Estimating hepatic glucokinase activity using a simple model of lactate kinetics

OBJECTIVE

Glucokinase (GCK) acts as a component of the “glucose sensor” in pancreatic β-cells and possibly in other tissues, including the brain. However, >99% of GCK in the body is located in the liver, where it serves as a “gatekeeper”, determining the rate of hepatic glucose phosphorylation. Mutations in GCK are a cause of maturity-onset diabetes of the young (MODY), and GCKR, the regulator of GCK in the liver, is a diabetes susceptibility locus. In addition, several GCK activators are being studied as potential regulators of blood glucose. The ability to estimate liver GCK activity in vivo for genetic and pharmacologic studies may provide important physiologic insights into the regulation of hepatic glucose metabolism.

RESEARCH DESIGN AND METHODS

Here we introduce a simple, linear, two-compartment kinetic model that exploits lactate and glucose kinetics observed during the frequently sampled intravenous glucose tolerance test (FSIGT) to estimate liver GCK activity (K_GK), glycolysis (K₁₂), and whole body fractional lactate clearance (K₀₁).

RESULTS

To test our working model of lactate, we used cross-sectional FSIGT data on 142 nondiabetic individuals chosen at random from the Finland–United States Investigation of NIDDM Genetics study cohort. Parameters K_GK, K₁₂, and K₀₁ were precisely estimated. Median model parameter estimates were consistent with previously published values.

CONCLUSIONS

This novel model of lactate kinetics extends the utility of the FSIGT protocol beyond whole-body glucose homeostasis by providing estimates for indices pertaining to hepatic glucose metabolism, including hepatic GCK activity and glycolysis rate.Liver glucokinase (GCK) is rate limiting for the phosphorylation rate of glucose and is an important determinant of glucose tolerance in vivo. It has become increasingly clear that it is important to assess the activity of hepatic GCK in vivo in humans as a key to observing changes in liver glucose phosphorylation. A novel group of GCK activators has been introduced and has been shown to reduce the blood glucose level after chronic administration, thus positioning them as possible candidates for treatment of diabetes (1). Additionally, a common variant in GCK regulatory protein (GKRP) (P446 L) has been shown to be associated with reduced fasting and 2-h glucose, elevation of triglycerides, and reduced risk of type 2 diabetes (T2D), presumably by altering the ability of the liver to adapt to hyperglycemia (2). Rare mutations in GCKR have also been identified in individuals with very high triglyceride levels (3). Furthermore, we have shown that the incretin analog exenatide acts to enhance liver glucose uptake, and this may reflect altered GKRP and/or GCK activity (4).It is impractical to estimate hepatic GCK activity directly in large populations of subjects because that would require liver biopsy. Thus, for genetic studies, there is a need to complement genotype information with simpler phenotyping to evaluate the importance of specific mutations for function. Here we introduce a novel approach for estimating GCK activity in vivo. The advantage of the approach is that it exploits clinical tests to extract information regarding glucose phosphorylation in the liver. Our approach uses blood samples taken during the frequently sampled intravenous glucose tolerance test (FSIGT), which previously has been widely performed to estimate insulin sensitivity, insulin response, β-cell function (disposition index [DI]), insulin clearance rate, and glucose effectiveness (5). FSIGTs were previously applied to a subset of the participants of the Finland–United States Investigation of NIDDM Genetics (FUSION) study of T2D genetics (6), but estimates of glucose phosphorylation have not been previously attempted.The idea behind our method to estimate liver glucose phosphorylation is as follows. During acute hyperglycemia, after intravenous glucose injection, much of the acute glucose disposal is due to liver glucose uptake, which is primarily glucose dependent (7). Although the fate of the glucose could well include hepatic glycogen synthesis by the “direct pathway”, most of the glucose taken up by the liver likely traverses the glycolytic pathway. Because there is little acute energy need for increased oxidation of the resulting three-carbon moieties, much of the resultant pyruvate is converted, via lactate dehydrogenase (LDH), to lactate, which is then easily exported into the hepatic venous effluent or stored as glycogen via the gluconeogenic pathway. Thus, it is possible to develop a mathematical model of the liver response to glucose injection, based only on the phosphorylation of glucose in the liver, glycolysis, and the ultimate export of the three-carbon compounds to lactate followed by lactate clearance from the blood. It is the dynamic relationship between plasma glucose and lactate that we use in the model to estimate hepatic glucose phosphorylation, and therefore activity of the enzyme liver GCK.     

Vomiting as a reliable sign of concussion

Concussion is the most common type of traumatic brain injury, with headache being the most frequent symptom of mild traumatic brain injury (MTBI) (including dizziness, vomiting, nausea, lack of motor coordination or difficulty balancing). Concussion may be caused by a blow to the head, or by acceleration forces without a direct impact. Often, MTBI occurs as the result of a sports injury. Loss of consciousness is always present, unlike vomiting. Therefore, we hypothesize vomiting to be considered as a cardinal sign of concussion. Stimulation of vomiting centres finally triggers vomiting. Professional boxers and mixed martial arts competitions reluctantly agree with stringent rules and protective clothing. We discuss the issue of further protection for those engaged in these and other sports.     

Rubella revisited: where are we on the road to disease elimination in Central Europe?

