Raised Fasting Glucose Research Articles

Prevalence of the Metabolic Syndrome among Outpatients with Schizophrenia or Schizoaffective Disorder

Objectives : The aim of this study were to assess a) the prevalence of metabolic syndrome in outpatients with schizophrenia or schizoaffective disorder, b) the comparison of characteristics of patients with or without the metabolic syndrome, c) the sensitivity, specificity and positive predictive values of individual criteria for metabolic syndrome. Methods : This study assessed the prevalence of the metabolic syndrome among 128 schizophrenia or schizoaffective disorder patients using the National Cholesterol Education Program-Adult Treatment Panel III. Results : Of patients, 54.7% (M : 49.3%, F : 61.4%) had metabolic syndrome. The metabolic syndrome was associated with medical history of diabetes, hypertension and dyslipidemia. Presence of abdominal obesity was most sensitive (97.1%), while raised fasting glucose was most specific (89.7%). Combining abdominal obesity/raised triglycerides and abdominal obesity/low HDL cholesterol had 100% sensitivity. Conclusion : The metabolic syndrome is highly prevalent among outpatients with schizophrenia or schizoaffective disorder. This study suggests that the measurement of abdominal obesity is a simple test to identify individuals at high risk for metabolic syndrome. (Korean J Schizophr Res 2012;15:39-45)

Number of children and change in markers of metabolic health over 9-years in men and women. Data from the DESIR study

Aim Parity is associated with an increased risk of coronary heart disease and type 2 diabetes, possibly mediated by long-term modification of metabolic health. Studying associations between the number of children with health and disease in men in addition to women allows for differentiation between the social and lifestyle influences of child-rearing, and the biological influences of childbearing. We sought to determine whether the number of children is associated with the incidence of raised fasting glucose (fasting plasma glucose ≥ 6.1 mmol/L) and changes in glucose, insulin, insulin resistance and β-cell function over 9-years. Methods Analysis of 1798 women and 1737 men from the DESIR study. Results The number of children was associated with change in fasting glucose for women ( P trend = 0.02) and men ( P trend = 0.03), and increased incidence of raised fasting glucose by 30% (95% CI: 15, 47%) per child for men, but not women (3% [95% CI: −8, 15%]). There was a J-shaped association between number of children and change in insulin ( P = 0.01) and insulin resistance ( P = 0.005) for women, and a reduction in β-cell function in parous women ( P = 0.07). Men with children had increases in insulin ( P = 0.02), insulin resistance ( P = 0.02), and β-cell function ( P = 0.07). Conclusions The number of children a person has is associated with changes in metabolic health indices long after childbirth for both men and women. The distinct gender differences in deterioration of metabolic health indices emphasize that childbearing and child-rearing are likely to have differential influences on metabolic health.

The longitudinal association of common susceptibility variants for type 2 diabetes and obesity with fasting glucose level and BMI

BackgroundVariation in the effects of genetic variants on physiological traits over time or with age may alter the trajectories of these traits. However, few studies have investigated this possibility for variants associated with type 2 diabetes or obesity, and these show little consensus. We aimed to characterise the possible longitudinal associations of common diabetes-susceptibility variants in the KCNJ11, PPARG, TCF7L2, IGF2BP2, CDKAL1, SLC30A8 and HHEX gene loci, with fasting glucose level; and of an obesity-associated variant in the FTO gene, with body mass index (BMI).MethodsThe study analysed data from the Busselton Health Study (n = 4,554). Cross-sectional association analyses included family data and used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.ResultsIn cross-sectional analyses, we observed associations of the T allele at the IGF2BP2 single nucleotide polymorphism (SNP) rs4402960 with raised fasting glucose (p = 0.045), and the A allele at the FTO SNP rs9939609 with raised BMI (p = 0.003). Longitudinal analyses showed no significant associations between SNPs and changes in fasting glucose or BMI in the same individuals, either over mean follow-up times of 18.7 and 21.8 years respectively, or with age during adulthood.ConclusionsThere was no indication that the effects of common type 2 diabetes variants on fasting glucose varied with age during adulthood or over time.

