**4.15. GLUT10** *(SLC2A10)*

GLUT8 raised the question of whether this isoform would be insulin-responsive and thereby compensate for GLUT4 in the respective knockout mice which are lacking the insulinresponsive glucose transporter yet near normal glucose tolerance. Indeed, in blastocysts of mice, GLUT8 has been found to account for insulin-stimulated glucose uptake. However, various groups performed extensive studies in primary rat adipocytes, 3T3L1 adipocytes, insulin-responsive CHO-cells as well as neuronal cell types such as N2A, PC12, and hippocampal neurons that all failed to identify a stimulus that leads to a plasma mem‐

The intracellular localization of GLUT8 is also observed *in vivo* under steady-state conditions. In the testis immunofluorescence microscopy shows intracellular localization of GLUT8 in a late-endosomal/lysosomal compartment. In the brain, immunogold labeling electron-micro‐ scopy localized GLUT8 in synaptic dense core vesicles of nerve terminals and secretory

The intracellular retention signal of GLUT8 has been characterized and found to contain the consensus sequence [D/E]XXXL[L/I] that represents a late-endosomal/lysosomal sorting motif. The DEXXXLL sorting signal of GLUT8 interacts with the adaptor proteins AP-1 and AP-2 and controls trafficking of the protein. Interestingly, both GLUT8 and GLUT12 contain a [D/ E]XXXL[L/I] sorting signal; however, the exact composition of the XXX residues seems to fine-

GLUT8 knockout mice appear healthy and exhibit normal growth, body weight development and glycemic control, indicating that GLUT8 does not play a significant role in maintenance of whole body glucose homeostasis. Offspring distribution from heterozygous matings indicated a deviation from the expected Mendelian distribution regarding birth of GLUT8 homozygous animals. This observation was attributed to a decreased sperm motility of GLUT8 deficient spermatocytes that is associated with lower ATP levels and a reduced mitochondrial membrane potential, while number and survival rate of spermatozoa is unchanged. The reduced amount of homozygous GLUT8 offspring is not related to impaired preimplantation embryo development – as might have been suggested by antisense studies in embryos-since mating of knockout mice produced viable, normally developing offspring in numbers comparable to those of a wildtype intercross. GLUT8 deficiency is associated with behavioural alterations indicating a significant physiological role for this isoform in the central nervous system. GLUT8 deficient mice have an increased proliferation of hippocampal cells and behavioral tests show increased arousal, a tendency to altered grooming, and a reduced risk assessment in those animals. However, despite the in depth characterization of the cell biology of GLUT8 and its physiology *in vivo* based on knockout mice, the function of the protein

brane translocation of GLUT8.

30 Glucose Homeostasis

granules of vasopressin neurons.

*4.14.1. GLUT8 physiology*

remains thus far unknown.

*Mouse Models of GLUT8 deficiency*

tune the routing and trafficking of the two proteins.

GLUT10 has been cloned from human liver cDNA by 3' and 5' RACE PCR based on an EST sequence that was identified via a homology search with known GLUT protein sequences. GLUT10 mRNA is present in the human heart, lung, brain, liver, skeletal muscle, pancreas, placenta and kidney. Expression of GLUT10 is also detected in human and mouse white adipose tissue as well as human and mouse adipocyte cell lines SGBS and 3T3L1, respectively. One remarkable structural feature is the absence of the PESPR motif just after helix 6 that is conserved for all the GLUT isoforms. Heterologous expression of GLUT10 in *Xenopus laevis* oocytes demonstrated 2-DG transport with high affinity (Km ~0.3 mM). Uptake of 2-DG can be competed with galactose and glucose and inhibited with phloretin.

Although no localization study has been performed for GLUT10 clearly demonstrating a plasma membrane or intracellular localization as seen for other Class III family members, immunocytochemical studies indicated an intracellular localization for GLUT10 under steadystate conditions. The presence of the potential internalization motif YSRI at the C terminus of the transporter supports these findings.

GLUT10 is located at the chromosomal region 20q12-13.1, a susceptibility locus that has been linked to type 2 diabetes in Caucasian Americans. Therefore, there has been particular interest in GLUT10 as a potential candidate or susceptibility gene involved in the disease. However, polymorphisms in GLUT10 were not associated to type 2 diabetes in Caucasian Americans, Danish, Finns, and Taiwanese populations.

## *4.15.1. GLUT10 physiology*
