that this early reduction in podocyte density is due in part to increased levels of reactive oxygen species as well as hyperglycemia.
PMCID: PMC1435876  PMID: 16539708

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