Original Data

Incomplete Killing And Enhanced Activation of Islet-Reactive CD8+ T Cells by FasL-Expressing Dendritic Cells Limits Protection from Diabetes

Mikael Maksimow^1,2, Catharina Alam¹, Arno Hänninen¹

Abstract

AIMS: Autologous dendritic cells (DC) are a promising tool for induction of cytotoxic CD8+ T cell immunity against tumors and chronic viral infections. When armed with the death-inducing Fas-ligand (FasL, CD195), DC attenuate delayed-type hypersensitivity reactions and allotransplant rejection by promoting activation-induced cell death in T cells. We investigated the possibility of using FasL-expressing DC to induce deletion of islet-reactive CD8+ T cells in vivo, and to prevent destruction of pancreatic islets in a model of autoimmune diabetes. METHODS: DC, propagated from mouse bone marrow cells, were purified and made to express FasL and islet-antigen via plasmid transfection. CD8+ T cells (OT-I cells) recognizing the antigen, ovalbumin, were adoptively transferred to transgenic mice expressing ovalbumin in islets (RIP-OVA^lo mice), and these mice were primed with ovalbumin. To test the potential of DC to prevent diabetes in this model, the mice were later intravenously vaccinated with the transfected DC. RESULTS: Transfected DC induced partial deletion of antigen-reactive CD8+ T cells in vivo and reduced the level of lymphocyte infiltration into pancreatic islets. Diabetes developed less frequently in vaccinated mice, but this effect was limited. Further in vitro analysis showed that FasL-expressing DC not only deleted many of the responding CD8+ T cells but also promoted the expansion of surviving cells and their IFN-γ production. CONCLUSIONS: FasL-expressing DC can also have stimulatory effects on CD8+ T cells warranting further investigation into the optimal design of tolerance-promoting DC-vaccination to prevent autoimmune diabetes.

Fulltext: HTML , PDF (531KB)

Initiating or Switching to Biphasic Insulin Aspart 30/70 Therapy in Subjects with Type 2 Diabetes Mellitus. An Observational Study

Leif Breum¹, Thomas Almdal^2,3, Pia Eiken⁴, Per Lund⁵, Erik Christiansen⁶, on behalf of the Danish BIAsp Study Group

Abstract

OBJECTIVE: To investigate tolerability and glycemic control over 26 weeks in patients with type 2 diabetes (T2D) who initiated insulin with, or switched to, biphasic insulin aspart 30/70 (BIAsp 30) in routine clinical care. METHODS: This was a non-randomized, non-interventional, open-label, observational study involving patients under the care of approximately 150 insulin-prescribing physicians in Denmark. All patients enrolled were prescribed BIAsp 30 in routine care. Starting dose, dose titration and injection frequency were determined individually by each physician. Information on serious adverse drug reactions (SADR), glycemic parameters and hypoglycemic events were obtained from patients’ notes, patients’ diaries and recall, and transferred to case report forms by physicians at baseline (during 4 weeks prior to BIAsp 30 therapy) and after 12 and 26 weeks of treatment. RESULTS: 421 subjects were recruited and 392 provided safety data. The age (mean ± SD) was 62.0 ± 11.4 years, body mass index (BMI) 30.4 ± 6.4 kg/m², duration of diabetes 9.1 ± 8.1 years and HbA1c (%) 9.4 ± 1.7. 199 subjects were prior insulin users and 193 were insulin-naïve patients. Four patients reported a SADR (3 hypoglycemia, 1 severe hypoglycemia). HbA1c was significantly reduced after 26 weeks of BIAsp 30 therapy: prior insulin users -1.2%, insulin-naïve patients -2.2% (both p < 0.001). 28% and 41% of patients, respectively, reached target HbA1c < 7%. Overall the hypoglycemia rate was lower for insulin-naïve patients than for prior insulin users: 5.0 vs. 6.6 episodes/patient-year (p < 0.05). CONCLUSION: Initiating insulin with, or switching insulin to, BIAsp 30 in routine care was safe and effective in patients with T2D.

Fulltext: HTML , PDF (427KB)

Effects of Gender and Height on the Oral Glucose Tolerance Test: The Isfahan Diabetes Prevention Study

Mohsen Janghorbani¹, Massoud Amini²

Abstract

BACKGROUND: Impaired fasting glucose (IFG) is more prevalent in men, whereas impaired glucose tolerance (IGT) is more prevalent in women. AIM: To determine whether gender difference in the prevalence of glucose intolerance is related to height. METHODS: A cross-sectional study of 2,368 first-degree relatives (FDR) of patients with type 2 diabetes was conducted between years 2003 to 2005. All participants (614 men and 1754 women) were in the age range 30-60 years, and were FDR of consecutive patients from outpatient clinics at Isfahan Endocrine and Metabolism Research Centre, Iran. All subjects underwent a standard 75 g 2-h oral glucose tolerance test (OGTT). Weight, height, waist and hip circumference, and glycated haemoglobin were also measured. RESULTS: IGT was more common amongst women (OR 0.66; 95% CI 0.51, 0.87),whereas diabetes (OR 1.31; 95% CI 0.96, 1.78), and IFG (OR 1.41; 95% CI 1.10, 1.80) was more common amongst men. Women had a lower mean fasting plasma glucose (FPG) (p < 0.001), but showed higher 2hPG, and FPG-2hPG increase (p < 0.001). The gender difference in mean 2hPG and FPG-2hPG increase, was not evident after adjustment for height. Negative correlation to height was observed in 2hPG and FPG-2hPG increase, both in men and women (p < 0.001), but height showed little association with FPG. CONCLUSIONS: Women had higher mean 2hPG and FPG-2hPG increase, but showed a lower FPG level than men. The inverse association between height and 2hPG and FPG-2hPG increase may be explained by gender difference.

Fulltext: HTML , PDF (343KB)