Original Data

German New Onset Diabetes in the Young Incident Cohort Study: DiMelli Study Design and First-Year Results

Leonore Thümer¹, Kerstin Adler¹, Ezio Bonifacio², Frank Hofmann³, Manfred Keller³, Christine Milz³, Axel Munte^3,4, Anette-Gabriele Ziegler^1,4

Abstract

BACKGROUND: Diabetes incidence in childhood and youth is increasing worldwide, including autoimmune and non-autoimmune cases. Recent findings suggest that there is a larger than expected proportion of type 2 diabetes in youth, and potential cases of intermediate diabetes phenotypes. Most pediatric diabetes registries focus on type 1 diabetes. Also, there is an absence of reliable data on type 2 diabetes incidence in youth. AIMS: The DiMelli study aims to establish a diabetes incidence cohort registry of patients in Germany, diagnosed with diabetes mellitus before age 20 years. It will be used to characterize diabetes phenotypes by immunologic, metabolic, and genetic markers. DiMelli will assess the contribution of obesity and socio-demographic factors to the development of diabetes in childhood and youth. METHODS: Recruitment of patients started in 2009, and is expected to continue at a rate of 250 patients per year. RESULTS: 84% of the 216 patients recruited within the first year were positive for multiple islet autoantibodies, 12% for one islet autoantibody, and 4% were islet autoantibody-negative. Patients with multiple islet autoantibodies were younger and had lower fasting C-peptide levels, compared to islet autoantibody-negative patients (median age 10.0 vs. 14.1 years, p < 0.01). CONCLUSIONS: Results from the first year of the study show that DiMelli will help to reveal new knowledge on the etiology of diabetes, and the contribution of genetic predisposition and environmental risk factors to the different types of diabetes.

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CXC Chemokine Ligand 10 DNA Vaccination Plus Complete Freund's Adjuvant Reverses Hyperglycemia in Non-Obese Diabetic Mice

Yoichi Oikawa^1,2, Akira Shimada^1,2, Yoshifumi Yamada¹, Yoshiaki Okubo¹, Takeshi Katsuki^1,2, Toshikatsu Shigihara¹, Jun-ichi Miyazaki³, Shosaku Narumi⁴, Hiroshi Itoh¹

Abstract

OBJECTIVE: Complete Freund's Adjuvant (CFA) is known to arrest autoimmune diabetes development in non-obese diabetic (NOD) mice. However, CFA alone cannot induce effective remission in diabetic NOD mice. Previously, we reported that anti-CXC chemokine ligand 10 (CXCL10) antibody can promote beta-cell proliferation in NOD mice. In the present study, we aimed to examine whether anti-CXCL10 plus CFA treatment can effectively reverse autoimmune diabetes development. METHODS: Systemic supply of anti-CXCL10 antibody by CXCL10 DNA vaccination in combination with CFA injection was performed in new-onset diabetic NOD mice. Remission rate of diabetes, histological characteristics of residual insulitis lesions, residual beta-cell mass, and regulatory T cell population in local pancreas were examined. RESULTS: A high frequency of diabetes reversal was observed after combination treatment with anti-CXCL10 plus CFA. In mice showing diabetes reversal, residual beta-cell mass was significantly increased, and some beta-cells were in a proliferative state. Although systemic cytokine profiles were unaffected, the frequency of "hybrid regulatory T cells", i.e. regulatory T cells expressing CXCR3, was significantly increased in local pancreatic lesions. This was possibly associated with the regulation of anti-islet autoimmunity. CONCLUSIONS: Anti-CXCL10 plus appropriate immune adjuvant therapy arrested, and reversed, type 1 diabetes development.

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Effects of Insulin Versus Sulphonylurea on Beta-Cell Secretion in Recently Diagnosed Type 2 Diabetes Patients: A 6-Year Follow-Up Study

Michael Alvarsson¹, Kerstin Berntorp², Eva Fernqvist-Forbes³, Ibe Lager⁴, Lars Steen⁵, Thomas Örn⁶, Valdemar Grill^1,7

