Reduction in the Risk of Peripheral Neuropathy and Lower Decrease in Kidney Function with Metformin, Linagliptin or Their Fixed-Dose Combination Compared to Placebo in Prediabetes: A Randomized Controlled Trial.

OBJECTIVE: To compare the effect of glucose-lowering drugs on peripheral nerve and kidney function in prediabetes. METHODS: Multicenter, randomized, placebo-controlled trial in 658 adults with prediabetes treated for 1 year with metformin, linagliptin, their combination or placebo. Endpoints are small fiber peripheral neuropathy (SFPN) risk estimated by foot electrochemical skin conductance (FESC < 70 µSiemens) and estimated glomerular filtration rate (eGFR). RESULTS: Compared to the placebo, the proportion of SFPN was reduced by 25.1% (95% CI:16.3-33.9) with metformin alone, by 17.3% (95% CI 7.4-27.2) with linagliptin alone, and by 19.5% (95% CI 10.1-29.0) with the combination linagliptin/metformin (p < 0.0001 for all comparisons). eGFR remained +3.3 mL/min (95% CI: 0.38-6.22) higher with the combination linagliptin/metformin than with the placebo (p = 0.03). Fasting plasma glucose (FPG) decreased more with metformin monotherapy -0.3 mmol/L (95%CI: -0.48; 0.12, p = 0.0009) and with the combination metformin/linagliptin -0.2 mmol/L (95% CI: -0.37; -0.03) than with the placebo (p = 0.0219). Body weight (BW) decreased by -2.0 kg (95% CI: -5.65; -1.65, p = 0.0006) with metformin monotherapy, and by -1.9 kg (95% CI: -3.02; -0.97) with the combination metformin/linagliptin as compared to the placebo (p = 0.0002). CONCLUSIONS: in people with prediabetes, a 1 year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a lower decrease in eGFR, than treatment with placebo.

Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data.

OBJECTIVES: To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. METHODS: Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. PARTICIPANTS: Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. INTERVENTION: Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. RESULTS: One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. CONCLUSIONS: ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. REGISTRATION: - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.

Recycling and Reinforcing Intimomedial Flap of the Infrarenal Aorta Using Anterior Longitudinal Ligament in Patients With Acute Trauma With Bowel Injuries.

We present a patient with blunt abdominal trauma with severe acute right limb ischemia and clinical signs of diffuse peritonitis. Computed tomography angiography showed circumferential dissection of the infrarenal aorta with occlusion of the right common iliac artery. We opted for simultaneous abdomen exploration and open repair of injured aorta. Critical weakening of the aortic wall with imminent rupture was identified intraoperatively. Aortotomy cranially from bifurcation showed circumferential intimomedial dissection. The fixation of fragile intimomedial flap of aortic dissection was achieved with reinforcement using an anterior longitudinal ligament. The long aortoiliac arteriotomy was repaired using a great saphenous vein patch. Patient had uneventful postoperative course and was discharged after 7 days. In patients with abdominal polytrauma with peritonitis, and no available endovascular tools, open surgery for circumferential aortic dissection is possible and successful. Described reinforcement of the posterior aortic wall to the anterior longitudinal ligament should be added to the armamentarium of aortic injury treatment.

Effects of total fibre or resistant starch-rich diets within lifestyle intervention in obese prediabetic adults.

