*Human GLUT2 deficiency and the FANCONI-BICKEL SYNDROME (OMIM #227810)*

Rare homozygous or compound heterozygous mutations within the GLUT2 gene cause a type of glycogen storage diseases (GSD), termed GSD XI. The first patient was described by Fanconi and Bickel's, therefore the GLUT2 deficiency is referred to as Fanconi-Bickel Syndrome (FBS). Thus far, 112 patients have been reported. Analysis of 63 patients revealed a total of 34 different *GLUT2* mutations with none of them being particularly frequent. The clinical symptoms of FBS are hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, tubular nephropathy, and severely stunted growth. In contrast to the metabolism of glucose and galactose**,** utilization of orally or intravenously administered fructose is normal in FBS patients.

Glucose homeostasis in FBS-patients is heavily disturbed and postprandial hyperglycemia is frequently observed. A few patients have been diagnosed with diabetes mellitus and have been treated with insulin. Hypoglycemia in fasting states is a feature of FBS. Hypoglycemia has very frequently been documented and plasma glucose levels as low as 18 mg/dl have been reported in FBS patients. Compared to other types of hepatic glycogen diseases hepatic adenomas or malignancies have never been observed in patients with FBS.

No specific treatment exists for patients with FBS. Symptomatic treatment is directed towards stabilization of glucose homeostasis and compensation for renal losses of various solutes. The amelioration of the consequences of renal tubulopathy includes the replacement of water and electrolytes. In order to control renal glucose loss and hepatic glycogen accumulation in FBS, patients receive a diet with adequate caloric intake with slowly absorbed carbohydrates.

The importance of GLUT2 in the regulation of glucose-stimulated insulin secretion from the β-cell of the islets of Langerhans has been well established for mice.

Investigations of GLUT2 mutations that have been linked to the Fanconi-Bickel syndrome [29] or patients with transient or permanent neonatal diabetes mellitus [30] indicated an important role for this transporter in pancreatic β-cell development and function in humans.

#### *Mouse models of GLUT2 deficiency*

The consequences of GLUT2 deficiency have been analyzed in detail for the various tissues where GLUT2 is involved and/or essential in maintaining whole body glucose homeostasis. Early on, the critical role for GLUT2 in the β-cell for glucose stimulated insulin-secretion *in vivo* became apparent in mice with transgenic overexpression of a GLUT2 antisense RNA specifically in pancreatic β-cell cells. Upon an 80% reduction of GLUT2 in β-cells those animals display hyperglycemia and develop diabetes.

Whole body GLUT2 knockout in mice results in offspring that appears completely normal at birth, but neonates develop early symptoms similar to type 2 diabetes and do not survive beyond the age of 3 weeks. Homozygous GLUT2 deficiency in mice results in hyperglycemia and elevated plasma levels of free fatty acids and β-hydroxybutyrate. *In vivo* glucose tolerance is abnormal and, *in vitro*, β-cells display a gradual loss of control of insulin gene expression by glucose. Glucose stimulated insulin secretion in islets was impaired by loss of the first, but not the second phase of insulin secretion. GLUT2 knockout mice show marked hyperglucagone‐ mia, and this is accompanied by alterations in the postnatal development of pancreatic islets, evidenced by a gradual inversion of the α-to β-cell ratio. A direct link between diet induced insulin resistance and β-cell dysfunction via disturbed GLUT2 plasma membrane localization has recently been demonstrated. Administration of a high-fat diet feeding in mice results in intracellular retention of the transporter due to improper glycosylation of the protein thereby leading to compromised glucose stimulated insulin secretion.

maltose, xylose and dehydroascorbic acid are substrates for GLUT3, fructose is not. GLUT3 is

Mammalian Sugar Transporters http://dx.doi.org/10.5772/58325 23

*Single nucleotide polymorphisms (SNP's) in the GLUT3 gene have been identified and linked to dyslexia* Dyslexia is one of the most common learning disorders in school-aged children. Dyslexic children show differences in event-related potential measurements, in particular for mismatch negativity (MMN), which reflects automatic speech deviance processing. Whole-genome association analysis in 200 dyslexic children, focusing on MMN measurements, identified two SNPs that both showed a significant association with mRNA-expression levels of *SLC2A3* on chromosome 12. It was suggested that a possible trans-regulation effect on *SLC2A3* might lead to glucose deficits in dyslexic children that might cause their attenuated MMN in passive

