Effects of intermittent fasting on periodontal inflammation and subgingival microbiota.

BACKGROUND: Studies on the impact of intermittent fasting on periodontal health are still scarce. Thus, this study evaluated the effects of long-term intermittent fasting on periodontal health and the subgingival microbiota. METHODS: This pilot study was part of a nonrandomized controlled trial. Overweight/obese participants (n = 14) entered an intermittent fasting program, specifically the 5:2 diet, in which they restricted caloric intake to about a quarter of the normal total daily caloric expenditure for two nonconsecutive days/week. Subjects underwent a thorough clinical and laboratory examination, including an assessment of their periodontal condition, at baseline and 6 months after starting the diet. Additionally, subgingival microbiota was assessed by 16S rRNA gene sequencing. RESULTS: After 6 months of intermittent fasting, weight, body mass index, C-reactive protein, hemoglobin A1c (HbA1c), and the cholesterol profile improved significantly (p < 0.05). Moreover, significant reductions were observed in bleeding on probing (p = 0.01) and the presence of shallow periodontal pockets after fasting (p < 0.001), while no significant change was seen in plaque index (p = 0.14). While we did not observe significant changes in α- or ß-diversity of the subgingival microbiota related to dietary intervention (p > 0.05), significant differences were seen in the abundances of several taxa among individuals exhibiting ≥60% reduction (good responders) in probing pocket depth of 4-5 mm compared to those with <60% reduction (bad responders). CONCLUSION: Intermittent fasting decreased systemic and periodontal inflammation. Although the subgingival microbiota was unaltered by this intervention, apparent taxonomic variability was observed between good and bad responders.

[Diabetes and periodontitis - common, important but often neglected]. / Diabetes och parodontit ­ viktig aspekt av diabetesvården.

Diabetes and periodontitis are two global epidemics. There is a two-way relationship between diabetes and periodontitis. Diabetes increases the risk of periodontitis and periodontitis increases the risk for deteriorating glucose levels, having undetected diabetes, and for future diabetes. A recent Cochrane report summarized that there is moderate-certainty evidence that periodontal treatment improves glycaemic control in people with both periodontitis and diabetes. The recent PAROKRANK study found that undetected dysglycaemia was independently associated to both myocardial infarction and to periodontitis. To increase awareness of oral health in people with diabetes this article summarizes recent evidence.

A follow-up cohort study on the risk of prediabetes, comparing women with previous preeclamptic or normotensive pregnancies.

Studies have shown that preeclampsia is associated insulin resistance and cardiovascular events later in life. However, knowledge is lacking regarding a possible association between PE and abnormal glucose tolerance/prediabetes. Thus, the current study aimed to compare the prevalence of prediabetes in women with previous severe preeclampsia to women with previous normotensive pregnancies. Women with severe preeclampsia (index women, n = 45) admitted to Danderyds University Hospital in 1999-2004 were compared to women with normotensive pregnancies, matched for age, parity, and year of delivery (control women, n = 53). In 2013-2016 BMI, blood pressure, waist circumference, insulin, C-peptide, hsCRP, Cystatin C, HDL, triglycerides, and HbA1c were measured and an OGTT was performed. Index women had a higher BMI (p < 0.001) and blood pressure (p < 0.001) in early pregnancy. At follow-up, prediabetes was more common among index women (p = 0.001), as were hypertension (p = 0.003), heredity for diabetes/cardiovascular disease (p = 0.020), and a larger waist circumference (p = 0.024). Preeclampsia increased the risk of having a fasting plasma glucose ≥ 5.6 mmol/l (aOR 7.28, 95% CI 2.44-21.76) and of prediabetes 11-16 years after index pregnancy (aOR 4.83, 95% CI 1.80-12.97). In conclusion, preeclampsia increases the risk of prediabetes independent of heredity, hypertension, and waist circumference. These findings may have implications for screening and prevention.

Effect of Isocaloric Meals on Postprandial Glycemic and Metabolic Markers in Type 1 Diabetes-A Randomized Crossover Trial.

