bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction of Exocrine and Endocrine Pancreas in Obesity Ciliopathies
Authors: HOSTELLEY TIMOTHY L. , DUNLEAVEY JESSICA , ZAGHLOUL NORANN A.
Published: June 2018

Ciliopathies are rare genetic disorders characterized by dysfunction in primary cilia. Two ciliopathies, Alström Syndrome and Bardet-Biedl Syndrome (BBS), are characterized by high rates of obesity. However, they have strikingly different rates of diabetes. The rate is much higher in Alström patients relative to BBS. To gain insight into genetic mechanisms for this discrepancy we performed whole transcriptome sequencing on zebrafish depleted of the Alström gene, alms1, or the BBS gene, bbs1. We identified gene expression changes and found 8 genes that were differentially expressed in opposite directions between the two models. Among these, several exocrine pancreas enzymes were downregulated in Alström and/or upregulated in BBS. Based on this, and our previous demonstration of β-cell mass changes in models of both disorders, we hypothesized that the expression of exocrine pancreas enzymes affects endocrine pancreas function. This might suggest that impaired β-cell function in Alström results from reduced expression of exocrine pancreas enzymes, while the opposite may be true in BBS. These findings also support a non-ciliary role for BBS and Alström genes as we found them to be expressed in the non-ciliated acinar cells. To test our hypothesis, we overexpressed each enzyme in transgenic zebrafish embryos, in which β-cells can be visualized. In control animals, overexpression of the exocrine pancreas enzymes significantly increased the number of β-cells, suggesting that these enzymes play a role in regulating β-cell mass and function. Overexpression could also rescue the loss of β-cells observed in animals depleted of alms1. We have also found that the inactive form of these enzymes are selectively taken up by β-cells in vitro and induce proliferation in cultured MIN6 β-cells. This suggests a direct interaction between the exocrine and endocrine pancreas. Taken together, these data support the possibility that exocrine pancreatic enzymes may play an important role in the modulation of β-cells in diabetes.

Disclosure

T.L. Hostelley: None. J. Dunleavey: None. N.A. Zaghloul: None.
Clinical Variables and Outcomes of Kidney Transplant Recipients with Type 2 Diabetes and New-Onset Diabetes after Transplantation in a Predominantly Minority Urban Population
Authors: ALEKSIC SANDRA , ANARAKI SARA ZAHEDPOUR , TSOMOS EFFIE , UPADHYAY LAXMI , JAPP EMILY , AJAIMY MARIA , AKALIN ENVER , ZONSZEIN JOEL
Published: June 2018

Background: Minority populations remain at a high risk for type 2 diabetes (T2D) and its complications. In kidney transplant recipients T2D and new onset diabetes after transplant (NODAT) are associated with worse outcomes, but data from minority populations are limited. We aimed to characterize clinical variables and outcomes in a predominantly minority kidney transplant recipients with T2D and NODAT.

Methods: We performed a retrospective chart review of all recipients of kidney transplant in a large urban university center from June 01, 2012 until December 31, 2014. Individuals with type 1 diabetes or pancreas transplant were excluded. NODAT was defined by the ADA criteria.

Results: We included 304 individuals, 40% Hispanic and 41% non-Hispanic black. Fifty percent had T2D. During a median follow-up of 37 (22-52) months, 36% of the recipients without diabetes developed NODAT. Hispanics and non-Hispanic blacks less frequently remained without diabetes compared to non-Hispanic whites (27% vs. 29% vs. 51%, p=0.001). Individuals with T2D had higher BMI compared to NODAT and no diabetes (29.9±7.4 vs. 28.1±6.5 vs. 27.2±5.7kg/m2, p=0.007). Individuals with T2D and NODAT were older than those without diabetes (60.8±9.5 vs. 56.5±13 vs. 47.9±14 years, p<0.0001), had more pretransplant cardiovascular disease (36 vs. 26 vs. 11%, p<0.0001), more deceased-donor transplants (90 vs. 93 vs. 75%, p=0.0007), and had significantly higher proteinuria at 6, 12, and 24 months posttransplant, but no difference was found in serum creatinine, graft survival (94 vs. 94 vs. 93%, p=0.904) or patient survival (93 vs. 96 vs. 95%, p=0.708).

Conclusions: In a predominantly minority cohort there was a high rate of both T2D and NODAT with only less than one fifth of individuals without diabetes. In this high-risk population, there was no difference in patient or graft survival over a relatively short observational period.

Disclosure

S. Aleksic: None. S. Zahedpour Anaraki: None. E. Tsomos: None. L. Upadhyay: None. E. Japp: None. M. Ajaimy: None. E. Akalin: None. J. Zonszein: Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Merck & Co., Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc..
Effect of Carnosine Supplementation on Cardiometabolic Risk Factors in Obesity, Prediabetes, and Diabetes—A Meta-analysis of Randomized Controlled Trials
Authors: MENON KIRTHI ARAVIND , MOUSA AYA , COURTEN BARBORA DE
Published: June 2018

The burden of diabetes is rapidly increasing in line with the growing obesity epidemic. Identification of simple and easily scalable interventions is therefore urgently needed. Carnosine (beta-alanyl-L-histidine), a dipeptide with anti-inflammatory, anti-oxidative, and anti-glycating properties, has been proposed as a potential strategy for the prevention of diabetes. However, previous studies examining the effects of carnosine on cardiometabolic risk factors have produced inconsistent results. Here, we present the first systematic review and meta-analysis examining the effects of carnosine supplementation on cardiometabolic risk factors. Electronic databases including Medline, CINAHL, EMBASE and EBM Reviews were searched to identify all randomized controlled trials (RCTs) comparing supplementation with carnosine vs. placebo, usual care or other interventions. In meta-analyses of five trials with 309 participants, carnosine-supplemented groups had lower HbA1c (mean difference (MD) [95% CI]= -0.5% [-0.4,-0.6], p<0.001); fasting glucose (MD [95% CI]= -0.6 mmol/L [-1.1, -0.1], p=0.03); postprandial glucose (MD [95% CI]= -1.0 mmol/L [-1.4, -0.6], p<0.001); triglycerides (MD [95% CI]= -0.4 mmol/L [-0.6, -0.3], p=0.005); and high-sensitivity C-reactive protein (MD [95% CI]= -0.4 mg/L [-0.6, -0.2], p<0.001) compared with placebo. Low statistical heterogeneity was observed for all outcomes (I2=0-1%) except fasting glucose (I2=84%). However, heterogeneity in study design was an important limitation, including the different populations studied, and the use of varying doses of carnosine and mixed supplementation. Nevertheless, our findings suggest that carnosine may improve cardiometabolic risk factors and further well designed randomized controlled trials are needed to confirm these findings.

