There is evidence that diabetes is characterized by taurine deficiency (1–4), which has been linked to diabetic retinopathy, neuropathy, and nephropathy (5–7). Taurine is involved in neuronal modulation, osmoregulation (8), and protection against oxidative stress (9). Its plasma levels are maintained within a normal range through protein intake, and de novo synthesis is limited by the activity of hepatic cysteinesulphinic acid decarboxylase, which is low in humans. Taurine depletion can occur rapidly (10), possibly leading to retinal, cardiac, neural, immune, and hemostatic dysfunction (4,11–14).
The reasons for taurine deficiency in diabetes remain unclear. A decrease in the overall body pool (1,2) and/or internal redistribution between the intra- and extracellular compartments are possibilities. The former can be secondary to decreased oral intake, poor intestinal absorption, renal wasting, or a combination of factors.
In diabetic rats, intestinal absorption of taurine is reduced (K.B., Camille Nassar, unpublished data), while urinary taurine excretion is enhanced (15). Kidney loss in uncontrolled diabetes is aggravated by severe hyperglycemia and ketoacidosis (4). Data are lacking, however, on urinary excretion and pharmacokinetics of taurine absorption in human diabetes with mild-to-moderate hyperglycemia. This pilot study was therefore conducted in patients with moderately impaired glucose control and in matched nondiabetic subjects to evaluate the pharmacokinetics of taurine absorption following an oral load and to elucidate the mechanism of taurine deficiency in diabetes.
RESEARCH DESIGN AND METHODS—
A total of 16 subjects were enrolled in the study: 6 patients with type 2 diabetes, 2 with type 1 diabetes, and 8 healthy subjects; subjects were pair-matched for age, sex, and BMI. The inclusion criteria for the patients were age 18–65 years, BMI 20–35 kg/m2, and A1C >7%. We excluded patients with chronic kidney disease, cholestatic liver disease, gastroparesis, malabsorption, and severe ophthalmopathy or neuropathy.
After a 10-h fast, blood was drawn for plasma taurine, fasting glucose, creatinine, triglycerides, and A1C. Height, weight, heart rate, and blood pressure were measured. A baseline urine specimen was collected for creatinine, microalbumin, and taurine, followed by six 500-mg tablets of taurine given once orally with water. Blood was then drawn every hour for 6 h, and urine was collected over the study period for taurine analysis.
Biochemical measurements were performed using established methods. The glomerular filtration rate values calculated by the Modification of Diet in Renal Disease Study formula (16) and the creatinine clearances based on 6-h urine collection were similar. Taurine was determined using reverse-phase chromatography (17). For each subject, hourly and peak plasma taurine and the time to achieve peak concentration following the oral taurine load were determined. The area under the curve was calculated, and linear regression analysis was performed on only the descending part of the curve. The rate constant (Ke) and half-life of elimination (t1/2) were derived from the slope of the curve (slope −Ke/2.3 and t1/2 0.693/Ke).
The urine taurine excretion rate was expressed in micromoles per hour. Fractional excretion is the ratio of taurine clearance to creatinine clearance, expressed as a percentage. The Mann-Whitney U test was used to compare variables between groups, and P values ≤0.05 were considered significant (SPSS version 14.0; SPSS, Chicago, IL).
RESULTS—
The baseline characteristics and the plasma and urine parameters of diabetic patients and control subjects are shown in Table 1. Subjects in both groups had normal kidney function.
There was a trend toward a lower baseline plasma taurine concentration in type 2 diabetic patients (P = 0.056), whereas the temporal pattern of the rise and decline in plasma taurine concentration was similar in both groups. After the taurine load, peak plasma concentration of taurine was significantly lower in diabetic subjects (P = 0.007). The increment in plasma taurine level from baseline to the first hour (hour 1) was lower in diabetic patients. The 1-h plasma taurine concentration was lower in diabetic subjects than in control subjects (P = 0.015). Moreover, area under the curve was significantly lower in diabetic subjects (P = 0.028). Both groups had comparable basal urine taurine levels. After the taurine load, diabetic patients had a higher urinary taurine excretion rate (P = 0.028) and higher taurine clearance (P < 0.001). This was reflected in doubling of the fractional excretion of taurine in the diabetic group.
CONCLUSIONS—
Our results indicate a difference in the pharmacokinetics of taurine in patients with diabetes compared with nondiabetic matched control subjects. After an oral taurine load, diabetic patients have a significantly lower plasma taurine concentration at peak. This might be due, in part, to impaired renal reabsorption with enhanced urinary clearance and fractional excretion. The lower plasma taurine concentration of the diabetic group in the first hour suggests that there may also be a component of decreased net intestinal absorption in diabetes. There was also a trend (although not significant) for a lower baseline plasma taurine level, consistent with previous reports. Ingested taurine is absorbed in the small intestine via its receptor (TAUT [taurine transporter]) (18) and is then distributed by active uptake to many organs against a concentration gradient (18,19).
