8. Taurine and metabolic disease - trnres.com El... · Taurine and metabolic disease Svend Høime Hansen1 and Ole Hartvig Mortensen2 ... Determined. However there is a striking difference

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Taurine in Health and Disease, 2012: 167-190 ISBN: 978-81-7895-520-9

Editors: A. El Idrissi and W. L’Amoreaux

8. Taurine and metabolic disease

Svend Høime Hansen1

and Ole Hartvig Mortensen2

1Department of Clinical Biochemistry, 3-01-1, Rigshospitalet, Copenhagen University Hospital

Blegdamsvej 9, DK-2100 Copenhagen, Denmark; 2Department of Biomedical Sciences

University of Copenhagen, Blegdamsvej 3, DK-2100 Copenhagen, Denmark

1.1. Introduction

Taurine is a sulfur-containing amino acid, which does not enter protein synthesis, and is traditionally considered as an inert molecule without any reactive groups. Besides the well-known conjugation with bile acids, taurine has a number of other physiological functions such as, intracellular osmolyte for volume regulation and some antioxidant properties (Bouckenooghe et al., 2006; Hansen, 2001; Huxtable, 1992; Jacobsen and Smith, 1968; Schuller- Levis and Park, 2003). Taurine is thus not expected to be directly involved in metabolic pathways. Nevertheless, taurine deficiency in the cat results in a marked dysfunction of energy demanding tissues (i.e. retina and heart) (Sturman, 1993), and similar observations are seen in the taurine-transporter knockout mouse (Warskulat et al., 2007).

1.2. Taurine and glucose metabolism - diabetes

Taurine was first shown to have an effect upon glucose homeostasis

in the 1930s (Ackermann and Heinsen, 1935), where it was reported to have a Correspondence/Reprint request: Dr. Ole Hartvig Mortensen, Department of Biomedical Sciences, Blegdamsvej

3, DK-2200 Copenhagen, Denmark. E-mail: [email protected]; Svend Høime Hansen, Rigshospitalet

Copenhagen University Hospital, Blegdamsvej 9, Dk-2100 Copenhagen, Denmark. E-mail: [email protected]

Svend Høime Hansen & Ole Hartvig Mortensen 168

hypoglycemic effect. Since then, a lot of studies have shown a clear

interaction between taurine and diabetes, as described in recent literature

reviews (Franconi et al., 2006; Hansen, 2001; Kim et al., 2007). Several

hypotheses as to how this interplay is orchestrated have been proposed, as

taurine has shown both developmental, osmoregulatory, anti-apoptotic, anti-

inflammatory, and anti-oxidant effects as well as effects on lipid, cholesterol,

and calcium homeostasis (Della Corte et al., 2002; Franconi et al., 2004; Lee

et al., 2005; Schaffer et al., 2009).

1.2.1. Humans

In diabetic patients, taurine homeostasis is dysregulated, as type 1

diabetic patients have an increased urinary taurine excretion (Hermansson

and Mårtensson, 1984) and both type 1 and type 2 diabetic patients have a

decreased plasma taurine concentration (De Luca et al., 2001b, 2001a;

Franconi et al., 1995). Furthermore, diabetes seem to cause long term

changes in taurine homeostasis, as non-diabetic women who had gestational

diabetes, but recovered, had a lower plasma taurine concentration several

years after giving birth (Seghieri et al., 2007).

Relatively few studies have examined the effect of taurine

supplementation upon glucose homeostasis in diabetic patients or patients

predisposed for developing diabetes. Elizarova et al. found that taurine

supplementation (0.5 g twice a day for 30 days) markedly decreased the

average daily plasma glucose levels and glycosuria independently of insulin

in type 1 diabetic patients (Elizarova and Nedosugova, 1996). In direct

contradiction to this study, Chauncey et al. found no effect of taurine

supplementation (1.5 g twice a day for 4 months) upon fasting glucose or

HaemoglobinA1c (HbA1c) levels in type 2 diabetic patients (Chauncey et al.,

2003). This finding is further corroborated by another study showing no

effect of taurine supplementation (0.75 g twice a day for 8 weeks) on fasting

glucose, glucose tolerance, fasting insulin and insulin sensitivity (as

measured by euglycemic hyperinsulinemic clamp) in obese healthy subjects

with a family history of type 2 diabetes (Brøns et al., 2004). Last, taurine

supplementation (1 g three times a day for 2 weeks) of obese non-diabetic

men did not have an effect on fasting plasma glucose, but taurine did prevent

intralipid-infusion-induced insulin resistance (Xiao et al., 2008). However,

these studies suffer from different limitations in their design making their

interpretation difficult: All studies lack a control group of completely healthy

subjects who receive only taurine, two studies has a very limited

characterization of the subjects (Elizarova and Nedosugova, 1996; Chauncey

et al., 2003), and one study lacks a placebo group (Elizarova and Nedosugova,

Metabolic disease 169

1996). The study with the best design (double-blinded, randomized crossover

study) examines subjects with a predominantly normal glucose tolerance

(Brøns et al., 2004). Furthermore, in several taurine supplementation studies

examining diabetic complications, differences in fasting plasma glucose,

insulin or HbA1c after taurine supplementation were not reported (Franconi

et al., 1996; Nakamura et al., 1999). Thus, whether or not taurine

supplementation has a positive effect upon glucose homeostasis in human

diabetic patients is at present impossible to ascertain and more clinical studies

examining the effect of taurine upon glucose homeostasis in diabetic patients

are needed.

1.2.2. Animal models

Whereas taurine homeostasis seems largely unaffected in streptozotocin

induced type 1 diabetes in rats (Trachtman et al., 1992), a genetic model of

type 2 diabetes, the Zucker fatty rat, shows increased taurine excretion in

urine (Williams et al., 2005) as well as an increase in the plasma taurine

concentration (Wijekoon et al., 2004). Furthermore, in high-fructose fed rats,

a well-known model of type 2 diabetes, a decrease in plasma and liver taurine

has been observed (Nandhini et al., 2005).

Several studies have shown that taurine protects β-cells against

destruction induced by streptozotocin in rodents, with most studies showing a

glucose lowering effect of taurine (Alvarado-Vásquez et al., 2003; Odetti

et al., 2003; Di Leo et al., 2004; Song et al., 2003; Hansen, 2001). The same

protective and glucose lowering effect was seen in studies on alloxan induced

type 1 diabetes in both mice (Lim et al., 1998), rats (Gavrovskaya et al.,

2008), and rabbits (Tenner et al., 2003; Winiarska et al., 2009). However, the

exact mechanisms by which taurine protects the β-cells against destruction

and lowers plasma glucose are largely unknown, but may be related to a

general mitochondrial protective effect asserted by taurine (Han et al., 2004)

or the recently reported taurine mediated remodeling of pancreatic islets

(El Idrissi et al., 2009).

Taurine has shown a beneficial effect in several animal models of type 2

diabetes. In the Otsuka Long-Evans Tokushima Fatty (OLETF) rats and in

high-fructose fed rats, taurine increased insulin sensitivity and reduced

hyperglycemia (El Mesallamy et al., 2010; Harada et al., 2004a; Nakaya

et al., 2000; Nandhini et al., 2005). However, taurine supplementation does

not show an effect in all animal models of type 2 diabetes, as in the GK rats,

taurine supplementation had no effect on plasma glucose levels (Nishimura

et al., 2002). As in type 1 diabetes, the exact mechanism by which taurine

exerts its effects upon glucose homeostasis in type 2 diabetes is largely


unknown, although the effect may be either tied together with the lipid

lowering effect of taurine (as increased plasma lipids are associated with

insulin resistance), by the effect of taurine upon insulin signaling (Nandhini

et al., 2005; Takatani et al., 2004) or by a mitochondrial protective effect, as

mitochondrial dysfunction seems to be associated with decreased insulin

secretion (Mulder and Ling, 2009; Maechler et al., 2010) and insulin

resistance (Kelley et al., 2002; Lowell and Shulman, 2005; Pagel-

Langenickel et al., 2010). It may also be possible that the effect of taurine is

mediated through its conjugation with bile acids, as a recent study showed

that tauro-ursodeoxycholic acid, a chemical chaperone and a derivative of

bile acids was found to protect against diet-induced insulin resistance by

relieving ER stress (Ozcan et al., 2006). Furthermore, taurine may also be an

important factor in regulation of the inflammatory response, as its normally

occuring derivative, taurine chloramine, is a potent anti-inflammatory agent

(Park and Schuller-Levis, 2003). Incidently, low-grade inflammation is

thought to play a key role in the development of obesity induced type 2

diabetes (Lee and Pratley, 2005).

