Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

Results of previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among people with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N = 469) and with type 2 diabetes (T2D) from Action to Control Cardiovascular Risk in Diabetes (ACCORD) (N = 7,973). Baseline CAN was ascertained with electrocardiogram-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss of ≥5 mL/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed-effects, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 mL/min/1.73 m2/year (95% CI -1.93 to -0.37; P = 4.0 × 10-3) in PERL and 0.34 mL/min/1.73 m2/year (95% CI -0.49 to -0.19; P = 6.3 × 10-6) in ACCORD. This translated to 2.11 (95% CI 1.23-3.63; P = 6.9 × 10-3) and 1.39 (95% CI 1.20-1.61; P = 1.1 × 10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (hazard ratio 2.60 [95% CI 1.15-5.45], P = 0.02, in PERL and hazard ratio 1.54 [95% CI 1.28-1.84], P = 3.8 × 10-6, in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help with development of new therapies to prevent kidney function decline in patients with diabetes.

Correlation of Iron Status and Micronutrients With Anaemia of Childhood Haematopoietic Malignancies: A Study From Northern India.

BACKGROUND: Most cancer patients undergoing chemotherapy develop anemia during their course of treatment. There is a need for early treatment for chemotherapy-induced anemia to prevent morbidity and mortality. MATERIAL AND METHOD: This is a hospital-based study, conducted over one year and included 59 children who are known cases of hematological malignancy aged up to 18 years. Standard methods were used to measure micronutrients and complete blood count. Statistical analysis was done using SPSS for Windows, Version 15.0 (Released 2006; SPSS Inc., Chicago, United States). RESULTS: The majority of subjects (n=21; 35.6%) were aged six to nine years with male dominance. Micronutrient deficiency and significant anemia were noted in 40-50% and 64.4% of cases, respectively. Both malignancy and blood indices showed no association with micronutrients. CONCLUSION: Anemia with micronutrient deficiency is common in children with hematopoietic malignancies receiving chemotherapy. However, no significant association was noted between red cell indices and levels of micronutrients.

Crystal structures of FNIP/FGxxFN motif-containing leucine-rich repeat proteins.

The Cafeteria roenbergensis virus (Crov), Dictyostelium, and other species encode a large family of leucine-rich repeat (LRR) proteins with FGxxFN motifs. We determined the structures of two of them and observed several unique structural features that set them aside from previously characterized LRR family members. Crov588 comprises 25 regular repeats with a LxxLxFGxxFNQxIxENVLPxx consensus, forming a unique closed circular repeat structure. Novel features include a repositioning of a conserved asparagine at the middle of the repeat, a double phenylalanine spine that generates an alternate core packing arrangement, and a histidine/tyrosine ladder on the concave surface. Crov539 is smaller, comprising 12 repeats of a similar LxxLxFGxxFNQPIExVxW/LPxx consensus and forming an unusual cap-swapped dimer structure. The phenylalanine spine of Crov539 is supplemented with a tryptophan spine, while a hydrophobic isoleucine-rich patch is found on the central concave surface. We present a detailed analysis of the structures of Crov588 and Crov539 and compare them to related repeat proteins and other LRR classes.

Clinical Correlation and Role of Cyclin D1 Expression in Glioblastoma Patients: A Study From North India.

Background/Aims Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Cyclin D1 is a protein that in humans is encoded by the CCND1 gene. Cyclin D1 protein is frequently overexpressed in malignant gliomas. Methods It is an observational study comprising 40 biopsy-proven cases of GBM in a span of one and half years. Immunohistochemistry (IHC) was used with Cyclin D1 monoclonal antibody. Cyclin D1 on the outcome was assessed using the Kaplan-Meier survival estimate and compared by log-rank test. Results Cyclin D1 was expressed in 60% of patients. The majority (72.5%) of patients expired during the study period, out of which 69% showed immune-expression in contrast to living subjects, out of which only 45.5% of patients exhibited expression. The maximum number of glioblastoma patients were aged between 41 and 50 years (40%), followed by those aged between 31 and 40 years (20%). The male to female ratio of study subjects was 3.44:1. Conclusion The study concluded that there is no significant association between Cyclin D1 expression status and different demographic, clinical, and outcome variables.