Disclosure

K. Aravind Menon: None. A. Mousa: None. B. de Courten: None.
Intrauterine Growth Retardation Induced Long-Term Gene Dysregulation Is Associated with Altered Histone Modifications in Rat Islets
Authors: LIEN YU-CHIN , WANG PAUL , SIMMONS REBECCA A.
Published: June 2018

Intrauterine growth retardation (IUGR) is associated with the development of type 2 diabetes in adulthood. Although the underlying mechanisms remain unclear, permanent alterations in gene expression implicate epigenetics. Using a rat model of IUGR induced by bilateral uterine artery ligation at e18, we sought to determine if histone modifications are a potential mechanism for permanent IUGR-induced gene dysregulation. We assessed genome-wide histone modifications in islets from 2 and 10 week control and IUGR rats using ChIP-Seq. IUGR induced significant changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in 2 week islets at 2181, 1482, and 4572 annotated genes, respectively. At 10 week there were far more changes in enrichment of these marks (9988, 3489, and 4355 genes, respectively). We then integrated our RNA-Seq transcriptome data obtained at the same ages and found that the expression levels of multiple genes in IUGR islets were correlated with changes in histone marks. In 10 week islets, the expression of 639, 355, and 400 genes correlated with changes in enrichment of H3K4me3, H3K27me3, and H3K27Ac, respectively; whereas in 2 week islets, only 43, 64, and 149 genes were correlated with enrichment of these marks. Interestingly, 6 genes in 10 week islets correlated with changes in all 3 histone marks, strongly suggesting that changes in gene expression were induced by histone modifications. Ingenuity pathway analysis of differential expressed genes that correlated with histone modifications revealed significant enrichment in pathways critical for normal islet function, such as cAMP-mediated signaling, immune function, axonal guidance, and VEGF family ligand-receptor interaction. Collectively, the present findings identify histone modification as a potential epigenetic mechanism that may contribute to long-term gene dysregulation and abnormal islet phenotype in IUGR animals.

Disclosure

Y. Lien: None. P. Wang: None. R.A. Simmons: None.
Prevalence of Peripheral Neuropathy in Prediabetes
Authors:   UAZMAN ALAM, OF LIVERPOOL DIABETES AND ENDOCRINE RESEARCH GROUP,   UNIVERSITY, EARLY NEUROPATHY ASSESSMENT GROUP, MANCHESTER
Published: June 2018

Objectives: There are conflicting evidence regarding the relationship of peripheral neuropathy in prediabetes. Our aim was to determine the prevalence of peripheral neuropathy in prediabetes through a systematic literature review and meta-analysis.

Methods: Five electronic databases, namely MEDLINE, EMBASE, PubMed, Web of Science and Cochrane Central Register of Controlled Trials were searched for studies published up to October 2017. Original full studies were included that provided prevalence data for a population with prediabetes, who were over 18 years of age. Additional studies were identified from reference lists and two reviewers independently identified eligible studies on predefined inclusion criteria.

Results: In total, 1314 studies were identified after duplicates were removed and subsequently 1255 were excluded. Of the 59 remaining studies, 23 studies (n=6494) met the inclusion criteria for the meta-analysis. The pooled prevalence estimate of neuropathy in prediabetes was 18% (95% CI: 13-22%) with a marked level of heterogeneity (I2 = 97%). The high level of heterogeneity between studies was partly explained by the method of neuropathy assessment. Subgroup analyses based on the method of neuropathy assessment was evaluated and the prevalence was highly dependent on the method of assessment. The prevalence depending on the type of test used was: quantitative tests: 16% (95% CI: 3-30%, I2 = 95%), physical examination: 24% (95% CI: 7-40%, I2 = 83%), questionnaires: 8% (95% CI: 2 -13%, I2 = 57%) and combination(s) of the three: 18% (95% CI: 13- 24%, I2 = 97%).

Conclusions: There is a higher than expected prevalence of peripheral neuropathy in prediabetes. Future large, population based studies using accurate and quantitative means of identifying neuropathy are required and an internationally agreed definition as to what constitutes prediabetic neuropathy is required.

Disclosure

U. Alam: Speaker's Bureau; Self; Sanofi, Novo Nordisk A/S.
LXRs Protect DRG Neurons from High-Fat Diet–Induced ER Stress and Allodynia
Authors: AUBERT VIRGINIE
Published: June 2018

Painful diabetic neuropathy (DN) affecting small sensory neurons is one of the most common complications of obesity and type 2 diabetes. While emerging clinical evidence demonstrates that DN is associated with dyslipidemia, the complex molecular and cellular neurobiology triggering the disease is unknown. Emerging evidence demonstrates the important contribution of complex pathways including endoplasmic reticulum stress and inflammation. Recent OMICs data analyzing peripheral nervous tissue (Dorsal root ganglia (DRG) and associated nerves) of obese individuals have also highlighted alterations in lipid nuclear receptors, which provide novel insight into the onset of DN. Liver X Receptors (LXR) α and β are nuclear transcription factors that respond to cholesterol or fatty acid metabolites. Nuclear LXRs control gene programs in liver cells, adipocytes, and macrophages to regulate lipid metabolism, inflammation and ER stress though the specific physiological role of LXRs in neurons is difficult to interpret given its broad tissue expression. Our tissue specific deletion model unmasks an important role of LXR in small sensory neurons in type 2 DN pathogenesis. Our results show that LXR deletion in sensory neurons worsens the hypersensitivity induced by a High fat Diet (HFD) associated with changes in DRG gene. In addition, treatment with the LXR agonist GW4965 improves the HFD-induced mechanical allodynia in vivo and protects mice DRG sensory neurons from lipid-induced ER stress in vitro and in vivo (ribo-tag model), further confirming a protective role for LXR in DN. Our data suggest that the lipid sensor LXRs in small sensory neurons could respond to dietary lipid to potentially maintain normal PNS function in the face of high-fat nutrition.

