Metabolic Unit

Haifa, Israel

Metabolic Unit

Haifa, Israel
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Derosa G.,University of Pavia | Franzetti I.,Metabolic Unit | Querci F.,Ospedale Pesenti Fenaroli | Fogari E.,University of Pavia | And 5 more authors.
Diabetes Research and Clinical Practice | Year: 2012

Aims: To evaluate the impact on glycemic control, insulin resistance, and insulin secretion of sitagliptin. +. metformin compared to metformin in type 2 diabetic patients. Methods: Patients were instructed to take metformin for 8 ± 2 months, then they were randomly assigned to sitaglipin 100. mg or placebo for 12 months. We evaluated at 3, 6, 9, and 12 months: body mass index (BMI), glycemic control, fasting plasma insulin (FPI), HOMA-IR, HOMA-β, fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), C-peptide, glucagon, adiponectin (ADN), and high sensitivity-C reactive protein (Hs-CRP). Before, and after 12 months since the addition of sitagliptin, patients underwent a combined euglycemic hyperinsulinemic and hyperglycemic clamp, with subsequent arginine stimulation. Results: Both treatments similarly decreased body weight, and BMI; on the other hand, they both improved glycemic control, glucagon and HOMA-IR, but sitagliptin. +. metformin were more effective in reducing these parameters. Sitagliptin. +. metformin, but not placebo. +. metformin, decreased FPPr, FPPR/FPI ratio, and increased C-peptide values, even if no differences between the groups were recorded. Sitaglitin. +. metformin gave also a greater increase of HOMA-β, M value, C-peptide response to arginine and disposition index compared to placebo. +. metformin group. Conclusions: Other than improving glycemic control, sitagliptin. +. metformin also improved β-cell function better than metformin alone. © 2012 Elsevier Ireland Ltd.


Geraghty M.T.,Metabolic Unit | Hogarth P.,Oregon Health And Science University | Hayflick S.,Oregon Health And Science University | Venkateswaran S.,University of Ottawa
Pediatrics | Year: 2015

β-propeller protein-associated neurodegeneration (BPAN) is a recently identified X-linked dominant form of neurodegeneration with brain iron accumulation caused by mutations in the WDR45 gene. BPAN commonly presents as global developmental delay in childhood with rapid onset of parkinsonism and dementia in early adulthood and associated pathognomonic changes seen on brain MRI. In this case report, we present a pediatric patient with mild cognitive delay and pathognomonic MRI changes indicative of BPAN preceding neurologic deterioration who is found to have a novel de novo mutation in the WDR45 gene. © 2015 by the American Academy of Pediatrics.


Rousso-Noori L.,Weizmann Institute of Science | Knobler H.,Metabolic Unit | Levy-Apter E.,Weizmann Institute of Science | Kuperman Y.,Weizmann Institute of Science | And 7 more authors.
Cell Metabolism | Year: 2011

Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation. © 2011 Elsevier Inc.


Burgansky-Eliash Z.,Edith Wolfson Medical Center | Barak A.,Tel Aviv Sourasky Medical Center | Barash H.,Optical Imaging Ltd. | Nelson D.A.,Optical Imaging Ltd. | And 4 more authors.
Retina | Year: 2012

PURPOSE: To compare retinal blood flow velocity in small vessels of patients with early diabetes mellitus (DM), without any morphologic changes related to diabetic retinopathy, with that in a control group. METHODS: The authors used the retinal function imager to measure blood flow velocities, from many small vessels, simultaneously. Twenty-three eyes of 14 patients with early DM and 51 eyes of 31 healthy subjects were enrolled. Differences between the patients and the control group were assessed by mixed linear models. RESULTS: Venous average velocity significantly increased in the DM group (3.8 ± 1.2 vs. 2.9 ± 0.5 mm/second, P < 0.0001) than in the healthy subjects. Arterial velocity of DM patients was also significantly higher (4.7 ± 1.7 vs. 4.1 ± 0.9 mm/second, P = 0.03). There was no statistically significant difference between groups in age, gender, heart rate, and systolic blood pressure. The diastolic blood pressure in the DM patients was lower than that in the healthy group (P = 0.03). CONCLUSION: There was an increase in arterial and venous retinal blood flow velocities of patients with early DM with no diabetic retinopathy. These findings support the notion that abnormalities in vessel function exist in diabetic eyes before the development of structural changes. This noninvasive approach facilitated the assessment of early hemodynamic abnormalities and may assist in screening and monitoring. Copyright © 2011 Lippincott Williams &Wilkins.