PURPOSE: Starting from the evidence-based health benefits that resistant starch (RS) shows when added to the diet, our aim in this study was to evaluate the effects of increased fibre intake with two different levels of RS coming from regular daily consumed foods on normalization of glycaemia within lifestyle intervention in the population with risk factors for developing diabetes. METHODS: Study included 47 overweight and obese men and women with disordered glucoregulation and dyslipidaemia, aged between 45-74, divided into RS and Fibre group. Participants were subjected to the lifestyle and dietary intervention with low-fat and high-fibre (>25 g/day) diet for 12 months and were offered two different dietary advices aimed at increasing total fibre intake in Fibre group and at increasing RS intake in RS group. RESULTS: The intake of macronutrients and total fibre was similar between groups at the end of the study, but achieved RS intake was two times higher in the RS group. Decrease in total cholesterol and non-HDL-cholesterol was more pronounced in RS group in comparison with Fibre group (p = 0.010, p = 0.031, respectively), whereas in Fibre group, a more pronounced effect on glucoregulation was observed: significant fall in glycaemia after 2-h oral glucose tolerance test (7.93 vs 6.96 mmol/L, p = 0.034). CONCLUSION: At the end of the study, RS-rich diet failed to affect glycaemic control in prediabetic obese individuals in contrast to the regular fibre-rich diet, which indicated that fibre profile could be an important determinant of the effect of dietary intervention.

Matrix metalloproteinase-9 index as a possible parameter for predicting acute coronary syndrome in diabetics.

BACKGROUND/AIM: Matrix metalloproteinase-9 (MMP-9) index is the ratio of active MMP-9 and total MMP-9 levels. It reflects the importance of MMP-9 in acute coronary syndrome (ACS). METHODS: The study included 3 groups of patients (n = 87): the group 1 - non-diabetic subjects without ACS (control); the group 2 - diabetic patients with ACS [subgroups with unstable angina pectoris (UAP), myocardial infarction (MI) or reinfarction]; and the group 3 non-diabetics patients with ACS. Total and active MMP-9 were measured and used to create MIP-9 index. RESULTS: MMP-9 index, as a marker showed good sensitivity and specificity, of ACS in diabetics, with a cut-off value over 58.2. MMP-9 was higher in the study groups than in the control one. MMP-9 correlated with ACS occurrence and type of cardiovascular event. A statistically significant difference was found among the groups according to active MMP-9 (p < 0.001). The same was found with active MMP-9 between the control and the group with MI (p < 0.001). The control was highly statistically significantly different from the group of patients with UAP (p < 0.01). Statically significant differences in MMP-9 index was found between the control and the diabetics with ACS (P < 0.001). Statistically significant difference of MMP-9 index was also found in the controls compared to the value in non-diabetic patients with ACS (p < 0.01). CONCLUSION: MMP-9 index may be a possible marker of atheromatous plaque rupture in diabetics.

Acquired Hypertrichosis Lanuginosa: Typical Presentation and Unusual Association.

Paraneoplastic syndrome might be the first clinical manifestation of malignancy. We present a menopausal female with the acquired hypertrichosis lanuginosa (AHL) as an initial clinical presentation of rectal adenocarcinoma, unusually associated with paraneoplastic cerebellar degeneration (PCD) and disseminated intravascular coagulation (DIC).

Liver function test changes in centrally obese youth with metabolic syndrome in a Serbian population.

OBJECTIVE: The aim of this study was to investigate the association between metabolic syndrome and liver enzymes in overweight and obese adolescents and young adults. METHODS: A total of 126 overweight and obese adolescents and young adults (age, 15-26 years), 55 (43.6%) with metabolic syndrome and 71 (56.4%) without metabolic syndrome, were studied. RESULTS: Patients with metabolic syndrome had significantly higher alanine aminotransferase (ALT), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP) levels compared to patients without metabolic syndrome [36.5±22.2 vs. 29.4±17.8 IU/L (P=0.043), 33.8±17.8 vs. 26.9±18.4 IU/L (P=0.002), and 84.3±32.2 vs. 75.7±29.5 IU/L (P=0.063)]. Aspartate aminotransferase (AST) levels were similar in both groups (24.1±9.8 vs. 23.3±9.0 IU/L, P=0.674). Elevated AST, ALT, GGT, and ALP levels were observed in 6, 15, 18, and 5 patients (11%, 27%, 14%, and 9%) with metabolic syndrome compared to 6, 17, 6, and 4 (8%, 24%, 8% and 5%) patients without metabolic syndrome (P=0.872, P=0.826, P<0.001, and P=0.035). In multivariate regression models adjusted for age and gender, metabolic syndrome was not a significant predictor of ALT (P=0.967), GGT (P=0.526), and ALP levels (P=0.221), but insulin resistance was a significant predictor for ALT and GGT levels (P=0.001, P=0.028). CONCLUSION: Changes in liver function tests were observed in obese patients with metabolic syndrome, compared to patients without metabolic syndrome, especially in ALT and GGT levels. Insulin resistance is an independent pathogenic mechanism in liver function test changes regardless of metabolic syndrome in nondiabetic centrally obese youth.

