GH replacement causing acute hyperglycaemia and ketonuria in a type 1 diabetic patient

Summary A state of insulin resistance is common to the clinical conditions of both chronic growth hormone (GH) deficiency and GH excess (acromegaly). GH has a physiological role in glucose metabolism in the acute settings of fast and exercise and is the only anabolic hormone secreted in the fasting state. We report the case of a patient in whom knowledge of this aspect of GH physiology was vital to her care. A woman with well-controlled type 1 diabetes mellitus who developed hypopituitarism following the birth of her first child required GH replacement therapy. Hours after the first dose, she developed a rapid metabolic deterioration and awoke with hyperglycaemia and ketonuria. She adjusted her insulin dose accordingly, but the pattern was repeated with each subsequent increase in her dose. Acute GH-induced lipolysis results in an abundance of free fatty acids (FFA); these directly inhibit glucose uptake into muscle, and this can lead to hyperglycaemia. This glucose–fatty acid cycle was first described by Randle et al. in 1963; it is a nutrient-mediated fine control that allows oxidative muscle to switch between glucose and fatty acids as fuel, depending on their availability. We describe the mechanism in detail. Learning points There is a complex interplay between GH and insulin resistance: chronically, both GH excess and deficiency lead to insulin resistance, but there is also an acute mechanism that is less well appreciated by clinicians. GH activates hormone-sensitive lipase to release FFA into the circulation; these may inhibit the uptake of glucose leading to hyperglycaemia and ketosis in the type 1 diabetic patient. The Randle cycle, or glucose–fatty acid cycle, outlines the mechanism for this acute relationship. Monitoring the adequacy of GH replacement in patients with type 1 diabetes is difficult, with IGF1 an unreliable marker. </jats:sec

The Jack and Jill Adaptive Working Memory Task: Construction, Calibration and Validation

Visuospatial working memory (VSWM) is essential to human cognitive abilities and is associated with important life outcomes such as academic performance. Recently, a number of reliable measures of VSWM have been developed to help understand psychological processes and for practical use in education. We sought to extend this work using Item Response Theory (IRT) and Computerised Adaptive Testing (CAT) frameworks to construct, calibrate and validate a new adaptive, computerised, and open-source VSWM test. We aimed to overcome the limitations of previous instruments and provide researchers with a valid and freely available VSWM measurement tool. The Jack and Jill (JaJ) VSWM task was constructed using explanatory item response modelling of data from a sample of the general adult population (Study 1, N = 244) in the UK and US. Subsequently, a static version of the task was tested for validity and reliability using a sample of adults from the UK and Australia (Study 2, N = 148) and a sample of Russian adolescents (Study 3, N = 263). Finally, the adaptive version of the JaJ task was implemented on the basis of the underlying IRT model and evaluated with another sample of Russian adolescents (Study 4, N = 239). JaJ showed sufficient internal consistency and concurrent validity as indicated by significant and substantial correlations with established measures of working memory, spatial ability, non-verbal intelligence, and academic achievement. The findings suggest that JaJ is an efficient and reliable measure of VSWM from adolescent to adult age

An efficient and adaptive test of auditory mental imagery

The ability to silently hear music in the mind has been argued to be fundamental to musicality. Objective measurements of this subjective imagery experience are needed if this link between imagery ability and musicality is to be investigated. However, previous tests of musical imagery either rely on self-report, rely on melodic memory, or do not cater in range of abilities. The Pitch Imagery Arrow Task (PIAT) was designed to address these shortcomings; however, it is impractically long. In this paper, we shorten the PIAT using adaptive testing and automatic item generation. We interrogate the cognitive processes underlying the PIAT through item response modelling. The result is an efficient online test of auditory mental imagery ability (adaptive Pitch Imagery Arrow Task: aPIAT) that takes 8 min to complete, is adaptive to participant’s individual ability, and so can be used to test participants with a range of musical backgrounds. Performance on the aPIAT showed positive moderate-to-strong correlations with measures of non-musical and musical working memory, self-reported musical training, and general musical sophistication. Ability on the task was best predicted by the ability to maintain and manipulate tones in mental imagery, as well as to resist perceptual biases that can lead to incorrect responses. As such, the aPIAT is the ideal tool in which to investigate the relationship between pitch imagery ability and musicality