During mouse preimplantation development GLUT3 is expressed at the apical membrane of the trophectoderm layer of the blastocyst and mediates glucose uptake by the embryo from the external (maternal) environment. Knockdown of the transporter by antisense-RNA at this time-point of development disrupts blastocyst development by diminishing uptake of glucose by the embryo. These data indicated a crucial role for GLUT3 during preimplantation embryo development and its deficiency in mice was assumed to result in embryonic lethality before implantation. Indeed, homozygous loss of GLUT3 leads to a complete loss of embryos at day 12.5. However, morulae develop normally to the blastocyst stage and implantation is not

Heterozygous GLUT3 knockout mice have been characterized especially for a potential neuron (brain) specific phenotype. These animals exhibit significantly enhanced cerebrocortical activity and are slightly more sensitive to an acoustic startle stimulus. However, behavior of these animals regarding coordination, reflexes, motor abilities, anxiety, learning, and memory

Zhao et al. described features of autism spectrum disorders in heterozygous GLUT3 knockout animals as being abnormal spatial learning, working memory, electroencephalographic seizures, and perturbed social behavior with reduced vocalization and stereotypes at low

Besides GLUT1, GLUT4 represents one of the most intensively studied glucose transporters which is attributed to its important physiological role regulating the rate-limiting step in insulin-stimulated glucose uptake of skeletal and cardiac muscle, brown and white adipose tissue. Thereby, impaired GLUT4 translocation is causally linked to insulin resistance and

GLUT4 was cloned in 1989 by various groups from human, rat, and mouse tissues. GLUT4 displays a similar affinity for glucose as GLUT1 with a Km of ~5 mM, and is also capable of

consequently to the disease condition of non-insulin dependent diabetes mellitus.

inhibited by cytochalasin B (Ki=0.4 µM), phloretin, and and phlorizin.

*4.3.1. GLUT3 physiology*

listening tasks.

*Mouse Models of GLUT3 deficiency*

affected by loss of GLUT3.

is normal.

frequency.

**4.4. GLUT4** *(SLC2A4)*

The early lethality of GLUT2 deficient mice shortly after birth hindered the analysis of GLUT2 physiology in the different tissues of its expression. Transgenic mice that overexpress GLUT1 specifically in β-cells under the control of the rat insulin promoter were generated (RIPGLUT1/ GLUT2-/-) to study the functional consequences of GLUT2 deficiency in tissues such as liver, kidney, intestine, and also in the brain.

In the liver, GLUT2 deficiency was expected to dramatically affect hepatic glucose output under fasting conditions. Interestingly, hepatic glucose output and glucagon response of the livers from mice lacking GLUT2 were normal. No counterregulation of other transporters known at that time was observed (GLUT1, 3, 4, 5 and SGLT1). Glucose output in GLUT2 deficient livers was not inhibited by cytochalasin B. An alternative membrane traffic-based pathway was proposed that releases glucose directly from the ER after glycogen breakdown or gluconeogenesis. The exact nature of this route has not been determined. In humans GLUT2 deficiency is associated with a marked hypoglycemia in the fasting state owing to a diminished hepatic glucose output and a failure of glucagon to increase plasma glucose. However, human patients with FBS do not generally develop diabetes and do not display a complete loss of their beta cell function, indicating that functionality of human pancreatic β-cells does not solely depend on GLUT2.

Deletion of GLUT2 specifically in the liver [31] or the central nervous system [32] showed, that GLUT2 mediated glucose-sensing mechanisms in both organs exist which control pancreatic β cell mass and function.

In the kidney, a role for GLUT2 in basolateral sugar reabsorption by tubular epithelial cells was postulated due the glucosuria that has been observed in RIPGLUT1/GLUT2-/-mice. GLUT2 complements the active sugar uptake at the apical epithelium mediated by SGLT2. The functional relevance for GLUT2 in the kidney in humans is supported by the observation of impaired kidney glucose reabsorption in patients with FBS.