1.2.3. The C57BL/6J mouse

The mouse strain C57BL/6J (or just B6) is one of the most widely-used

animal models for understanding metabolic diseases, especially concerning

lipid metabolism and atherosclerosis and when reporting the mouse genome,

this mouse strain was chosen as the reference strain. C57BL/6J is also very

susceptible to development of obesity and atherosclerosis when using a high

fat diet (Nishina et al., 1990, 1993; Paigen et al., 1985). Based on data from

July 2010 approximately 50% of all genetically modified mouse strains in the

Mouse Genome Informatics database (http://www.informatics.jax.org) are

based on this strain.

In the 1950s, a defect in the taurine renal reabsorption was reported for

the C57BL/6J mouse strain (Harris and Searle, 1953), and further

characterisation of the transporter defect was done in the 1970s and 1980s

(Chesney et al., 1976; Jean et al., 1984; Mandla et al., 1988; Rozen et al.,

1983). Later genetic studies have not been reported. When interpreting the

results of studies using transgenic mice, the effect of taurine is only discussed

in specific taurine supplementation studies, but taurine could play the role as

silent partner, especially for metabolic studies in transgenic models back

crossed to C57BL/6J mice. In terms of supplementation studies in C57BL/6J

mice, the taurine effects could possibly be interpreted as compensation for the

renal absorption defect. Whether or not the difference in taurine homeostasis

between mice strains is important for glucose homeostasis remains to be


Figure 1. Possible mechanisms by which taurine exerts its anti-diabetic effect as well

as possible target tissues. AGE) advanced glycation end products.

Determined. However there is a striking difference in glucose homeostasis

and insulin response in different mice strains as well as their responsiveness

to a high fat diet (Andrikopoulos et al., 2005; Berglund et al., 2008; Funkat

et al., 2004; Kaku et al., 1988).

1.3. Taurine and diabetic complications

A number of long-term complications typically accompany the general

metabolic dysfunction in diabetes (Hansen, 2001). Most serious for the

patients are possibly the vascular complications. Diabetic retinopathy:

Microvascular complications in the eyes lead to damage of the retina, and

thus reduced visual field or in the worst case blindness. Diabetic neuropathy:

Dysfunction of the peripheral nerves causing diverse symptoms and neural

dysfunction. Diabetic nephropathy can lead to chronic renal failure and

subsequent need for haemodialysis. Besides, some of the macrovascular

complications can be fatal, e.g. cardiomyopathy and atherosclerosis (see

below). The diabetic vascular complications have all been related to

dysfunction of the endothelium. A recent study on young male type 1

diabetes patients demonstrated that taurine supplementation can reverse the

endothelial dysfunction (Moloney et al., 2010).


One of the suggested hypotheses for understanding the microvascular

diabetic late complications is based on the so-called sorbitol pathway and

subsequent osmolyte depletion hypothesis. The hypothesis is based on the

fact that high glucose levels lead to intracellular sorbitol accumulation due to

aldose reductase. Sorbitol cannot in itself be transported across the cellular

membrane, and thus more labile osmolytes like taurine or myo-inositol will

gradually be depleted from the intracellular environment. Finally, the

sorbitol-producing cells will swell due to impaired volume regulation and

dysregulation of the taurine transporter (Askwith et al., 2009; Hansen, 2001;

Stevens et al., 1993). Furthermore additional taurine depletion can be caused

by intracellular scavenging of reactive carbonyl compounds and thus

prevention of AGE formation (Hansen, 2001).

The weakness of this hypothesis based on the sorbitol accumulation and

taurine depletion is the fact that it gives no direct biochemical link to the

cellular dysfunction observed in the diabetic complications. It should be noted

Figure 2. Simplified model for development of diabetic complications. Hyper-

glycemia causes sorbitol accumulation in the aldose reductase containing cells. This

causes a gradual depletion of transportable osmolytes like taurine. Consequently, cell

volume regulation becomes dysfunctional in the tissue. The process is accompanied

by a slow intracellular depletion of taurine from the mitochondrial compartment

resulting in increasing mitochondrial dysfunction.


that the types of tissue and organs involved in diabetic complications are all

very energy-demanding, and when comparing the clinical manifestations of

diabetic complications with those found in patients with mitochondrial

diseases (Kisler et al., 2010), major correspondence can be found. However,

it must be reasonable to assume that a gradual taurine depletion in the

intracellular environment will be expected to be accompanied by

mitochondrial depletion of taurine. Accepting taurine as an necessary

compound for mitochondrial function (see below), either as matrix pH buffer

(Hansen et al., 2006, 2010) and/or as a requirement for mitochondrial

translation being found in mitochondrial tRNA (Suzuki et al., 2002; Schaffer

et al., 2009), taurine depletion can possibly be a direct cause of mitochondrial

dysfunction. This mitochondrial role of taurine should thus be included in the

suggested viewpoint (Brownlee, 2005) of mitochondrial dysfunction as a

possible unifying hypothesis for diabetic complications.

1.4. Taurine and lipid metabolism – obesity

1.4.1. Cholesterol catabolism and bile acids

In most physiology and biochemistry text books, taurine is mentioned

solely as a component of the bile acids. Cholesterol catabolism and

subsequent excretion from the body occurs through the bile acids as the

major metabolic pathway (se Figure 3). Cholesterol is oxidized in the liver to

cholic acid by a complex enzyme framework (Russell, 2003). Cholic acid is

subsequently conjugated with either taurine or glycine predominantly in the

hepatocyte peroxisomes (Ferdinandusse et al., 2009; Solaas et al., 2000) by

the enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT) (Falany

et al., 1994; He et al., 2003; Sfakianos et al., 2002). Species differences in the

amount of bile acids conjugated to glycine or taurine exist. Thus, in rat,

hamster, pig, and human the enzyme is capable of performing taurine as well as

glycine conjugation. In cat and rat, taurine conjugation is almost exclusively

performed, and in mouse and dog, only taurine conjugation occurs (Falany

et al., 1997; He et al., 2003; Kwakye et al., 1991; Rabin et al., 1976; Sfakianos

et al., 2002; Trautwein et al., 1999). In the rabbit only glycine conjugation has

traditionally been reported (Wildgrube et al., 1986), but findings in a more

recent study raises doubt about this fact (Hagey et al., 1998). Animal experiments in rats have demonstrated that taurine

supplementation can alleviate the consequences of a high cholesterol diet by

enhancing the excretion of bile acids, either due to enhanced activity of the

hepatic 7α-hydroxylase (Nishimura et al., 2003), enhancement by taurine of

bile acid conjugation (Sugiyama et al., 1989), and/or by inhibiting the ileal


bile acid reabsorption (Nishimura et al., 2009). Similar studies have been

performed in rabbits, but as rabbits almost exclusively conjugate bile acids

with glycine, taurine supplementation studies in rabbit on cholesterol

metabolism (Balkan et al., 2002, 2004) are difficult to interpret.

Only a few human studies, all with a small number of participating

subjects (N=3-11), seem to exist on taurine supplementation, subsequent bile

acid turnover and lipid metabolism (Hepner et al., 1973; Hardison and Grundy,

1983; Sjovall, 1959; Truswell et al., 1965; Tanno et al., 1989). It seems clear

that in humans, taurine is the preferred partner in bile acid conjugation

compared with glycine, as taurine supplementation clearly increases the

taurine/glycine conjugation ratio in the studies. As the bile acids are the main

way of cholesterol excretion from the body, the relative proportions of

the taurine or glycine conjugation are of interest, as relative differences in the

Figure 3. Overview of the bile acid production, bile acid conjugation with either

glycine or taurine by the bile acid CoA:amino acid:N-acyltransferase (BAAT)

enzyme, intestinal bile acid reabsorption and partly fecal excretion.


reabsorption of the conjugates are expected, as the water solubility is better

for taurocholate due to the sulfonic acid group in taurine.