Cardiovascular risk and heart rate variability in young adults with type 2 diabetes and arterial stiffness: The SEARCH for Diabetes in Youth Study.

AIMS: To evaluate cardiovascular risk factors and heart rate variability (HRV) in young adults with type 2 diabetes and arterial stiffness and to explore the relationship between HRV and arterial stiffness. METHODS: We studied 185 young adults with youth-onset T2D enrolled in the SEARCH for Diabetes in Youth Study. Cardiovascular risk factors and HRV were compared between individuals with and without type 2 diabetes and arterial stiffness (defined as a pulse wave velocity greater than the 90th percentile of healthy controls, >6.767 m/s). Semiparametric regression evaluated the independent relationship between HRV and PWV. RESULTS: Participants with T2D and arterial stiffness were more likely to be older, non-Hispanic Black, have higher systolic and diastolic blood pressure, greater adiposity and obesity-related dyslipidemia (higher triglycerides and lower HDLC). Participants with T2D and arterial stiffness also had lower overall HRV (lower SDNN) with parasympathetic loss (lower RMSSD and PNN50), p < 0.05. Lower HRV tended to be but was not significantly associated with arterial stiffness after adjustment for age, race/ethnicity, sex and cardiovascular risk factors (beta coefficient = -1.11, p = 0.08). CONCLUSIONS: Youth with T2D and arterial stiffness have a worse cardiovascular risk profile, specifically risk factors related to the metabolic syndrome and lower HRV.

Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes.

While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA1c 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels-asparagine and glutamine-correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA1c, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.

Therapeutic Lifestyle Changes Improve HDL Function by Inhibiting Myeloperoxidase-Mediated Oxidation in Patients With Metabolic Syndrome.

OBJECTIVE: Phagocyte-derived myeloperoxidase (MPO) and proinflammatory HDL are associated with metabolic syndrome (MetS) and increased cardiovascular disease risk. Therapeutic lifestyle changes (TLCs), such as a Mediterranean diet and exercise, decrease this risk. However, the link among TLCs, HDL, and MPO-mediated oxidative stress remains unclear. RESEARCH DESIGN AND METHODS: In this study, we characterized changes in cholesterol efflux capacity (CEC), a metric of HDL function; MPO-mediated oxidation; and the HDL proteomic profile in 25 patients with MetS who underwent 12 weeks of TLCs. RESULTS: After 12 weeks, before significant changes to HDL levels, most MetS components improved as a result of the TLCs. CEC was significantly increased, and HDL MPO oxidation products, 3-chlorotyrosine and 3-nitrotyrosine, were decreased with TLCs. The changes in CEC were inversely related to the unit changes in 3-chlorotyrosine after we controlled for changes in the other MetS components. TLCs did not remodel the HDL proteome. CONCLUSIONS: In summary, TLCs improved HDL function by inhibiting MPO-mediated oxidative stress even before appreciable changes in HDL levels.

Is there an association between non-dipping blood pressure and measures of glucose variability in type 1 diabetes?