The aim of this study was to assess the effect of four isocaloric meals with different macronutrient compositions on postprandial blood glucose, lipids, and glucagon in adults with type 1 diabetes (T1D). Seventeen subjects tested four isocaloric meals in a randomized crossover design. The meal compositions were as follows: high-carbohydrate (HC); high-carbohydrate with extra fiber (HC-fiber); low-carbohydrate high-protein (HP); and low-carbohydrate high-fat (HF). Blood glucose and lipid measurements were collected up to 4 h and glucagon up to 3 h postprandially. Mean postprandial glucose excursions were lower after the HP compared to the HC (p = 0.036) and HC-fiber meals (p = 0.002). There were no differences in mean glucose excursions after the HF meal compared to the HC and HP meals. The HF meal resulted in higher triglyceride excursions compared to the HP meal (p < 0.001) but not compared to the HC or HC-fiber meals. Glucagon excursions were higher at 180 min after the HP meal compared to the HC and HF meals. In conclusion, the low-carbohydrate HP meal showed the most favorable glycemic and metabolic effects during a 4 h postprandial period in subjects with T1D.

Mitochondrial impairment and intracellular reactive oxygen species alter primary cilia morphology.

Primary cilia have recently emerged as cellular signaling organelles. Their homeostasis and function require a high amount of energy. However, how energy depletion and mitochondria impairment affect cilia have barely been addressed. We first studied the spatial relationship between a mitochondria subset in proximity to the cilium in vitro, finding similar mitochondrial activity measured as mitochondrial membrane potential compared with the cellular network. Next, using common primary cilia cell models and inhibitors of mitochondrial energy production, we found alterations in cilia number and/or length due to energy depletion and mitochondrial reactive oxygen species (ROS) overproduction. Finally, by using a mouse model of type 2 diabetes mellitus, we provided in vivo evidence that cilia morphology is impaired in diabetic nephropathy, which is characterized by ROS overproduction and impaired mitochondrial metabolism. In conclusion, we showed that energy imbalance and mitochondrial ROS affect cilia morphology and number, indicating that conditions characterized by mitochondria and radicals imbalances might lead to ciliary impairment.

Diabetes downregulates the antimicrobial peptide psoriasin and increases E. coli burden in the urinary bladder.

Diabetes is known to increase susceptibility to infections, partly due to impaired granulocyte function and changes in the innate immunity. Here, we investigate the effect of diabetes, and high glucose on the expression of the antimicrobial peptide, psoriasin and the putative consequences for E. coli urinary tract infection. Blood, urine, and urine exfoliated cells from patients are studied. The influence of glucose and insulin is examined during hyperglycemic clamps in individuals with prediabetes and in euglycemic hyperinsulinemic clamped patients with type 1 diabetes. Important findings are confirmed in vivo in type 2 diabetic mice and verified in human uroepithelial cell lines. High glucose concentrations induce lower psoriasin levels and impair epithelial barrier function together with altering cell membrane proteins and cytoskeletal elements, resulting in increasing bacterial burden. Estradiol treatment restores the cellular function with increasing psoriasin and bacterial killing in uroepithelial cells, confirming its importance during urinary tract infection in hyperglycemia. In conclusion, our findings present the effects and underlying mechanisms of high glucose compromising innate immunity.

Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes.

Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.

Adiponectin, IGFBP-1 and -2 are independent predictors in forecasting prediabetes and type 2 diabetes.

Objective: Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT). Design: Subjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men). Methods: The evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test. Results: After adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone. Conclusion: Differences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.

HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients.

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1ß, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. KEY MESSAGES: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1ß and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.

Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study.