Disclosure

V. Aubert: None.
Palmitoylethanolamide in Add-On to Alpha Lipoic Acid for Control of Symptoms of Diabetic Peripheral Neuropathy
Authors: MADDALONI ERNESTO , MAURIZI ANNA RITA , MINUTOLO ALESSANDRA , FIORITI ELVIRA , TORO ROSSELLA DEL , NACIU ANDA MIHAELA , PIERALICE SILVIA , ROSATI MILENA M. , MANFRINI SILVIA , POZZILLI PAOLO
Published: June 2018

Background: Palmitoylethanolamide (PEA) is an amide with “autacoid local inflammation antagonism” effects, protecting nerve degeneration due to mast cell degranulation. PEA add-on to alpha-lipoic acid (ALA) is successfully used as treatment of neuropathic pain, but there are no data in diabetic peripheral neuropathy (DPN) specifically.

Aim: To evaluate whether PEA in add-on to ALA has potentials in controlling DPN symptoms.

Methods: In this pilot longitudinal observational study, clinical and biochemical data from ninety-eight consecutive subjects with type 1 diabetes (T1D) evaluated for DPN symptoms between January and July 2017 in our outpatient clinic were retrospectively retrieved. DPN symptoms were assessed by Neuropathy Symptoms Score (NSS). Follow-up data were retrieved for patients with NSS ≥3 and receiving treatment with ALA 600mg/daily ± PEA 600mg/daily or receiving no treatment.

Results: NSS was ≥3 in 34 (34.7%) subjects. Of these, 17 were treated with ALA ± PEA (9 with ALA in monotherapy and 8 with PEA in add-on to ALA), and 17 were not treated. After a mean follow-up of 8.1±3.4 months, NSS was ≥3 in 76.5% of non-treated subjects vs. 29.4% of treated subjects (p<0.01). The percentage of subjects with NSS≥3 did not differ between subjects treated with ALA vs. those treated with ALA+PEA (p=0.62). The mean time for symptoms resolution (NSS<3) was lower in subject treated with ALA+PEA than in those treated with ALA in monotherapy (14.0±8.6 vs. 25.0±9.1 days, p<0.05). Among treated subjects, baseline HDL-cholesterol was inversely related to the time to symptoms resolution (p=0.026)

Conclusions: PEA add-on to ALA accelerates the resolution of neuropathic symptoms in T1D subjects with DPN. This study also suggests HDL-cholesterol may be a biomarker for the response to treatment with ALA ± PEA.

Disclosure

E. Maddaloni: Speaker's Bureau; Self; Merck & Co., Inc.. Research Support; Self; European Foundation for the Study of Diabetes. A. Maurizi: None. A. Minutolo: None. E. Fioriti: None. R. Del Toro: None. A. Naciu: None. S. Pieralice: None. M.M. Rosati: None. S. Manfrini: None. P. Pozzilli: Research Support; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; Merck Sharp & Dohme Corp..
Amelioration of Peripheral Neuropathy in Mouse Models of Diabetes by Dietary Reversal
Authors: O'BRIEN PHILLIPE D. , GUO KAI , HINDER LUCY M. , HAYES JOHN M. , MENDELSON FAYE , TABBEY MAEGAN A. , HUR JUNGUK , FELDMAN EVA L.
Published: June 2018

Peripheral neuropathy (PN) is a common complication of prediabetes and type 2 diabetes (T2D). Lifestyle changes, including dietary reversal (DR), can reverse PN, although the mechanisms involved remain unclear. The goal of this study was to identify the mechanisms that underlie PN development in prediabetes and T2D and understand which of these are corrected upon DR. To achieve this, we used two models of PN and looked at the effects of DR on global gene expression and lipid profiles in peripheral nerves.

C57BL/6J mice were fed a standard diet (10% kcal fat; SD) or high fat diet (60% kcal fat; HF) from 5 week. A subset of HF mice were injected with STZ at 12 week to induce hyperglycemia, reflecting a more diabetic-like phenotype. At 16 week, subsets of HF and HF-STZ mice were placed on the standard diet for 8 week (HF-DR and HF-STZ-DR, respectively) until 24 week when terminal phenotyping was performed. At baseline and at study completion, sciatic nerve tissue was processed for gene expression by RNAseq or for lipid species profiling by untargeted shotgun lipidomics.

HF and HF-STZ mice display PN compared to controls. In contrast, peripheral nerve function of HF-DR and HF-STZ-DR mice was corrected upon DR. Neural gene expression analysis revealed numerous differentially expressed genes (DEG) when comparing SD to HF or HF-STZ mice. Interestingly, a proportion of the genes dysregulated in HF and HF-STZ, were similarly reversed by DR. KEGG enrichment of these genes revealed that lipid metabolism pathways were enriched. Lipidomic analysis revealed a similar pattern of differentially altered lipids that were reversed by DR in HF and HF-STZ mouse models. Lipids reversed by DR include diacylglycerol, a known mediator of insulin resistance.

We demonstrate that DR of HF and HF-STZ mice can restore peripheral nerve function. We also show that genes related to lipid function are dysregulated in diseased states and are reversed by DR. This study supports the idea that DR improves peripheral nerve function by restoring lipid homeostasis.

