Use of Analog and Human Insulin in a European Hemodialysis Cohort With Type 2 Diabetes: Associations With Mortality, Hospitalization, MACE, and Hypoglycemia

RATIONALE & OBJECTIVE: Poor glycemic control may contribute to the high mortality rate in patients with type 2 diabetes receiving hemodialysis. Insulin type may influence glycemic control, and its choice may be an opportunity to improve outcomes. This study assessed whether treatment with analog insulin compared with human insulin is associated with different outcomes in people with type 2 diabetes and kidney failure receiving hemodialysis. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: People in the Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) study with kidney failure commencing hemodialysis and type 2 diabetes being treated with insulin within 288 dialysis facilities between 2007 and 2009 across 7 European countries. Study participants were followed for 3 years. People with type 1 diabetes were excluded using an established administrative data algorithm. EXPOSURE: Treatment with an insulin analog or human insulin. OUTCOME: All-cause mortality, major adverse cardiovascular events (MACE), all-cause hospitalization, and confirmed hypoglycemia (blood glucose<3.0mmol/L sampled during hemodialysis). ANALYTICAL APPROACH: Inverse probability weighted Cox proportional hazards models to estimate hazard ratios for analog insulin compared with human insulin. RESULTS: There were 713 insulin analog and 733 human insulin users. Significant variation in insulin type by country was observed. Comparing analog with human insulin at 3 years, the percentage of patients experiencing end points and adjusted hazard ratios (AHR) were 22.0% versus 31.4% (AHR, 0.808 [95% CI, 0.66-0.99], P=0.04) for all-cause mortality, 26.8% versus 35.9% (AHR, 0.817 [95% CI, 0.68-0.98], P=0.03) for MACE, and 58.2% versus 75.0% (AHR, 0.757 [95% CI, 0.67-0.86], P<0.001) for hospitalization. Hypoglycemia was comparable between insulin types at 14.1% versus 15.0% (AHR, 1.169 [95% CI, 0.80-1.72], P=0.4). Consistent strength and direction of the associations were observed across sensitivity analyses. LIMITATIONS: Residual confounding, lack of more detailed glycemia data. CONCLUSIONS: In this large multinational cohort of people with type 2 diabetes and kidney failure receiving maintenance hemodialysis, treatment with analog insulins was associated with better clinical outcomes when compared with human insulin. PLAIN-LANGUAGE SUMMARY: People with diabetes who are receiving dialysis for kidney failure are at high risk of cardiovascular disease and death. This study uses information from 1,446 people with kidney failure from 7 European countries who are receiving dialysis, have type 2 diabetes, and are prescribed either insulin identical to that made in the body (human insulin) or insulins with engineered extra features (insulin analog). After 3 years, fewer participants receiving analog insulins had died, had been admitted to the hospital, or had a cardiovascular event (heart attack, stroke, heart failure, or peripheral vascular disease). These findings suggest that analog insulins should be further explored as a treatment leading to better outcomes for people with diabetes on dialysis

Preservation of thalamic neuronal function may be a prerequisite for pain perception in diabetic neuropathy: A magnetic resonance spectroscopy study

IntroductionIn this study, we used proton Magnetic Resonance Spectroscopy (1H-MRS) to determine the neuronal function in the thalamus and primary somatosensory (S1) cortex in different subgroups of DPN, including subclinical- and painful-DPN.MethodOne-hundred and ten people with type 1 diabetes [20 without DPN (no-DPN); 30 with subclinical-DPN; 30 with painful-DPN; and 30 with painless-DPN] and 20 healthy volunteers, all of whom were right-handed men, were recruited and underwent detailed clinical and neurophysiological assessments. Participants underwent Magnetic Resonance Imaging at 1.5 Tesla with two 1H-MRS spectra obtained from 8 ml cubic volume voxels: one placed within left thalamus to encompass the ventro-posterior lateral sub-nucleus and another within the S1 cortex.ResultsIn the thalamus, participants with painless-DPN had a significantly lower NAA:Cr ratio [1.55 + 0.22 (mean ± SD)] compared to all other groups [HV (1.80 ± 0.23), no-DPN (1.85 ± 0.20), sub-clinical DPN (1.79 ± 0.23), painful-DPN (1.75 ± 0.19), ANOVA p &lt; 0.001]. There were no significant group differences in S1 cortical neurometabolites.ConclusionIn this largest cerebral MRS study in DPN, thalamic neuronal dysfunction was found in advanced painless-DPN with preservation of function in subclinical- and painful-DPN. Furthermore, there was a preservation of neuronal function within the S1 cortex in all subgroups of DPN. Therefore, there may be a proximo-distal gradient to central nervous system alterations in painless-DPN, with thalamic neuronal dysfunction occurring only in established DPN. Moreover, these results further highlight the manifestation of cerebral alterations between painful- and painless-DPN whereby preservation of thalamic function may be a prerequisite for neuropathic pain in DPN

The Microvascular Perfusion Characteristics of the Pain Matrix of the Brain in subjects with Type 1 Diabetes and Painful Neuropathy

