Callum Livingstone

Hypothalamic GLUT 4 expression: a glucose- and insulin-sensing mechanism?

The insulin-regulatable glucose transporter, GLUT 4, is expressed primarily in peripheral tissues (skeletal muscle and adipose tissue). In response to insulin this transporter moves rapidly from an intracellular storage site to the plasma membrane, thus accounting for the substantial increase in glucose uptake by these tissues following insulin stimulation. The recent finding that GLUT 4 is also expressed in the hypothalamus suggests that this brain region, which is outside the blood-brain barrier and therefore sensitive to circulating insulin, may experience stimulation of glucose uptake in response to insulin. We propose that this may allow regions of the hypothalamus to respond directly to elevated blood glucose, constituting a form of metabolic regulation by allowing circulating glucose (and therefore insulin) in concert with other mechanisms to maintain blood glucose homeostasis. We consider the possible physiological role of such a mechanism and speculate that disturbances of this mechanism may occur in endocrine disease associated with insulin resistance.

Dynamics of insulin-stimulated translocation of GLUT4 in single living cells visualised using green fluorescent protein

Insulin increases glucose uptake by promoting the translocation of the GLUT4 isoform of glucose transporters to the plasma membrane. We have studied this process in living single cells by fusing green fluorescent protein (GFP) to the N‐terminus (GFP·GLUT4) or C‐terminus (GLUT4·GFP) of GLUT4. Both chimeras were expressed in a perinuclear compartment of CHO cells, and in a vesicular distribution through the cytosol. Insulin promoted an increase in plasma membrane fluorescence as a result of net translocation of the chimeras to the cell surface. GLUT4·GFP, but not GFP·GLUT4, was re‐internalised upon the removal of insulin suggesting that a critical internalisation signal sequence exists in the N‐terminus of GLUT4. The use of GFP thus allows an analysis of GLUT4 trafficking in single living cells.

Hormonal regulation of the insulin-responsive glucose transporter, GLUT4: some recent advances.

gradient chimique a travers la membrane de la cellule. I1 est possible de proposer une explication cette diversit6 d’expression basee sur l’analyse des proprietes cinetiques et fonctionnelles de ces diffirents isoformes. Ainsi, on pense que GLUT1 est impliquC dans le transport du glucose 2 travers les barrikres entre le sang et les organes tels que la rCtine, et a travers la barrih-e entre le sang et le cerveau; il est aussi impliquC dans le maintien de niveaux basals ou d’entretien de I’activitC de transport du glucose dans beaucoup de types de cellules, sinon dans tous. GLUT;! est un transporteur a haute capacitC et

Insulin resistance in diabetes mellitus. Defective insulin-regulatable glucose transport plays an important role.

DIABETES is a major health problem, being responsible for a great deal ofmorbidity and mortality in the western world. The majority ofpatients with diabetes are not dependent for their survival upon insulin treatment and their condition, non-insulin-dependent diabetes mellitus (NIDDM), is characterised by hyperglycemia in the face of a normal or elevated level ofcirculating insulin, ie insulin resistance. It has long been known that the abnormality impairing insulins ability to stimulate glucose disposal into peripheral tissues (adipose tissue and skeletal muscle) lies distal to the binding of the hormone to its plasma membrane receptor. Such an abnormality could in principle lie anywhere along the pathway leading from sig~al generation at the insulin receptor itselfthrough to elevation of glucose transport. However, as the details of this pathway have yet to be fully elucidated, research efforts have focussed on the two main areas best understood in the process, firstly activation ofthe insulin receptor-associated tyrosine kinase and secondly glucose uptake into the cell. There is considerable evidence for abnormalities at both these sites contributing to the molecular basis of peripheral insulin resistance in NIDDM patients. Here we discuss advances made in the study of insulin-stimulated glucose transport in these patients.