Disclosure

P.D. O'Brien: None. K. Guo: None. L.M. Hinder: None. J.M. Hayes: None. F. Mendelson: None. M.A. Tabbey: None. J. Hur: None. E.L. Feldman: None.
The Association between Urinary N-Acetyl-ß-D-Glucosaminidase and Cardiovascular Autonomic Neuropathy in Patients with Diabetes
Authors: CHOI MIN SUN , JUN JI EUN , KIM GYURI , JIN SANG-MAN , HUR KYU YEON , LEE MOON-KYU , KIM JAE HYEON
Published: June 2018

Background: Cardiovascular autonomic neuropathy (CAN) is a microvascular complication of diabetes, which involves autonomic nerve fibers innervating the heart and vessels, resulting in increased cardiovascular morbidity and mortality. Previous studies reported that diabetic CAN is related to microalbuminuria. However, it is unclear whether CAN is related with urinary N-acetyl-β-D-glucosaminidase (uNAG), which was suggested as an early marker of renal tubular injury in diabetic nephropathy recently.

Methods: Cross-sectional data of 1052 patients with diabetes were analyzed who had tests for uNAG and autonomic function test at outpatient clinic. The presence and severity of CAN were assessed by the five autonomic function tests.

Results: The association between uNAG and the presence of CAN in patients with type 1 diabetes (T1D) (n=161) was significant in multivariate analysis (OR 1.20, 95% CI 1.03-39; p = 0.018) after correction of variables including age, duration of diabetes, glycemic index and albuminuria, but it was insignificant in patients with type 2 diabetes (T2D) (n=891). Among quartile groups divided by uNAG levels, prevalence of CAN was significantly increased across with higher quartiles of uNAG level only in patients with T1D (p = 0.013). The association between uNAG and the total CAN score, assessed as the severity of CAN, was significant in both patients with T1D (p = 0.033) and T2D (p = 0.006) in multivariate analyses.

Conclusion: Elevated uNAG is associated with the prevalence of CAN only in patients with T1D, and it is also related to the severity of CAN in both patients with T1D and T2D. It suggests that elevated uNAG might be a potential marker for the development and progression of CAN in patients with diabetes.

Disclosure

M. Choi: None. J. Jun: None. G. Kim: None. S. Jin: None. K. Hur: None. M. Lee: None. J. Kim: None.
Analysis of Different Methods for the Diagnosis of Subclinical and Clinical Stages Polyneuropathy in Patients with Type 2 Diabetes Mellitus
Authors: FOKINA ANASTASIIA , ZILOV ALEXEY , STROKOV IGOR , SURNINA ZOYA
Published: June 2018

Many patients with T2DM have a late complication at the time of diagnosis,most commonly diabetic peripheral neuropathy (DPN).We explored whether clinical indiced of polyneuropathy correlate with large and small nerve fiber pathology.

The goal of this study is to analyzed various diagnostic techniques for the detection of lesions of nerve fibers in patients with T2DM and subclinical and clinical stages of DNP by electrophysiology study and nerve conduction velocity (NCV),skin biopsy and corneal confocal microscopy (CCM) with use of the author's algorithm for calculating the tortuosity and orientation of the nerve fibers of the cornea.

Materials and methods: Electrophysiological study of large nerve fibers and microscopic examination of small nerve fibers in patients with T2DM with subclinical (n=50) and clinical stages of DPN (n=50) were performed.

Results: The changes in the S-response and in NCV were received the most frequently in patients with subclinical and clinical stages of DPN in the study of the sensory gastrocnemius nerve.At stimulation of the motor nerves,the changes were related to the M-response and NCV of the peroneal and tibial nerves.At skin biopsy,we saw that the intraepidermal nerve fibers density (IENFD) in patients with T2DM was significantly reduced in subclinical and clinical stages of DPN.In the subclinical form of DPN,some values of CCM significant correlate with IENFD and with NCV along the gastrocnemius nerve in the entire studied population,but this correlation was not strong.At symptomatic DPN,a strong correlation was found between IENFD and parameters of NCV (p<0.05),as well as with data of electroneyromyograpry (p<0.05).

Conclusion: The results of the study showed that the changes in large fiber function accompany the loss of small nerve fibers and occurs in patients with T2DM already in the preclinical stage of DPN. CCM can be a powerful tool for non-invasive early diagnosis of neuropathy in subclinical stage DPN.

Disclosure

A. Fokina: None. A. Zilov: None. I. Strokov: None. Z. Surnina: None.
The Reference Distribution of Annual Change in Corneal Nerve Fibre Length in Diabetes Mellitus
Authors: LEWIS EVAN J.H. , TAVAKOLI MITRA , LOVBLOM LEIF ERIK , HALPERN ELISE M. , JEZIORSKA MARIA , PACAUD DANIÈLE , PRITCHARD NICOLA , SHTEIN RONI M. , EFRON NATHAN , BRIL VERA , MALIK RAYAZ A. , PERKINS BRUCE A.
Published: June 2018

The measurement of corneal nerve fibre length (CNFL) by in vivo corneal confocal microscopy is a biomarker for the presence of diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, its prevalence in T1D and T2D, and its clinical predictors. We examined longitudinal data from 94 nondiabetic controls and 297 diabetes participants (224 T1D and 73 T2D) from an ongoing multi-centre NIH-funded study of IVCCM in diabetes. Participants were included if they had at least 1-year of follow-up data and were classified as progressors with “rapid corneal nerve fibre loss” (RCNFL) if the loss of CNFL was beyond the 5th percentile (-14%/y) of the nondiabetic controls. Nondiabetic controls were 43.0±15.8 y, had a median of 2 follow-up visits over a median of 2 y, baseline CNFL of 15.4±4.2 mm/mm2, and the median annual change in CNFL was -1.7%[90% CI, -14.3 to 30.9%]. Diabetes participants were 49.6±15.5 y, had a median of 3 visits over a median of 2 y, baseline CNFL of 14.3±4.4 mm/mm2 and the median annual change in CNFL was 1.8%[90% CI, -26.1 to 25.0%]. There were 33(11.1%) cases of RCNFL in the diabetes sub-cohort, which was comparable between T1D (26(11.6%)) and T2D (7(9.6%)). Progressors did not differ from non-progressors for baseline levels of age, sex, BMI, HbA1c or CNFL levels. However, progressors were more likely to have baseline DSP (16(50%) vs. 83(32%), p=0.048), lower cooling detection threshold (21.3 C±8.5 vs. 25.3 C±7.2, p=0.048) and lower heart rate variability (26.3±13.1 vs. 38.2±25.4, p=0.036). A more rapid loss of CNFL (RCNFL) exceeding 14%/y occurs in ∼11% of diabetes patients. This more rapid of corneal nerves may identify patients at highest risk for the development or progression of DSP.