Gutfreund S.,Assaf Harofeh Medical Center | Izkhakov E.,Metabolic Unit | Pokroy R.,Assaf Harofeh Medical Center | Yaron M.,Metabolic Unit | And 4 more authors.
Graefe's Archive for Clinical and Experimental Ophthalmology | Year: 2013

Background: Metabolic syndrome (MetS) is characterized by obesity, insulin resistance, dyslipidemia, and hypertension. The Retinal Function Imager (RFI) is a new technique for measuring retinal blood-flow velocity. This study aims to compare retinal blood flow velocity between MetS and healthy subjects. Methods: Twenty eyes of 20 MetS males and 21 eyes of 21 aged-matched healthy males underwent RFI and carotid-femoral pulse wave velocity (PWV) measurement as well as assessment of MetS parameters. The results in MetS and healthy subjects were compared. Results: The average venular velocity in the MetS patients was significantly higher than in the healthy subjects (2.7 ± 0.0 mm/sec versus 2.5 ± 0.0 mm/sec respectively, P = 0.013), following adjustment for age, heart rate and systolic blood pressure. Carotid-femoral PWV was higher in the MetS population than the healthy controls (10.3 ± 1.2 mm/sec versus 9.3 ± 1.5 mm/sec respectively, P = 0.005). The diastolic blood pressure and MAP were correlated strongly with the arterial blood flow velocities in healthy subjects (r = 0.503, P = 0.020 and r = 0.474, P = 0.030 respectively) but not in MetS subjects. Conclusions: The RFI was able to distinguish between the retinal blood flow of normal and MetS subjects. Higher venular blood flow velocity and the poor correlation between velocity and blood pressure of MetS subjects suggest that MetS causes microvascular damage. © 2013 Springer-Verlag Berlin Heidelberg.


PubMed | Hebrew University of Jerusalem, University of Santiago de Chile, University of Bergen, Genetic Institute and 3 more.
Type: Case Reports | Journal: Journal of medical genetics | Year: 2016

Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes.To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy.We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy.Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion.We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.


Senniappan S.,Great Ormond Street Hospital for Children NHS Trust | Senniappan S.,University College London | Shanti B.,Metabolic Unit | James C.,Great Ormond Street Hospital for Children NHS Trust | And 3 more authors.
Journal of Inherited Metabolic Disease | Year: 2012

Hyperinsulinaemic hypoglycaemia (HH) is due to the unregulated secretion of insulin from pancreatic β-cells. A rapid diagnosis and appropriate management of these patients is essential to prevent the potentially associated complications like epilepsy, cerebral palsy and neurological impairment. The molecular basis of HH involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) which regulate insulin secretion. The most severe forms of HH are due to loss of function mutations in ABCC8/KCNJ11 which encode the SUR1 and KIR6.2 components respectively of the pancreatic β-cell K ATP channel. At a histological level there are two major forms (diffuse and focal) each with a different genetic aetiology. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localised to a small region of the pancreas. The focal form can now be accurately localised pre-operatively using a specialised positron emission tomography scan with the isotope Fluroine-18L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET). Focal lesionectomy can provide cure from the hypoglycaemia. However the diffuse form is managed medically or by near total pancreatectomy (with high risk of diabetes mellitus). Recent advances in molecular genetics, imaging with 18F-DOPA-PET/CT and novel surgical techniques have changed the clinical approach to patients with HH. © SSIEM and Springer 2012.