Type 1 diabetes is a chronic autoimmune disease requiring insulin treatment for survival. Prolonged duration of type 1 diabetes is associated with increased risk of microvascular complications. Although chronic hyperglycemia and diabetes duration have been considered as the major risk factors for vascular complications, this is not universally seen among all patients. Persons with long-term type 1 diabetes who have remained largely free from vascular complications constitute an ideal group for investigation of natural defense mechanisms against prolonged exposure of diabetes. Transcriptomic signatures obtained from RNA sequencing of the peripheral blood cells were analyzed in non-progressors with more than 30 years of diabetes duration and compared to the patients who progressed to microvascular complications within a shorter duration of diabetes. Analyses revealed that non-progressors demonstrated a reduction in expression of the oxidative phosphorylation (OXPHOS) genes, which were positively correlated with the expression of DNA repair enzymes, namely genes involved in base excision repair (BER) machinery. Reduced expression of OXPHOS and BER genes was linked to decrease in expression of inflammation-related genes, higher glucose disposal rate and reduced measures of hepatic fatty liver. Results from the present study indicate that at transcriptomic level reduction in OXPHOS, DNA repair and inflammation-related genes is linked to better insulin sensitivity and protection against microvascular complications in persons with long-term type 1 diabetes.

IGF-I and IGFBP-1 in Relation to Body Composition and Physical Performance in Female Olympic Athletes.

Introduction: Insulin- like growth factor-I (IGF-I) is an anabolic hormone that may affect athletic performance in female athletes, and insulin-like growth factor binding protein-1 (IGFBP-1) is an important regulator of bioactive IGF-I. There is limited knowledge of the role of endogenous IGF-I and IGFBP-1 for body composition and physical performance in female elite athletes. Purpose: To examine IGF-I, age adjusted IGF-I (IGFSD), IGFBP-1 and insulin in female Olympic athletes compared with controls and different sport categories, and in relation to body composition and physical performance in the athletes. Methods: Female athletes (n=103) and untrained controls (n=113) were included in this cross-sectional study. Body composition was established by dual-energy X-ray absorptiometry. Serum IGF-I and IGFBP-1 were analyzed by radioimmunoassay and IGFSD was calculated. Insulin was analyzed by electrochemiluminescence immunoassay. Athletes were offered to participate in standardized physical fitness tests. Results: The athletes demonstrated significantly higher IGF-I, IGFSD and IGFBP-1 and lower insulin levels than controls (p<0.05, p<0.05, p<0.01, p<0.001 respectively). Power athletes had significantly higher IGFSD compared to both endurance and technical athletes (p<0.05, p<0.01, respectively). In athletes and controls combined, significant positive correlations were found between IGF variables and higher bone mineral density (BMD) and lean mass and lower fat percent. IGF-I was positively correlated with squat jump (rs = 0.28, p<0.05) and IGFBP-1 correlated positively with squats (rs =0.35, p<0.05). Conclusion: We found higher IGF-I, IGFSD and IGFBP-1 in female athletes than controls, and the highest IGFSD in power athletes. IGF-I and IGFBP-1 were related to increased BMD and lean mass and lower fat percent, as well as were positively associated with physical fitness tests. Future studies are needed to elucidate if these results reflect adaptive responses to physical activity or genetic predisposition.

Effects of a three-armed randomised controlled trial using self-monitoring of daily steps with and without counselling in prediabetes and type 2 diabetes-the Sophia Step Study.

BACKGROUND: This aimed to evaluate the effects of self-monitoring of daily steps with or without counselling support on HbA1c, other cardiometabolic risk factors and objectively measured physical activity (PA) during a 2-year intervention in a population with prediabetes or type 2 diabetes. METHODS: The Sophia Step Study was a three-armed parallel randomised controlled trial. Participants with prediabetes or type 2 diabetes were recruited in a primary care setting. Allocation (1:1:1) was made to a multi-component intervention (self-monitoring of steps with counselling support), a single-component intervention (self-monitoring of steps without counselling support) or standard care. Data were collected for primary outcome HbA1c at baseline and month 6, 12, 18 and 24. Physical activity was assessed as an intermediate outcome by accelerometer (ActiGraph GT1M) for 1 week at baseline and the 6-, 12-, 18- and 24-month follow-up visits. The intervention effects were evaluated by a robust linear mixed model. RESULTS: In total, 188 subjects (64, 59, 65 in each group) were included. The mean (SD) age was 64 (7.7) years, BMI was 30.0 (4.4) kg/m2 and HbA1c was 50 (11) mmol/mol, 21% had prediabetes and 40% were female. The dropout rate was 11% at 24 months. Effect size (CI) for the primary outcome (HbA1c) ranged from -1.3 (-4.8 to 2.2) to 1.1 (-2.4 to 4.6) mmol/mol for the multi-component vs control group and from 0.3 (-3.3 to 3.9) to 3.1 (-0.5 to 6.7) mmol/mol for the single-component vs control group. Effect size (CI) for moderate-to-vigorous physical activity ranged from 8.0 (0.4 to 15.7) to 11.1 (3.3 to 19.0) min/day for the multi-component vs control group and from 7.6 (-0.4 to 15.6) to 9.4 (1.4 to 17.4) min/day for the single-component group vs control group. CONCLUSION: This 2-year intervention, including self-monitoring of steps with or without counselling, prevented a decrease in PA but did not provide evidence for improved metabolic control and cardiometabolic risk factors in a population with prediabetes or type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02374788 . Registered 2 March 2015-Retrospectively registered.

