Diabetic Nephropathy
|
We know that Wobenzym
can increase levels of C-peptide in autoimmune mediated
diabetes, such as type 1 diabetes. In addition to showing
much insulin the pancreas can still make, C-peptide
decreases the progression so the common complications of
diabetes, including the
diabetic nephropathy.
We also note that systemic enzymes can decrease the formation of “advanced glycation end products” (AGEs), which are associated with diabetic nephropathy and other complications of diabetes. IN addition, abnormal cytokines levels are normalized, including transforming growth factor beta-1 (TGF-b1), and interleukin 6. What we have come to realize, is that the complications of diabetes are strongly mediated by the immune system. We see that controlling blood sugar with insulin is not enough to prevent complications such as diabetic nephropathy. The abnormal cytokine levels that occur with diabetes can safely and effectively be normalized with Wobenzym. From FREQUENTLY ASKED QUESTIONS, with answers by Joseph J Collins, RN, ND Read the special section: KIDNEY AND BLADDER CONDITIONS & WOBENZYM® |
What the literature says about Systemic Enzyme Support and:
Diabetic Nephropathy
Enzyme
Therapy in Diabetic Nephropathy – Experimental and First Clinical
Data
*Stauder G., *Wood G., **Paczek L. Enzyme Therapy
in Diabetic Nephropathy – Experimental and First Clinical Data. 6th
Taormina Course of Nephrology. October 20th - 22th, 2000, pp.
227-232, Editoriale Bios 2000 PZ 22 (5-14-3)-(19-11-3) [Czech
summary] * Mucos Pharma,
Geretsried, Germany. ** Transplantation Institute, University
Warsaw, Poland
English summary of lecture
Diabetic nephropathy is characterized by cell
hypertrophy, thickening of the basement membranes and accumulation
of extracellular matrix (ECM), that is attributed to an elevated
protein synthesis and an inhibition of protein degradation, the
latter due to reduced proteolytic activity.
The main trigger for this process is
overexpression of transforming growth factor beta-1 (TGF-b1). This
is induced by numerous factors such as hyperglycemia, stimulation of
the RAS, formation of advanced glycation endproducts (AGE), elevated
IL-6 levels, and increased mesangial stretch. A reduction of TGF-b1
levels was documented to be associated with a retardation of disease
progression. Based on the findings in endothelial cells that the
receptor for AGEs (RAGE) is trypsin-sensitive, the modulatory action
of this serine protease was investigated in tubule cells. The
distinct overexpression of TGF-b1 as well as the hypertrophy of the
cells, induced by AGE-BSA, were normalized after coincubation with
trypsin. In addition, the cellular accumulation of AGEs was markedly
reduced. The enzyme therapy (12 mg/day of a mixture of the active
ingredients of Phlogenzym®) was able to reduce the increased
intraglomerular TGF-b content in rats. In a second study in
uninephrectomized, STZ induced diabetes in rats the combination of
Phlogenzym® with the ACE inhibitor enalapril showed an almost 67%
reduction of glomerular sclerosis, while single treatment with
either enalapril or Phlogenzym® led to a 20-30% reduction only,
indicating clear additive effect.
In human studies (patients with rheumatoid
arthritis or myelofibrosis), elevated serum levels of TGF-b
were diminished by oral enzyme therapy. A clinical pilot study in
patients with diabetic nephropathy demonstrated that oral enzyme
therapy (2 tablets t.i.d.) is able to reduce enhanced levels of IL-6
both in serum and urine.A clinical double-blind placebo controlled
pilot study on 24 patients with diabetic nephropathy, stages III or
IV, was performed in 4 centers in Germany and Poland. Either the
enzyme preparation Phlogenzym® or placebo was administered
double-blinded for 16 weeks. 21 patients, mean age 51.3, and 53.5
years, respectively, were evaluated. Five patients in the enzyme
group were suffering from diabetes type I, 5 patients from type II;
in the placebo group 5 patients were suffering from the type I and 6
patients from type II. Five patients (enzyme group) had stage III
nephropathy (microalbuminuria), 5 patients stage IV
(macroalbuminuria); in the placebo group 4 patients had stage III,
and 7 patients stage IV. At baseline, 7 patients in the enzyme group
had proteinuria <1 g/day, 3 patients >1 g/day; in the placebo group
7 patients had proteinuria <1 g/day, and 4 patients >1 g/day. The
groups were comparable. Blood glucose and mean blood pressure were
controlled effectively.