Deposition of trans Fatty Acid from Industrial Sources and Its Effect on Different Growth Phases in Rats

Although the effects of trans fatty acids (TFA) from industrially produced sources (IP-TFA), such as partially hydrogenated vegetable oil, are reported, their implications on metabolism and growth are still not fully disclosed. In this study, female Wistar rats were assigned to control diet (AIN-93G) or Trans diet groups (5% IP-TFA) after gestation. The male offspring were classified and grouped as infant, weanling, and young adult (YA) rats (n = 10), and received the same control or Trans diets throughout their life span. Samples of abdominal adipose tissue, liver and plasma were collected to determine fatty acid profile and fasting glycemia. Morphometric analysis of the liver and hepatosomatic index determination were conducted. Deposition of TFA was observed in the liver, adipose tissue and plasma of IP-TFA-fed rats. Fasting glycemia concentration was higher in Trans YA rats than in the control YA group (p = 0.004). A higher accumulation of fat was observed in the liver of the Trans group than in the control group during the three phases. Hepatosomatic index was higher in the YA Trans group than in the YA control group (p < 0.05). Dietary TFA was deposited in the tissues and plasma and raised fasting glucose in growing rats.

Variants within the calpain-10 gene and relationships with type 2 diabetes (T2DM) and T2DM-related traits among Tunisian Arabs

Background Common variations in the calpain 10 (CAPN10) gene variants UCSNP-43, UCSNP-19 and UCSNP-63, and the 112/121 diplotype, are associated with an increased risk of type 2 diabetes (T2DM) and T2DM-related traits. Methods The association of UCSNP-43, -19 and -63 CAPN10 SNPs with T2DM was assessed in 917 Tunisian T2DM patients and 748 ethnically matched non-diabetic controls. CAPN10 genotyping was done by PCR-RFLP. Results Significant differences in UCSNP-19 MAF, but not UCSNP-43 or -63, and genotype distribution were seen between patients and controls. Heterogeneity in UCSNP-19, but not UCSNP-43 and -63, genotype distribution was noted according to geographical origin. Obesity was associated with UCSNP-19, while raised fasting glucose was associated with UCSNP-63, and increased HDL was associated with UCSNP-43. Enrichment of homozygous UCSNP-19 2/2 was seen in overweight and obese compared with lean patients; logistic-regression analyses demonstrated a positive association of the 2/2 genotype with overweight [ P = 0.003; OR (95% CI) = 2.07 (1.28–3.33)] and obese [ P = 0.021; OR (95% CI) = 1.83 (1.10–3.07)] patients. Of the six CAPN10 haplotypes identified, significant enrichment of only haplotype 111 was seen in T2DM patients [ Pc = 0.034; OR (95% CI) = 1.22 (1.06–1.41)], while the frequency of all identified CAPN10 diplotypes, including the high-risk 112/121, was comparable between patients and controls. Conclusion While CAPN10 UCSNP-19 SNP and haplotype 111 contribute to the risk of T2DM in Tunisian subjects, no significant association between CAPN10 diplotypes and T2DM was demonstrated.

Mouse models of the metabolic syndrome

The metabolic syndrome (MetS) is characterized by obesity concomitant with other metabolic abnormalities such as hypertriglyceridemia, reduced high-density lipoprotein levels, elevated blood pressure and raised fasting glucose levels. The precise definition of MetS, the relationships of its metabolic features, and what initiates it, are debated. However, obesity is on the rise worldwide, and its association with these metabolic symptoms increases the risk for diabetes and cardiovascular disease (among many other diseases). Research needs to determine the mechanisms by which obesity and MetS increase the risk of disease. In light of this growing epidemic, it is imperative to develop animal models of MetS. These models will help determine the pathophysiological basis for MetS and how MetS increases the risk for other diseases. Among the various animal models available to study MetS, mice are the most commonly used for several reasons. First, there are several spontaneously occurring obese mouse strains that have been used for decades and that are very well characterized. Second, high-fat feeding studies require only months to induce MetS. Third, it is relatively easy to study the effects of single genes by developing transgenic or gene knockouts to determine the influence of a gene on MetS. For these reasons, this review will focus on the benefits and caveats of the most common mouse models of MetS. It is our hope that the reader will be able to use this review as a guide for the selection of mouse models for their own studies.