Dehydro-Tocotrienol-ß Counteracts Oxidative-Stress-Induced Diabetes Complications in db/db Mice.

Hyperglycemia, hyperlipidemia, and adiposity are the main factors that cause inflammation in type 2 diabetes due to excessive ROS production, leading to late complications. To counteract the effects of increased free radical production, we searched for a compound with effective antioxidant properties that can induce coenzyme Q biosynthesis without affecting normal cellular functions. Tocotrienols are members of the vitamin E family, well-known as efficient antioxidants that are more effective than tocopherols. Deh-T3ß is a modified form of the naturally occurring tocotrienol-ß. The synthesis of this compound involves the sequential modification of geranylgeraniol. In this study, we investigated the effects of this compound in different experimental models of diabetes complications. Deh-T3ß was found to possess multifaceted capacities. In addition to enhanced wound healing, deh-T3ß improved kidney and liver functions, reduced liver steatosis, and improved heart recovery after ischemia and insulin sensitivity in adipose tissue in a mice model of type 2 diabetes. Deh-T3ß exerts these positive effects in several organs of the diabetic mice without reducing the non-fasting blood glucose levels, suggesting that both its antioxidant properties and improvement in mitochondrial function are involved, which are central to reducing diabetes complications.

L-Carnosine Stimulation of Coenzyme Q10 Biosynthesis Promotes Improved Mitochondrial Function and Decreases Hepatic Steatosis in Diabetic Conditions.

Mitochondrial dysfunction in type 2 diabetes leads to oxidative stress, which drives disease progression and diabetes complications. L-carnosine, an endogenous dipeptide, improves metabolic control, wound healing and kidney function in animal models of type 2 diabetes. Coenzyme Q (CoQ), a component of the mitochondrial electron transport chain, possesses similar protective effects on diabetes complications. We aimed to study the effect of carnosine on CoQ, and assess any synergistic effects of carnosine and CoQ on improved mitochondrial function in a mouse model of type 2 diabetes. Carnosine enhanced CoQ gene expression and increased hepatic CoQ biosynthesis in db/db mice, a type 2 diabetes model. Co-administration of Carnosine and CoQ improved mitochondrial function, lowered ROS formation and reduced signs of oxidative stress. Our work suggests that carnosine exerts beneficial effects on hepatic CoQ synthesis and when combined with CoQ, improves mitochondrial function and cellular redox balance in the liver of diabetic mice. (4) Conclusions: L-carnosine has beneficial effects on oxidative stress both alone and in combination with CoQ on hepatic mitochondrial function in an obese type 2 diabetes mouse model.

Process evaluation of the Sophia Step Study- a primary care based three-armed randomized controlled trial using self-monitoring of steps with and without counseling in prediabetes and type 2 diabetes.