Background: Painful diabetic peripheral neuropathy (Painful-DPN) affects between 10-28% of those with diabetes, but treatments are not effective for all those with the condition. Our understanding of the risk factors that underlie the development of chronic neuropathic pain is limited. Increased thalamic vascularity has been reported in a pilot study of subjects with painful-DPN, but the microvascular perfusion characteristics of other pain processing areas of the brain (pain matrix) have not been assessed. It was hypothesised that quantification of perfusion, using dynamic susceptibility contrast magnetic resonance imaging, could be a biomarker for the perception of pain in the brain. The main aim of this study was to measure cerebral perfusion of the pain processing areas of the brain using Dynamic Susceptibility Contrast magnetic resonance imaging (DSC-MRI) at rest and during an experimental pain condition. The secondary aims of this study were to characterise participants using clinical, metabolic and psychological parameters to identify features that may be markers of painful diabetic peripheral neuropathy; to assess the reproducibility of four quantitative perfusion parameters: regional blood volume (RBV), regional blood flow (RBF), mean transit time (MTT), and Time-to-peak concentration (TTP) using quantitative dynamic susceptibility contrast magnetic resonance imaging; and to investigate if perfusion parameters and proton magnetic resonance spectroscopy (1H-MRS) neuronal metabolite ratios in the thalamus of subjects with painful diabetic peripheral neuropathy are associated. These parameters could be used to identify phenotypes to be targets for novel treatments and to monitor treatment response in trials of new agents. Methods: This was an observational, cross sectional cohort study of 54 subjects with type 1 diabetes mellitus: 19 with painful-DPN, 23 with painless-DPN, 13 with type 1 diabetes mellitus and no neuropathy (DM-NN) and 19 healthy non-diabetic volunteers (HV). Clinical examination, questionnaires and blood tests were performed. DSC-MRI measurements were made at baseline and during a painful thermal stimulus. The reproducibility was assessed by blinded comparison of measurements by two raters. Proton Magnetic resonance spectroscopy measurements (1H-MRS) were obtained at 3T and compared with perfusion measurements by DSC-MRI. Results: Time-to-peak (TTP)concentration of gadolinium, when adjusted for pain perception (Likert scale) and group interaction, was significantly longer for the painful-DPN group as compared with healthy volunteers, at the left and right thalamus, left and right insula cortex and the left and right primary sensory cortex. Mean transit time was shorter at baseline between healthy volunteers (HV) and all diabetes groups, with the greatest difference between HV and diabetes with no neuropathy (DM-NN). In a subgroup analysis subjects experiencing neuropathic pain at the time of scanning had an shorter TTP at baseline. Discriminant function analysis using measures of mood, and somatic focus significantly differentiated painful-DPN from other groups in this study. Additionally, there was a significant negative correlation between scores on measures of anxiety and depression and N-Acetyl Aspartarte/Creatine (NAA/Cr) ratio measured by 1H-MRS in the thalamus. Reproducibility of the perfusion technique was measured and TTP had an “excellent” intraclass correlation coefficient of 0.837, RBF =0.710 and MTT= 0.618, and fair for RBV=0.443. Conclusion: This is the first study to suggest that during a baseline state there may be hyper-perfusion in the cerebro-vascular bed, analogous to hyper-perfusion in the kidney and peripheral nerve, in subjects with diabetes and particularly diabetes with no neuropathy (DM-NN) which is reflected by a shorter mean transit time in the studied regions of interest. Additionally, this is the first study to our knowledge that describes a difference between painful-DPN and other groups using CNS microvascular perfusion measures and can link this perfusion change to the perception of neuropathic pain. Subgroup analysis of subjects with painful-DPN, who were experiencing neuropathic pain during the baseline scan, revealed that TTP and MTT is significantly shorter in this group, suggesting that peripheral pain is measurable centrally, and perfusion changes are secondary to pain perception rather than structural abnormalities. Therefore, pain at the time of the scan is an important parameter that must be accounted for in painful-DPN studies. We have reported the novel finding that dynamic pain response is altered in those with painful-DPN as compared to healthy volunteers. When experimental pain is applied TTP significantly lengthens for subjects with painful-DPN whilst healthy volunteers shorten their TTP, after adjustment for pain perception. Possibilities for the observation of this phenomena may be due to primed descending or ascending inhibition of pain in the painful-DPN group, or inappropriately sluggish response due to a failure of neurovascular coupling. This apparently paradoxical perfusion response to a pain stimulus may be key to understanding central nervous system contribution to symptoms of painful-DPN, and should be the focus of future studies as a promising biomarker of this condition. Future studies will be designed to interrogate perfusion responses at different levels of stimulus to understand inhibitory mechanisms that may be exploited to enhance symptom relief and develop perfusion response as a biomarker of painful-DPN. This is the first study to show somatic focus as a correlate of painful-DPN. The results show that negative psychological traits such as somatic focus, mood and pain catastrophising are strongly associated with, and can predict cases of painful-DPN. Finally, we report a novel finding describing a link between mood disorders and neuronal metabolites in the context of painful-DPN. NAA/Cr ratio is more strongly associated with measures of depression and anxiety than measures of perfusion or neuropathy. H1-MRS studies must be carefully characterised for depression and anxiety to minimise the confounding effect of mood disorders in studies of painful-DPN. This is a cross sectional study therefore the contribution of mood disorders to the development and persistence of painful-DPN requires further longitudinal study. In summary, this study found that there are unique perfusion states and responses of subjects with painful-DPN that are measurable with the quantifiable technique of DSC-MRI

Early intervention with a small molecule inhibitor for tumor necrosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease

AbstractBackgroundChronic neuroinflammation is an important component of Alzheimer’s disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer’s because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer’s disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.MethodsTo investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer’s disease mice (harboring PS1M146V, APPSwe, and tauP301L transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6′-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.Results3,6′-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice.In comparison to non-transgenic controls, triple transgenic Alzheimer’s disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6′-dithiothalidomide.ConclusionsThese results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer’s disease

Early intervention with a small molecule inhibitor for tumor necrosis factor-alpha prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease

AbstractBackgroundChronic neuroinflammation is an important component of Alzheimer’s disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer’s because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer’s disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.MethodsTo investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer’s disease mice (harboring PS1M146V, APPSwe, and tauP301L transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6′-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.Results3,6′-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice.In comparison to non-transgenic controls, triple transgenic Alzheimer’s disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6′-dithiothalidomide.ConclusionsThese results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer’s disease