Taurine-conjugated bile acids are readily reabsorbed in the intestine by

an active ileal transport (Krag and Phillips, 1974), so a larger circulating bile

acid pool becomes the first result of taurine supplementation. However, it is

reasonable to assume that the reabsorption becomes down-regulated through a

feedback mechanism from the circulating bile acids as in the rat (Nishimura

et al., 2009) and then enhanced excretion of cholesterol will ensue. Alternately,

the human studies could indicate that the increased circulating levels of bile

acids (including taurocholate) would downregulate the cholesterol biosynthesis.

Furthermore, bile acids and bile acid receptors have been found to participate

in metabolic regulation. Such effects of bile acids can be found reviewed

elsewhere (Lefebvre et al., 2009; Staels et al., 2010; Trauner et al., 2010).

Finally, it should be noted that a reported stimulation by tauroconjugation on

fecal bacterial degradation of cholic acid (Van Eldere et al., 1996) could

actually cause an increase of excretion of cholic acid by taurine.

1.5. Lipid metabolism

The direct involvement of taurine in cholesterol catabolism seems to

have made the majority of taurine studies to concentrate on cholesterol levels,

lipid accumulation and atherosclerotic lesions in the vessels (Kondo et al.,

2001; Militante and Lombardini, 2004; Murakami et al., 1999). A few studies

in mouse, hamster, rat or recently quail have included quantitative

determinations of lipids and/or triglycerides in plasma, liver tissue or fat

deposition (Gandhi et al., 1992; Harada et al., 2004b; Kondo et al., 2001;

Murakami et al., 2002, 2010; Mochizuki et al., 1999; Nakaya et al., 2000;

Sethupathy et al., 2002; Tsuboyama-Kasaoka et al., 2006; Yokogoshi and

Oda, 2002; Yan et al., 1993). Generally taurine supplementation causes a

decrease in plasma lipids and triglycerides. It should specifically be noticed

that taurine supplementation could reverse obesity and increase energy

expenditure in C57BL/6J mice fed a high-fat diet (Tsuboyama-Kasaoka et al.,

2006).

A clinical study with taurine supplementation to a minor group of

overweight or obese non-diabetic subjects found a minor decrease in plasma

triglycerides, but no change in plasma cholesterol (Zhang et al., 2004). In one

study (Mochizuki et al., 1999) no effect of taurine supplementation was

found on the liver lipids, but a minor decrease was observed on liver

cholesterol. In all the other studies, taurine supplementation demonstrated a

clear decrease in lipid and triglyceride levels. Finally, an epidemiologic


cohort study has shown that urinary taurine excretion (due to intake of fish

and shellfish) was inversely correlated to the risk of developing

artherosclerosis (Yamori, 2004, 2006). No explanation was presented in any

of the studies for the possible biochemical role of taurine.

As discussed in the previous section taurine supplementation must be

expected to increase the bile acid pool and thus improve bile acid-assisted

lipid transport mechanisms and associated metabolic regulation. Alternately,

taurine supplementation could be interpreted to enhance the mitochondrial

oxidation of fatty acids. Following this argumentation, the observed

improvements of lipid metabolism could be considered as support for the

recently presented hypothesis of taurine as mitochondrial matrix pH buffer.

Taurine supplementation will increase matrix pH buffering capacity and thus

stabilise the oxidative environment in the mitochondrial matrix to reduce

release of reactive oxygen species (ROS), and perhaps even more important

stabilise the very pH-dependent beta-oxidation of the fatty acids by the acyl-

CoA dehydrogenase enzymes (Hansen et al., 2006, 2010).

1.6. Taurine and fetal programming of metabolic disease

During the last two decades, it has become apparent that nutrition and

environment during pregnancy and early life have a lasting effect upon the

metabolic phenotype in adult life. The idea that there is a link between early

life conditions and subsequent disease was already discovered in the 1930s

(Smith and Kuh, 2001). However, it was not until Barker in 1986 reported a

correlation between childhood nutrition and ischemic heart disease (Barker

and Osmond, 1986) and in subsequent studies Barker and Hales during the

early 1990s coined the “thrifty phenotype” hypothesis (Hales and Barker,

1992) that the correlation was rediscovered. The hypothesis suggests that

early pre- and postnatal life is a critical period during which environmental

exposures that hinder growth will lead to an adaptation of metabolism to a

limited supply of nutrients, or other types of growth restraints. This

adaptation will contribute to increased risk for disease in adult life if

sufficient nutrients are provided. The term “fetal programming” can be used

to describe the hypothesized, yet unknown, mechanism behind the “thrifty

phenotype” hypothesis (Desai and Hales, 1997; Hales and Barker, 2001).

Several human studies have thus convincingly shown that fetal

malnutrition during pregnancy, which often leads to low birth weight or a

small for gestational age fetus, confers an increased risk of obesity, insulin

resistance, type 2 diabetes and a general low life expectancy (Jones and

Ozanne, 2009; Poulsen et al., 1997; Ravelli et al., 1999; Roseboom et al.,

2001a, 2001b). Several animal models in species ranging from rodents to


monkeys and of fetal malnutrition or low birth weight has been used to study

fetal programming, or intrauterine growth retardation (IUGR), with some of

the most popular ones being protein or dietary restriction during gestation,

intrauterine artery ligation and dexamethasone treatment of the pregnant dam

(Martin-Gronert and Ozanne, 2007). Human IUGR exhibit decreased taurine

levels in the fetus (Cetin et al., 1990; Economides et al., 1989), something

which is reflected in animal models of IUGR as well (Reusens et al., 1995;

Wu et al., 1998).

Taurine is considered to be an essential amino acid during development,

as the endogenous synthesis of taurine is inadequate in the fetus (Hibbard

et al., 1990). Thus, the fetus is dependent on the maternal supply of taurine.

Taurine deficiency leads to a smaller birth weight in both cats (Sturman,

1991) and rodents (Ejiri et al., 1987). The offspring of cats (which are unable

to synthesize taurine) reared on a taurine free diet, exhibit profound

developmental abnormalities, among these being: Smaller body weight,

smaller brain weight, abnormal hind leg development as well as a

degeneration or abnormal development of the retina and visual cortex

(Sturman, 1991). Furthermore, mice deficient in the taurine transporter gene

(TauT), show a smaller overall size, however no information regarding

birthweight is available (Warskulat et al., 2007). TauT knockout mice also

show defects in heart and skeletal muscle development, most likely due to

mitochondrial effects (Ito et al., 2008; Warskulat et al., 2004). In humans, a

low plasma taurine concentration in the infant has been linked to detrimental

mental development (Heird, 2004; Wharton et al., 2004), something which

has been corroborated by animal studies (Sturman, 1993). Furthermore,

taurine supplementation in mice has shown that the exact timing of taurine

supplementation during brain development influence the learning ability,

with taurine sufficiency being most important during the perinatal and

postnatal period (Suge et al., 2007). Experimental animal studies suggest that

taurine may be a marker of fetal well being (de Boo and Harding, 2007).

Several studies have documented that taurine ameliorates some of the

harmful effects that detrimental fetal programming may confer upon the

offspring in terms of the risk of developing metabolic disease and notably,

taurine is able to at least partially prevent an experimental induced decrease

in birth weight in several animal models of fetal programming. Thus, taurine

supplementation has been shown to normalize proliferation and

vascularization of the pancreas following gestational protein restriction

(Boujendar et al., 2002, 2003) and to decrease the sensitivity of the pancreas

towards cytokines (Merezak et al., 2001, 2004). In fact, taurine prevented all

changes in mRNA expression levels in the pancreas in newborns caused by

gestational protein restriction (Reusens et al., 2008). Likewise, taurine


prevented a large portion of the changes in mRNA expression levels in both

skeletal muscle and liver caused by gestational protein restriction (Mortensen

et al., 2010). Interestingly these studies of the fetal gene expression profile in

both pancreas, liver and skeletal muscle suggest that the rescue effect taurine

exerts may have a mitochondrial component. This may also be important in

human development, as a reduced activity of the placental taurine

transporters has been observed in low birth weight in humans (Norberg et al.,

1998), something which may explain the low taurine concentrations in fetal

plasma often observed in this pregnancy complication (Cetin et al., 1990). A

recent study suggest that excessive taurine during gestation may also have

detrimental effects later in life, as taurine supplementation of pregnant rats

resulted in increased obesity and insulin resistance in the offspring (Hultman

et al., 2007). Collectively these studies suggest that taurine has a programming

Figure 4. The different pathways by which taurine supplementation influences fetal

programming mediated development of type 2 diabetes.


or rescuing effect during fetal development, perhaps via epigenetic and/or

organogenesis related mechanisms.

