Highly phosphomannosylated enzyme replacement therapy for GM2 gangliosidosis.

OBJECTIVE: Novel recombinant human lysosomal ß-hexosaminidase A (HexA) was developed for enzyme replacement therapy (ERT) for Tay-Sachs and Sandhoff diseases, ie, autosomal recessive GM2 gangliosidoses, caused by HexA deficiency. METHODS: A recombinant human HexA (Om4HexA) with a high mannose 6-phosphate (M6P)-type-N-glycan content, which was produced by a methylotrophic yeast strain, Ogataea minuta, overexpressing the OmMNN4 gene, was intracerebroventricularly (ICV) administered to Sandhoff disease model mice (Hexb⁻/⁻ mice) at different doses (0.5-2.5 mg/kg), and then the replacement and therapeutic effects were examined. RESULTS: The Om4HexA was widely distributed across the ependymal cell layer, dose-dependently restored the enzyme activity due to uptake via cell surface cation-independent M6P receptor (CI-M6PR) on neural cells, and reduced substrates, including GM2 ganglioside (GM2), asialo GM2 (GA2), and oligosaccharides with terminal N-acetylglucosamine residues (GlcNAc-oligosaccharides), accumulated in brain parenchyma. A significant inhibition of chemokine macrophage inflammatory protein-1 α (MIP-1α) induction was also revealed, especially in the hindbrain (< 63%). The decrease in central neural storage correlated with an improvement of motor dysfunction as well as prolongation of the lifespan. INTERPRETATION: This lysosome-directed recombinant human enzyme drug derived from methylotrophic yeast has the high therapeutic potential to improve the motor dysfunction and quality of life of the lysosomal storage diseases (LSDs) patients with neurological manifestations. We emphasize the importance of neural cell surface M6P receptor as a delivery target of neural cell-directed enzyme replacement therapy (NCDERT) for neurodegenerative metabolic diseases.

Asymptomatic leukocyturia and the autonomic nervous system in women.

BACKGROUND: The present study sought to investigate the relationship between asymptomatic leukocyturia (ASL) and autonomic nervous function by power spectral analysis of the R-R intervals in women. METHODS: One hundred and forty-two female outpatients aged 23-91 years were studied. We regarded ASL to be present if two consecutive samples were found to have 10 or more leukocytes/high-power field at x400 magnification in a centrifuged midstream urine sample. The R-R intervals of all subjects were measured by the wavelet transform analysis system. This system detected R-R variation data distributed in two bands: low-frequency power (LF) (0.04-0.15 Hz) and high-frequency power (HF) (0.15-0.40 Hz). The ratio of LF to HF (LF/HF) was also determined. Post-void residual urine volume was measured using an automated, compact 3-D ultrasound device. RESULTS: The patients with ASL had diabetes mellitus more frequently than those without ASL. Residual urine volume was significantly higher in the former than in the latter, while the HF values in both a recumbent position and a standing position were significantly lower in the former than in the latter (P = 0.003, P = 0.001, respectively). However, there were no significant differences in LF or LF/HF values in either a recumbent or a standing position between the two groups. The HF values in both a recumbent position and in a standing position were independent indicators of ASL, even after adjustment for age, diabetes mellitus and residual urine volume. CONCLUSION: The present study reveals the relationship between ASL and impairment of the parasympathetic nervous system in women.

Daily blood glucose profiles of glibenclamide and gliclazide taken once or twice daily in elderly type 2 diabetic patients.

AIM: The aim of this study was to evaluate the difference in daily blood glucose profiles between once- and twice-daily regimens of a moderate daily dose of glibenclamide or gliclazide in elderly patients with type 2 diabetes. METHODS: Daily blood glucose profile data were evaluated in 18 elderly type 2 diabetic patients treated with 80 mg/day gliclazide or 5 mg/day glibenclamide as monotherapy. The first daily blood glucose profile of the twice-daily regimen was performed approximately 1 week before hospital discharge, and the second was performed after taking a once-daily regimen for 4-7 days. Plasma glucose and plasma immunoreactive insulin (IRI) concentrations were measured daily at 12 time points: 08.00 (before breakfast); 10.00; 12.00 (before lunch); 14.00; 18.00 (before dinner); 20.00; 0.00; 02.00; 03.00; 04.00; 06.00; and 08.00 hours the next morning. RESULTS: Daily blood glucose profiles and plasma IRI profiles did not differ between the once- and twice-daily regimen groups in either the gliclazide group or the glibenclamide group. Plasma glucose values between midnight and early morning tended to be lower than the 08.00 hours plasma glucose value in the glibenclamide group, but not in the gliclazide group. CONCLUSION: These results suggest that the blood glucose-lowering effects of a once- and twice-daily moderate daily dose of glibenclamide or gliclazide do not differ in elderly type 2 diabetic patients. However, glibenclamide, regardless of the dosage schedule, tends to lower the plasma glucose values between midnight and early morning.

Colestimide lowers plasma glucose levels and increases plasma glucagon-like PEPTIDE-1 (7-36) levels in patients with type 2 diabetes mellitus complicated by hypercholesterolemia.

BACKGROUND: Colestimide has been reported to lower blood glucose levels in patients with type 2 diabetes complicated by hypercholesterolemia. AIM: To examine the mechanism by which colestimide decreases plasma glucose levels in the above patients. METHODS: A total of 16 inpatients with type 2 diabetes complicated by hypercholesterolemia received colestimide for 1 week after their plasma glucose levels stabilized. We measured plasma glucose, serum immunoreactive insulin (IRI), serum lipid, plasma glucagon, and plasma glucagon-like peptide-1 (GLP-1) levels. These variables at baseline and 1 week of colestimide administration were compared. RESULTS: Preprandial plasma glucose levels (baseline: 132 +/- 33 mg/dL vs. completion: 118 +/- 43 mg/dL, P=0.073) tended to decrease after colestimide administration, while 1-hr postprandial plasma glucose levels (baseline: 208 +/- 49 mg/dL vs. completion: 166 +/- 30 mg/dL, P<0.001) and 2-hr postprandial plasma glucose levels (baseline: 209 +/- 56 mg/dL vs. completion: 178 +/- 39 mg/dL, P=0.015) decreased significantly at 1 week of colestimide administration. The 2-hr postprandial plasma GLP-1 level was significantly (P=0.015) higher at 1 week of colestimide administration as compared with the baseline level, while there were no significant changes in preprandial and 1-hr postprandial plasma GLP-1 levels. CONCLUSIONS: The GLP-1-increasing activity of colestimide may explain, at least in part, the mechanism of its blood glucose-lowering activity in patients with type 2 diabetes complicated by hypercholesterolemia.