AIM: To assess the relationship between glucose variability (GV) and non-dipping of blood pressure (BP) as a marker of cardiovascular autonomic neuropathy (CAN) among patients with type 1 diabetes (T1D). METHODS: Forty-one subjects with T1D (age 34 ±â€¯13 years, duration 13 ±â€¯6 years, HbA1c 8 ±â€¯1.2%) without cardiovascular disease, dyslipidemia, or hypertension at baseline were enrolled in a 3-year observational cohort study. Subjects were phenotyped for CAN with heart rate variability, cardiovascular autonomic reflex tests, and 24-h BP profiles at baseline and during follow-up. Non-dipping was defined as nocturnal systolic and diastolic BP fall of ≤10%. Reverse dipping BP was defined as a <0% change in the day to night for systolic and diastolic BP. Indices of GV were derived from 5-day continuous glucose monitoring obtained at 3-month intervals, and serum inflammatory biomarkers in all subjects. RESULTS: At baseline 10% of the T1D subjects were non-dippers. The dippers and non-dippers were similar in age, diabetes duration, glucose control, traditional cardiovascular risk factors, GV and inflammatory markers. No significant correlations were found at baseline between non-dipping nocturnal blood pressure and measures of GV. At 3 years there were no differences in risk factor profile of subjects who were non-dippers over time (progressors) and those who were dippers (non-progressors). CONCLUSION: In a cohort of contemporary patients with T1D following the current standard of care in diabetes, the prevalence of non-dipping is relatively low. There were no clear phenotypes that explained the difference in the risk for non-dipping, including GV. Ambulatory blood pressure monitoring could be used as a tool for improved CVD risk stratification and development of therapeutic interventions in these patients.

Cardiovascular autonomic neuropathy in adolescents and young adults with type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Cohort Study.

OBJECTIVE: To estimate the prevalence of and risk factors for cardiovascular autonomic neuropathy (CAN) in adolescents and young adults with type 1 and type 2 diabetes enrolled in the SEARCH for Diabetes in Youth Study. METHODS: The study included 1646 subjects with type 1 diabetes (age 18 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.1 ± 1.9%, 76% non-Hispanic Whites) and 252 with type 2 diabetes (age 22 ± 4 years, diabetes duration 8 ± 2 years, HbA1c 9.2 ± 3.0%, 45% non-Hispanic Blacks). Cross-sectional and longitudinal risk factors were assessed at baseline and follow-up visits. Area under the curve (AUC) was used to assess the longitudinal glycemic exposure and cardiovascular risk factors. CAN was assessed by time and frequency domain indices of heart rate variability (HRV). CAN was defined as the presence of ≥3 of 5 abnormal HRV indices. RESULTS: The prevalence of CAN was 12% in adolescents and young adults with type 1 diabetes and 17% in those with type 2 diabetes. Poor long-term glycemic control (AUC HbA1c), high blood pressure, and elevated triglyceride levels were correlates of CAN in subjects with type 1 diabetes. In those with type 2 diabetes, CAN was associated with elevated triglycerides and increased urinary albumin excretion. CONCLUSIONS: The prevalence of CAN in this multiethnic cohort of adolescents and young adults with type 1 and type 2 diabetes are comparable to those reported in adults with diabetes. Suboptimal glycemic control and elevated triglycerides were the modifiable risk factors associated with CAN.

Structured lifestyle intervention in patients with the metabolic syndrome mitigates oxidative stress but fails to improve measures of cardiovascular autonomic neuropathy.

AIMS: To assess the role of oxidative stress in mediating adverse outcomes in metabolic syndrome (MetS) and resultant cardiovascular autonomic neuropathy (CAN), and to evaluate the effects of lifestyle interventions on measures of oxidative stress and CAN in subjects with MetS. METHODS: Pilot study in 25 non-diabetic subjects with MetS (age 49±10years, 76% females) participating in a 24-week lifestyle intervention (supervised aerobic exercise/Mediterranean diet), and 25 age-matched healthy controls. CAN was assessed by cardiovascular reflex tests, heart rate variability (HRV) and PET imaging with sympathetic analog [11C] meta-hydroxyephedrine ([11C]HED). Specific oxidative fingerprints were measured by liquid-chromatography/mass-spectrometry (LC/MS). RESULTS: At baseline, MetS subjects had significantly higher oxidative stress markers [3-nitrotyrosine (234±158 vs. 54±47µmol/mol tyrosine), ortho-tyrosine (59±38 vs. 18±10µmol/molphenylalanine, all P<0.0001], and impaired HRV at rest and during deep breathing (P=0.039 and P=0.021 respectively) compared to controls. Twenty-four-week lifestyle intervention significantly reduced all oxidative stress markers (all P<0.01) but did not change any of the CAN measures. CONCLUSIONS: Subjects with MetS present with signs of CAN and increased oxidative stress in the absence of diabetes. The 24-week lifestyle intervention was effective in ameliorating oxidative stress, but did not improve measures of CAN. Larger clinical trials with longer duration are required to confirm these findings.

Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study.

OBJECTIVE: We assessed the prevalence of and risk factors for diabetic peripheral neuropathy (DPN) in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) enrolled in the SEARCH for Diabetes in Youth (SEARCH) study. RESEARCH DESIGN AND METHODS: The Michigan Neuropathy Screening Instrument (MNSI) was used to assess DPN in 1,734 youth with T1D (mean ± SD age 18 ± 4 years, T1D duration 7.2 ± 1.2 years, and HbA1c 9.1 ± 1.9%) and 258 youth with T2D (age 22 ± 3.5 years, T2D duration 7.9 ± 2 years, and HbA1c 9.4 ± 2.3%) who were enrolled in the SEARCH study and had ≥5 years of diabetes duration. DPN was defined as an MNSI exam score of >2. Glycemic control over time was estimated as area under the curve for HbA1c. RESULTS: The prevalence of DPN was 7% in youth with T1D and 22% in youth with T2D. Risk factors for DPN in youth with T1D were older age, longer diabetes duration, smoking, increased diastolic blood pressure, obesity, increased LDL cholesterol and triglycerides, and lower HDL cholesterol (HDL-c). In youth with T2D, risk factors were older age, male sex, longer diabetes duration, smoking, and lower HDL-c. Glycemic control over time was worse among those with DPN compared with those without for youth with T1D (odds ratio 1.53 [95% CI 1.24; 1.88]) but not for youth with T2D (1.05 [0.7; 1.56]). CONCLUSIONS: The high rates of DPN among youth with diabetes are a cause of concern and suggest a need for early screening and better risk factor management. Interventions in youth that address poor glycemic control and dyslipidemia may prevent or delay debilitating neuropathic complications.

Sudomotor dysfunction as a measure of small fiber neuropathy in type 1 diabetes.

BACKGROUND: This study evaluated whether measuring the electrochemical skin conductance (ESC), as an indirect measure of sudomotor function, may be also a reliable surrogate for early cardiovascular autonomic neuropathy (CAN). METHODS: Longitudinal study included 37 type 1 diabetes (T1D) subjects (mean age 38±13years, duration 15±7years, HbA1c 7.9±1.1%, no known complications at baseline), and 40 age-matched healthy control (HC) subjects. Mean hands ESC (ESChands) and feet (ESCfeet) were measured with the SUDOSCAN (Impeto Medical, France). CAN was assessed with heart rate variability (HRV) studies (ANSAR Inc., PA), cardiovascular autonomic reflex tests (deep-breathing, Valsalva, postural test), and positron emission tomography with sympathetic analogue [11C]meta-hydroxyephedrine. Associations between measures of CAN and ESC were estimated using Spearman correlations. Longitudinal changes were analyzed using paired t-test. RESULTS: At baseline, there were no differences between T1D and HC in ESChands (69±14 vs. 69±13µS; P=0.84) or ESCfeet (82±8 vs. 78±9µS; P=0.12), while some indices of HRV and Valsalva ratio were significantly lower in T1D vs. HC. T1D subjects experienced a significant decline in both ESChands and ESCfeet at 12months (mean change -7.2±11.6µS, P=0.0006; -2.8±7.3µS, P=0.023 respectively). No significant correlations were consistently found between ESC and measures of CAN at baseline or at 12months. CONCLUSION: Comparing patients with T1D to controls, no differences in ESC were observed at baseline. The associations between ESC and established measures of CAN were inconsistent, which does not support ESC as a reliable surrogate for CAN. While both hands and feet ESC declined over time, the significance of this finding is unclear and warrants further reliability testing.

Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3.

Primary cilia are highly specialized small antenna-like cellular protrusions that extend from the cell surface of many eukaryotic cell types. The protein content inside cilia and cytoplasm is very different, but details of the sorting process are not understood for most ciliary proteins. Recently, we have shown that prenylated proteins are sorted according to their affinity to the carrier protein PDE6δ and the ability of Arl3 but not Arl2 to release high affinity cargo inside the cilia (Fansa, E. K., Kösling, S. K., Zent, E., Wittinghofer, A., and Ismail, S. (2016) Nat. Commun. 7, 11366). Here we address the question whether a similar principle governs the transport of myristoylated cargo by the carrier proteins Unc119a and Unc119b. We thus analyzed the binding strength of N-terminal myristoylated cargo peptides (GNAT1, NPHP3, Cystin1, RP2, and Src) to Unc119a and Unc119b proteins. The affinity between myristoylated cargo and carrier protein, Unc119, varies between subnanomolar and micromolar. Peptides derived from ciliary localizing proteins (GNAT1, NPHP3, and Cystin1) bind with high affinity to Unc119 proteins, whereas a peptide derived from a non-ciliary localizing protein (Src) has low affinity. The peptide with intermediate affinity (RP2) is localized at the ciliary transition zone as a gate keeper. We show that the low affinity peptides are released by both Arl2·GppNHp and Arl3·GppNHp, whereas the high affinity peptides are exclusively released by only Arl3·GppNHp. Determination of the x-ray structure of myristoylated NPHP3 peptide in complex with Unc119a reveals the molecular details of high affinity binding and suggests the importance of the residues at the +2 and +3 positions relative to the myristoylated glycine for high and low affinities. The mutational analysis of swapping the residues at the +2 and +3 positions between high and low affinity peptides results in reversing their affinities for Unc119a and leads to a partial mislocalization of a low affinity mutant of NPHP3.

Deciphering the Molecular and Functional Basis of RHOGAP Family Proteins: A SYSTEMATIC APPROACH TOWARD SELECTIVE INACTIVATION OF RHO FAMILY PROTEINS.

RHO GTPase-activating proteins (RHOGAPs) are one of the major classes of regulators of the RHO-related protein family that are crucial in many cellular processes, motility, contractility, growth, differentiation, and development. Using database searches, we extracted 66 distinct human RHOGAPs, from which 57 have a common catalytic domain capable of terminating RHO protein signaling by stimulating the slow intrinsic GTP hydrolysis (GTPase) reaction. The specificity of the majority of the members of RHOGAP family is largely uncharacterized. Here, we comprehensively investigated the sequence-structure-function relationship between RHOGAPs and RHO proteins by combining our in vitro data with in silico data. The activity of 14 representatives of the RHOGAP family toward 12 RHO family proteins was determined in real time. We identified and structurally verified hot spots in the interface between RHOGAPs and RHO proteins as critical determinants for binding and catalysis. We have found that the RHOGAP domain itself is nonselective and in some cases rather inefficient under cell-free conditions. Thus, we propose that other domains of RHOGAPs confer substrate specificity and fine-tune their catalytic efficiency in cells.

Left ventricular metabolism, function, and sympathetic innervation in men and women with type 1 diabetes.

