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xylitol and low dosages of insulin - Peritoneal Dialysis International


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                                                    XYLITOL AND LOW DOSAGES OF INSULIN: NEW
                                                PERSPECTIVES FOR DIABETIC UREMIC PATIENTS ON CAPD

          Giorgio Bazzato Ugo                  turned towards normal levels mainly during      carbohydrate intolerance with insulin
                  Coli                         the first four months. The daily absorption     resistance (5).
             Silvano Landini                   ofxylitol in amounts less than 150 9 was           Following the experimental studies of
           Agostino Fracasso                   well tolerated by the patients, while greater   Tsan-Chin Yen on peritoneal dialysis with
           Paolo Morachiello                   amounts caused clinical symptoms such as        xylitol-containing solutions (7), we used
          Flavio Righetto and                  nausea and vomiting. The main advantage         xylitol (instead of glucose) as an osmotic
           Flavio Scanferla                    of using xylitol in uremic diabetic patients    agent in four diabetic uremic patients on
                                               on CAPD was the decrease in insulin             CAPD, in our efforts to overcome the
                                               requirements to those required for the          untoward effect of glucose loading. This
The authors describe six months'               metabolism of dietary carbohydrate only.        paper describes our experience.
experience with CAPD using xylitol in
dialysis solution in four diabetic patients.   Xylitol, an aliphatic polyalcohol, is a
                                                                                               PATIENTS AND METHODS
The laboratory and clinical data thus          nonnal     intennediary    metabolite     of
obtained, demonstrate that this polyalcohol    glucuronic acid in mammalians and a             Four-insulin dependent uremic patients
is an effective osmotic agent, which is        constituent of many foods, mostly               (three men and one woman) ranging in age
particularly suitable for uremic diabetics     vegetables (1,2). This pentitol represents a    from 31 to 52 years, were treated on CAPD
because of its insulin-independent metabo-     ready source of calories, which is almost       for six months, using dialysis solutions
lism.     Serum     phosphates     markedly    completely metabolized by the liver; for        containing xylitol as an osmotic agent.
decreased while lactic and uric acid           this reason during the past decade xylitol      Previously these patients had been treated
showed a steady increase; the latter was       has been used, during the postoperative         with conventional glucose CAPD and
more pronounced and required treatment         period, for parenteral nutrition in patients    intraperitoneal insulin for a period ranging
with allopurinol. HDL cholesterol and          with multiple injuries (3). Because of its      from seven to 13 months.
triglycerides re                               insulinindependent metabolism and its               The composition of dialysate with
                                               small effect on blood sugar , xylitol has       xylitol was: Na+136, K+O-2, CI-I03,
                                               also been used in diabetic subjects (4) and     Ca++4, Mg++l, acetate 38.5 mEq/l, xylitol
From the Nephrology and Dialysis Depart-
                                               in uremic patients who frequently exhibit       1.5-3 g%, osmolality 387-482 mOsmlkg.
ment, Umberto I Hospital, Venice-Mestre,
                                                                                               The daily therapeutic pro
 gram included four exchanges of two liter bags,
 three of which contained I. 5 g% xylitol and one
 was hypertonic with 3% xylitol. During night,
 only one-half litre of 1.5 g% xylitol was left in
 the peritoneal cavity. This schedule was able to
 promote an ultrafiltration with removal of about
 1500 ml of fluid each day.
     During the treatment, arterial blood pressure,
 body weight and the following laboratory data
 were monitored: Blood sugar , serum creatinine,
 uric acid, electrolytes (Na+, K+, CI-, Ca++, P),
 acid-base balance, lactic acid, lipid profile, Hb-
 glycosylated, SGOT and SGPT, bilirubin, GT,
 CPK, LDH, alkaline phosphatase and serum
 xylitol (enzymatic method) (8).
     The following parameters were also measured
 in the effluent fluid: Xylitol, Na+, K+, CI-,
 Ca++, P, BUN, creatinine and protein. Insulin
 administration via peritoneal membrane was
 related to the dietary carbohydrate intake at a

                                                                                                                                                                    Downloaded from by guest on March 26, 2013
 daily rate of 55 I. U. (mean values).
     During both periods of study (glucose and
 xylitol), the patients followed a similar diet of
 about 35 Kcal/kg BW with a protein intake of 1.2
 g/kg BW.