Characterisation of dietary fibre components in cereals and legumes used in Serbian diet.

The typical Serbian diet is characterised by high intake of cereal products and also legumes are often used. The content of total fibre as well as certain fibre fractions was determined in cereals, cereal products, and cooked legumes. The content of total fibre in cooked cereals and cereal products ranged from 2.5 to 20.8 g/100 g, and in cooked legumes from 14.0 to 24.5 g/100 g (on dry matter basis). Distribution of analysed fibre fractions and their quantities differed significantly depending on food groups. Fructans and arabinoxylans were the most significant fibre fractions in rye flakes, and ß-glucan in oat flakes, cellulose and resistant starch were present in significant amounts in peas and kidney beans. When the size of regular food portions was taken into consideration, the best sources of total dietary fibre were peas and kidney beans (more than 11 g/serving). The same foods were the best sources of cellulose (4.98 and 3.56 g/serving) and resistant starch (3.90 and 2.83 g/serving). High intake of arabinoxylans and fructans could be accomplished with cooked wheat (3.20 g and 1.60 g/serving, respectively). Oat (1.39 g/serving) and barley flakes (1.30 g/serving) can be recommended as the best sources of ß-glucan.

Episodes of extremely high concentrations of SO2 and particulate matter in the urban environment of Bor, Serbia.

This paper presents the extremely high concentrations of SO2 and particulate matter measured in the urban area of the town Bor (Serbia) during August 2011. Concentrations of SO2 above 125 µg m(-3) and concentrations of particulate matter above 200 µg m(-3) recorded over several days indicate significant risk to human health and the ecosystem in this region.

Influence of the purification of human adult pancreatic islets on insulin secretion.

BACKGROUND/AIM: The most effective method for human adult pancreatic islets purification is density-gradient centrifugation. The aim of this study was to analyze the effects of non-automated purification on preservation of functional capacity of human adult pancreatic islet cells. METHODS: Human pancreata were obtained after pancreatectomy in the patients with chronic pancreatitis or benign tumors. Pancreatic islets were purified by non-automated method in discontinuous Ficoll density gradient. The samples were divided in 2 fractions: purified (P) and non-purified (NP) cultures. Islets were stained with diphenyl-thiocarbazone. The efficiency of separation was determined by comparing percentage of stained cells in P and NP cultures on day 1, 3 and 7 of shortterm cultivation. Glucose-stimulated insulin secretion was expressed as stimulation index (SI). RESULTS: The results obtained showed a statistically significant difference (p < 0.01) between P and NP cultures. P cultures had higher percentages of stained cells (70.43 +/- 3.97%, 73.77 +/- 4.22% and 71.34 +/- 4.69% on the first, third and seventh day of cultivation, respectively) than NP cultures (53.68 +/- 1.71%, 57.14 +/- 3.94% and 43.97 +/- 4.56%, respectively). P cultures had higher values of SI for the first, third and seventh day of cultivation than NP cultures (0.45 +/- 0.08, 0.80 +/- 0.21, 1.28 +/- 0.15 and 0.46 +/- 0.10, 0.752 +/- .0.16, 0.76 +/- 0.11 for P and NP cultures respectively). The difference was statistically significant on day seven (p = 0.01). CONCLUSION: Although during purification process islets were exposed to a number of insults that might result in cellular damage and functional impairment, our assessments showed that islets in P cultures preserved their functional capacity better than islets in NP cultures, since they had greater insulin secretion.