State of the Tropics 2014 report

[Extract] Is life in the Tropics getting better? The landmark State of the Tropics 2014 Report addresses this nominally simple question. It provides the first in-depth, objective assessment of the Tropics as an environmental and geopolitical entity in its own right. Drawing on the knowledge, experience and diverse backgrounds of leading institutions across the Tropics the report assesses the state of the region and examines the implications of the immense changes the region is experiencing. The assessment demonstrates that nations in the Tropics have made extraordinary progress across a wide range of environmental, social and economic indicators in recent decades. Rapid population and economic growth mean its influence is set to rise dramatically in coming decades. The nature of this influence will depend on how the region addresses its many challenges, and whether it realises its potential and opportunities. The report provides a basis from which to work towards a prosperous, sustainable and equitable future for the Tropics and will be a valuable resource for policy makers, geopolitical analysts, researchers, students and other stakeholders interested in the Tropics

Lack of regulation of 11β-hydroxysteroid dehydrogenase type 1 during short-term manipulation of GH in patients with hypopituitarism

OBJECTIVE: Evidence from long-term clinical studies measuring urinary steroid ratios, and from in vitro studies, suggests that GH administered for longer than 2 months down-regulates 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), thereby reducing cortisol regeneration in liver and adipose tissue. We aimed to measure acute effects of GH on 11beta-HSD1 in liver and adipose tissue in vivo, including using a stable isotope tracer. DESIGN: Observational studies of GH withdrawal and reintroduction in patients with hypopituitarism. METHODS: Twelve men with benign pituitary disease causing GH and ACTH deficiency on stable replacement therapy for >6 months were studied after GH withdrawal for 3 weeks, and after either placebo or GH injections were reintroduced for another 3 weeks. We measured cortisol kinetics during 9,11,12,12-(2)H(4)-cortisol (d4-cortisol) infusion, urinary cortisol/cortisone metabolite ratios, liver 11beta-HSD1 by appearance of plasma cortisol after oral cortisone, and 11beta-HSD1 mRNA levels in subcutaneous adipose biopsies. RESULTS: GH withdrawal and reintroduction had no effect on 9,12,12-[(2)H](3)-cortisol (d3-cortisol) appearance, urinary cortisol/cortisone metabolite ratios, initial appearance of cortisol after oral cortisone, or adipose 11beta-HSD1 mRNA. GH withdrawal increased plasma cortisol 30-180 min after oral cortisone, increased d4-cortisol clearance, and decreased relative excretion of 5alpha-reduced cortisol metabolites. CONCLUSIONS: In this setting, GH did not regulate 11beta-HSD1 rapidly in vivo in humans. Altered cortisol metabolism with longer term changes in GH may reflect indirect effects on 11beta-HSD1. These data do not suggest that glucocorticoid replacement doses need to be increased immediately after introducing GH therapy to compensate for reduced 11beta-HSD1 activity, although dose adjustment may be required in the longer term

Effect of Supervised Progressive Resistance-Exercise Training Protocol on Insulin Sensitivity, Glycemia, Lipids, and Body Composition in Asian Indians With Type 2 Diabetes

OBJECTIVE—To evaluate the effect of supervised progressive resistance-exercise training (PRT) protocol on insulin sensitivity, glycemia (blood glucose and A1C levels), lipids, and body composition in Asian Indians with type 2 diabetes

Pyruvate Dehydrogenase Kinase 4: Regulation by Thiazolidinediones and Implication in Glyceroneogenesis in Adipose Tissue

OBJECTIVE—Pyruvate dehydrogenase complex (PDC) serves as the metabolic switch between glucose and fatty acid utilization. PDC activity is inhibited by PDC kinase (PDK). PDC shares the same substrate, i.e., pyruvate, as glyceroneogenesis, a pathway controlling fatty acid release from white adipose tissue (WAT). Thiazolidinediones activate glyceroneogenesis. We studied the regulation by rosiglitazone of PDK2 and PDK4 isoforms and tested the hypothesis that glyceroneogenesis could be controlled by PDK

Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes