Background Wnt1-inducible signaling pathway protein 1, or cellular communication network factor 4 (CCN4), a member of CCN family of secreted, extracellular matrix associated signaling proteins, recently was validated as a novel adipose tissue derived cytokine. Objective To assess the relationships between circulating CCN4, adipose tissue distribution and function, and chronic low-grade inflammation in subjects with type 2 diabetes. Methods We observed 156 patients with type 2 diabetes and 24 healthy controls. Serum levels of CCN4, hsCRP and alpha1-acid glycoprotein (alpha1-AGP) were measured by ELISA. Serum concentrations of leptin, resistin, visfatin, adipsin, adiponectin, IL-6, IL-8, IL-18 and TNF-alpha were determined by multiplex analysis. Fat mass and distribution was assessed by DEXA. Mean diameter of adipocytes was estimated in samples of subcutaneous adipose tissue. Results Patients with diabetes had higher levels of circulating CCN4, leptin, resistin, adipsin, visfatin, hsCRP, alpha1-AGP, and IL-6 (all p < 0.02). The CCN4 concentration correlated positively with percentage of fat mass in central abdominal area, as well as with leptin, resistin and visfatin levels; negative correlation was found between CCN4 and mean adipocyte diameter. In multiple regression analysis fat mass in central abdominal area was independent predictor for CCN4 concentration. Conclusion In subjects with type 2 diabetes serum levels of CCN4 are associated with central abdominal fat mass and adipose tissue dysfunction. Keywords WISP-1/CCN4. Type 2 diabetes. Cytokines. Obesity. Adipose tissue Olga Pivovarova-Ramich and Natalia Rudovich contributed equally to this work.

Background: Lipohypertrophy is primary dermal complication of insulin therapy. The data on the prevalence of lipohypertrophy in diabetic subjects are inconsistent, that may be due to the lack of sensitivity and subjectivity of palpation as diagnostic technique. Meanwhile, the reliability of lipohypertrophy detection can be increased by ultrasound. Aims: to compare clinical and ultrasound characteristics and to determine the risk factors of insulin-induced lipohypertrophy in diabetic subjects. Materials and methods: We observed 82 patients, including 26 individuals with type 1 diabetes and 56 subjects with type 2 diabetes. Duration of insulin therapy varied from 3 months to 37 years (median 14 years). The sites of insulin injections were assessed by palpation and ultrasound. Visualization protocol included gray-scale densitometry, strain elastography, and 3D Doppler power ultrasound. Scaled evaluation of ultrasound sings was applied. Insulin injection technique was assessed by questionnaire. Serum levels of insulin antibodies were determined by ELISA. Results: Lipohypertrophy was revealed by palpation and ultrasound in 57 and 80 patients (70% and 98%) respectively. Total lipohypertrophy area, acoustic density and total ultrasound score showed weak positive correlations with daily insulin dose (r=0.3, r=0.3 and r=0.35, respectively, all p0.006). Patients receiving insulin analogues had smaller area of abdominal lipohypertrophy than those on human insulin (p=0.03). A positive correlation was found between abdominal lipohypertrophy area and mean postprandial glucose (r=0.35, p=0.001). A rare needle change and injections in lipohypertrophy sites were the most common deviations in insulin injection technique (70 and 47 subjects, 85% and 53% respectively). The levels of insulin antibodies showed no association with lipohypertrophy parameters. Conclusions: Patients with type 1 and type 2 diabetes demonstrate high prevalence of lipohypertrophy in insulin injection sites. Ultrasonography is more sensitive method of diagnostics of lipohypertrophy compared with palpation. Insulin-induced lipohypertrophy is associated with errors in injection technique and higher insulin doses.