Comparative analysis of collagenase XI and liberase H1 for the isolation of human pancreatic islets.

BACKGROUNDS/AIMS: The aim of this study was to compare efficacy of two enzymes, Liberase HI and Collagenase XI in human adult pancreatic islet isolation. METHODOLOGY: Pancreatic tissue samples were digested either with Liberase HI or Collagenase XI, using a non-automated method. We investigated the effect of both enzymes on yield, function and percent viability of the islets. RESULTS: No significant differences were found regarding islet yield when comparing Liberase HI to Collagenase XI. Viability of Collagenase-isolated islets was initially lower, but following 3 days of culture they attained a higher viability than the Liberase treated islets. Although the stimulation index tended to be higher in the Liberase-isolated islets no significant differences were observed between the two enzymes, except on the first day of cultivation; SI values for all Liberase concentrations were significantly higher than for Collagenase (p < 0.05). CONCLUSIONS: We conclude that during the isolation procedure using Collagenase XI, the functional capacity of the isolated islets decline, but this is restored during a subsequent cultivation. On the other hand, during digestion with Liberase HI, the islets suffer less functional damage, resulting in better preservation of their functional capacity immediately after the isolation, as well as the subsequent 7 days of cultivation.

Prothrombogenic factors and reduced antioxidative defense in children and adolescents with pre-metabolic and metabolic syndrome.

BACKGROUND: The aim of this study was to examine prothrombogenic factors and antioxidative defense in obese children and adolescents with pre-metabolic and metabolic syndrome, and to analyze insulin secretion and resistance, early glycoregulation disorders and lipid status. METHODS: Insulin sensitivity was determined using the homeostasis model assessment for insulin resistance (HOMA-IR), while insulin secretion was determined using the homeostasis model assessment beta (HOMA-beta). Prothrombogenic factors analyzed were plasma plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Superoxide dismutase and glutathione peroxidase were measured as markers of antioxidative defense. RESULTS: Patients with metabolic syndrome were characterized with increased body mass index (BMI), waist circumference, and HOMA-IR and HOMA-beta levels, and all had increased blood pressure and triglyceride levels, low high-density lipoprotein cholesterol levels, increased PAI-1 levels and reduced antioxidative defense levels. Patients with pre-metabolic syndrome had higher levels of basal and mean insulinemia during an oral glucose tolerance test, higher levels of HOMA-beta and lower levels of antioxidative defense compared to patients with metabolic syndrome. CONCLUSIONS: Negative correlations between antioxidative defense parameters and BMI, abdominal obesity, insulin secretion, systolic blood pressure and atherogenic lipid factors, as well as correlations between PAI-1 and insulin resistance and basal glycemia in the metabolic syndrome group contribute to accelerated atherosclerosis. Positive correlations between PAI-1 and waist circumference and BMI, and negative correlations between BMI and antioxidative defense in the pre-metabolic syndrome patients show that this early stage preceding the metabolic syndrome is also characterized by atherosclerotic complication risks and evident hyperinsulinism and insulin resistance.

Parameters of antioxidative defense in type 2 diabetic patients with cardiovascular complications.