1.7. Taurine, mitochondrial function and metabolic disease –

the missing link?

Recently, taurine has been suggested to have an important role in the

mitochondria as it has been suggested as a pH buffer in the mitochondrial

matrix to stabilize mitochondrial beta-oxidation of fatty acids. This oxidative

process requires mildly alkaline conditions in the mitochondrial matrix with

taurine as optimal pH buffer (Hansen et al., 2006, 2010). In addition, taurine

could have a direct role in the metabolic regulation of the pyruvate

dehydrogenase (Lombardini, 1998). Besides, taurine may be required for

optimal mitochondrial protein synthesis through taurine modified tRNAs

(Suzuki et al., 2002; Schaffer et al., 2009). High mitochondrial taurine

concentrations immediately explains the pivotal requirement for taurine

during fetal development (Suzuki et al., 2002), especially for the strongly

oxidative and thus mitochondria-rich tissues like liver and skeletal muscle as

well as pancreatic -cells. Consequently, taurine deficiency either during

development or adult life may cause impaired mitochondrial oxidation, fatty

acid oxidation and altered mitochondrial protein synthesis.

The role of mitochondrial dysfunction in insulin resistance and type 2

diabetes is debated and may actually be a consequence of insulin resistance

rather than a causal factor (Abdul-Ghani and DeFronzo, 2010; Dumas et al.,

2009; Holloszy, 2009; Schiff et al., 2009; Schrauwen et al., 2010; Turner and

Heilbronn, 2008). However, many studies have found a correlation between

decreased mitochondrial function or amount, or gene expression patterns and

type 2 diabetes. In addition, a recent viewpoint (Brownlee, 2005) has

suggested mitochondrial dysfunction as a possible unifying hypothesis for

diabetic complications. Hence, taurine deficiency as seen in diabetes may

increase the mitochondrial dysfunction and/or be involved in a vicious cycle

that ultimately lead to a worsening of the diabetic condition and

mitochondrial function. Thus it will be important in to examine the TauT

knockout mice in terms of susceptibility to diet induced type 2 diabetes.

1.7.1. Therapeutic perspectives for taurine as supplementation

Several animal studies have demonstrated positive effect on cholesterol

and lipid metabolism with subsequent prevention in the development of

atherosclerosis. These studies strongly support the idea of using taurine for

alleviating impaired lipid metabolism in atherosclerosis, type 2 diabetes and


obesity. The arguments for using taurine to prevent diabetic complication are

also convincing, possibly in combination with aldose reductase inhibitors, as

taurine uptake in the affected cells might be prevented due to sorbitol

accumulation, which can be prevented with these inhibitors.

Taurine is today available as supplementation or in high concentrations

in energy drinks like the Austrian brand Red Bull or the Japanese brand

Lipovitan. However, the availability as commercial consumer products also

seems to represent a hindrance for establishing health recommendations with

regards to daily intake of taurine, as the number of associated clinical

metabolism studies is very limited. Even a recent meta-analysis on the role of

taurine in development and growth from Cochrane (Verner et al, 2007) does

not include any convincing biochemical arguments.

We hope that this review encourages future research, as the therapeutic

perspectives of the presented hypotheses need to be tested.

1.8. References

1. Abdul-Ghani, M. A., and DeFronzo, R. A. (2010). Pathogenesis of insulin

resistance in skeletal muscle. J. Biomed. Biotechnol. 2010, 476279.

2. Ackermann, D., and Heinsen, H. (1935). Über die physiologische Wirkung des

Asterubins und anderer, zum Teil neu dargestellter schwelfelhaltiger

Guanidinderivate. Hoppe Seyles Z. Physiol. Chemie. 235, 115-121.

3. Alvarado-Vásquez, N., Zamudio, P., Cerón, E., Vanda, B., Zenteno, E., and

Carvajal-Sandoval, G. (2003). Effect of glycine in streptozotocin-induced

diabetic rats. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 134, 521-527.

4. Andrikopoulos, S., Massa, C. M., Aston-Mourney, K., Funkat, A., Fam, B. C.,

Hull, R. L., Kahn, S. E., and Proietto, J. (2005). Differential effect of inbred

mouse strain (C57BL/6, DBA/2, 129T2) on insulin secretory function in response

to a high fat diet. J. Endocrinol. 187, 45-53.

5. Askwith, T., Zeng, W., Eggo, M. C., and Stevens, M. J. (2009). Oxidative stress

and dysregulation of the taurine transporter in high-glucose-exposed human

Schwann cells: implications for pathogenesis of diabetic neuropathy. Am. J.

Physiol. Endocrinol. Metab. 297, E620-E628.

6. Balkan, J., Kanbağli, O., Hatipoğlu, A., Kücük, M., Cevikbaş, U., Aykaç-Toker,

G., and Uysal, M. (2002). Improving effect of dietary taurine supplementation on

the oxidative stress and lipid levels in the plasma, liver and aorta of rabbits fed on

a high-cholesterol diet. Biosci. Biotechnol. Biochem. 66, 1755-1758.

7. Balkan, J., Oztezcan, S., Hatipoglu, A., Cevikbas, U., Aykac-Toker, G., and

Uysal, M. (2004). Effect of a taurine treatment on the regression of existing

atherosclerotic lesions in rabbits fed on a high-cholesterol diet. Biosci.

Biotechnol. Biochem. 68, 1035-1039. 8. Barker, D. J., and Osmond, C. (1986). Infant mortality, childhood nutrition, and

ischaemic heart disease in England and Wales. Lancet. 327, 1077-1081.


9. Berglund, E. D., Li, C. Y., Poffenberger, G., Ayala, J. E., Fueger, P. T., Willis, S. E.,

Jewell, M. M., Powers, A. C., and Wasserman, D. H. (2008). Glucose metabolism in

vivo in four commonly used inbred mouse strains. Diabetes. 57, 1790-1799.

10. Bouckenooghe, T., Remacle, C., and Reusens, B. (2006). Is taurine a functional

nutrient? Curr. Opin. Clin. Nutr. Metab. Care 9, 728-33.

11. Boujendar, S., Reusens, B., Merezak, S., Ahn, M., Arany, E., Hill, D., and

Remacle, C. (2002). Taurine supplementation to a low protein diet during foetal

and early postnatal life restores a normal proliferation and apoptosis of rat

pancreatic islets. Diabetologia 45, 856-66.

12. Boujendar, S., Arany, E., Hill, D., Remacle, C., and Reusens, B. (2003). Taurine

supplementation of a low protein diet fed to rat dams normalizes the

vascularization of the fetal endocrine pancreas. J. Nutr. 133, 2820-5.

13. Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying

mechanism. Diabetes 54, 1615-1625.

14. Brøns, C., Spohr, C., Storgaard, H., Dyerberg, J., and Vaag, A. (2004). Effect of

taurine treatment on insulin secretion and action, and on serum lipid levels in

overweight men with a genetic predisposition for type II diabetes mellitus. Eur. J.

Clin. Nutr. 58, 1239-1247.

15. Cetin, I., Corbetta, C., Sereni, L. P., Marconi, A. M., Bozzetti, P., Pardi, G., and

Battaglia, F. C. (1990). Umbilical amino acid concentrations in normal and

growth-retarded fetuses sampled in utero by cordocentesis. Am. J. Obstet.

Gynecol. 162, 253-261.

16. Chauncey, K. B., Tenner, T. E., Lombardini, J. B., Jones, B. G., Brooks, M. L.,

Warner, R. D., Davis, R. L., and Ragain, R. M. (2003). The effect of taurine

supplementation on patients with type 2 diabetes mellitus. Adv. Exp. Med. Biol.

526, 91-96.

17. Chesney, R. W., Scriver, C. R., and Mohyuddin, F. (1976). Localization of the

membrane defect in transepithelial transport of taurine by parallel studies in vivo

and in vitro in hypertaurinuric mice. J. Clin. Invest. 57, 183-193.