Lipodystrophy at the injection sites is most common local complication of insulin therapy. The history of its study started in 1926, when first cases of lipoatrophy at the sites of insulin injections were described. As we moved to human insulin and insulin analogues, immune mediated atrophic form of lipodystrophy has been replaced by hypertrophic one, which reflects anabolic and mitogenic effect of insulin. Lipohypertrophy at the injection sites is detected by physical examination in 40-70% of insulin-treated subjects. The detection efficiency depends on health care provider`s skills. Therefore, training of medical doctors and nurses in physical examination of injection sites seems to be reasonable. In recent years, ultrasound was introduced for diagnostics of insulin-induced lipohypertrophy. The method is more sensitive compared to palpation; ultrasound-verified lipohypertropthy was detected in more than 80% of cases. In patients with wide-spread lipohypertrophy ultrasound can be used to find suitable sites for injections (ultrasound injection map). Strain sonoelastography and 3D-power Doppler ultrasound can be used for quantitative estimation of rigidity and vascularization of lipohypertrophy. Both MRI and infrared images are considered as promising diagnostic tools. In a number of studies, it has been shown that the presence of lipohypertrophy is associated with high HbA1c levels, enhanced glycemic variability, unexplained hypoglycemia, and increased insulin doses. Thereby, lipohypertrophy aggravates the diabetes-related costs. The main risk factor for lipohypertrophy is inappropriate injection technique, including the lack of the site rotation, injections into lipodystrophic lesions, small injection area, reuse or excessive length of the needles. Accordingly, training patients in the injection technique is the basis for prevention of complication. The cessation of injections in lipohypertrophy areas and regular site rotation is essential for adequate titration of insulin dose and achievement of glycemic targets.

1 Научно-исследовательский институт клинической и экспериментальной лимфологии -филиал ФГБНУ «Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук», Новосибирск 2 Новосибирский государственный медицинский университет, Новосибирск обоснование. Дисфункция жировой ткани (ЖТ) играет важную роль в развитии метаболических нарушений при ожирении и сахарном диабете 2 типа (СД2). Роль распределения, гипертрофии и васкуляризации ЖТ в нарушении секреции адипокинов нуждается в уточнении.цель. Определить взаимосвязи между концентрациями адипокинов в сыворотке крови, массой и распределением ЖТ, диаметром адипоцитов и васкуляризацией подкожной ЖТ у больных СД2. материалы и методы. Обследовано 125 пациентов с СД2, включая 82 с ожирением. Контролем являлись 30 здоровых лиц, сопоставимых по полу и возрасту. Концентрации лептина, резистина, висфатина, адипсина и адипонектина в сыворотке крови натощак определяли с помощью мультиплексного анализа. Массу и распределение ЖТ оценивали с помощью двухэнергетической рентгеновской абсорбциометрии. Образцы подкожной ЖТ (ПЖТ) были забраны из околопупочной области с помощью ножевой биопсии у 25 пациентов и у 15 лиц, погибших от внешних причин. Кровеносные и лимфатические сосуды в ПЖТ типировали с помощью иммуногистохимии, используя антитела к CD34 и к подопланину соответственно. Оценивали объемную, численную плотность и ультраструктуру кровеносных и лимфатических сосудов, а также диаметр подкожных адипоцитов.результаты. Пациенты с диабетом, по сравнению с контролем, имели значительно более высокие уровни лептина, резистина, адипсина и висфатина (все р≤0,0003). Уровень адипонектина не показал различий. Концентрации лептина, резистина, висфатина, адипсина и адипонектина прямо коррелировали с массой ЖТ на бедрах. Уровни лептина и адипсина, кроме того, положительно коррелировали с массой ЖТ на туловище и в центральной области живота. Концентрация лептина, но не других адипокинов, была ассоциирована с гипертрофией подкожных адипоцитов. В ПЖТ больных СД наблюдались уменьшение объемной плотности микрососудов (р=0,01) и увеличение объемной и численной плотности лимфатических сосудов (p=0,02 в обоих случаях). В лимфатических капиллярах выявлено набухание цитоплазмы, митохондрий, цистерн гранулярной эндоплазматической сети и сниженное содержание микропиноцитарных везикул. Резистин и висфатин показали обратные ассоциации с объемной плотностью сосудов.заКлЮЧение. Эндокринная дисфункция ЖТ у больных СД2, проявляющаяся увеличением концентрации лептина, резистина, висфатина и адипсина в сыворотке крови, ассоциирована с массой и распределением ЖТ, гипертрофией подкожных адипоцитов и с изменениями васкуляризации ПЖТ.КЛЮЧЕВЫЕ СЛОВА: сахарный диабет; ожирение; жировая ткань; адипокины; кровеносные сосуды; лимфатические сосуды Serum adipokine concentrationS in patientS with type 2 diabeteS: the relationShipS with diStribution, hypertrophy and vaScularization of SubcutaneouS adipoSe tiSSue backGround: Adipose tissue (AT) dysfunction plays an important r...