In our uremic patients, solutions with
1.5 and 3 g% of xylitol as the osmotic agent did
not produce any important side effects when the
amount of xylitol absorbed was less than 150
g/day. Daily blood sugar appeared to be better
controlled than during the previous treatment
with glucose in dialysis solution, as
demonstrated by a decrease in glycohemoglobin
levels from 13.3 :!: 0.9 to 9.8:!: 1.4% (mean
values:!: SE). At the same time we observed a
marked reduction in the intraperitoneal insulin
requirements from 113 :!: 18, to 55 :!: 12 I. U
./day (mean values:!: SE) (Fig. 1).                    toward nonnal levels, showed a late mild               sured in the effluent fluid were not different than
    With regard to the acid-base balance, we did       increase, while HDL-cholesterol returned and           that observed with glucosecontaining dialysate.
not observe any significant change in pH (7.35         remained in the nonnal range (Fig. 3). Serum           Mean arterial pressure (MAP) and body weight
:!: 0.05) and blood bicarbonates (25 :!: 2.6           phosphates fell significantly from 5:!: 1.2 to 3 :!:   (BW) were not significantly different during the
mEq/L) while lactic acid showed a progressive          0.9 mg%, while uric acid rose steadily from 6:!:       glucose (MAP 101 :!: II mm Hg, BW 57.6:!: 9.8
increase from 8 :!: 2.6 to 22 :!: 3.1 mg% ) ,          1.4 to 10:!: 2.3 mg%, requiring the use of             kg) and xylitol (MAP 99 :!: 8.9 mm Hg, BW
during the treatment period with xylitol (Fig. 2).     Allopurinol (Fig.4). Serum electrolytes (Na+,
                                                                                                              56.7 :!: 10.3) periods.
Triglycerides and cholesterol, after a sharp initial   K+, CI-, Ca++, P), hepatic and muscular en-
                                                                                                                 After a hypertonic exchange (3g/dl),
decrease                                               zymes (SOOT, SGPT , GT, LDH, CPK) and
                                                                                                              serumxylitolroseto91:!: 18.6mg/dlat one hour
                                                       bilirubin remained within nonnal values. The
                                                                                                              and decreased sharply to 15 :!: 6.2 mg/dl three
                                                       amount of xylitol recovered in the effluent fluid
                                                                                                              hours later. With 1.5 g/dl solution, the peak
                                                       was about 20% of the amount administered.
                                                                                                              levels were lower (38 :!: 10.7 mg/dl).
                                                       Protein loss was similar to that observed during
                                                       the use of glucose-containing dialysate with an
                                                       average of 12.4 g/day. Also the electrolytes           DISCUSSION
                                                       (Na+, K+, CI-, Ca++, P)mea                             In the past, for surgical patients in the
                                                                                                           phosphates being trapped within the liver as a
                                                                                                           result of xylitol phosphorilation by ATP (5). In
                                                                                                           fact, it is well known that xylitol is metabolized
                                                                                                           mainly by liver (85%) while the remainder is
                                                                                                           metabolized by extra hepatic tissues. Xylitol also
                                                                                                           was found to stimulate the release of insulin
                                                                                                           through a direct effect on the pancreatic B-cells
                                                                                                           (10). On the basis of this metabolic
                                                                                                           characteristics, xylitol should prove to be a useful
                                                                                                           source of calories in uremia with carbohydrate
                                                                                                           intolerance and insulin resistance, especially in
                                                                                                           diabetics (11).
                                                                                                               Our patients' need for insulin was about one-
                                                                                                           half of that required during the period of CAPD
                                                                                                           with glucosecontaining dialysate. The daily
                                                                                                           dosage of insulin administrated during the xylitol
                                                                                                           period was proportional to the amount of
                                                                                                           carbohydrates supplied by the diet.
                                                                                                               During a six months' experience, using xylitol