Taurine is then conjugated in the liver to bile salts or excreted by the kidneys. The final outcome of taurine homeostasis is through fecal excretion after deconjugation by the bacterial flora or renal excretion as intact molecules (19,21–23). In this study at similar half-life in both groups, the urinary excretion rate of taurine was higher in diabetic subjects. Because the kidneys regulate the body taurine pool, a high-taurine diet induces hypertaurinuria and reduces renal tubular uptake (24), and the opposite happens on a low-taurine diet. At a comparable glomerular filtration rate but lower plasma taurine concentration at each hour of assessment, the filtered load of taurine in diabetic subjects is lower than that of control subjects. The higher taurine excretion rate suggests that renal tubular reabsorption is decreased in diabetes. The latter finding may be confounded to some extent by hyperglycemia in the diabetic group (209 ± 49 mg/dl) inducing osmotic diuresis or, alternatively, may theoretically involve a decrease in the activity of the brush-border taurine transport protein in the proximal tubule of the kidney.
In experimental diabetes, taurine supplementation may improve metabolic control (25), restore the endothelium-dependent vascular relaxation (26), improve insulin sensitivity, attenuate hypertension, prevent diabetic cardiomyopathy (27), reverse neuropathy (28), and reduce mortality (29). Such beneficial effects may be mediated through binding of taurine to the insulin receptor (4), decreasing glucose absorption (30), and/or directly modulating hepatic glucose metabolism (31). Human studies on taurine supplementation are thus far inconclusive (32,33).
This is the first study to demonstrate that, after a taurine load, diabetic patients waste taurine more extensively in urine than matched control subjects and probably have a lower rate of net intestinal absorption. The pathogenesis of the renal findings is most likely through decreased tubular reabsorption, whereas the gastrointestinal effect is likely through decreased intestinal transfer, as further supported by animal studies. It is tempting to postulate that diminution in the activity of the brush-border taurine transport protein in the proximal tubule and in the luminal cell membrane of the small intestine can account for both the enhanced renal excretion and the impaired intestinal taurine absorption. Further studies are required to test this postulate and to assess other parameters such as fecal excretion, liver utilization, and tissue distribution.
Baseline characteristics, plasma, and urine taurine parameters in diabetic patients and control subjects
. | All patients . | All control subjects . | P* . | Type 2 diabetic patients . | Control subjects . | P† . |
---|---|---|---|---|---|---|
n | 8 | 8 | 6 | 6 | ||
Age (years) | 44 ± 18 | 45 ± 15 | 0.87 | 48 ± 18 | 48 ± 15 | 0.9 |
Sex (female/male) | 3/5 | 3/5 | — | 1/5 | 1/5 | — |
Duration of diabetes (years) | 8.8 ± 7.8 | — | — | 9.5 ± 8.7 | — | — |
Hypertension (n) | 3/8 | 1/8 | — | 3/8 | 1/8 | — |
Blood glucose (mg/dl) | 209 ± 49 | 89 ± 12 | 0.001 | 187 ± 32 | 92 ± 13 | 0.001 |
A1C (%) | 8.2 ± 1.4 | 5.5 ± 0.5 | <0.001 | 8.6 ± 1.2 | 5.5 ± 0.5 | 0.001 |
BMI (kg/m2) | 27.2 ± 2.6 | 28 ± 4.0 | 0.32 | 28.3 ± 1.94 | 30.2 ± 2.8 | 0.217 |
Systolic blood pressure (mmHg) | 135 ± 12 | 113 ± 10 | 0.007 | 137 ± 14 | 117 ± 5.3 | 0.008 |
Diastolic blood pressure (mmHg) | 80 ± 9 | 70 ± 13 | 0.105 | 82.5 ± 8.8 | 69.5 ± 15 | 0.105 |
Baseline creatinine (mg/dl) | 0.77 ± 0.18 | 0.77 ± 0.15 | 0.95 | 0.8 ± 0.2 | 0.7 ± 0.2 | 0.744 |
GFR MDRD (ml/min per 1.73 m2) | 111 ± 19 | 105 ± 32 | 0.16 | 111 ± 20 | 110 ± 36 | 0.985 |