At baseline, a proteinuria (median) of 0.4 g/day
was measured in the enzyme group, 0.8 g/day in the placebo group.
After 16 weeks the value was unchanged in the enzyme group (0.36
g/day), whereas it slightly deteriorated to 1.08 g/day in the
placebo group (p > 0.05).
The albuminuria tended to lower levels (from
242.5 mg/day to 200.0 mg/day) in the enzyme group; in the placebo
group, a slight increase from 508.0 mg/day to 562.0 mg/day was
observed (p > 0.05). Creatinine clearance did not change in either
group during the 16-week treatment period (which was not at all
expected in this short time), while serum creatinine tended to
decline in the enzyme group (from 1.05 mg/dl at baseline to 0.95
mg/dl), and remained unchanged (at 1.2 mg/dl) in the placebo group
(p = 0.0279).
There were recorded only 2 drug related side
effects, 1 under placebo (mild diarrhea) and 1 (mild constipation)
under enzyme therapy. Thus, the enzyme therapy proved to be safe.
Another double-blind, placebo controlled clinical
trial with Phlogenzym® will be performed in 16 centers in Europe.
Poster Reference Number 35.
Advanced
glycation end products (AGEs)-induced expression of TGF-b1 is
suppressed by a protease in the tubule cell line LLC-PK1
Xiang G., Schinzel R., Simm A., Münch G.,
Sebekova K., Kasper M., Niwa T.,
Schmitz Ch. and Heidland1 A. Advanced glycation
end products (AGEs)-induced expression of TGF-b1 is suppressed by a
protease in the tubule cell line LLC-PK1. Nephrol Dial Transplant
2001, Vol. 16, pp. 1562-1569. 555 KA [Czech abstract]
Abstract: Background. Advanced glycation end
products (AGEs) are assumed to play a key role in diabetic
nephropathy (DN). Since little is known about their action in tubule
cells, we investigated in LLC-PK1 cells: (i) whether AGE-bovine
serum albumin (AGE-BSA) affects cell proliferation and expression of
transforming growth factor-b (TGF-b1); and (ii) whether the
AGE-induced effects can be modulated by trypsin due to interference
with its binding proteins at the cell surface.
Methods. Arrested cells were exposed to vehicle
(control), AGE-BSA (19-76 mM) and BSA (38 mM) in the presence or
absence of trypsin (0.625-5.0 mg/ml) (2.5 mg/ml) for 24 h. We
evaluated cell proliferation by cell count and by [3H]thymidine
incorporation, TGF-b1 expression by reverse transcription-polymerase
chain reaction (RT-PCR), and TGF-b1 protein by ELISA. In addition,
cell accumulation of AGEs was studied by immunohistochemical
staining of the AGE imidazolone.
Results. AGE-BSA inhibited [3H]thymidine
incorporation, lowered cell number and increased cell protein
content as well as TGF-b1 mRNA and protein as compared with control
and BSA. Immunohistochemical staining revealed a marked
intracellular accumulation of the AGE imidazolone. Co-incubation of
AGE-BSA with trypsin ameliorated the impaired thymidine
incorporation, the decreased cell count and the enhanced cell
protein content. TGF-b1 overexpression was normalized, while TGF-b1
protein declined insignificantly. Intracellular imidazolone
accumulation was strikingly suppressed.
Conclusions. In the tubule cell line LLC-PK1,
AGE-BSA exerts an antiproliferative effect, most probably due to
TGF-b1 overproduction. The co-administration of trypsin abrogated
this alteration, very likely as a result of an interaction with
AGE-binding protein(s), which is supported by the decreased
intracellular AGE accumulation. These findings may be the starting
point for the development of specific proteolytic enzymes to
interfere with the interaction between AGEs and their
receptors/binding proteins.
Keywords: AGEs; cell proliferation; imidazolone;
TGF-b1 mRNA; trypsin and tubule cells
Advanced
glycation end products impair protein turnover in LLC-PK1:
Amelioration by trypsin.
Xiang G., Schinzel R., Simm A., Sebekova K.,
Heidland A. Advanced glycation end products impair protein turnover
in LLC-PK1: Amelioration by trypsin. Kidney International 2001, Vol.