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                                                                                                           at 1.5 and 3 g% concentration in dialysate
                                                                                                           solution, we observed no major biochemical
                                                                                                           derangements. This finding is in disagreement
                                                                                                           with the observations of Thomas et al (1972)
                                                                                                           who have reported metabolic acidosis with an
                                                                                                           increase in lactic and uric acid associated with
                                                                                                           hepatorenal parenchymal damage in patients
                                                                                                           acutely infused with great amounts of hypertonic
                                                                                                           (50%) solutions (12). On the other hand, studies
                                                                                                           by Lang et al showed that a short -term infusion
                                                                                                           of xylitol at high concentration (30% ) did not
                                                                                                           cause any toxic effect on parenchymal tisues
                                                                                                           (13). Similar to the experience of Lang et al, we
                                                                                                           found that the electrolytes and acid-base balance
                                                                                                           remained essentially unchanged; but uric acid
                                                                                                           increased progressively from 6 to 10 mg%
                                                                                                           .Lactic acid also increased from 8 to 22 mg% but
                                                                                                           remained within the normal range.
                                                                                                               Rather than other sugars xylitol also has been
                                                                                                           employed in pediatric patients as a source of
                                                                                                           calories, because it is tolerated well and has an
postoperative period, high concentrations of xy      patients with renal diseases and concluded that       antiketogenic effect (14). These characteristics
litol have been employed as a source of calories     xylitol is well utilized in renal failure and that,   are explained by the fact that xylitol readily
(4.06 Kcal/g) during parenteral nutrition (9).       after long-term IV administration in diabetic         penetrates into muscle and liver cells independent
However , patients receiving large doses of intra-   patients, fasting blood sugar, serum cholesterol,     of insulin. While the entry into the cells is a
venously administered xylitol develop severe         total lipids, triglycerides and FFA were              passive diffusion process, cellular metabolism is
metabolic disturbances, such as metabolic            unchanged (5).                                        regulated by the enzymatic action of an
acidosis, associated with increase in lactic acid,       In our four diabetic uremic patients ,
oliguria with azotemia and elevated serum uric       triglycerides, cholesterol and HDLcholesterol
acid levels (8,9). Also, Yagamata et al (1965)       became normal during the first four months of
infused xylitol in normal and diabetic subjects to   treatment. Phosphoremia, although sharply
evaluate the effects of short and long-term          reduced in the previous period of CAPD with
administration (4) .Their results have suggested     glucose-showed a further fall after six months of
that xylitol has a beneficial effect on the          treatment with xylitol. This drop was interpreted
metabolic disorders of diabetes. In 1970, Spitz et   as evidence of the prompt metabolism of xylitol
al studied the metabolism of xylitol in healthy      by muscle, but other authors assert that
subjects and in                                      hypophosphatemia may be the result of
                                                     treatment, we noted no clinical evidence of               drate and lipid metabolism in diabetes.
                                                     calcium oxalate deposits such as worsening in             Lancet 1965;6:918.
                                                     cerebral or residual kidney function.                  5. Spitz IM. Rubenstein AH. Bershon I,
                                                         The peritoneal membrane was not adversely             Bassler KH. Metabolism of xylitol in
                                                                                                               healthy subjects and patients with renal
                                                     affected by the use of this substance as osmotic
                                                                                                               disease. Metabolism 1971;9:24.
                                                     agent and, with the amount employed, we                6. Flynn CT. Continuous ambulatory peritoneal
                                                     observed no untoward effects as demonstrated by           dialysis in diabetic patients. Proc Int Symp
                                                     the same removal of fluid and unchanged                   on CAPD, Paris 1979: 187.
                                                     biochemical data. The lipid abnormalities              7. Tsan-Shin Yen. Experimental study on
                                                     appeared to be ameliorated during this period of          peritoneal dialysis using xylitol containing
                                                                                                               solution. J Fonnosan Med Assoc
                                                     observation, suggesting a better outlook during
                                                     chronic treatment than that observed with              8. Bassler KH, Unbehaun V, Prelwitzz W.
                                                     glucose (18).                                             EnziIIIatische best hmung von xylit in
                                                         In conclusion these preliminary data suggest          biologischem       material.    Biochemische
                                                     that xylitol is a promising osmotic agent in              Zeitschrift 1962;35:336.
                                                     patients on CAPD and particularly is indicated in      9. Thomas DW, Gilligan JE, Edwards JB.
                                                     insulindependent, uremic diabetic patients. The           Edwards RG. Lactic acidosis and osmotic
                                                                                                               diuresis produced by xylitol infusion. Med J
                                                     main advantage consists in (Table I) a marked
                                                                                                               Aust 1972; 1: 1246.
                                                     reduction in insulin requirements because of its      10. Montagne W, Taylo r KW. Pentitol and
                                                     insulin-independent metabolism via the pentose            insulin release by isolated rat islets of
                                                     phosphate cycle. Data so far collected suggest            Langerhans. BiochemJ 1968:109:333.