18. de Boo, H. A., and Harding, J. E. (2007). Taurine as a marker for foetal

wellbeing? Neonatology 91, 145-54

19. De Luca, G., Calpona, P. R., Caponetti, A., Macaione, V., Di Benedetto, A.,

Cucinotta, D., and Di Giorgio, R. M. (2001a). Preliminary report: Amino acid

profile in platelets of diabetic patients. Metab. Clin. Exp 50, 739-741.

20. De Luca, G., Calpona, P. R., Caponetti, A., Romano, G., Di Benedetto, A.,

Cucinotta, D., and Di Giorgio, R. M. (2001b). Taurine and osmoregulation:

platelet taurine content, uptake, and release in type 2 diabetic patients. Metab.

Clin. Exp. 50, 60-64.

21. Della Corte, L., Crichton, R. R., Duburs, G., Nolan, K., Tipton, K. F., Tirzitis, G.,

and Ward, R. J. (2002). The use of taurine analogues to investigate taurine

functions and their potential therapeutic applications. Amino Acids 23, 367-379.

22. Desai, M., and Hales, C. N. (1997). Role of fetal and infant growth in

programming metabolism in later life. Biol. Rev. Camb. Philos. Soc. 72,

329-348.


23. Di Leo, M. A. S., Santini, S. A., Silveri, N. G., Giardina, B., Franconi, F., and

Ghirlanda, G. (2004). Long-term taurine supplementation reduces mortality rate

in streptozotocin-induced diabetic rats. Amino Acids 27, 187-191.

24. Dumas, J., Simard, G., Flamment, M., Ducluzeau, P., and Ritz, P. (2009). Is

skeletal muscle mitochondrial dysfunction a cause or an indirect consequence of

insulin resistance in humans? Diabetes Metab. 35, 159-167.

25. Economides, D. L., Nicolaides, K. H., Gahl, W. A., Bernardini, I., Evans, M. I.

(1989). Plasma amino acids in appropriate- and small-for-gestational-age fetuses.

Am. J. Obstet. Gynecol. 161, 1219-1227.

26. Ejiri, K., Akahori, S., Kudo, K., Sekiba, K., and Ubuka, T. (1987). Effect of

guanidinoethyl sulfonate on taurine concentrations and fetal growth in pregnant

rats. Biol. Neonate. 51, 234-240.

27. El Idrissi, A., Boukarrou, L., and L'Amoreaux, W. (2009). Taurine

supplementation and pancreatic remodeling. Adv. Exp. Med. Biol. 643, 353-358.

28. El Mesallamy, H. O., El-Demerdash, E., Hammad, L. N., and El Magdoub, H. M.

(2010). Effect of taurine supplementation on hyperhomocysteinemia and markers

of oxidative stress in high fructose diet induced insulin resistance. Diabetol.

Metab. Syndr. 2, 46.

29. Elizarova, E. P., and Nedosugova, L. V. (1996). First experiments in taurine

administration for diabetes mellitus. The effect on erythrocyte membranes. Adv.

Exp. Med. Biol. 403, 583-588.

30. Falany, C. N., Fortinberry, H., Leiter, E. H., and Barnes, S. (1997). Cloning,

expression, and chromosomal localization of mouse liver bile acid CoA:amino

acid N-acyltransferase. J. Lipid Res. 38, 1139-1148.

31. Falany, C. N., Johnson, M. R., Barnes, S., and Diasio, R. B. (1994). Glycine and

taurine conjugation of bile acids by a single enzyme. Molecular cloning and

expression of human liver bile acid CoA:amino acid N-acyltransferase. J. Biol.

Chem. 269, 19375-19379.

32. Ferdinandusse, S., Denis, S., Faust, P. L., and Wanders, R. J. A. (2009). Bile

acids: the role of peroxisomes. J. Lipid Res. 50, 2139-2147.

33. Franconi, F., Bennardini, F., Mattana, A., Miceli, M., Ciuti, M., Mian, M.,

Gironi, A., Anichini, R., and Seghieri, G. (1995). Plasma and platelet taurine are

reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine

supplementation. Am. J. Clin. Nutr. 61, 1115-1119.

34. Franconi, F., Miceli, M., Fazzini, A., Seghieri, G., Caputo, S., DiLeo, M. A.,

Lepore, D., and Ghirlanda, G. (1996). Taurine and diabetes. Humans and

experimental models. Adv. Exp. Med. Biol. 403, 579-582.

35. Franconi, F., Di Leo, M. A. S., Bennardini, F., and Ghirlanda, G. (2004). Is

taurine beneficial in reducing risk factors for diabetes mellitus? Neurochem. Res.

29, 143-150.

36. Franconi, F., Loizzo, A., Ghirlanda, G., and Seghieri, G. (2006). Taurine

supplementation and diabetes mellitus. Curr. Opin. Clin. Nutr. Metab. Care 9, 32-36.

37. Funkat, A., Massa, C. M., Jovanovska, V., Proietto, J., and Andrikopoulos, S.

(2004). Metabolic adaptations of three inbred strains of mice (C57BL/6, DBA/2,

and 129T2) in response to a high-fat diet. J. Nutr. 134, 3264-3269.


38. Gandhi, V. M., Cherian, K. M., and Mulky, M. J. (1992). Hypolipidemic action

of taurine in rats. Indian J. Exp. Biol. 30, 413-417.

39. Gavrovskaya, L. K., Ryzhova, O. V., Safonova, A. F., Matveev, A. K., and

Sapronov, N. S. (2008). Protective effect of taurine on rats with experimental

insulin-dependent diabetes mellitus. Bull. Exp. Biol. Med. 146, 226-228.

40. Hagey, L. R., Schteingart, C. D., Rossi, S. S., Ton-Nu, H. T., and Hofmann, A. F.

(1998). An N-acyl glycyltaurine conjugate of deoxycholic acid in the biliary bile

acids of the rabbit. J. Lipid Res. 39, 2119-2124.

41. Hales, C. N., and Barker, D. J. (2001). The thrifty phenotype hypothesis. Br.

Med. Bull. 60, 5-20.

42. Hales, C. N., and Barker, D. J. (1992). Type 2 (non-insulin-dependent) diabetes

mellitus: the thrifty phenotype hypothesis. Diabetologia 35, 595-601.

43. Han, J., Bae, J. H., Kim, S., Lee, H., Jang, B., Lee, I., Cho, C., Lim, J., Suh, S.,

Kwon, T., et al. (2004). Taurine increases glucose sensitivity of UCP2-

overexpressing beta-cells by ameliorating mitochondrial metabolism. Am. J.

Physiol. Endocrinol. Metab. 287, E1008-1018.

44. Hansen, S. H. (2001). The role of taurine in diabetes and the development of

diabetic complications. Diabetes Metab. Res. Rev. 17, 330-46.

45. Hansen, S., Andersen, M., Cornett, C., Gradinaru, R., and Grunnet, N. (2010). A

role for taurine in mitochondrial function. Journal of Biomedical Science. J.

Biomed. Sci. 17 Suppl. 1:S23 (8 pages).

46. Hansen, S. H., Andersen, M. L., Birkedal, H., Cornett, C., and Wibrand, F.

(2006). The important role of taurine in oxidative metabolism. Adv. Exp. Med.

Biol. 583, 129-135.

47. Harada, N., Ninomiya, C., Osako, Y., Morishima, M., Mawatari, K., Takahashi,

A., and Nakaya, Y. (2004a). Taurine alters respiratory gas exchange and nutrient

metabolism in type 2 diabetic rats. Obes. Res. 12, 1077-1084.

48. Harada, N., Ninomiya, C., Osako, Y., Morishima, M., Mawatari, K., Takahashi,

A., and Nakaya, Y. (2004b). Taurine alters respiratory gas exchange and nutrient

metabolism in type 2 diabetic rats. Obes. Res. 12, 1077-1084.

49. Hardison, W. G., and Grundy, S. M. (1983). Effect of bile acid conjugation

pattern on bile acid metabolism in normal humans. Gastroenterology 84, 617-620.

50. Harris, H., and Searle, A. G. (1953). Urinary amino-acids in mice of different

genotypes. Ann. Eugen. 17, 165-167.

51. He, D., Barnes, S., and Falany, C. N. (2003). Rat liver bile acid CoA:amino acid

N-acyltransferase: expression, characterization, and peroxisomal localization. J.