BACKGROUND: In type I diabetes (T1DM), alterations in LV function may occur due to changes in innervation, metabolism, and efficiency. OBJECTIVES: We evaluated the association between sympathetic nerve function, oxidative metabolism, resting blood flow, LV efficiency and function in healthy diabetics, and assessed gender differences. METHODS: Cross-sectional study of 45 subjects with T1DM, 60% females, age 34 ± 13 years, and 10 age-matched controls. Positron emission tomography (PET) imaging with [(11)C]acetate and [(11)C]meta-hydroxyephedrine was performed, in addition to cardiac magnetic resonance imaging. RESULTS: There were no significant differences in LV function, innervation, or oxidative metabolism between T1DM and controls. Cardiac oxidative metabolism was positively associated with higher levels of sympathetic activation, particularly in women. Diabetic women had significantly lower efficiency compared with diabetic men. Resting flow was significantly higher in diabetic women compared with diabetic men, and tended to be higher in female controls as well. CONCLUSIONS: Measures of myocardial function, metabolism, blood flow, and sympathetic activation were preserved in young, otherwise healthy, T1DM patients. However, T1DM women presented with greater myocardial oxidative metabolism requirements than men. Ongoing studies are evaluating changes over time.

Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes.

AIMS: Cardiovascular autonomic neuropathy (CAN) predicts clinical diabetic nephropathy (DN). We investigated the relationship between DN structural lesions and CAN. METHODS: Sixty three Pima Indians with type 2 diabetes underwent kidney biopsies following a 6-year clinical trial testing the renoprotective efficacy of losartan vs. placebo. CAN was assessed a median 9.2years later. CAN variables included expiration/inspiration ratio (E/I), standard deviation of the normal R-R interval (sdNN), and low and high frequency signal power and their ratio (LF, HF, LF/HF); lower values reflect more severe neuropathy. Associations of CAN with renal structural variables were assessed by linear regression adjusted for age, sex, diabetes duration, blood pressure, HbA1c, glomerular filtration rate, and treatment assignment during the trial. RESULTS: Global glomerular sclerosis was negatively associated with sdNN (partial r=-0.35, p=0.01) and LF (r=-0.32, p=0.02); glomerular basement membrane width was negatively associated with all measures of CAN except for LF/HF (r=-0.28 to -0.42, p<0.05); filtration surface density was positively associated with sdNN, LF, and HF (r=0.31 to 0.38, p<0.05); and cortical interstitial fractional volume was negatively associated with HF (r=-0.27, p=0.04). CONCLUSIONS: CAN associates with DN lesions.

Specificity of Lipoprotein Chaperones for the Characteristic Lipidated Structural Motifs of their Cognate Lipoproteins.

Lipoprotein-binding chaperones mediate intracellular transport of lipidated proteins and determine their proper localisation and functioning. Understanding of the exact structural parameters that determine recognition and transport by different chaperones is of major interest. We have synthesised several lipid-modified peptides, representative of different lipoprotein classes, and have investigated their binding to the relevant chaperones PDEδ, UNC119a, UNC119b, and galectins-1 and -3. Our results demonstrate that PDEδ recognises S-isoprenylated C-terminal peptidic structures but not N-myristoylated peptides. In contrast, UNC119 proteins bind only mono-N-myristoylated, but do not recognise doubly lipidated and S-isoprenylated peptides at the C terminus. For galectins-1 and -3, neither binding to N-acylated, nor to C-terminally prenylated peptides could be determined. These results shed light on the specificity of the chaperone-mediated cellular lipoprotein transport systems.

Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

OBJECTIVE: Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Forty-six T2D subjects (age 54±10years, diabetes duration 8±5years, HbA1c 8.2±1.3%) with mild to moderate DPN at baseline were randomized to receive either twice daily exenatide (n=22) or daily insulin glargine (n=24). The subjects, with similar HbA1c levels, were followed for 18months. The primary end point was the prevalence of confirmed clinical neuropathy (CCN). Changes in measures of CAN, other measures of small fiber neuropathy such as intra-epidermal nerve fiber density (IENFD), and quality of life were also analyzed. RESULTS: Glucose control was similar in both groups during the study. There were no statistically significant treatment group differences in the prevalence of CCN, IENFD, measures of CAN, nerve conductions studies, or quality of life indices. CONCLUSIONS: In this pilot study of patients with T2D and mild to moderate DPN, 18months of exenatide treatment had no significant effect on measures of neuropathy compared with glargine treatment.