Elevated Fasting Plasma Cortisol Is Associated with Ischemic Heart Disease and Its Risk Factors in People with Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the metabolic syndrome, but whether circulating cortisol levels predict cardiovascular end points is less clear. People with type 2 diabetes are at increased cardiovascular disease risk and thus are suitable to study associations of plasma cortisol with cardiovascular risk. We aimed to assess whether altered HPA axis activity was associated with features of the metabolic syndrome and ischemic heart disease in people with type 2 diabetes. We conducted a cross-sectional cohort study in the general community, including 919 men and women aged 67.9 (4.2) yr with type 2 diabetes (the Edinburgh Type 2 Diabetes Study). We measured fasting morning plasma cortisol. Associations between cortisol levels, features of the metabolic syndrome, obesity, and ischemic heart disease were determined. Elevated plasma cortisol levels were associated with raised fasting glucose and total cholesterol levels (P < 0.001). These findings remained significant after adjustment for potential confounding factors (P < 0.001). Elevated cortisol levels were associated with prevalent ischemic heart disease (>800 vs. <600 nmol/liter; odds ratio, 1.58; P = 0.02). This association remained significant after adjustment for duration and control of diabetes and other cardiovascular risk factors (P = 0.03). The previously described associations between HPA axis activation and features of the metabolic syndrome are present among people with type 2 diabetes. Elevated plasma cortisol is also associated with a greater prevalence of ischemic heart disease, independent of conventional risk factors. Understanding the role of cortisol in the pathogenesis of ischemic heart disease merits further exploration.

Harmonizing the Metabolic Syndrome

A cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus, which occur together more often than by chance alone, have become known as the metabolic syndrome. The risk factors include raised blood pressure, dyslipidemia (raised triglycerides and lowered high-density lipoprotein cholesterol), raised fasting glucose, and central obesity. Various diagnostic criteria have been proposed by different organizations over the past decade. Most recently, these have come from the International Diabetes Federation and the American Heart Association/National Heart, Lung, and Blood Institute. The main difference concerns the measure for central obesity, with this being an obligatory component in the International Diabetes Federation definition, lower than in the American Heart Association/National Heart, Lung, and Blood Institute criteria, and ethnic specific. The present article represents the outcome of a meeting between several major organizations in an attempt to unify criteria. It was agreed that there should not be an obligatory component, but that waist measurement would continue to be a useful preliminary screening tool. Three abnormal findings out of 5 would qualify a person for the metabolic syndrome. A single set of cut points would be used for all components except waist circumference, for which further work is required. In the interim, national or regional cut points for waist circumference can be used.

The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits

Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels. The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models. The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007). The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

Association Among Metabolic Syndrome, Testosterone Level and Severity of Erectile Dysfunction

The purpose of this study was to determine the influence of metabolic syndrome (MS) and serum testosterone in patients with erectile dysfunction (ED) and their possible association. A total of 103 men with ED were enrolled. The International Index of Erectile Function (IIEF) questionnaire was used to assess erectile condition. MS was defined according to the criteria formulated by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF). The mean age of the study population was 57.5 +/- 10.7 years, with an average IIEF of 14.7 +/- 6.7. The age and prevalence of MS using the NCEP ATP III criteria, but not the IDF criteria, were significantly different between mild and moderate/severe ED patients (p = 0.031 and 0.009, respectively). The percentage of hypertension (78.6% vs. 36.2%; p < 0.001) and raised fasting glucose levels (46.4% vs. 19.1%; p = 0.004) were significantly higher in the moderate/severe ED group, and both differences remained significant in multivariate analysis (p = 0.001 and 0.042, respectively). In addition, serum testosterone levels were significantly lower in ED patients with MS (p = 0.002). In summary, the presence of MS is associated with more severe ED. Among the components of MS, elevated blood pressure and fasting blood glucose were independent risk factors. NCEP ATP III criteria seem to correlate better with the degree of ED than the IDF definition. Our results also indicate that MS is associated with a lower testosterone level in patients with ED.

