A novel, long-acting agonist of glucose-dependent insulinotropic polypeptide suitable for once-daily administration in type 2 diabetes

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone with a potentially therapeutic role in type 2 diabetes. Rapid degradation by dipeptidylpeptidase IV has prompted the development of enzyme-resistant N-terminally modified analogs, but renal clearance still limits in vivo bioactivity. In this study, we report long-term antidiabetic effects of a novel, N-terminally protected, fatty acid-derivatized analog of GIP, N-AcGIP(LysPAL(37)), in obese diabetic (ob/ob) mice. Once-daily injections of N-AcGIP(LysPAL(37)) over a 14-day period significantly decreased plasma glucose, glycated hemoglobin, and improved glucose tolerance compared with ob/ob mice treated with saline or native GIP. Plasma insulin and pancreatic insulin content were significantly increased by N-AcGIP(LysPAL(37)). This was accompanied by a significant enhancement in the insulin response to glucose together with a notable improvement of insulin sensitivity. No evidence was found for GIP receptor desensitization and the metabolic effects of NAcGIP(LysPAL(37)) were independent of any change in feeding or body weight. Similar daily injections of native GIP did not affect any of the parameters measured. These data demonstrate the ability of once-daily injections of N-terminally modified, fatty acid-derivatized analogs of GIP, such as N-AcGIP(LysPAL(37)), to improve diabetes control and to offer a new class of agents for the treatment of type 2 diabetes.

Reduced estimated glomerular filtration rate in Alzheimer's disease

OBJECTIVES:

Renal disease is increasingly regarded as an independent risk factor for vascular disease which in itself is believed to influence risk of AD. Alterations in amyloid homeostasis via reduced renal clearance of peripheral beta-amyloid (A|*beta*|) may represent another potential role for variation in renal function leading to increased risk of AD. We sought to examine estimates of glomerular filtration rate in AD and control groups.
METHODS:

AD patients were randomly recruited from the Memory Clinic of the Belfast City Hospital (n = 83). Genomic DNA was extracted from peripheral leucocytes and was genotyped for Apolipoprotein E using standard methods. Using creatinine values, age and gender, estimated Glomerular Filtration Rates (eGFR) were calculated using the isotope dilution mass spectrometry (IDMS)-traceable Modification of Diet in Renal Disease (MDRD) Study equation (using the United Kingdom National External Quality Assessment Scheme (UKNEQAS) correction factor). IDMS eGFR values were then compared between AD and control groups.

RESULTS:

Significant baseline differences in age, diastolic blood pressure, education level attained and APOE |*epsilon*|4 carriage were noted between cases and controls. The AD group had a significantly lower eGFR versus controls (69 vs 77 ml/min) which persisted after adjustment for possible confounders (p = 0.045).

CONCLUSIONS:

This case-control analysis suggests that using a relatively accurate estimate of renal function, patients with AD have greater renal impairment than cognitively normal controls. This may reflect impaired renal clearance of peripheral A|*beta*| or be a marker of shared vascular processes altering cerebral and renal functioning.

Late referral for assessment of renal failure

It has been recommended that adult patients with a serum creatinine above 150 µmol/l should be referred to a nephrologist for specialist assessment. This study ascertained all patients in Northern Ireland with creatinine above this concentration in 2001 (n?=?19 286 ) to see if this triggered referral within the subsequent year. After exclusion of those who were already known to a nephrologist and those who had acute renal failure, it was found that younger patients and diabetic patients were more likely to be referred. There was no difference in referral rates between male and female patients. However, only 6.5% of all non-diabetic subjects and 19% of diabetic patients were referred within 12 months after a first increased serum creatinine test.

An Investigation of the Flow Field through a Variable Geometry Turbine Stator with Vane Endwall Clearance

Variable geometry turbines provide an extra degree of flexibility in air management in turbocharged engines. The pivoting stator vanes used to achieve the variable turbine geometry necessitate the inclusion of stator vane endwall clearances. The consequent leakage flow through the endwall clearances impacts the flow in the stator vane passages and an understanding of the impact of the leakage flow on stator loss is required. A numerical model of a typical variable geometry turbine was developed using the commercial CFX-10 computational fluid dynamics software, and validated using laser doppler velocimetry and static pressure measurements from a variable geometry turbine with stator vane endwall clearance. Two different stator vane positions were investigated, each at three different operating conditions representing different vane loadings. The vane endwall leakage was found to have a significant impact on the stator loss and on the uniformity of flow entering the turbine rotor. The leakage flow changed considerably at different vane positions and flow incidence at vane inlet was found to have a significant impact.

“Islands” in Holocene forests: implications for forest openness, landscape clearance and “culture-steppe” species

Human activity has undoubtedly had a major impact on Holocene forested ecosystems, with the concurrent expansion of plants and animals associated with cleared landscapes and pasture, also known as 'culture-steppe'. However, this anthropogenic perspective may have underestimated the contribution of autogenic disturbance (e.g. wind-throw, fire), or a mixture of autogenic and anthropogenic processes, within early Holocene forests. Entomologists have long argued that the north European primary forest was probably similar in structure to pasture woodland. This idea has received support from the conservation biologist Frans Vera, who has recently strongly argued that the role of large herbivores in maintaining open forests in the primeval landscapes of Europe has been seriously underestimated. This paper reviews this debate from a fossil invertebrate perspective and looks at several early Holocene insect assemblages. Although wood taxa are indeed important during this period, species typical of open areas and grassland and dung beetles, usually associated with the dung of grazing animals, are persistent presences in many early woodland faunas. We also suggest that fire and other natural disturbance agents appear to have played an important ecological role in some of these forests, maintaining open areas and creating open vegetation islands within these systems. More work, however, is required to ascertain the role of grazing animals, but we conclude that fossil insects have a significant contribution to make to this debate. This evidence has fundamental implications in terms of how the palaeoecological record is interpreted, particularly by environmental archaeologists and palaeoecologists who may be more interested in identifying human-environment interactions rather than the ecological processes which may be preserved within palaeoecological records.