Baseline plasma taurine (μmol/l) | 53.5 ± 11 | 68.1 ± 20 | 0.195 | 51.3 ± 11 | 72.2 ± 21 | 0.056 |
Plasma concentration at 1 h (μmol/l) | 351 ± 120 | 621 ± 255 | 0.017 | 335 ± 134 | 654 ± 291 | 0.035 |
Plasma concentration at peak (μmol/l) | 568 ± 68 | 742 ± 162 | 0.007 | 552 ± 67 | 772 ± 179 | 0.019 |
AUC (μmol · h−1 · l−1) | 1,499.5 ± 266 | 2,119 ± 642 | 0.028 | 1,485 ± 312 | 2,173 ± 729 | 0.059 |
Time to peak (h) | 1.8 ± 0.3 | 1.8 ± 1.1 | 0.6 | 1.8 ± 0.4 | 1.8 ± 1.3 | 1.0 |
t1/2 (h) | 2.3 ± 0.7 | 2 ± 0.61 | 0.5 | 2.5 ± 0.8 | 1.9 ± 0.5 | 0.241 |
Urine taurine excretion rate (μmol/h) | 1,225 ± 206 | 932 ± 245 | 0.028 | 1,266 ± 221 | 938 ± 279 | 0.048 |
Urinary taurine clearance (l/h) | 4.2 ± 0.9 | 2.4 ± 0.5 | <0.001 | 4.5 ± 0.8 | 2.4 ± 0.57 | 0.001 |
Urinary fractional excretion (%) | 0.6 ± 0.1 | 0.34 ± 0.13 | 0.002 | 0.58 ± 0.1 | 0.37 ± 0.1 | 0.008 |
. | All patients . | All control subjects . | P* . | Type 2 diabetic patients . | Control subjects . | P† . |
---|---|---|---|---|---|---|
n | 8 | 8 | 6 | 6 | ||
Age (years) | 44 ± 18 | 45 ± 15 | 0.87 | 48 ± 18 | 48 ± 15 | 0.9 |
Sex (female/male) | 3/5 | 3/5 | — | 1/5 | 1/5 | — |
Duration of diabetes (years) | 8.8 ± 7.8 | — | — | 9.5 ± 8.7 | — | — |
Hypertension (n) | 3/8 | 1/8 | — | 3/8 | 1/8 | — |
Blood glucose (mg/dl) | 209 ± 49 | 89 ± 12 | 0.001 | 187 ± 32 | 92 ± 13 | 0.001 |
A1C (%) | 8.2 ± 1.4 | 5.5 ± 0.5 | <0.001 | 8.6 ± 1.2 | 5.5 ± 0.5 | 0.001 |
BMI (kg/m2) | 27.2 ± 2.6 | 28 ± 4.0 | 0.32 | 28.3 ± 1.94 | 30.2 ± 2.8 | 0.217 |
Systolic blood pressure (mmHg) | 135 ± 12 | 113 ± 10 | 0.007 | 137 ± 14 | 117 ± 5.3 | 0.008 |
Diastolic blood pressure (mmHg) | 80 ± 9 | 70 ± 13 | 0.105 | 82.5 ± 8.8 | 69.5 ± 15 | 0.105 |
Baseline creatinine (mg/dl) | 0.77 ± 0.18 | 0.77 ± 0.15 | 0.95 | 0.8 ± 0.2 | 0.7 ± 0.2 | 0.744 |
GFR MDRD (ml/min per 1.73 m2) | 111 ± 19 | 105 ± 32 | 0.16 | 111 ± 20 | 110 ± 36 | 0.985 |
Baseline plasma taurine (μmol/l) | 53.5 ± 11 | 68.1 ± 20 | 0.195 | 51.3 ± 11 | 72.2 ± 21 | 0.056 |
Plasma concentration at 1 h (μmol/l) | 351 ± 120 | 621 ± 255 | 0.017 | 335 ± 134 | 654 ± 291 | 0.035 |
Plasma concentration at peak (μmol/l) | 568 ± 68 | 742 ± 162 | 0.007 | 552 ± 67 | 772 ± 179 | 0.019 |
AUC (μmol · h−1 · l−1) | 1,499.5 ± 266 | 2,119 ± 642 | 0.028 | 1,485 ± 312 | 2,173 ± 729 | 0.059 |
Time to peak (h) | 1.8 ± 0.3 | 1.8 ± 1.1 | 0.6 | 1.8 ± 0.4 | 1.8 ± 1.3 | 1.0 |
t1/2 (h) | 2.3 ± 0.7 | 2 ± 0.61 | 0.5 | 2.5 ± 0.8 | 1.9 ± 0.5 | 0.241 |
Urine taurine excretion rate (μmol/h) | 1,225 ± 206 | 932 ± 245 | 0.028 | 1,266 ± 221 | 938 ± 279 | 0.048 |
Urinary taurine clearance (l/h) | 4.2 ± 0.9 | 2.4 ± 0.5 | <0.001 | 4.5 ± 0.8 | 2.4 ± 0.57 | 0.001 |
Urinary fractional excretion (%) | 0.6 ± 0.1 | 0.34 ± 0.13 | 0.002 | 0.58 ± 0.1 | 0.37 ± 0.1 | 0.008 |
Data are means ± SD unless otherwise indicated.
P < 0.05 for all patients vs. all control subjects and P < 0.05 for all type 2 diabetic patients vs. control subjects. (Mann-Whitney U test). Glomerular filtration rate was estimated by the Modification of Diet in Renal Disease Study formula. The study was approved by the institutional review board at the American University of Beirut. t1/2, half-life. AUC, area under the curve; GFR, glomeruler filtration rate; MDRD, Modification of Diet in Renal Disease Study.
Article Information
This study was supported by a research grant from the Medical Practice Plan at the American University of Beirut Medical Center.
References
Published ahead of print at http://care.diabetesjournals.org on 18 July 2007. DOI: 10.2337/dc07-0872.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
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