Abstract

BACKGROUND: Early insulin treatment is considered more beneficial than anti-diabetic medication with sulphonylureas, because the latter may exert negative effects on beta-cell function, while the former may help preserve it. In a previous study, we found that C-peptide response was increased in the insulin-treated group, whereas it was decreased in the glibenclamide group. However, it was not certain whether the advantage remained in the longer term. AIM: In this study, we tested whether early insulin treatment is more beneficial than glibenclamide against a 6-year follow-up perspective. METHODS: We designed a randomized clinical trial in subjects with newly diagnosed type 2 diabetes. Glucagon stimulatory tests, measuring C-peptide and islet amyloid polypeptide (IAPP), were performed after 2, and 3, days of temporary insulin and glibenclamide withdrawal. RESULTS: 18 subjects initially randomized to glibenclamide, and 16 randomized to two daily injections of insulin, participated in end-of-study investigations. C-peptide response to glucagon deteriorated (p < 0.01 vs. baseline) in initially glibenclamide-treated patients (n = 18), but not in insulin-treated patients (p < 0.05 for difference between groups, after 2 days of treatment withdrawal). The IAPP response to glucagon declined in the glibenclamide group (p < 0.001), but not in insulin-treated subjects (p = 0.05 for difference between groups). CONCLUSIONS: Early insulin treatment preserves beta-cell secretory function better than glibenclamide even in a 6-year perspective.

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Effects of Different Protein Sources on Plasminogen Inhibitor-1 and Factor VII Coagulant Activity Added to a Fat-Rich Meal in Type 2 Diabetes

Lene S. Mortensen, Claus Thomsen, Kjeld Hermansen

Abstract

BACKGROUND: Exaggerated postprandial triglyceride concentration is believed to be atherogenic, and to influence the risk of thrombosis. Both elevated plasminogen inhibitor 1 (PAI-1) and increased factor VII coagulant activity (FVIIc) are potential important contributors to the increased risk of cardiovascular disease in type 2 diabetes. AIM: We aimed to investigate the effect of adding four different protein types (i.e. casein, whey, cod, and gluten) to a fat-rich meal on postprandial responses of PAI-1 and FVIIc in type 2 diabetic patients. METHODS: Twelve type 2 diabetic patients ingested four isocaloric test meals in random order. The test meals contained 100 g of butter and 45 g of carbohydrate in combination with 45 g of casein (Cas-meal), whey (Whe-meal), cod (Cod-meal), or gluten (Glu-meal), respectively. Plasma concentrations of PAI-1 and FVIIc were measured before meal, and at regular intervals for 8-h postprandially. RESULTS: The postprandial PAI-1 concentration decreased significantly by 49% to 56% in response to the four test meals. There were no significant differences between the outcomes from the four test-meals. The FVIIc levels decreased by 8% to 11% after the meals. Again, we observed no significant differences in outcomes between the four protein-enriched meals. CONCLUSIONS: The four proteins casein, whey, cod, and gluten, added to a fat-rich meal, all decreased the PAI-1 and FVIIc concentrations postprandially in type 2 diabetic subjects. However, postprandial levels of PAI-1 and FVIIc were not acutely influenced by the protein source.

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Gender-Specific Differences in the Association of Adiponectin Gene Polymorphisms with Body Mass Index

Ozra Tabatabaei-Malazy¹, Shirin Hasani-Ranjbar¹, Mahsa M. Amoli¹, Ramin Heshmat¹, Mohammadali Sajadi², Reza Derakhshan², Parvin Amiri¹, Mahsa Namakchian¹, Ebrahim Rezazadeh², Javad Tavakkoly-Bazzaz^1,3, Abbasali Keshtkar^1,4, Bagher Larijani¹

Abstract

OBJECTIVE: Adiponectin gene polymorphisms are associated with obesity, metabolic syndrome and type 2 diabetes (T2D). The study evaluated possible associations of +45T/G and -11391G/A adiponectin gene polymorphisms with body mass index (BMI), waist circumferences (WC), and blood pressure in diabetic and non-diabetic Iranians. METHODS: This cross-sectional study involved two groups of subjects: 243 diabetic patients and 173 non-diabetic subjects recruited from Rafsanjan city in the south-east of Iran. RESULTS: No significant association was found between +45T/G and -11391G/A adiponectin gene polymorphisms and systolic or diastolic blood pressure. However, male carriers of the TT genotype of +45T/G had a significantly higher mean BMI than male GG homozygotes (p = 0.018). Also, male carriers of the GG genotype of -11391G/A had significantly higher mean BMI than male GA or AA homozygotes (p = 0.041). Female carriers of the GG genotype of -11391G/A had significantly higher mean WC than female GA or AA homozygotes (p = 0.038). CONCLUSIONS: We observed a significantly higher BMI in women, and GA or AA carriers of -11391G/A polymorphism. Also, there was a significantly lower WC in females and GG carriers of +45T/G. These results point to a gender-specific impact of the studied genotypes on BMI and WC.

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