Disclosure

E.J.H. Lewis: Employee; Self; Nutarniq Corp. M. Tavakoli: None. L. Lovblom: None. E.M. Halpern: None. M. Jeziorska: None. D. Pacaud: Research Support; Self; Eli Lilly and Company, Novo Nordisk Inc., National Institute of Diabetes and Digestive and Kidney Diseases, Versartis, Inc. N. Pritchard: Other Relationship; Self; JDRF, NHMRC. R.M. Shtein: None. N. Efron: None. V. Bril: Consultant; Self; Alexion Pharmaceuticals, Inc.. Research Support; Self; CSL Behring, Grifols. Advisory Panel; Self; CSL Behring. Consultant; Self; Grifols. Research Support; Self; Shire. Advisory Panel; Self; Pfizer Inc.. R.A. Malik: None. B.A. Perkins: Advisory Panel; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH, Novo Nordisk Inc.. Advisory Panel; Self; Novo Nordisk Inc., Abbott. Speaker's Bureau; Self; Abbott, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Insulet Corporation. Speaker's Bureau; Self; Insulet Corporation, Dexcom, Inc..
Dapagliflozin Doesn't Increase Dietary Intake in Japanese
Authors: KITAOKA MASAFUMI , FUJII HITOMI , IMAI KENTA , ECHIDA YOSHIHISA , KANNO KAZUO , MIYAKAWA TAKAICHI , SHIGETA MASAYUKI
Published: June 2018

Purpose: We randomly allocate to dapagliflozin (DAPA) administered group (group A) and the group continuing current treatment (group B) for type 2 diabetic patients with stable glycemic control and investigate whether changes in eating behavior are observed or not.

Method: group A orally administer 5 mg of DAPA once daily for 12 weeks in addition to current diet therapy · exercise therapy and diabetes drugs. In the group B, the current diet therapy/exercise therapy and diabetes drugs are continued for 12 weeks. Blood test and urinalysis were conducted 0 weeks, 4 weeks, 12 weeks after. The main endpoint was the comparison between the two groups of total calorie intake change using brief-type self-administered diet history questionnaire (BDHQ) at 12 weeks. And the secondary endpoints were comparison between two groups of the following items before and after treatment. 1.) nutritional status based on BDHQ, 2.) body weight, abdominal girth, blood pressure, grip strength, 3.) blood glucose profile, 4.) lipid profile.

Subject: There were 76 cases of consent to participation in this study, but since there were three dropout cases, the analysis subjects were 35 patients in group A, 38 patients in group B.

Result: In the group A, HbA1c (7.47±0.67 vs. 7.09±0.56 p<0.0001) and body weight (70.20±11.79 vs. 69.15±12.13 p<0.0002) decreased significantly, but no change in total caloric intake by BDHQ (1675.23±580.67 vs. 1636.92±625.32) was observed. On the other hand, in the group B, no changes in total calorie intake by BDHQ, HbA1c, body weight, were observed.

Discussion: This study indicated that no increase in dietary intake was observed upon weight loss by DAPA. It has already been reported that weight loss due to DAPA improves patients’ QoL. Improvement of this QoL may be expected to have a positive influence on improvement of treatment motivation and diet therapy/exercise therapy which is the basis of diabetes treatment. This study suggests that in humans, unlike animal experiments, calorie loss by DAPA may have a positive effect on dietary behavior.

Disclosure

M. Kitaoka: Research Support; Self; AbbVie Inc., AstraZeneca, Ono Pharmaceutical Co., Ltd.. H. Fujii: None. K. Imai: None. Y. Echida: None. K. Kanno: Research Support; Self; Astellas Pharma Inc.. Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi K.K., MSD K.K.. Research Support; Self; Taisho Toyama Pharmaceutical Co., Ltd.. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, Takeda Phamaceutical Company Ltd. T. Miyakawa: Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company, MSD K.K.. M. Shigeta: None.
Screening for Diabetic Retinopathy in African Immigrants—The Africans in America Study
Authors: CHRISTAKIS PANOS G. , KABAKAMBIRA JEAN DAMASCENE , BRIKER SARA M. , DUBOSE CHRISTOPHER , SUMNER ANNE E. , CHEW EMILY
Published: June 2018

The degree to which retinopathy occurs in Africans with abnormal glucose tolerance is unknown. Therefore, the objective of this study was to screen for diabetic retinopathy in self-identified healthy African immigrants. A total of 167 Africans now living in the Washington DC area underwent a medical workup and eye exam at the NIH. Visual acuity, intraocular pressure, slit lamp biomicroscopy and dilated fundus biomicroscopy were performed. Diagnostic testing included color fundus photography, fundus autofluorescence, and optical coherence tomography of the macula and optic nerve. The participants were 41 ± 10 years old (mean ±SD) and duration of stay in the U.S.A was 12 ± 10y. BMI was 28 ± 4 kg/m2, and 17 (10%) participants were being treated for hypertension. OGTT revealed diabetes in 15 (9%) participants, and prediabetes in 58 (35%) participants. Retinopathy was detected in 7 (4.2%) participants, 5 of whom had findings consistent with mild non-proliferative diabetic retinopathy in the setting of diabetes (n=3) or prediabetes (n=2) on OGTT. One participant had a flame shaped hemorrhage due to untreated Stage 2 hypertension, and one participant without vascular risk factors had peripheral dot-blot hemorrhages. Participants with retinopathy were older (49 ± 10 vs. 40 ± 10 years old, p=0.02), had higher systolic BP (140 ± 25 vs. 119 ± 14 mmHg, p<0.001) and higher A1C (6.4 ± 2.2% vs. 5.4 ± 0.6%, p<0.001) than participants without retinopathy. There was no difference in retinopathy rates based on sex, African region, BMI, education level, income, drinking/smoking status, physical activity, or sickle cell/HbC trait status. In short, OGTT testing reveals that African immigrants who self-identify as healthy have high rates of undetected diabetes and prediabetes. Some (4.2%) already have retinopathy, and require annual follow-up to monitor for progression. Vascular risk factors including hypertension and prediabetes were associated with retinopathy, and we would recommend screening at-risk individuals.

