*4.2.1. GLUT2 physiology*

from the blood into cerebrospinal fluid. Defective glucose transport across the blood-brain barrier was first described 1991 [27] and linked to GLUT1 deficiency in 1998 [28]. About a 100 cases have been identified worldwide, including a wide spectrum of heterozygous mutations, including nonsense, missense, insertion, deletion and splice-site mutations, and hemizygosity

Since ketone bodies bypass the blood-brain barrier and enter the brain via a monocarboxylic acid transporter (MCT1) they provide an alternative energy source for the brain under conditions of GLUT1 deficiency. Accordingly, a ketogenic diet is effective in controlling the seizures and other symptoms of the GLUT1 deficiency syndrome. However, this treatment is less effective regarding neurobehavioral symptoms. Correlations between genotype and

Although representing the first GLUT isoform that was discovered, and despite being well characterized, mouse models for GLUT1 deficiency were only described recently. Mice that are transgenic for a homozygous GLUT1 anti-sense transgene are lethal during gestation; heterozygosity for the GLUT1 anti-sense cDNA was associated with growth retardation and

In mice, homozygous knockout of GLUT1 was associated with embryonic lethality around day E10dpc and E13-14dpc, while heterozygous animals were viable and showed no differ‐ ences in body weight development and growth. Decreased brain weights were reported, however, histological abnormalities were not found. While plasma glucose levels were normal in the heterozygous animals, glucose was decreased in the cerebrospinal fluid (CSF). As shown by PET-scan analysis, glucose uptake and metabolism were reduced in brains of heterozygous GLUT1 knockout animals. These animals also showed deficits in motor activity, balance and coordination as well as spontaneous cortical seizures. Overall, heterozygosity for GLUT1 in

The second transporter of the GLUT family was cloned in 1988 from human liver and kidney cDNA libraries. The initial characterization detected GLUT2 mainly in the liver, kidney and intestine but the transporter was later demonstrated to be present specifically in the insulin producing β-cells of the pancreas. GLUT2 is a low-affinity, high capacity transporter and with a Km in the range of ~17 mM, it has the highest Km for glucose among the known members of the GLUT family. GLUT2 also transports galactose (~92 mM), D-mannose (~125 mM), and Dfructose (~76 mM). Recently, GLUT2 was shown to transport glucosamine with high affinity (Km=~0.8 mM). Structurally, GLUT2 lacks the QLS motif in helix 7 which is thought to confer substrate specificity of the transporter, and which may explain the high affinity for glucosa‐

GLUT2 is located in the basolateral membrane of the epithelial cells of the intestine and kidney, where it participates in the release of absorbed (via SGLT1 in the intestine) or reabsorbed (via

mice resembles features of humans with the GLUT1 deficiency syndrome.

SGLT1 and 2 in the kidney) glucose into the blood stream.

of the GLUT1 gene.

20 Glucose Homeostasis

phenotype still remain elusive. *Mouse Models of GLUT1 deficiency*

developmental malformations.

**4.2. GLUT2** *(Slc2a2)*

mine.