Prevalence of Metabolic Syndrome in Retired National Football League Players

The National Institute of Occupational Safety and Health mortality study of National Football League (NFL) players concluded that retired NFL linemen have an increased risk of cardiovascular death compared with both nonlinemen and the general population. Though elevated body mass index contributed to the increased cardiac risk of linemen, it could not fully account for the mortality observed, suggesting that other unmeasured cardiovascular risk factors were involved. We performed a cross-sectional prevalence study of metabolic syndrome (MS), and its individual component criteria, in 510 retired NFL players who were recruited to multicity health screenings from February 2004 through June 2006. The International Diabetes Federation criteria were used to define MS. The MS component criteria of body mass index>30 kg/m2, reduced high-density lipoprotein, and raised fasting glucose were more prevalent in linemen compared with nonlinemen (85.4% vs 50.3%, p<0.001; 42.1% vs 32.7%, p=0.04; 60.4% vs 37.6%, p<0.001, respectively). Metabolic syndrome was more prevalent in linemen compared with nonlinemen (59.8% vs 30.1%, p<0.001). In conclusion, linemen exhibited a high prevalence of MS, almost double the prevalence of their nonlinemen counterparts. These findings may partially explain the increased risk for cardiovascular death observed in retired linemen and could have significant public health implications for preprofessional training regimens and postprofessional health maintenance.

Myocardial hipertrophy in hypertensive patients with and without metabolic syndrome

Beside arterial hypertension as the most important factor of a myocardial hypertension development, very important risk factors are obesity, hypercholesterolemia, insulin resistance, etc. The aim of the study was to examine the influence of metabolic syndrome (MetS) on left ventricular hypertrophy in patients with arterial hypertension. We checked medical records for 138 patients with arterial hypertension, and compared them with the control group of 44 normotensive subjects. The patients with arterial hypertension were divided into two groups considering the presence of MetS: with MetS (59 patients), and without MetS (79 patients). We defined MetS as presence of three (or more) within five criteria: central obesity (> 102 cm male, > 88 cm female), raised triglycerides (> 1.7 mmol/L, or drug treatment for elevated triglycerides), reduced high density lipoprotein (HDL) cholesterol (< 1.03 mmol/L male, < 1.3 mmol/L female), raised blood pressure (> 130 mmHg systolic, > 90mmHg diastolic), raised fasting glucose (> 6.11 mmol/L, or drug treatment for elevated glucose level). In each group routine laboratory, echocardiography and 24-hour ambulatory blood pressure monitoring were performed. We found statisticaly significant higher left ventricular mass in both subgroups hypertensive patients in comparison with the control group (p < 0.05). We did not find statistically significant difference (227.31 +/- 63.44 vs 219 +/- 59.5, p > 0.05) in left ventricular mass between these two groups of patients. In the patients with arterial hypertension and MetS we found hypertrophy more frequently than in the subgroup without MetS (43/57 vs 34/69, p < 0.001). Our results suggest that associated cardiometabolic risks increase the prevalence of myocardial hypertrophy, but do not influence left ventricular mass.

Association Between the Number of Cardiovascular Risk Factors and Each Risk Factor Level in Elementary School Children

Little is known regarding the association between numbers of cardiovascular (CV) risk factors and the level of each risk factor in elementary school children based on a longitudinal study. A descriptive study of 319 obese children aged 6-11 years who participated in a screening program for comorbidity of obesity between 2003 and 2005, and who participated in consecutive years thereafter, was performed. Abdominal obesity, hypertension, dyslipidemia (low high-density lipoprotein-cholesterol levels and/or high triglyceride levels), and raised fasting glucose levels were used as the CV risk factors. Metabolic syndrome and each CV risk factor were defined using the criteria newly established by a Task Force financed by the Health and Labour Science Research in Japan. An increase in the total number of CV risk factors implied a worsening of each CV risk factor level over a 1-year interval, and vice versa. Abdominal obesity in males and insulin resistance in females were prevalent in children who were at elementary school level. We should assess not only obesity but all CV risk factor levels, because a cluster of risk factors implies a worsening of the individual risk factor levels in children as young as those in elementary school.

Age of Menarche and the Metabolic Syndrome in China

In western populations, young age of menarche is associated with increased cardiovascular risk. Little is known about the potential impact of menarche on the metabolic syndrome (as a proxy for cardiovascular risk) in rapidly economically developing populations where age of menarche is falling. We sought to determine the relation between age of menarche and the metabolic syndrome in a rapidly developing Chinese population. We carried out a retrospective historical cohort study of 7349 women from the Guangzhou Biobank Cohort Study, China, enrolled in 2003-2004. Cardiovascular risk factors were obtained from physical examination; age of menarche was obtained from self-report. The main outcome measure was the metabolic syndrome and its components. Adjusted for age, education, and number of pregnancies, young age of menarche (<12.5 years) compared with age of menarche > or =14.5 years was associated with a higher risk of the metabolic syndrome (odds ratio = 1.49; 95% confidence interval = 1.22-1.82), central obesity (1.35; 1.10-1.65), raised blood pressure (1.34; 1.09-1.65), raised fasting glucose (1.40; 1.15-1.71), and higher triglyceride levels (1.36; 1.12-1.67). Further adjustment by waist circumference attenuated these effects, but the odds ratios remained elevated. Earlier age of menarche experienced by younger women in China today, now 12.5 years on average in urban populations, may contribute to an increase in the metabolic syndrome and thereby an increase in cardiovascular disease as these women age. These results further highlight the importance of childhood antecedents of adulthood disease.