Struys E.A.,Metabolic Unit | Jansen E.E.W.,Metabolic Unit | Salomons G.S.,Metabolic Unit
Journal of Inherited Metabolic Disease | Year: 2014

We have conducted biochemical studies with commercial available pyrroline-5-carboxylate (P5C) reductase (PYCR1) to investigate whether this enzyme plays a role in L-lysine degradation. Our recent studies with antiquitin/ALDH7A1 deficient fibroblasts revealed an alternative genesis of L-pipecolic acid, and we then hypothesized that PYCR1 was responsible for the conversion of Δ1-piperideine-6-carboxylate (P6C) into pipecolic acid.We here present evidence that PYCR1 is indeed able to produce L-pipecolic acid from P6C preparations, and the observed Km for this conversion is of the same magnitude as the Km described for the conversion of P5C to L-proline by PYCR1. Urine samples from antiquitin deficient individuals, who accumulate P6C, were also incubated with PYCR1 which resulted in a marked decrease of P6C and a huge increase of L-pipecolic acid as measured by LC-MS/MS, confirming that indeed PYCR1 generates L-pipecolic acid from P6C. © SSIEM and Springer Science+Business Media 2014.


Alberstein M.,Weizmann Institute of Science | Zornitzki T.,Metabolic Unit | Zick Y.,Weizmann Institute of Science | Knobler H.,Metabolic Unit
Journal of Viral Hepatitis | Year: 2012

Chronic infection with hepatitis C virus (HCV), mainly genotype 1, has been shown to be associated with insulin resistance and type 2 diabetes. The mechanisms underlying this association are partly understood. Increased levels of tumor necrosis factor (TNF)-α occurring in HCV infection have an important role in HCV-mediated insulin resistance; however, other direct effects of HCV core protein on disrupting insulin signalling have been suggested. The insulin receptor substrate (IRS) proteins are key players in insulin signal transduction and are the major substrates of the insulin receptor. To further elucidate the direct effect of HCV core protein on insulin signalling. We studied the direct effects of HCV core protein in two cell lines transfected with HCV core protein. We found several impairments in the insulin signalling cascade which could be attributed to a significant proteasomal degradation of IRS-1 protein, in a dose-dependent way. In addition, our data show that liver cells transfected by HCV core protein show a marked attenuation of the regulatory inhibitory role of insulin on insulin growth factor binding protein-1 (IGFBP-1) expression. Since IGFBP-1 may have a role in glucose regulation and hepatic insulin sensitivity, this effect of HCV core protein can contribute to insulin resistance in chronic HCV infection. Our data suggest that the degradation of IRS-1 by HCV core protein translates to impaired ability of insulin to inhibit the expression of the target gene IGFBP-1 in the liver and may serve as a novel mechanism for insulin resistance and hyperglycaemia. © 2011 Blackwell Publishing Ltd.


Romano S.,Metabolic Unit | Valayannopoulos V.,Metabolic Unit | Valayannopoulos V.,University of Paris Descartes | Touati G.,Metabolic Unit | And 6 more authors.
Journal of Pediatrics | Year: 2010

Objective: To evauluate the relationship between propionic acidemia (PA) and cardiomyopathy. Study design: We retrospectively compared clinical and metabolic results of patients with PA with and without cardiomyopathy. Results: Of 26 patients with PA who survived the first year of age, a dilated cardiomyopathy developed in 6 (group 1) at a median age of 7 years (range, 5-11 years). They were compared with 14 patients without cardiomyopathy for whom data were available (group 2). Their median age at the time of the study was 11 years (range, 3-21 years). PA was diagnosed in the neonatal period in 5 of 6 patients in group 1 and 11 of 14 patients in group 2. All patients received similar medical treatment. Two patients in group 1 died of cardiac arrest. In 2 patients, the cardiomyopathy was reversed during the year after orthotopic liver transplantation (OLT). In 2 other patients, OLT was contraindicated because of severe heart disease. The number of metabolic distress episodes was similar in both groups. Excretion of propionate metabolites in urine did not correlate with the occurrence of cardiomyopathy. Conclusion: Dilated cardiomyopathy, a frequent complication of PA, develops independent of any specific metabolic profile and is reversible after OLT. © 2010 Mosby, Inc. All rights reserved.

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