BACKGROUND: Describing implementation features of an intervention is required to compare interventions and to inform policy and best practice. The aim of this study was to conduct a process evaluation of the first 12 months of the Sophia Step Study: a primary care based RCT evaluating a multicomponent (self-monitoring of daily steps plus counseling) and a single component (self-monitoring of steps only) physical activity intervention to standard care on cardiometabolic health. METHODS: The evaluation was guided by the Medical Research Council Guidance for complex interventions. To describe the implementation communication with the health professionals implementing the interventions, attendance records and tracking of days with self-monitored pedometer-determined steps were used. Change in physical activity behaviour was measured at baseline, 6 and 12 months as daily steps by accelerometry. RESULTS: During April 2013 to January 2018 188 participants were randomized and intervened directly after inclusion. Response rate was 49% and drop out was 10%. A majority, 78%, had type 2 diabetes and 22% were diagnosed with prediabetes. Mean [Standard deviation (SD)] body mass index was 30.4 (4.4) kg/m2 and steps per day was 6566 (3086). The interventions were delivered as intended with minor deviation from the protocol and dose received was satisfying for both the multicomponent and single component group. The mean [95% Confidence Interval (CI)] change in daily steps from baseline to 6 months was 941(227, 1655) steps/day for the multicomponent intervention group, 990 (145, 1836) step/day for the single component group and - 506 (- 1118, 107) for the control group. The mean (95% CI) change in daily steps from baseline to 12 months was 31(- 507, 570) steps/day for the multicomponent intervention group, 144 (- 566, 853) step/day for the single component group and - 890 (- 1485, - 294) for the control group. There was a large individual variation in daily steps at baseline as well as in step change in all three groups. CONCLUSIONS: Applying self-monitoring of steps is a feasible method to implement as support for physical activity in the primary care setting both with and without counseling support. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02374788 . Registered 2 March 2015.

Type 2 diabetes risk in sarcoidosis patients untreated and treated with corticosteroids.

BACKGROUND: The rate of type 2 diabetes mellitus (T2D) is increased in sarcoidosis patients but it is unknown if corticosteroid treatment plays a role. We investigated whether the T2D risk is higher in untreated and corticosteroid-treated sarcoidosis patients compared with the general population. METHODS: In this cohort study, individuals with two or more International Statistical Classification of Diseases and Related Health Problems (ICD) codes for sarcoidosis were identified from the Swedish National Patient Register (NPR) (n=5754). Corticosteroid dispensations within 3 months before or after the first sarcoidosis diagnosis were identified from the Swedish Prescribed Drug Register (PDR). General population comparators without sarcoidosis were matched to cases 10:1 on age, sex and region of residence (n=61 297). Incident T2D was identified using ICD codes (NPR) and antidiabetic drug dispensations (PDR). Follow-up was from the second sarcoidosis diagnosis/matching date until T2D, emigration, death or study end (December 2013). Cox regression models adjusted for age, sex, education, country of birth, healthcare regions and family history of diabetes were used to estimate hazard ratios (HRs). We used flexible parametric models to examine the T2D risk over time. RESULTS: 40% of sarcoidosis patients were treated with corticosteroid at diagnosis. The T2D rate was 7.7 per 1000 person-years in untreated sarcoidosis, 12.7 per 1000 person-years in corticosteroid-treated sarcoidosis and 5.5 per 1000 person-years in comparators. The HR for T2D was 1.4 (95% CI 1.2-1.8) associated with untreated sarcoidosis and 2.3 (95% CI 2.0-3.0) associated with corticosteroid-treated sarcoidosis. The T2D risk was highest for corticosteroid-treated sarcoidosis in the first 2 years after diagnosis. CONCLUSIONS: Sarcoidosis is associated with an increased risk of T2D especially in older, male, corticosteroid-treated patients at diagnosis. Screening for T2D for these patients is advisable.

Selenium and Coenzyme Q10 Supplementation Improves Renal Function in Elderly Deficient in Selenium: Observational Results and Results from a Subgroup Analysis of a Prospective Randomised Double-Blind Placebo-Controlled Trial.

A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q10, and the impact of intervention with selenium and coenzyme Q10 on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 117) or placebo (n = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 µg/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo (p = 0.0002 and p = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference (p < 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q10, low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation.