Insulin Secretion and Insulin Sensitivity in Relation to Fasting Glucose in Healthy Subjects

This study evaluated insulin secretion and insulin sensitivity in healthy subjects with normal fasting glucose. A total of 148 healthy women (aged 53-70 years) underwent a glucose-dependent arginine stimulation test and a 2-h euglycemic-hyperinsulinemic clamp. In the arginine test, arginine (5 g) was injected intravenously under baseline (fasting) conditions and after raising the glucose levels to 15 and >28 mmol/l. From this test, the acute insulin response (AIR) to arginine during the three glucose levels (AIR1, AIR2, and AIR3) were estimated. The subjects were divided into quartiles of fasting glucose (n = 37 in each group [range <4.32; 4.33-4.84; 4.85-5.22; and 5.23-6.1 mmol/l, respectively). The results show that 1) AIR1 was higher in subjects in the two highest quartiles (P = 0.004), 2) AIR3 was higher in the quartile with the highest fasting glucose (P = 0.012), and 3) insulin sensitivity was reduced in subjects in the highest quartile (P = 0.026) compared with the lower quartiles. The results also show, in contrast, that AIR2 did not show a similar trend to be increased at higher fasting glucose. It is concluded that 1) raised fasting glucose (albeit still within normal values) augments baseline and maximal arginine-induced insulin secretion in healthy subjects, and 2) this is associated with reduced insulin sensitivity. This suggests that high, but still normal, fasting glucose may contribute to the augmented insulin secretion in subjects with low insulin sensitivity.

The association between increased alanine aminotransferase activity and metabolic factors in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has been associated with metabolic disorders, including central obesity, dyslipidema, hypertension, and hyperglycemia. Metabolic syndrome, obesity, and insulin resistance are major risk factors in the pathogenesis of NAFLD. The aim of this study was to identify the relative contribution of the metabolic syndrome, obesity, and insulin resistance to alanine aminotransferase (ALT) activity in NAFLD. A total of 3091 subjects diagnosed with fatty liver by ultrasonography were enrolled. All components of metabolic syndrome criteria, anthropometric parameters, fasting insulin levels, high-sensitivity C-reactive protein (hs-CRP) as an inflammation marker, and ALT were measured in each subject. Homeostasis model assessment—insulin resistance (HOMA-IR) as a measure of insulin resistance and body mass index (BMI) as a measure of obesity were calculated. The prevalence of increased ALT levels (>40 IU/L) was 26.7%. Increased ALT activity was significantly associated with the following characteristics: male sex, young age, increased triglycerides, fasting glucose, fasting insulin, HOMA-IR, hs-CRP, waist circumference, BMI and diastolic blood pressure, and decreased high-density lipoprotein cholesterol (HDL-C). According to the increase in the number of metabolic syndrome components, BMI, HOMA-IR, and hs-CRP, the prevalence and odds ratio for having increased ALT activity were significantly increased. Central obesity, raised triglycerides, reduced HDL-C, and raised fasting glucose were strongly associated with increased ALT activity. In conclusion, a number of metabolic syndrome components, obesity, insulin resistance, and hs-CRP, are strong predictors of increased ALT activity in NAFLD. Central obesity, raised triglycerides, reduced HDL-C, and raised fasting glucose are metabolic syndrome components that contributed to increased ALT activity.