59, Suppl. 78, pp. S-53-S-57. SO 130 (5-07-1) [Czech translation of
abstract]Department of Internal Medicine, Institute of Physiological
Chemistry, and Institute of Clinical Biochemistry and
Pathobiochemistry, University of Würzburg, Würzburg, Germany; and
Institute of Preventive and Clinical Medicine, Bratislava, Slovakia
Background. Advanced glycation end products
(AGEs) are assumed to play a key role in the pathogenesis of
diabetic nephropathy (DN) and other diabetic complications. While
AGEs have been shown to exert marked effects on mesangial and
endothelial cells as well as on monocytes/macrophages, little is
known about their effects on tubule cells. Therefore, we addressed
the questions of (1) whether AGE-bovine serum albumin (AGE-BSA)
impairs the protein metabolism in the tubule cells, and if so, (2)
whether the AGE-induced effects are mediated via a protease
sensitive mechanism.
Methods. Arrested LLC-PK1 cells were exposed to a
medium containing the vehicle (control, serum free), AGE-BSA (38
mmol/L), or BSA (38 mmol/L) in the presence or absence of trypsin
(2.5 mg/mL) for 24 hours. We evaluated cell number, cell size, and
cell protein content, as well as protein synthesis and protein
degradation.
Results. After an incubation period of 24 hours,
AGE-BSA decreased the cell number to 84.5 ± 5.5% of control and 82.5
± 5.6% of BSA-treated cells (P < 0.05). [3H]-thymidine incorporation
declined to 66% of control (P < 0.05), while BSA was without any
effect. The same AGE-BSA dose reduced protein degradation (P < 0.05)
and stimulated total protein synthesis slightly, as determined by
L-[14C]Phe incorporation into acidicinsoluble proteins. These
effects resulted in a rise in cell protein content (AGE-BSA vs.
control, 21.9 ± 6.7%; AGE-BSA vs. BSA, 11.1 ± 6.0%, P < 0.05) and
cell volume (AGE-BSA vs. control 9.4 ± 3.2%, AGE-BSA vs. BSA 18.4 ±
3.7%, P < 0.05). Coincubation with AGE-BSA and trypsin was
associated with an amelioration of all investigated parameters
concerning cell number, cell proliferation, raised cell protein
content, decreased protein degradation, and enhanced protein
synthesis.
Conclusion. These data indicate that AGE-BSA
impairs cell proliferation and protein turnover in LLC-PK1 cells
with a consequent rise in cell protein. Since these alterations were
abrogated by coincubation with trypsin, an interference of this
serine protease with the AGE-binding proteins on cell surfaces is
assumed.
Keywords: diabetic nephropathy, tubule cells,
protein metabolism, cell proliferation, serine protease.
Beneficial effect of proteases on TGF-beta production in glomeruli
from streptozotocin induced diabetes mellitus in rats.
Paczek L.1, Gaciong Z.1,
Bartlomiejczyk I.1, Czyzyk A.1, Heidland A.2.
Beneficial effect of proteases on TGF-beta production in glomeruli
from streptozotocin induced diabetes mellitus in rats. Inter.
Journal of Tissue Reactions 1997, Vol. XIX, No. 1/2, pp 93, abstract
115, ISSN 0250-0868 149K/245 (19-04-2) 1. Warsaw
School of Medicine, Warsaw, Poland
7th Interscience World Conference on
Inflammation, Antirheumatics, Analgesics, Immunomodulators, May
19-21, Geneva, Switzerland -
The purpose of this study was to assess TGF-b and
FN accumulation in glomeruli obtained from streptozotocin induced
diabetes mellitus in rats treated via intraperitoneal route daily
for 21 days with 12 mg protease mixture (Phlogenzym®, Mucos Pharma,
Germany). To prevent ketoacidosis, the rats were treated daily with
subcutaneous injections of ultralente insulin in a dosage of 0.5 U.
TGF-b and FN were measured with EIA.
The data indicate that in glomeruli from diabetic
rats TGF-b production increased significantly and the treatment with
Phlogenzym restores the production to the normal level. Increased
accumulation of FN observed in diabetic glomeruli was significantly
reduced after enzyme treatment.