Disclosure

P.G. Christakis: None. J. Kabakambira: None. S.M. Briker: None. C. DuBose: None. A.E. Sumner: None. E. Chew: None.
Male Type 2 Diabetic Patients Have Higher Diabetic Retinopathy Prevalence
Authors: CHERCHI SARA , GIGANTE ALFONSO , CONTINI PIERPAOLO , PISTIS DANILA , PILOSU ROSANGELA M. , SPANU MARIA A. , FOIS MARIA A. , LAI ALESSIO , MELONI GISELLA , TONOLO GIANCARLO
Published: June 2018

Diabetic retinopathy (DR) is one of the main causes of visual loss in individuals aged 20-64 years old. Some evidence indicate clear sex gender differences in diabetes complications, but studies focused on sex-gender differences in DR do not give clear data. The aim of this study was to investigate sex gender difference in DR type 2 diabetic patients (T2DM).

Methods: During 2015-2017 in seven diabetic out- patient clinics in Sardinia we examined under midriatic funduscopy 19.951 (11.409 males, 8.542 females) T2DM with known diabetes duration more than 5 years. Patients were classified as having: a) No DR (NRD),b) Mild non proliferative DR (RDNP), c) pre-proliferative and proliferative DR (RDPP), maculopathy (MAC). Each patient had full clinical and laboratory data available. In the same period in three diabetic outpatient clinics we performed also non midriatic retinography in other 1916 T2DM during the outpatient visit using a semi automated digital fundus camera and each imagine was evaluated by an experienced diabetologist/oculist.

Results: Diabetic retinopathy was more frequent under midriatic fundoscopy in males than females: (RDNP 15.9% vs. 14.3%,p<0.01 and RDPP 5,0% vs. 4.0%, p<0.001). Semi automated non midriatic retinography allowed to exclude DR in 68% of patients.

Conclusions: Our preliminary results indicate that: a) In this large sample of T2DM with known diabetes duration more than 5 years, DR is present in 24.1% of the subjects, with unit 3 having the highest prevalence (27.6%) and unit 6 the lowest (16.5%), P<0.00001 b) females have significantly less DR than males (p<0.00001), this effect is evident also excluding Unit 3 p=0.0002. c) retinography may allows to exclude DR in almost 68% of outpatient T2DM patients avoiding the more expensive classical oculist assessment. Further analysis is under way in order to identify possible markers of sex gender difference in DR.

Disclosure

S. Cherchi: None. A. Gigante: None. P. Contini: None. D. Pistis: None. R.M. Pilosu: None. M.A. Spanu: None. M.A. Fois: None. A. Lai: None. G. Meloni: None. G. Tonolo: None.
High Prevalence of Distress among Patients with Type 2 Diabetes (T2DM)—A Hospital-Based Cross-Sectional Study from South India
Authors: SANKAR PRASANTH , SASIKUMAR PRIYANKA , MEDAYIL RITUNA , JACOB RITTIN , SASIDHARAN SARANYA
Published: June 2018

Background: Diabetes distress (DD) refers to unique, often hidden emotional burdens and worries, distinct from clinical depression, that are part of the spectrum of patient experience when managing diabetes.

Aim: To assess DD and its association with various parameters in patients with T2DM.

Methodology: A cross sectional study was done on 262 out-patients with T2DM in a multispecialty hospital in South India. DD was measured by DDS-17, a 17-item self-reported DD scale used with subscales in 4 domains - Emotional burden (EB), Physician, Regimen and Interpersonal distress. Overall score <2.0 was little or no distress, 2.0-2.9 moderate, ≥3.0 was high distress. Data was analysed using SPSS version 11.5.

Results: Mean age of participants was 59.7 ± 9.1 years. Females constituted 71.8%. BMI was ≤ 25kg/m2 in 32.8%. Duration of diabetes was <10 years in 42%. Insulin was used by 45%. Mean HbA1c was 8.7±1.7%. Prevalence of DD was 27.9%, with moderate distress in 22.1% and high distress in 5.7%. Mean total DD score was 1.67± 0.59. Mean for EB, physician-related, regimen-related and interpersonal distress were (2.1 ± 1.02), (1.09 ± 0.33), (1.92 ± 0.89), (1.30± 0.76) respectively. Total DD had significant association with BMI (p=0.04), duration of T2DM (p=0.04), HbA1c (p=0.01), neuropathy (p=0.002) and nephropathy (p=0.008). EB, considered most important domain, was associated with duration of T2DM (p=0.02), insulin use (p=0.002), neuropathy (p<0.001), nephropathy (p=0.008), high HbA1c levels (p=0.001), ASCVD in females (p<0.001). Regimen related distress was more in those with high HbA1c (p=0.001) and smokers (p=0.04).

Discussion: The study, first of its kind from South India, identifies high prevalence of DD in this population. Assessment of DD should be integrated into patients’ self-care plan. Patients become more involved in managing diabetes if their specific emotional distress are taken care of, and have a better sense of social care, health control and self-efficacy.