C-Reactive protein and the metabolic syndrome in older Chinese: Guangzhou Biobank Cohort Study

Objective To examine the association between serum c-reactive protein (CRP) concentration and the metabolic syndrome (MS) using the International Diabetes Federation Metabolic Syndrome Guidelines (April, 2005) definition in an older Chinese population. Methods Three thousand and fourteen men and 7275 women aged 50–85 years were recruited and received a full medical check-up including measurement of blood pressure, obesity indices, fasting total, LDL-, HDL-cholesterol, triglycerides, glucose and c-reactive protein. Data describing socioeconomic and lifestyle factors was also collected. Results Vascular risk factors including waist circumference, weight gain and waist gain since the age of 18, body mass index, waist–hip-ratio, triglyceride, HDL-cholesterol, and systolic and diastolic blood pressures were positively associated with CRP in both men and women ( p from <0.001 to 0.016). Compared to those without MS components, adjusted odds ratios for having elevated CRP increased in those with the MS or its components compared those without MS or components (all p < 0.001), except for the low HDL-cholesterol in both genders and raised fasting glucose in men. Similarly, the risk of elevated CRP increased with escalating MS components even after adjustment of a range of potential confounders. Conclusions There is a strong relationship between CRP and the constellation of MS components and associated vascular risk in this older Chinese population.

Is there an estrogenic component in the metabolic syndrome?

One of the major upcoming concerns leading to health related problems in the industrialized societies is the metabolic syndrome which is characterized by central obesity, hypertension, raised fasting glucose and triglyceride levels. The focus of this review is on a potential estrogenic linkage between the metabolic mechanisms involved into the development of this disease cluster and specific estrogen related regulatory pattern. The candidate molecules for this link are insulin and insulin-like growthfactor, C-reactive protein, peroxisome-proliferation-activatingreceptorgamma, and leptin which all seem to interact with each other and show a responsiveness to changing estrogen levels. From this perspective they might also represent target molecules for a phytochemical intervention with phytoestrogens.

Insights into the Structure and Regulation of Glucokinase from a Novel Mutation (V62M), Which Causes Maturity-onset Diabetes of the Young

Glucokinase (GCK) serves as the pancreatic glucose sensor. Heterozygous inactivating GCK mutations cause hyperglycemia, whereas activating mutations cause hypoglycemia. We studied the GCK V62M mutation identified in two families and co-segregating with hyperglycemia to understand how this mutation resulted in reduced function. Structural modeling locates the mutation close to five naturally occurring activating mutations in the allosteric activator site of the enzyme. Recombinant glutathionyl S-transferase-V62M GCK is paradoxically activated rather than inactivated due to a decreased S0.5 for glucose compared with wild type (4.88 versus 7.55 mM). The recently described pharmacological activator (RO0281675) interacts with GCK at this site. V62M GCK does not respond to RO0281675, nor does it respond to the hepatic glucokinase regulatory protein (GKRP). The enzyme is also thermally unstable, but this lability is apparently less pronounced than in the proven instability mutant E300K. Functional and structural analysis of seven amino acid substitutions at residue Val62 has identified a non-linear relationship between activation by the pharmacological activator and the van der Waals interactions energies. Smaller energies allow a hydrophobic interaction between the activator and glucokinase, whereas larger energies prohibit the ligand from fitting into the binding pocket. We conclude that V62M may cause hyperglycemia by a complex defect of GCK regulation involving instability in combination with loss of control by a putative endogenous activator and/or GKRP. This study illustrates that mutations that cause hyperglycemia are not necessarily kinetically inactivating but may exert their effects by other complex mechanisms. Elucidating such mechanisms leads to a deeper understanding of the GCK glucose sensor and the biochemistry of beta-cells and hepatocytes.

Gestational diabetes

Gestational diabetes (GDM) involves huge issues of population screening, treatment, obstetric intervention and health service resources. Uncertainty and controversy surround the subject because the scientific base is insecure. GDM with persistently raised fasting glucose, in women not previously known to be diabetic, does occur and incurs fetal risk; the prevalence varies with the population. Whether there is a substantial, independent fetal risk of lesser degrees of glucose intolerance is uncertain. Baby size does relate to post-meal glucose, but the extent to which size can be altered with treatment, and how desirable this is, are not clear. Women with GDM are at increased risk of developing overt diabetes, but effective, preventive programmes are lacking. Intrauterine events, probably fetal hyperinsulinaemia, may programme susceptibility to obesity and insulin resistance in the offspring. This may have contributed to the current global epidemic of diabetes. Fetal hyperinsulinaemia does provide a real end-point to audit pregnancy management. It seems likely that post-meal glucose excursions are a main stimulus to fetal hyperinsulinism and that optimal management should target this. Individual clinical need and population screening are quite separate programmes. Population screening needs to be subject to the same public health assessment as other screening tests.