OBJECTIVE: Diabetes-associated oxidative stress is a consequence of both increased production of free radicals and reduced capacity of antioxidative defense. Prolonged hyperglycemia is the major factor in the pathogenesis of atherosclerosis in diabetes which can lead to cardiovascular complications. The aim of this study was to test the parameters of antioxidative defense in type 2 diabetic patients. METHODS: A total of 117 type 2 diabetics with and without cardiovascular complications were examined in order to find out the influence of hyperglycemia, type and duration of complications and duration of diabetes on the extent of disorder of antioxidative parameter values: superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and total antioxidant status (TAS). RESULTS: Compared to healthy control subjects, type 2 diabetic patients with cardiovascular complications (CVC) had significantly lower SOD (P<0.0001), GSH-Px (P<0.0001), GR ( P = 0.0002) and TAS values (P<0.0001). In type 2 diabetic subjects with CVC, males had significantly lower SOD (778.7+/-103.2 U/gHb, P<0.01) and GR activities (52.2+/-8.9 U/L, P<0.001) compared to females (839.3+/-94.9 U/gHb; 58.5+/-9.1 U/L). Significant and positive correlation was found between glucose levels and SOD (r = 0.375 for P<0.05) and GSH-Px (r = 0.384, P<0.05 ) activity in the group of complications-free diabetics, while significant negative correlation between glucose and GSH-Px values (r = -0.382, P<0.05) was found in the group of type 2 diabetics with coronary artery disease (CAD) and hypertension (HTA) and with CAD and acute myocardial infarction (AMI) (r = -0.860 P<0.05), and highly negative correlation between glucose and SOD levels (r = -0.590, P<0.05) in the group of diabetic subjects with CAD, AMI and HTA. Likewise, there was highly significant negative correlation of SOD (r = -0.949, P<0.05) and TAS (r = -0.393 for P = 0.038) with duration of diabetes in the group of diabetics with CAD and HTA. CONCLUSION: Our results confirm the hypothesis that there is reduced antioxidative defense in type 2 diabetics with prominent cardiovascular complications, which negatively correlates with glucose concentrations and duration of diabetes and cardiovascular complications.

Dietary fat intake as risk factor for the development of diabetes: multinational, multicenter study of the Mediterranean Group for the Study of Diabetes (MGSD).

OBJECTIVE: To investigate the role of dietary factors in the development of type 2 diabetes. RESEARCH DESIGN AND METHODS: In the context of the Multinational MGSD Nutrition Study, three groups of subjects were studied: 204 subjects with recently diagnosed diabetes (RDM), 42 subjects with undiagnosed diabetes (UDM) (American Diabetes Association criteria-fasting plasma glucose [FPG] > or =126 mg/dl), and 55 subjects with impaired fasting glucose (IFG) (FPG > or =110 and <126 mg/dl). Each group was compared with a control group of nondiabetic subjects, matched one by one for center, sex, age, and BMI. Nutritional habits were evaluated by a dietary history method, validated against the 3-day diet diary. In RDM, the questionnaire referred to the nutritional habits before the diagnosis of diabetes. Demographic data were collected, and anthropometrical and biochemical measurements were taken. RESULTS: Compared with control subjects, RDM more frequently had a family history of diabetes (49.0 vs. 14.2%; P < 0.001), exercised less (exercise index 53.5 vs. 64.4; P < 0.01), and more frequently had sedentary professions (47.5 vs. 27.4%; P < 0.001). Carbohydrates contributed less to their energy intake (53.5 vs. 55.1%; P < 0.05), whereas total fat (30.2 +/- 0.5 vs. 27.8 +/- 0.5%; P < 0.001) and animal fat (12.2 +/- 0.3 vs. 10.8 +/- 0.3%; P < 0.01) contributed more and the plant-to-animal fat ratio was lower (1.5 +/- 0.1 vs. 1.8 +/- 0.1; P < 0.01). UDM more frequently had a family history of diabetes (38.1 vs. 19.0%; P < 0.05) and sedentary professions (58.5 vs. 34.1%; P < 0.05), carbohydrates contributed less to their energy intake (47.6 +/- 1.7 vs. 52.8 +/- 1.4%; P < 0.05), total fat (34.7 +/- 1.5 vs. 30.4 +/- 1.2%; P < 0.05) and animal fat (14.2 +/- 0.9 vs. 10.6 +/- 0.7%; P < 0.05) contributed more, and the plant-to-animal fat ratio was lower (1.6 +/- 0.2 vs. 2.3 +/- 0.4; P < 0.05). IFG differed only in the prevalence of family history of diabetes (32.7 vs. 16.4%; P < 0.05). CONCLUSIONS: Our data support the view that increased animal fat intake is associated with the presence of diabetes.