Degradation and glycemic effects of His(7)-glucitol glucagon-like peptide-1(7-36)amide in obese diabetic ob/ob mice

Glucagon-like peptide-1(7-36)amide (tGLP-1) has attracted considerable potential as a possible therapeutic agent for type 2 diabetes. However, tGLP-1 is rapidly inactivated in vivo by the exopeptidase dipeptidyl peptidase IV (DPP IV), thereby terminating its insulin releasing activity. The present study has examined the ability of a novel analogue, His(7)-glucitol tGLP-1 to resist plasma degradation and enhance the insulin-releasing and antihyperglycemic activity of the peptide in 20-25-week-old obese diabetic ob/ob mice. Degradation of native tGLP-1 by incubation at 37 degreesC with obese mouse plasma was clearly evident after 3 h (35% intact). After 6 h, more than 87% of tGLP-1 was converted to GLP-1(9-36)amide and two further N-terminal fragments, GLP-1(7-28) and GLP-1(9-28). In contrast, His7-glucitol tGLP-1 was completely resistant to N-terminal degradation. The formation of GLP-1(9-36)amide from native tGLP-1 was almost totally abolished by addition of diprotin A, a specific inhibitor of DPP IV. Effects of tGLP-1 and His7-glucitol tGLP-1 were examined in overnight fasted obese mice following i.p. injection of either peptide (30 nmol/kg) together with glucose (18 mmol/kg) or in association with feeding. Plasma glucose was significantly lower and insulin response greater following administration of His7-glucitol tGLP-1 as compared to glucose alone. Native tGLP-1 lacked antidiabetic effects under the conditions employed, and neither peptide influenced the glucose-lowering action of exogenous insulin (50 units/kg). Twice daily s.c. injection of ob/ob mice with His(7)-glucitol tGLP-1 (10 nmol/kg) for 7 days reduced fasting hyperglycemia and greatly augmented the plasma insulin response to the peptides given in association with feeding. These data demonstrate that His(7)-glucitol tGLP-1 displays resistance to plasma DPP IV degradation and exhibits antihyperglycemic activity and substantially enhanced insulin-releasing action in a commonly used animal model of type 2 diabetes. (C) 2001 Elsevier Science B.V. All rights reserved.

Improved glycaemic control in obese diabetic ob/ob mice using N-terminally modified gastric inhibitory polypeptide

Gastric inhibitory polypeptide (GIP) is an important insulin-releasing hormone of the enteroinsular axis which is rapidly inactivated by the exopeptidase dipeptidyl peptidase (DPP) IV. The present study has examined the ability of Tyr(1)-glucitol GIP to be protected from plasma degradation and to enhance insulin-releasing and antihyperglycaemic activity in 20- to 25-week-old obese diabetic ob/ob mice. Degradation of GIP by incubation at 37 degrees C with obese mouse plasma was clearly evident after 3 h (35% degraded). After 6 h, more than 61% of GIP was converted to GIP(3-42) whereas N-terminally modified Tyr(1)-glucitol GIP was resistant to degradation in plasma (>99% intact after 6 h). The formation of GIP(3-42) was almost completely abolished by inhibition of plasma DPP IV with diprotin A. Effects of GIP and Tyr(1)-glucitol GIP were examined in overnight-fasted obese mice following i.p. injection of either peptide (20 nmol/kg) together with glucose (18 mmol/kg) or in association with feeding. Most prominent effects were observed in the former group where plasma glucose values at 60 min together with the area under the curve (AUC) for glucose were significantly lower following GIP (AUC, 874 +/- 72 mmol/l.min; P

Body mass and sex-biased parasitism in wood mice Apodemus sylvaticus

Male sex-biased parasitism (SBP) occurs across a range of mammalian taxa and two contrasting sets of hypotheses have been suggested for its establishment. The first invokes body size per se and suggests that larger individuals are either a larger target for parasites, trade off growth at the expense of immunity or cope better with parasitism than smaller individuals. The second suggests a sex-specific handicap whereby males have reduced immunocompetence compared to females due to the immunodepressive effects of testosterone. The current study investigated whether sex-biased parasitism is driven by host 'body size' or 'sex' using a rodent-tick (Apodemus sylvaticus-. Ixodes ricinus) system. Moreover, the presence or absence of large mammals at study sites were used to control the presence of immature ticks infesting wood mice, allowing the impacts of parasitism on host body mass and female reproduction to be assessed. As expected, male mice had greater tick loads than females and analyses suggested this sex-bias was driven by body mass as opposed to sex. It is therefore likely that larger individuals are a larger target for parasites, trade off growth at the expense of immunity or adapt behavioural responses to parasitism based on their body size. Parasite load had no effect on host body mass or female reproductive output suggesting individuals may alter behaviour or life history strategies to compensate for costs incurred through parasitism. Overall, this study lends support to the 'body size' hypothesis for the formation of sex-biased parasitism.

Basking is affected by season and influences oxygen consumption in desert-living striped mice

Small mammals that inhabit arid and temporally unproductive environments use several methods to conserve energy. Here, we investigate the energetic role of sun basking in striped mice Rhabdomys pumilio from the Succulent Karoo desert in South Africa. We observed mice in front of their nests for 140 h and recorded the time they spent basking during the non-breeding (dry) and the breeding (wet) seasons. We measured temperature changes in model mice to provide an indication of the heat that can be absorbed from the sun. Finally, we measured the oxygen consumption (circle dot O-2) of mice at their basking sites in the field both in the sun and in the shade. This was accomplished using a portable respirometry system with a metabolism chamber, which could be placed in and out of the sun. Observations showed that mice basked more often during the non-breeding than during the breeding season. During the former season, mice spent an average of 11.9 +/- 1.1 min (se) in the morning and 5.5 +/- 0.5 min in the afternoon per day basking. Within the metabolism chamber, circle dot O-2 decreased when the animal was in the sunshine compared with the shade. This effect occurred independent of the ambient temperature (T-a), indicating that a significant amount of radiant energy was absorbed from the sun. Basking may be an alternative to other energy-acquisition behaviours, such as foraging, which might be particularly useful at times when food is scarce.