Increased Plasma Soluble Interleukin-2 Receptor Alpha Levels in Patients With Long-Term Type 1 Diabetes With Vascular Complications Associated With IL2RA and PTPN2 Gene Polymorphisms.

Type 1 diabetes (T1D) is largely considered an autoimmune disease leading to the destruction of insulin-producing pancreatic ß cells. Further, patients with T1D have 3-4-fold increased risk of developing micro- and macrovascular complications. However, the contribution of immune-related factors contributing to these diabetes complications are poorly understood. Individuals with long-term T1D who do not progress to vascular complications offer a great potential to evaluate end-organ protection. The aim of the present study was to investigate the association of inflammatory protein levels with vascular complications (retinopathy, nephropathy, cardiovascular disease) in individuals with long-term T1D compared to individuals who rapidly progressed to complications. We studied a panel of inflammatory markers in plasma of patients with long-term T1D with (n = 81 and 26) and without (n = 313 and 25) vascular complications from two cross-sectional Scandinavian cohorts (PROLONG and DIALONG) using Luminex technology. A subset of PROLONG individuals (n = 61) was screened for circulating immune cells using multicolor flow cytometry. We found that elevated plasma levels of soluble interleukin-2 receptor alpha (sIL-2R) were positively associated with the complication phenotype. Risk carriers of polymorphisms in the IL2RA and PTPN2 gene region had elevated plasma levels of sIL-2R. In addition, cell surface marker analysis revealed a shift from naïve to effector T cells in T1D individuals with vascular complications as compared to those without. In contrast, no difference between the groups was observed either in IL-2R cell surface expression or in regulatory T cell population size. In conclusion, our data indicates that IL2RA and PTPN2 gene variants might increase the risk of developing vascular complications in people with T1D, by affecting sIL-2R plasma levels and potentially lowering T cell responsiveness. Thus, elevated sIL-2R plasma levels may serve as a biomarker in monitoring the risk for developing diabetic complications and thereby improve patient care.

Predictors of normalized HbA1c after gastric bypass surgery in subjects with abnormal glucose levels, a 2-year follow-up study.

Clinical biomarkers can predict normalization of HbA1c after Roux-en-Y gastric bypass (RYGB) surgery, but it is unclear which are the most predictive.The aim of this study was to compare biomarkers for insulin sensitivity and other clinical parameters in the prediction of normalization of HbA1c after RYGB surgery. This study included 99 (23 men) obese subjects (BMI > 35 kg/m2) undergoing a laparoscopic RYGB. Clinical and biochemical examinations were performed pre-operatively and up to 2 years after surgery. Pre-operatively, normal fasting glucose levels were found in 25 individuals (NG), prediabetes in 46 and type 2 diabetes (T2DM) in 28. At baseline IGF-I (SD), IGFBP-1 and adiponectin levels were low while leptin was high. Weight loss was observed in all three groups, most in the prediabetes group. After 2 years HbA1c was decreased in prediabetes and T2DM. In all three groups insulin, HOMA-IR, lipids and blood pressure improved, IGFBP-1 and adiponectin increased and leptin decreased. IGF-I (SD) increased only in T2DM. In those with prediabetes or T2DM (n = 74), HbA1c at 2 years correlated to baseline BMI (r = -0.27, p = 0.028), age (r = 0.43, p < 0.001), HbA1c (r = 0.37, p = 0.001) and IGFBP-1 (r = 0.25, p = 0.038), and was normalized in 45/74 (61%) at 1 year and in 36 subjects (49%) at 2 years. These responders were younger, had higher BMI, larger waist circumference, lower HbA1c and lower IGFBP-1 levels at baseline. In a multiple regression model age (negative, p = 0.021) and waist circumference (positive, p = 0.047) were the only predictors for normalized HbA1c. RYGB normalized HbA1c in 49% at two years follow-up, which was predicted by low baseline IGFBP-1 level, a marker of hepatic insulin sensitivty and insulin secretion. However,. younger age and larger waist circumference were the only predictors of normalized HbA1c in multivariate analysis.

Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the ICAM1 gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of ICAM1 E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the ICAM1 E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.