A number of GCK activators for treating T

A number of GCK activators for treating T2D have been developed and tested but not progressed successfully from clinical trials into therapy [45]. Our observations suggest that increased risk of hypoglycemia might be possible, particularly if drugs penetrate into brain. A further possibility is that GCK inhibition could offer a therapeutic approach to increase hypoglycemia counter-regulatory defences in diabetes. Our findings also provide a physiological explanation for observations seen in clinical practice when treating GCK-MODY diabetes, where there is a reduced response to exogenous insulin including during pregnancy [46], [47]. We found that insulin suppression and glucagon release occur at a higher glucose levels in GCK-MODY than T2D and that there is an exaggerated 52 6 australia response to glucose lowering in GCK-MODY. This supports the clinical observations that large doses of insulin may be needed to achieve pregnancy glucose targets in women with GCK-MODY and those who reach pregnancy glucose targets frequently report autonomic symptoms of hypoglycemia [personal communications ATH & MH Shepherd].
Conclusions
Acknowledgements
Rodent studies were funded by the Juvenile Diabetes Research Foundation [1-2006] and Diabetes UK (RD05/003059 and 13/0004680) to MLE, the Wellcome Trust (WT098012) and UK Biotechnology and Biosciences Research Council (BB/N017838/1) to LKH and Cambridge Medical Research Council Centre for Study of Obesity and Related Disorders (MRC-CORD). Human studies were supported by Diabetes UK and performed in the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. ATH is a Wellcome Trust Senior Investigator. RDC is supported by the UK Medical Research Council (MC_U142661184). In addition, PhD studentships/fellowships were supported for EOB (Yousef Jameel Fund), PSH (Sir Jules Thorn Trust), WJM (Wellcome Trust), SPM (Elmore Fund), and C-YY (Chang Gung University College of Medicine). The Behavioural and Clinical Neuroscience Institute is funded by a joint award from the Wellcome Trust (093875/Z/10/Z) and UK Medical Research Council (G1000183). The University of Cambridge has received salary support for MLE from the National Health Service in the East of England through the Clinical Academic Reserve. Study funders played no role in the collection, analysis and interpretation of data, writing of the report or decision to submit the article for publication.
Introduction A characteristic feature of type 2 diabetes is increased endogenous glucose production, largely due to increased hepatic glucose production (HGP) [1], [2], [3], [4]. Two rate-limiting enzymes of HGP are glucose 6-phosphatase catalytic subunit (encoded by G6PC) and phosphoenolpyruvate carboxykinase (encoded by PCK1 and PCK2). As the expression of these enzymes is suppressed by insulin, it has been widely held that patients with type 2 diabetes (T2D) would have increased expression of G6PC and PCK, due to hepatic insulin resistance. However, it has been challenging to correlate expression of these enzymes with diabetes or glycemia in humans [5], [6]. Another determinant of hepatic glucose homeostasis is glucokinase (encoded by GCK). G6PC and GCK act in opposition to regulate the intracellular levels of free glucose; thus, the coordinated regulation of these two enzymes ultimately determines the gradient and flux of glucose into or out of the hepatocyte [7]. An increased ratio of G6PC/GCK, as occurs during fasting, causes glucose efflux to the bloodstream, whereas a decreased ratio causes increased influx. Previous work has indicated that GCK activity is decreased in type 2 diabetes [8], [9], [10], [11], [12]. Although mutations in the GCK gene cause maturity onset diabetes of the young type 2 (MODY2), GCK mutations are not found in the etiology of classical T2D. Thus, the decrease in GCK activity is likely due to transcriptional or posttranslational effects. However, the expression of liver GCK during T2D has not yet been established.