Rubella is a contagious viral disease with few complications except when contracted by pregnant women. Rubella infection in pregnancy can result in miscarriage, stillbirth or an infant born with congenital rubella syndrome (CRS) which comprises deafness, heart disease, cataracts and other permanent congenital manifestations. Clinical diagnosis of rubella is difficult due to overlapping symptoms with many other diseases and confirmation of rubella is not possible without laboratory testing.Effective vaccination programmes are critical to the elimination of rubella and prevention of CRS. Such programmes have been successful in several countries in Europe and around the world. However, rubella outbreaks still occur due to suboptimal vaccine coverage and in the past 10 years rubella has been reported in Central European countries such as Romania and Poland. Over the past decade the elimination of rubella and prevention of congenital rubella infection in Europe has been a high priority for the WHO European Regional Office. In 2010 the WHO regional committee for Europe renewed its commitment to the elimination of rubella and prevention of CRS with a new target of 2015.This paper examines the current situation for rubella and CRS in Central Europe and describes the different rubella vaccination programmes in the region. The Central European Vaccination Advisory Group (CEVAG) recommends that two doses of measles, mumps and rubella vaccine, MMR, should be given to all children. The first dose should be given between 12 and 15 months of age. The second dose can be given between the ages of 21 months and 13 years with the exact age of administration of the second dose depending on the situation specific to each country. All suspected rubella cases should be laboratory-confirmed and monitoring systems to detect and investigate cases of CRS should be strengthened.     

Colorectal anastomosis dehiscence following radical surgical operation for rectal carcinoma

BACKGROUND/AIM. Colorectal cancer (CRC) is one of the biggest health problems of modern humanity, especially in highly developed countries. In Serbia about 3,200 patients suffer from CRC, out of whom about 1,100 patients suffer from rectal cancer (RC), while about 2,100 patients suffer from other colon segments cancer. The aim of the study was to show the incidence genesis of one of the possible early postoperative complications regarding dehiscence of the colorectal anastomosis (CRA) with a group of patients suffering from RC and operated by using sphincter-saving procedures, in the period from 1993 to 2007, and then to compare the incidence genesis of these complications with those in the published series of the reporting colorectal institutions. METHODS: The research included 242 patients radically operated on for RC in a 15-year period using some of sphincter-saving procedures following by a careful analysis of the symptoms of subclinical dehyscencias not solved with the reintervention as well as of the clinically evidented dehyscencias mostly solved by reoperation. RESULTS: With 22 (9.1%) patients in the first 10 postoperative days there were early postoperative symptoms of CRA dehiscence. In 6 (2.47%) of the patients there were subclinical signs of raised body temperature, less quantity of feces content, and after the conservative treatment they ended in spontaneous process of rehabilitation. In 16 (6.61%) patients there was clinically evidented anastomosis dehiscence followed by abundant drainage of feces content, signs of local peritonitis, pelvic sepsis, so we had to undertake surgical intervention. CONCLUSION. Comparing the results of a few tenths of published studies with our results we proved that performing and operative technique of colorectal anastomosis in the patients suffered and radically surgically treated for RC, is quite adequate with the operative technique in reporting world institutions that are engaged in surgical treatment of RC.     

Serum lipid concentrations in Croatian veterans with post-traumatic stress disorder,post-traumatic stress disorder comorbid with major depressive disorder,or major depressive disorder

The aim of this study was to assess eventual differences in serum cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, LDL-C/HDL-C ratio between veterans with combat-related post-traumatic stress disorder (PTSD) only or comorbid with major depressive disorder (MDD), veterans with combat experiences with MDD, and healthy control group. PTSD and/ or MDD were diagnose according to structured clinical interview based on DSM-IV criteria. Additional criteria to diagnose PTSD were Clinician Administered PTSD Scale (CAPS), and to diagnose MDD Montgomery-Asberg Depression Rating Scale (MADRAS). Serum lipid concentrations were determined by using the enzyme-assay method. Veterans with combat-related PTSD as well as veterans with combat-related PTSD comorbid with MDD showed significantly higher concentrations of cholesterol (F=9.858, p<0.01), triglycerides (F=10.112, p<0.01), LDL-C (F=11.145, p<0.01), and LDL-C/HDL-C ratio (F=8.346, p<0.01) vs. veterans with MDD or healthy control group. Contrary healthy control group and veterans with MDD showed significantly higher concentrations of HDL-C (F=8.421, p<0.01), vs. veterans with PTSD or PTSD comorbid with MDD. In conclusion, there are no differences in serum lipid concentrations between veterans with combat-related PTSD and PTSD comorbid with MDD, but they have higher lipid concentrations than veterans with MDD or healthy control subjects.     

A cold shock response triggering acute myocardial infarction

Acute risk factors are activities and events that suddenly and transiently increase the risk of acute cardiac events, as reported recently in International Journal of Cardiology. It has already been reported that sudden submersion in cold water may provoke myocardial infarction in both subjects with atherosclerotic coronary disease and young people with angiographically normal coronary arteries.We report a case of an acute myocardial infarction triggered by sudden exposure to cold air temperature extreme in a young person with acutely occluded proximal part of the left anterior descending coronary artery and normal other coronary arteries who had extreme obesity and cigarette smoking as cardiovascular risk factors.Our report indicates that the sudden cold exposure and the resulting cold shock response may provoke acute myocardial infarction in young susceptible patients.