Lipid Res. 44, 2242-2249.

52. Heird, W. C. (2004). Taurine in neonatal nutrition--revisited. Arch. Dis. Child.

Fetal Neonatal Ed. 89, F473-474.

53. Hepner, G. W., Sturman, J. A., Hofmann, A. F., and Thomas, P. J. (1973).

Metabolism of steroid and amino acid moieties of conjugated bile acids in man.

3. Cholyltaurine (taurocholic acid). J. Clin. Invest. 52, 433-440.

54. Hibbard, J. U., Pridjian, G., Whitington, P. F., and Moawad, A. H. (1990).

Taurine transport in the in vitro perfused human placenta. Pediatr. Res. 27, 80-84.


55. Holloszy, J. O. (2009). Skeletal muscle "mitochondrial deficiency" does not

mediate insulin resistance. Am. J. Clin. Nutr. 89, 463S-6S.

56. Hultman, K., Alexanderson, C., Mannerås, L., Sandberg, M., Holmäng, A., and

Jansson, T. (2007). Maternal taurine supplementation in the late pregnant rat

stimulates postnatal growth and induces obesity and insulin resistance in adult

offspring. J. Physiol. (Lond.) 579, 823-833.

57. Huxtable, R. J. (1992). Physiological actions of taurine. Physiol. Rev 72, 101-163.

58. Ito, T., Kimura, Y., Uozumi, Y., Takai, M., Muraoka, S., Matsuda, T., Ueki, K.,

Yoshiyama, M., Ikawa, M., Okabe, M., et al. (2008). Taurine depletion caused by

knocking out the taurine transporter gene leads to cardiomyopathy with cardiac

atrophy. J. Mol. Cell. Cardiol. 44, 927-937.

59. Jacobsen, J. G., and Smith, L. H. (1968). Biochemistry and physiology of taurine

and taurine derivatives. Physiol. Rev. 48, 424-511.

60. Jean, T., Poujeol, P., and Ripoche, P. (1984). Taurine transport in brush border

membrane vesicles isolated from hyper- and normotaurinuric mouse kidney. Ren

Physiol. 7, 349-356.

61. Jones, R. H., and Ozanne, S. E. (2009). Fetal programming of glucose-insulin

metabolism. Mol. Cell. Endocrinol. 297, 4-9.

62. Kaku, K., Fiedorek, F. T., Province, M., and Permutt, M. A. (1988). Genetic

analysis of glucose tolerance in inbred mouse strains. Evidence for polygenic

control. Diabetes 37, 707-713.

63. Kelley, D. E., He, J., Menshikova, E. V., and Ritov, V. B. (2002). Dysfunction of

mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944-2950.

64. Kim, S., Gupta, R. C., and Lee, H. W. (2007). Taurine-diabetes interaction: from

involvement to protection. Curr. Diabetes Rev. 3, 165-75.

65. Kisler, J. E., Whittaker, R. G., and McFarland, R. (2010). Mitochondrial diseases

in childhood: a clinical approach to investigation and management. Dev Med

Child Neurol. 52, 422-433.

66. Kondo, Y., Toda, Y., Kitajima, H., Oda, H., Nagate, T., Kameo, K., and

Murakami, S. (2001). Taurine inhibits development of atherosclerotic lesions in

apolipoprotein E-deficient mice. Clin. Exp. Pharmacol. Physiol. 28, 809-815.

67. Krag, E., and Phillips, S. F. (1974). Active and passive bile acid absorption in

man. Perfusion studies of the ileum and jejunum. J. Clin. Invest. 53, 1686-1694.

68. Kwakye, J. B., Johnson, M. R., Barnes, S., and Diasio, R. B. (1991). A

comparative study of bile acid CoA:amino acid:N-acyltransferase (BAT) from

four mammalian species. Comp. Biochem. Physiol., B 100, 131-136.

69. Lee, Y., and Pratley, R. E. (2005). The evolving role of inflammation in obesity

and the metabolic syndrome. Curr. Diab. Rep. 5, 70-75.

70. Lee, Y. Y., Park, K. S., Pak, Y. K., and Lee, H. K. (2005). The role of

mitochondrial DNA in the development of type 2 diabetes caused by fetal

malnutrition. J. Nutr. Biochem. 16, 195-204.

71. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., and Staels, B. (2009). Role of bile

acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147-191.

72. Lim, E., Park, S., and Kim, H. (1998). Effect of taurine supplementation on the

lipid peroxide formation and the activities of glutathione-related enzymes in the


liver and islet of type I and II diabetic model mice. Adv. Exp. Med. Biol. 442,

99-103.

73. Lombardini, J. B. (1998). Increased phosphorylation of specific rat cardiac and

retinal proteins in taurine-depleted animals: isolation and identification of the

phosphoproteins. Adv. Exp. Med. Biol. 442, 441-447.

74. Lowell, B. B., and Shulman, G. I. (2005). Mitochondrial dysfunction and type 2

diabetes. Science 307, 384-387.

75. Maechler, P., Li, N., Casimir, M., Vetterli, L., Frigerio, F., and Brun, T. (2010).

Role of mitochondria in beta-cell function and dysfunction. Adv. Exp. Med. Biol.

654, 193-216.

76. Mandla, S., Scriver, C. R., and Tenenhouse, H. S. (1988). Decreased transport in

renal basolateral membrane vesicles from hypertaurinuric mice. Am. J. Physiol.

255, F88-95.

77. Martin-Gronert, M. S., and Ozanne, S. E. (2007). Experimental IUGR and later

diabetes. J. Intern. Med. 261, 437-52.

78. Merezak, S., Hardikar, A. A., Yajnik, C. S., Remacle, C., and Reusens, B. (2001).

Intrauterine low protein diet increases fetal beta-cell sensitivity to NO and IL-1

beta: the protective role of taurine. J. Endocrinol. 171, 299-308.

79. Merezak, S., Reusens, B., Renard, A., Goosse, K., Kalbe, L., Ahn, M. T.,

Tamarit-Rodriguez, J., and Remacle, C. (2004). Effect of maternal low-protein

diet and taurine on the vulnerability of adult Wistar rat islets to cytokines.

Diabetologia 47, 669-75.

80. Militante, J., and Lombardini, J. (2004). Dietary taurine supplementation:

hypolipidemic and antiatherogenic effects. Nutrition Research 24, 787-801.

81. Mochizuki, H., Takido, J., Oda, H., and Yokogoshi, H. (1999). Improving effect

of dietary taurine on marked hypercholesterolemia induced by a high-cholesterol

diet in streptozotocin-induced diabetic rats. Biosci. Biotechnol. Biochem. 63,

1984-1987.

82. Moloney, M. A., Casey, R. G., O' Donnell, D. H., Fitzgerald, P., Thompson, C.,

and Bouchier-Hayes, D. J. (2010). Two weeks taurine supplementation reverses

endothelial dysfunction in young male type 1 diabetics. Diab. Vasc. Dis. Res. 7,

300-10.

83. Mortensen, O. H., Olsen, H. L., Frandsen, L., Nielsen, P. E., Nielsen, F. C.,

Grunnet, N., and Quistorff, B. (2010). Gestational protein restriction in mice has

pronounced effects on gene expression in newborn offspring's liver and skeletal

muscle; protective effect of taurine. Pediatr. Res. 67, 47-53.

84. Mulder, H., and Ling, C. (2009). Mitochondrial dysfunction in pancreatic beta-

cells in Type 2 diabetes. Mol. Cell. Endocrinol. 297, 34-40.

85. Murakami, S., Kondo-Ohta, Y., and Tomisawa, K. (1999). Improvement in

cholesterol metabolism in mice given chronic treatment of taurine and fed a high-

fat diet. Life Sci. 64, 83-91.

86. Murakami, S., Kondo, Y., Toda, Y., Kitajima, H., Kameo, K., Sakono, M., and

Fukuda, N. (2002). Effect of taurine on cholesterol metabolism in hamsters:

up-regulation of low density lipoprotein (LDL) receptor by taurine. Life Sci. 70,

2355-2366.


87. Murakami, S., Sakurai, T., Tomoike, H., Sakono, M., Nasu, T., and Fukuda, N.

(2010). Prevention of hypercholesterolemia and atherosclerosis in the

hyperlipidemia- and atherosclerosis-prone Japanese (LAP) quail by taurine

supplementation. Amino Acids 38, 271-278.