Disclosure

P. Sankar: None. P. Sasikumar: None. R. Medayil: None. R. Jacob: None. S. Sasidharan: None.
Alterations in Somatomotor Network Functional Connectivity in Painful Diabetic Neuropathy—A Resting State Functional Magnetic Resonance Imaging Study
Authors: SELVARAJAH DINESH , AWADH MOHAMMED , GANDHI RAJIV , WILKINSON IAIN D. , TESFAYE SOLOMON
Published: June 2018

Aims: Painful diabetic neuropathy (Painful-DN) is a common disabling condition, with no objective biomarkers and less than optimal treatments. RS-fMRI is a quick (5 minute) functional imaging method that evaluates regional cortical interactions that occur when a subject is at rest. The aim of this study was to explore resting functional connectivity of the somotomotor network in painful DN as a possible objective biomarker for neuropathic pain.

Methods: 46 patients with diabetes (No DN, n=16; Painful DN, n=15; Painless DN, n=15) and 16 healthy volunteers underwent detailed clinical and neurophysiological assessments. RS-fMRI data were acquired at 3T (Philips Healthcare) and functional connectivity analysis was performed using FSL (www.fmrib.ox.ac.uk/fsl).

Results: There was reduced functional connectivity in the sensorimotor network (postcentral gyrus -42,-22,56; all TFCE, corrected p<0.05) and default mode network (precuneus -6,-46,40; p<0.05), superior frontal gyrus (34,62,60; p<0.05), Heschl’s gyrus (-42,-22,12; p<0.05), insular cortex (34,62,60; p<0.05) and superior parietal lobule (-22,-42,68; p<0.05). Somatomotor network functional connectivity significantly correlated with quantitative pain assessments (Short Form 36, r=-0.52; p=0.03 and Chronic Pain Acceptance Questionnaire r=-0.55, p=0.045).

Conclusion: These findings demonstrate that chronic pain has a widespread impact on overall brain function in diabetes, and suggests that disruptions of the resting state networks may underlie the cognitive and behavioural impairments accompanying chronic pain. Specifically within the somatomotor network, we have demonstrated abnormal functional connectivity in painful DPN which correlates with clinical measures of pain and behaviour. RS-fMRI has the potential to serve as an objective biomarker for the chronic pain condition in DPN.

Disclosure

D. Selvarajah: None. M. Awadh: None. R. Gandhi: None. I.D. Wilkinson: None. S. Tesfaye: Speaker's Bureau; Self; Pfizer Inc.. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Takeda Development Centre Europe Ltd.. Advisory Panel; Self; Wörwag Pharma GmbH & Co. KG.
Lipoprotein(a) Levels Are Twice as High in Left-Handed T2DM Patients
Authors: HERMANS MICHEL P. , AHN SYLVIE A. , ROUSSEAU MICHEL F.
Published: June 2018

Background: We previously reported that T2DM patients with elevated lipoprotein(a) [Lp(a)] were characterized by lesser insulin resistance and high frequency of left-handedness.

Objective: The aim of this work was therefore to characterize the lipids and lipoproteins in T2DM, to see if there were quantitative or qualitative differences depending on motor laterality.

Methods: The cardiometabolic phenotype of 517 Caucasian patients with type 2 diabetes (T2DM) was determined according to laterality, 444 patients being right-handed (RHs; 86%) and 73 left-handed or ambidextrous (non-RHs; 14%). Besides routine lipids, Lp(a), non-Lp(a)-LDL-C, apoB100, apoA-I, and atherogenic dyslipidemia were also measured, including pre-/post-statin levels in treated paitients.

Results: Non-RHs had a stronger family history of early-onset CVD, were more insulin- sensitive, and were less often treated with insulin. RHs and non-RHs did not differ as regards use and intensity of statins, routine lipids, apoB100, apoA-I, prevalence/severity of atherogenic dyslipidemia, and LDL size. In contrast, Lp(a) levels were significantly higher in non-RHs (median 37.0 vs. 18.7 nmol/L in RHs; p 0.0018), resulting in 32% of non-RHs having pathological Lp(a) vs. 20% in non-HRs (p 0.0467). Although pre-statin LDL-C was 15% higher in non-RHs, partly related to higher Lp(a), on-statin LDL-C did not differ between groups, suggesting better response/compliance to statins.

Conclusion: Lp(a) levels are twice as high in left-handed diabetic patients, while routine lipids and lipoproteins are unaffected by motor laterality. Elevated Lp(a) in left-handers also underlies higher LDL-C before statins, yet on-treatment LDL-C in left-handers decreased more after statins than that of right-handers, hinting to better compliance and/or greater response to statins.

Disclosure

M.P. Hermans: Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim GmbH, Mylan. Advisory Panel; Self; Novo Nordisk A/S, OmniPod. Speaker's Bureau; Self; Servier. Advisory Panel; Self; Sanofi-Aventis, Merck Sharp & Dohme Corp.. S.A. Ahn: None. M.F. Rousseau: None.
Atorvastatin Increases Fatty Acid Desaturases (FADSs) and Elongation of Very-Long-Chain Fatty Acids (ELOVLs) through Geranylgeranyl Pyrophosphate (GGPP)-Dependent Rho Kinase Pathway in HepG2 Cells
Authors: TATSUNO ICHIRO , TANAKA SHOU , ISHIHARA NORIKO
Published: June 2018

Background: The plasma concentration of arachidonic acid, one of the omega-6 long-chain polyunsaturated fatty acids (LCPUFAs), was increased by the treatment of statin in several clinical studies indicating that statin affects the endogenous synthesis of LCPUFAs, which is regulated by the action of the fatty acid desaturases (FADSs) and elongation of very long-chain fatty acids (ELOVLs).

Aims: We investigated the roles of the intrinsic mevalonate cascade and rho-dependent pathway in the statin-induced regulation of these desaturases and elongases using human hepatocellular carcinoma cell line HepG2 cells.

Methods: Cell viability was assessed by measuring mitochondrial activity of WST-8, and the activity of caspase-3 and -7 (caspase-3/7) was measured. Gene expression was analyzed by quantitative real-time PCR. Protein expressions were detected by Western blot analysis.

