Postnatal Development of Numbers and Mean Sizes of Pancreatic Islets and Beta-Cells in Healthy Mice and GIPRdn Transgenic Diabetic Mice

The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPRdn transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPRdn transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta-cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPRdn transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPRdn transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPRdn transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPRdn transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis

Lipid peroxidation.

<p>Serum malondialdehyde (MDA) levels of GIPR^dn transgenic (tg) and control (co) mice at 45, 90 and 180 days of age. Data represent means and SEM;</p><p>*p<0.05 vs. age-matched control;</p><p>+ p<0.05 vs. previous time point.</p

Representative islet profiles, sampling of sections, counting Q⁻ islets.

<p>Example of an islet profile of a control (A) and a GIPR^dn transgenic mouse (B) immunohistochemically stained for insulin; (C) Sampling scheme for drawing primary and reference sections; (D) Primary section and (E) reference section for counting Q⁻ islets, one Q⁻ may be counted in the example (arrow in E).</p

Islet-cell replication, isolated beta-cells, and islet-cell apoptosis.

<p>(A) number of BrdU positive islet cells per 10⁵ cells (N_(BrdU)), (B) total volume of isolated beta-cells (V_(Neo,Pan), (C) number of apoptotic islet cells per 10⁵ cells (N_(Apoptosis)). Open bars: female control mice; filled bars: female GIPR^dn transgenic mice; Data represent means and SEM. * p<0.05 vs. age-matched control; +p<0.05 vs. previous time point.</p

In vivo insulin secretion studies at 10 days of age.

<p>(A) Blood glucose, (B) serum insulin levels, (C) increase of serum insulin levels from basal levels (fold insulin secretion), (D) serum insulin to pancreatic insulin ratio; Open bars: control mice; filled bars: GIPR^dn transgenic mice; Data represent means and SEM. * p<0.05 vs. age-matched control; + p<0.05 vs. basal values.</p

In vivo investigations.

<p>(A) Randomly fed (10 days) and fasting blood glucose (45-180 days), and (B) randomly fed (10 days) and postprandial serum insulin levels (45–90 days), (C) insulin tolerance test, (D), and area under glucose curve (AUC) during insulin tolerance test shown in C; co, control; tg, GIPR^dn transgenic; Data represent means and SEM, * p<0.05 vs. age-matched control.</p

Quantitative-stereological investigations of the endocrine pancreas.

<p>(A) Total islet volume (V_(Islets,Pan), (B) total beta-cell volume (V_{(B-cells,Islets)}, (C) Number of islets (N_{(Islets, Pan)}, (D) mean islet volume (v_(islets), (E) beta-cell number (N_{(B-cells,Islets)}, (F) mean beta-cell volume (v_(B-cells). Open bars: female control mice; filled bars: female GIPR^dn transgenic mice; Data represent means and SEM. * p<0.05 vs. age-matched control; +p<0.05 vs. previous time point.</p

Successful intra-class switching among IL-17 antagonists: a multicentre, multinational, retrospective study

IL-17 blockers are among the newer anti-psoriatic treatment options and little is known about the interclass switching. We have thus initiated a multi-center, multi-national, retrospective study to assess the treatment response of patients who were switched from one IL-17 blocker to another. Analysis consisted of data from patients with moderate-to-severe psoriasis who did not respond satisfactorily to one of the available IL-17 blockers (secukinumab, ixekizumab, brodalumab) and were subsequently switched to another drug of this class. After 12 weeks of treatment, patients’ PASIs were evaluated. Treatment success was defined as reaching PASI 75 after 12 weeks. Topical treatment was allowed and used in all patients. 26 patients were included (13 male, 13 female) and 29 switches were evaluated. Overall, 29 switches in 21 patients were evaluated. 18 patients changed their therapy from secukinumab to ixekizumab, or in 7 cases to brodalumab. Brodalumab was used in 3 cases after failure of treatment with ixekizumab. Only in one case, non-response of brodalumab resulted in a therapy switch to secukinumab. In 15 (52%) cases, PASI 75 was reached. In 6 (20%) patients, the switch led to a PASI 50 response. No success of treatment was seen among 8 (28%) participants. When patients fail to respond or do not tolerate an IL-17 blocker, switching to another anti-IL-17A/RA is a promising viable option. Larger studies are needed to confirm our results