88. Mårtensson, J., and Hermansson, G. (1984). Sulfur amino acid metabolism in

juvenile-onset nonketotic and ketotic diabetic patients. Metab. Clin. Exp 33, 425-428.

89. Nakamura, T., Ushiyama, C., Suzuki, S., Shimada, N., Ohmuro, H., Ebihara, I.,

and Koide, H. (1999). Effects of taurine and vitamin E on microalbuminuria,

plasma metalloproteinase-9, and serum type IV collagen concentrations in

patients with diabetic nephropathy. Nephron 83, 361-362.

90. Nakaya, Y., Minami, A., Harada, N., Sakamoto, S., Niwa, Y., and Ohnaka, M.

(2000). Taurine improves insulin sensitivity in the Otsuka Long-Evans

Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Am. J. Clin. Nutr.

71, 54-58.

91. Nandhini, A. T. A., Thirunavukkarasu, V., and Anuradha, C. V. (2005). Taurine

modifies insulin signaling enzymes in the fructose-fed insulin resistant rats.

Diabetes Metab. 31, 337-44.

92. Nishimura, N., Umeda, C., Oda, H., and Yokogoshi, H. (2003). The effect of

taurine on the cholesterol metabolism in rats fed diets supplemented with

cholestyramine or high amounts of bile acid. J. Nutr. Sci. Vitaminol. 49, 21-26.

93. Nishimura, N., Umeda, C., Ona, H., and Yokogoshi, H. (2002). The effect of

taurine on plasma cholesterol concentration in genetic type 2 diabetic GK rats. J.

Nutr. Sci. Vitaminol. 48, 483-490.

94. Nishimura, N., Yamamoto, T., and Ota, T. (2009). Taurine feeding inhibits bile

acid absorption from the ileum in rats fed a high cholesterol and high fat diet.

Adv. Exp. Med. Biol. 643, 285-291.

95. Nishina, P. M., Verstuyft, J., and Paigen, B. (1990). Synthetic low and high fat

diets for the study of atherosclerosis in the mouse. J. Lipid Res 31, 859-869.

96. Nishina, P. M., Wang, J., Toyofuku, W., Kuypers, F. A., Ishida, B. Y., and

Paigen, B. (1993). Atherosclerosis and plasma and liver lipids in nine inbred

strains of mice. Lipids 28, 599-605.

97. Norberg, S., Powell, T. L., and Jansson, T. (1998). Intrauterine growth restriction

is associated with a reduced activity of placental taurine transporters. Pediatr.

Res. 44, 233-238.

98. Odetti, P., Pesce, C., Traverso, N., Menini, S., Maineri, E. P., Cosso, L.,

Valentini, S., Patriarca, S., Cottalasso, D., Marinari, U. M., et al. (2003).

Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney

damage in long-term experimental diabetes. Diabetes 52, 499-505.

99. Ozcan, U., Yilmaz, E., Ozcan, L., Furuhashi, M., Vaillancourt, E., Smith, R. O.,

Görgün, C. Z., and Hotamisligil, G. S. (2006). Chemical chaperones reduce ER

stress and restore glucose homeostasis in a mouse model of type 2 diabetes.

Science 313, 1137-40.

100. Pagel-Langenickel, I., Bao, J., Pang, L., and Sack, M. N. (2010). The role of

mitochondria in the pathophysiology of skeletal muscle insulin resistance.

Endocr. Rev. 31, 25-51.


101. Paigen, B., Morrow, A., Brandon, C., Mitchell, D., and Holmes, P. (1985).

Variation in susceptibility to atherosclerosis among inbred strains of mice.

Atherosclerosis 57, 65-73.

102. Poulsen, P., Vaag, A. A., Kyvik, K. O., Møller Jensen, D., and Beck-Nielsen, H.

(1997). Low birth weight is associated with NIDDM in discordant monozygotic

and dizygotic twin pairs. Diabetologia 40, 439-446. 103. Rabin, B., Nicolosi, R. J., and Hayes, K. C. (1976). Dietary influence on bile acid

conjugation in the cat. J. Nutr. 106, 1241-1246. 104. Ravelli, A. C., van Der Meulen, J. H., Osmond, C., Barker, D. J., and Bleker, O.

P. (1999). Obesity at the age of 50 y in men and women exposed to famine prenatally. Am. J. Clin. Nutr. 70, 811-816.

105. Reusens, B., Sparre, T., Kalbe, L., Bouckenooghe, T., Theys, N., Kruhøffer, M., Orntoft, T. F., Nerup, J., and Remacle, C. (2008). The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation. Diabetologia 51, 836-845.

106. Reusens, B., Dahri, S., Snoech, A., Bennis-Taleb, N., Remacle, C., and Hoet, J. (1995). Long-term Consequences of Diabetes and Its Complications May Have a Fetal Origin: Experimental and Epidemiological Evidence. Nestle Nutrition Workshop Series 35, 187-198.

107. Roseboom, T. J., van der Meulen, J. H., Osmond, C., Barker, D. J., Ravelli, A. C., and Bleker, O. P. (2001a). Adult survival after prenatal exposure to the Dutch famine 1944--45. Paediatr Perinat Epidemiol 15, 220-225.

108. Roseboom, T. J., van der Meulen, J. H., Ravelli, A. C., Osmond, C., Barker, D.

J., and Bleker, O. P. (2001b). Effects of prenatal exposure to the Dutch famine on

adult disease in later life: an overview. Mol. Cell. Endocrinol 185, 93-98.

109. Rozen, R., Scriver, C. R., and Mohyuddin, F. (1983). Hypertaurinuria in the

C57BL/6J mouse: altered transport at the renal basolateral membrane. Am. J.

Physiol 244, F150-155.

110. Russell, D. W. (2003). The enzymes, regulation, and genetics of bile acid

synthesis. Annu. Rev. Biochem. 72, 137-174.

111. Schaffer, S. W., Azuma, J., and Mozaffari, M. (2009). Role of antioxidant

activity of taurine in diabetes. Can. J. Physiol. Pharmacol. 87, 91-99.

112. Schiff, M., Loublier, S., Coulibaly, A., Bénit, P., de Baulny, H. O., and Rustin, P.

(2009). Mitochondria and diabetes mellitus: untangling a conflictive relationship?

J. Inherit. Metab. Dis 32, 684-698.

113. Schrauwen, P., Schrauwen-Hinderling, V., Hoeks, J., and Hesselink, M. K. C.

(2010). Mitochondrial dysfunction and lipotoxicity. Biochim. Biophys. Acta.

1801, 266-271.

114. Schuller-Levis, G. B., and Park, E. (2003). Taurine: new implications for an old

amino acid. FEMS Microbiol. Lett. 226, 195-202.

115. Seghieri, G., Tesi, F., Bianchi, L., Loizzo, A., Saccomanni, G., Ghirlanda, G.,

Anichini, R., and Franconi, F. (2007). Taurine in women with a history of

gestational diabetes. Diabetes Res. Clin. Pract. 76, 187-192.

116. Sethupathy, S., Elanchezhiyan, C., Vasudevan, K., and Rajagopal, G. (2002).

Antiatherogenic effect of taurine in high fat diet fed rats. Indian J. Exp. Biol. 40,

1169-1172.


117. Sfakianos, M. K., Wilson, L., Sakalian, M., Falany, C. N., and Barnes, S. (2002).

Conserved residues in the putative catalytic triad of human bile acid Coenzyme

A:amino acid N-acyltransferase. J. Biol. Chem. 277, 47270-47275.

118. Sjovall, J. (1959). Dietary glycine and taurine on bile acid conjugation in man;

bile acids and steroids 75. Proc. Soc. Exp. Biol. Med. 100, 676-678.

119. Smith, G. D., and Kuh, D. (2001). Commentary: William Ogilvy Kermack and

the childhood origins of adult health and disease. Int. J. Epidemiol. 30, 696-703.

120. Solaas, K., Ulvestad, A., Söreide, O., and Kase, B. F. (2000). Subcellular

organization of bile acid amidation in human liver: a key issue in regulating the

biosynthesis of bile salts. J. Lipid Res. 41, 1154-1162.

121. Song, X., Chen, C., Dong, B., Shi, Y., Zhang, W., Yan, L., and Luo, G. (2003).

[Study on the intervening mechanism of taurine on streptozotocin-induced

diabetic cataracts]. Zhonghua Yan Ke Za Zhi 39, 605-609.

122. Staels, B., Handelsman, Y., and Fonseca, V. (2010). Bile acid sequestrants for

lipid and glucose control. Curr. Diab. Rep. 10, 70-77.

123. Stevens, M. J., Lattimer, S. A., Kamijo, M., Van Huysen, C., Sima, A. A., and

Greene, D. A. (1993). Osmotically-induced nerve taurine depletion and the

compatible osmolyte hypothesis in experimental diabetic neuropathy in the rat.

Diabetologia 36, 608-614.

124. Sturman, J. A. (1991). Dietary taurine and feline reproduction and development.

J. Nutr. 121, S166-170.

125. Sturman, J. A. (1993). Taurine in development. Physiol. Rev. 73, 119-147.

126. Suge, R., Hosoe, N., Furube, M., Yamamoto, T., Hirayama, A., Hirano, S., and

Nomura, M. (2007). Specific timing of taurine supplementation affects learning

ability in mice. Life Sci 81, 1228-1234.

127. Sugiyama, K., Ohishi, A., Ohnuma, Y., and Muramatsu, K. (1989). Comparison

between the Plasma Cholesterol-lowering Effects of Glycine and Taurine in Rats

Fed on High Cholesterol Diets. Agric. Biol. Chem. 53, 1647-1652.

128. Suzuki, T., Suzuki, T., Wada, T., Saigo, K., and Watanabe, K. (2002). Taurine as

a constituent of mitochondrial tRNAs: new insights into the functions of taurine

and human mitochondrial diseases. EMBO J. 21, 6581-6589.

129. Takatani, T., Takahashi, K., Uozumi, Y., Matsuda, T., Ito, T., Schaffer, S. W.,

Fujio, Y., and Azuma, J. (2004). Taurine prevents the ischemia-induced apoptosis

in cultured neonatal rat cardiomyocytes through Akt/caspase-9 pathway.

Biochem. Biophys. Res. Commun. 316, 484-489.

130. Tanno, N., Oikawa, S., Koizumi, M., Fujii, Y., Hori, S., Suzuki, N., Sakuma, E.,

Kotake, H., Namai, K., and Toyota, T. (1989). Effect of taurine administration on

serum lipid and biliary lipid composition in man. Tohoku J. Exp. Med 159, 91-99.

131. Tenner, T. E., Zhang, X. J., and Lombardini, J. B. (2003). Hypoglycemic effects

of taurine in the alloxan-treated rabbit, a model for type 1 diabetes. Adv. Exp.

Med. Biol. 526, 97-104.

132. Trachtman, H., Futterweit, S., and Sturman, J. A. (1992). Cerebral taurine

transport is increased during streptozocin-induced diabetes in rats. Diabetes 41,

1130-1140.


133. Trauner, M., Claudel, T., Fickert, P., Moustafa, T., and Wagner, M. (2010). Bile

acids as regulators of hepatic lipid and glucose metabolism. Dig Dis 28, 220-224.

134. Trautwein, E. A., Kunath-Rau, A., and Erbersdobler, H. F. (1999). Increased

fecal bile acid excretion and changes in the circulating bile acid pool are involved

in the hypocholesterolemic and gallstone-preventive actions of psyllium in

hamsters. J. Nutr. 129, 896-902.

135. Truswell, A. S., McVeigh, S., Mitchell, W. D., and Bronte-Stewart, B. (1965).

Effect in man of feeding taurine on bile acid conjugation and serum cholesterol

levels. J Atheroscler Res. 5, 526-529.

136. Tsuboyama-Kasaoka, N., Shozawa, C., Sano, K., Kamei, Y., Kasaoka, S.,

Hosokawa, Y., and Ezaki, O. (2006). Taurine (2-aminoethanesulfonic acid)

deficiency creates a vicious circle promoting obesity. Endocrinology 147,

3276-3284.

137. Turner, N., and Heilbronn, L. K. (2008). Is mitochondrial dysfunction a cause of

insulin resistance? Trends Endocrinol. Metab. 19, 324-330.

138. Van Eldere, J., Celis, P., De Pauw, G., Lesaffre, E., and Eyssen, H. (1996).

Tauroconjugation of cholic acid stimulates 7 alpha-dehydroxylation by fecal

bacteria. Appl. Environ. Microbiol. 62, 656-661.

139. Warskulat, U., Flögel, U., Jacoby, C., Hartwig, H., Thewissen, M., Merx, M. W.,

Molojavyi, A., Heller-Stilb, B., Schrader, J., and Häussinger, D. (2004). Taurine

transporter knockout depletes muscle taurine levels and results in severe skeletal

muscle impairment but leaves cardiac function uncompromised. FASEB J 18,

577-579.

140. Warskulat, U., Heller-Stilb, B., Oermann, E., Zilles, K., Haas, H., Lang, F., and

Häussinger, D. (2007). Phenotype of the taurine transporter knockout mouse.

Meth. Enzymol. 428, 439-458.

141. Wharton, B. A., Morley, R., Isaacs, E. B., Cole, T. J., and Lucas, A. (2004). Low

plasma taurine and later neurodevelopment. Arch. Dis. Child. Fetal Neonatal Ed

89, F497-498.

142. Wijekoon, E. P., Skinner, C., Brosnan, M. E., and Brosnan, J. T. (2004). Amino

acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and

of type 2 diabetes. Can. J. Physiol. Pharmacol. 82, 506-514.

143. Wildgrube, H. J., Stockhausen, H., Petri, J., Füssel, U., and Lauer, H. (1986).

Naturally occurring conjugated bile acids, measured by high-performance liquid

chromatography, in human, dog, and rabbit bile. J. Chromatogr. 353, 207-213.

144. Williams, R. E., Lenz, E. M., Evans, J. A., Wilson, I. D., Granger, J. H., Plumb,

R. S., and Stumpf, C. L. (2005). A combined (1)H NMR and HPLC-MS-based

metabonomic study of urine from obese (fa/fa) Zucker and normal Wistar-

derived rats. J. Pharm. Biomed. Anal. 38, 465-471.

145. Winiarska, K., Szymanski, K., Gorniak, P., Dudziak, M., and Bryla, J. (2009).

Hypoglycaemic, antioxidative and nephroprotective effects of taurine in alloxan

diabetic rabbits. Biochimie. 91, 261-270.

146. Wu, G., Pond, W. G., Ott, T., and Bazer, F. W. (1998). Maternal dietary protein

deficiency decreases amino acid concentrations in fetal plasma and allantoic fluid

of pigs. J. Nutr. 128, 894-902.


147. Xiao, C., Giacca, A., and Lewis, G. F. (2008). Oral taurine but not

N-acetylcysteine ameliorates NEFA-induced impairment in insulin sensitivity

and beta cell function in obese and overweight, non-diabetic men. Diabetologia

51, 139-46.

148. Yamori, Y. (2006). Food factors for atherosclerosis prevention: Asian perspective

derived from analyses of worldwide dietary biomarkers. Exp Clin Cardiol 11,

94-98.

149. Yamori, Y. (2004). Worldwide epidemic of obesity: hope for Japanese diets.

Clin. Exp. Pharmacol. Physiol. 31 Suppl. 2, S2-4.

150. Yan, C. C., Bravo, E., and Cantàfora, A. (1993). Effect of taurine levels on liver

lipid metabolism: an in vivo study in the rat. Proc. Soc. Exp. Biol. Med. 202, 88-96.

151. Yokogoshi, H., and Oda, H. (2002). Dietary taurine enhances cholesterol

degradation and reduces serum and liver cholesterol concentrations in rats fed a

high-cholesterol diet. Amino Acids 23, 433-439.

152. Zhang, M., Bi, L. F., Fang, J. H., Su, X. L., Da, G. L., Kuwamori, T., and

Kagamimori, S. (2004). Beneficial effects of taurine on serum lipids in

overweight or obese non-diabetic subjects. Amino Acids 26, 267-271.

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8. Taurine and metabolic disease - trnres.com El... · Taurine and metabolic disease Svend Høime Hansen1 and Ole Hartvig Mortensen2 ... Determined. However there is a striking difference