Results: Although atorvastatin decreased the cell viability with increasing activity of caspase-3/7 in a dose-dependent manner, both mRNA and protein expression of FADS2 were stimulated by atorvastatin at lower dose of 12.5 and 25 uM, where mRNA expression of FADS1 and Elovl5 also increased. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), not cholesterol, fully restored the atorvastatin-induced inhibition of cell viability, and the atorvastatin-induced upregulation of mRNA and protein of FADS2. The Rho-associated protein kinase (ROCK) inhibitor Y-27632 inhibits the restoration of mevalonate and GGPP. Both EPA and DHA, but not AA, significantly suppressed the atorvastatin-induced upregulation of gene expression of FADS1, FADS2 and Elovl5.

Conclusions: These data demonstrated that statin may affect the endogenous synthesis of LCPUFAs by the regulation of these desaturases and elongases through GGPP-dependent rho kinase pathway in HepG2 cells.

Disclosure

I. Tatsuno: None. S. Tanaka: None. N. Ishihara: None.
Effects of High-Intensity Statins on Glucose Homeostasis in Patients with Type 2 Diabetes
Authors: THONGTANG NUNTAKORN , SRIUSSADAPORN SUTIN , TANGKITTIKASEM NATTHAKAN
Published: June 2018

Statin use has been reported to increase the risk of new onset diabetes, and potentially worsen glycemic control in patients with type 2 diabetes (T2D). The risk of new onset diabetes from statin is higher with increased dose of statin administration. This study was aimed to evaluate the effects of high-intensity statins as compared to the lower intensity statins on glucose homeostasis and glycemic control in patients with T2D. T2D who were taking simvastatin up to 20 mg/day (N=100) were randomized to continue using the same dosage of simvastatin (low- to moderate-intensity statin group; LS) for 12 weeks or change to atorvastatin 40 mg/day for 6 weeks and if tolerable increased to atorvastatin 80 mg/day for 6 weeks (high-intensity statin group; HS). Fasting plasma glucose (FPG), HbA1c, fasting plasma insulin, HOMA-IR and HOMA-B were assessed at baseline, 6 weeks and 12 weeks. Oral hypoglycemic agents were unchanged throughout the study period and patients who were on human insulin were excluded from the analysis. Ninety-eight patients completed the study (73% female), mean age 58.9±9.6 years, mean BMI 27.3±4.5 kg/m2, median duration of diabetes was 102 (48-180) months. Mean baseline FPG and HbA1c were 130.4±35.3 mg/dl and 6.9±0.9%, respectively. Median baseline insulin level, HOMA-IR, and HOMA-B were 10.8 (7.5-17.7) mIU/L, 3.3 (2.2-5.5), and 65.5 (37.7-113.8), respectively. There was no significant difference in baseline characteristic and baseline glucose homeostasis parameters between the LS (n=49) and HS group (n=51). There was a slight increase in HbA1c in the HS group as compared to the LS group at 6 weeks (+0.1% vs. 0%, p=0.05), and 12 weeks (+0.1% vs. -0.1%, p=0.13) respectively. However; there were no significant changes in FPG, fasting plasma insulin, HOMA-IR and HOMA-B between the LS and HS group.

In conclusion, there was no significant deterioration in glucose homeostasis with high-intensity statins as compared to low dose statins in patients with T2D.

Disclosure

N. Thongtang: Other Relationship; Self; Pfizer Inc.. S. Sriussadaporn: None. N. Tangkittikasem: None.
Ophthalmologic Findings in Congenital Generalized Lipodystrophy—A Possible Marker of Metabolic Disorders
Authors: FERNANDES VIRGINIA O. , GOMES LORENA M.A. , MONTENEGRO ANA PAULA D.R. , PONTE CLARISSE M.M. , BATISTA LIVIA A.A. , ARAGÃO RICARDO E.M. , SILVA JAILTON V. , MONTENEGRO RENAN M.
Published: June 2018

Background and Aims: Metabolic disorders can present ophthalmologic changes. Congenital Generalized Lipodystrophy (CGL) is characterized by severe metabolic manifestations such as insulin resistance, diabetes and hypertriglyceridemia, but there are few data published about ophthalmologic findings in this condition. The purpose of this study is to describe ocular abnormalities in patients with CGL.

Materials and Methods: It was a cross sectional study with 15 patients with CGL of both sex, aged between 2 and 29 years old. We evaluated the symptoms of surface eye disease and visual acuity. In the slit lamp, were evaluated the anterior segment of the eye, the break up time of the tear film with fluorescein and the corneal findings. Under mydriasis, the eye fundus examination was performed.

Results: All subjects had dyslipidemia: 15/15 (100%) hypertriglyceridemia; 15/15 (100%) low HDL-c; 4/15 (26,7%) and high levels of LDL-c. Diabetes was presented in 7/15 (46,7%) cases. Symptoms of surface eye disease (blurred vision, pruritus, hyperemia or dry eye sensation) were presented in 9/15 (60%) patients and 8/15 (53%) had refractive errors: 5/8 (62,5%) astigmatism, 2/8 (25%) myopia and 1/8 (13%) myopia and astigmatism. In the slit lamp, 12/15 (80%) presented anterior blepharitis (seborrheic or meibomite), 13/15 (87%) decrease in the break up time of the tear (less than 8 seconds) and 5/15 (33,3%) keratitis. In the fundoscopy, 2/15 (13,3%) presented retinopathy (one with nonproliferative diabetic retinopathy and another presented proliferative diabetic retinopathy).

Conclusion: These findings demonstrate high frequency of blepharites and its complications in patients with CGL, even in young subjects without diabetes. These data allow us to speculate that the presence of abnormalities in the anterior segment of the eye may be a marker of metabolic disorders as dyslipidemia and insulin resistance.

Disclosure

V.O. Fernandes: None. L.M.A. Gomes: None. A.D.R. Montenegro: None. C.M.M. Ponte: None. L.A.A. Batista: None. R.E.M. Aragão: None. J.V. Silva: None. R.M. Montenegro: None.