                                                                                                                                                               Downloaded from by guest on March 26, 2013
                                                     that, during long-term treatment, serum lipid         11. Bassler KH, Prelwitz W. Insulin und der
                                                     patterns will not undergo the same alterations            verteilnungraum von xylit bei eviscerierten
                                                     noted with glucose in short and medium-term               rat ten. Klin Wschr 1964; 42:94.
hepatic dehydrogenase with a ratelimiting step                                                             12. Thomas DW, Edwards JB, Gilligan JE et al.
(15).                                                periods on CAPD.
                                                                                                               Complications       following     intravenous
    Absorption of xylitol in amounts greater than                                                              administration of solutions containing
150 g/day seems to induce plasma accumulation                                                                  xylitol. Med J Aust 1972; I : 1238.
                                                                                                           13. Lang K. Utilization of xyitol in animal and
and/or production of abnormal metabolites,
                                                                                                               man. Int Symp on Pentose and Pentitols.
which act as toxic substances .                      REFERENCES
                                                                                                               Hakone 1967;19:7.
    When we had to use many hypertonic bags           1. Gat ti GL, S    alvatore G. L.impiego de11o       14. Toussaint W, Roggenkamp K, Bassler KH.
for over-loaded patients, we have observed               xilitolo e rifles si tossicologici. Parte I. La       Behaudlung der ketonemia im kindersalter
                                                                                                               mit xylit. Kinderheilk 1967;98:146.
clinical side effects such as nausea, vomiting,          Rivistadella Societa Italiana di Scienza dell'
                                                                                                           15. LangK. Xyit. Biochemischeundphys-
weakness, and anorexia, associated with                  Alimentazione 1978:5: 387.                            iologishce eigenschaften und therapeutische
transient elevations of serum transaminase,          2. Gat ti GL. Salvatore G. L.impiego dello                Moglichkeiten. Fortsch Med 1970:88.
alkaline phosphatase, bilirubin, lactic and uric         xilitolo e riflessi tossicologici. Parte II. La   16. Hauschildt S, Chalmers RA, Lawson AN
acid. Similar symptoms have been reported by             Rivista della Societa Italiana di Scienza dell.       etal. Metabolic investigations after
                                                         Alimentazione 1978;5:387.                             xylitolinfusion in human subjects. AmJ Clin
Thomas et al (10) after infusion of solutions with                                                             Nutr 1976.
                                                     3. Zeni L. L 'impiego dello xilitolo nel periodo
a high xylitol concentration: In our patients the                                                          17. Schroder R. Storungen im Osalaure-
                                                         postoperatorio e nella nutrizione parenterale.
absorption of less than 150 g/day of xylitol was                                                               stoffwechsel bei parenteraler eranarungen
                                                         Gaz Med It 1977; 136:437.                             mit xylit. Deutsche Med Wschr
well tolerated and produced no alterations in
                                                     4. Yagamata S. Goto Y, Ohneda A et al.                    1980;105:997.
hepatic function.
                                                         Clinical effects of xylitol on carbohy            18. Bazzato G, Coli U, Landini S et al. Nuove
   It has also been mentioned that when infused                                                                prospettive terapeutiche del paziente
rapidly with large doses of xylitol, patients with                                                             diabetico uremico in CAPD: Minime dosi di
renal failure are prone to develop oxalosis                                                                    insulina con I.impiego dello xilitolo. At ti
because of great amounts of glycolic acid forma-                                                               del XXII Congresso della Societa Italiana di
                                                                                                               Nefrologia 1981:281.
tion ( 16-17); during this period of

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