Diagnostic challenges of diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the most common microvascular complications of both type 1 and type 2 diabetes and the most common cause of the end-stage renal disease (ESRD). It has been evidenced that targeted interventions at an early stage of DKD can efficiently prevent or delay the progression of kidney failure and improve patient outcomes. Therefore, regular screening for DKD has become one of the fundamental principles of diabetes care. Long-established biomarkers such as serum-creatinine-based estimates of glomerular filtration rate and albuminuria are currently the cornerstone of diagnosis and risk stratification in routine clinical practice. However, their immanent biological limitations and analytical variations may influence the clinical interpretation of the results. Recently proposed new predictive equations without the variable of race, together with the evidence on better accuracy of combined serum creatinine and cystatin C equations, and both race- and sex-free cystatin C-based equation, have enabled an improvement in the detection of DKD, but also require the harmonization of the recommended laboratory tests, wider availability of cystatin C testing and specific approach in various populations. Considering the complex pathophysiology of DKD, particularly in type 2 diabetes, a panel of biomarkers is needed to classify patients in terms of the rate of disease progression and/or response to specific interventions. With a personalized approach to diagnosis and treatment, in the future, it will be possible to respond to DKD better and enable improved outcomes for numerous patients worldwide.

Human complement component C3 N-glycome changes in type 1 diabetes complications.

Aim: Changes in N-glycosylation have been described in numerous diseases and are being considered as biomarkers of ongoing pathological condition. Previous studies demonstrated the interrelation of N-glycosylation and type 1 diabetes (T1D), particularly linking serum N-glycan changes with complications accompanying the disease. Moreover, the role of complement component C3 in diabetic nephropathy and retinopathy has been implicated, and C3 N-glycome was found to be altered in young T1D patients. Therefore, we investigated associations between C3 N-glycan profiles and albuminuria and retinopathy accompanying T1D, as well as glycosylation connection with other known T1D complication risk factors. Research design and methods: Complement component C3 N-glycosylation profiles have been analyzed from 189 serum samples of T1D patients (median age 46) recruited at a Croatian hospital centre. Using our recently developed high-throughput method, relative abundances of all six of the C3 glycopeptides have been determined. Assessment of C3 N-glycome interconnection with T1D complications, hypertension, smoking status, estimated glomerular filtration rate (eGFR), glycaemic control and duration of the disease was done using linear modelling. Results: Significant changes of C3 N-glycome in severe albuminuria accompanying type 1 diabetes were observed, as well as in T1D subjects with hypertension. All except one of the C3 glycopeptides proved to be associated with measured HbA1c levels. One of the glycoforms was shown to be changed in non-proliferative T1D retinopathy. Smoking and eGFR showed no effect on C3 N-glycome. Furthermore, C3 N-glycosylation profile was shown to be independent of disease duration. Conclusion: This study empowered the role of C3 N-glycosylation in T1D, showing value in distinguishing subjects with different diabetic complications. Being independent of the disease duration, these changes may be associated with the disease onset, making C3 N-glycome a potential novel marker of the disease progression and severity.

Associations between plasma protein, IgG and IgA N-glycosylation and metabolic health markers in pregnancy and gestational diabetes.

BACKGROUND: Monitoring human circulating N-glycome could provide valuable insight into an individual's metabolic status. Therefore, we examined if aberrant carbohydrate metabolism in gestational diabetes mellitus (GDM) associates with alterations in plasma protein, immunoglobulin G (IgG) and immunoglobulin A (IgA) N-glycosylation. METHODS: Plasma protein, IgG and IgA N-glycans were enzymatically released, purified and chromatographically profiled in 48 pregnant women with normal glucose tolerance and 41 pregnant women with GDM, all sampled at 24-28 weeks of gestation. Linear mixed models adjusting for age and multiple testing (FDR<0.05) were used to investigate the associations between glycosylation features, metabolic markers and GDM status. RESULTS: Fasting insulin exhibited significant associations to numerous glycan traits, including plasma protein galactosylation, sialylation, branching, core fucosylation and bisection, to IgG core fucosylated, bisected (FA2B) and afucosylated disialylated (A2G2S2) glycan and to IgA trisialylated triantennary (A3G3S3) glycan (padj range: 4.37x10-05-4.94x10-02). Insulin resistance markers HOMA2-IR and HOMA2-%B were mostly associated to the same glycan structures as fasting insulin. Both markers showed positive association with high-branched plasma glycans (padj = 1.12x10-02 and 2.03x10-03) and negative association with low-branched plasma glycans (padj = 1.21x10-02 and 2.05x10-03). Additionally, HOMA2-%B index was significantly correlated with glycosylation features describing IgG sialylation. Multiple plasma protein IgG and IgA glycans showed significant associations with total cholesterol and triglyceride levels. None of the tested glycan traits showed a significant difference between GDM and normoglycemic pregnancies. CONCLUSION: Markers of glucose homeostasis and lipid metabolism in pregnancy show extensive associations to various N-glycosylation features. However, plasma protein, IgG and IgA N-glycans were not able to differentiate pregnant women with and without GDM, possibly due to numerous physiological changes accompanying pregnancy, which confound the impact of GDM on protein glycosylation.

Effect of coadministration of enriched Korean Red Ginseng (Panax ginseng) and American ginseng (Panax quinquefolius L) on cardiometabolic outcomes in type-2 diabetes: A randomized controlled trial.

BACKGROUND: Diabetes mellitus and hypertension often occur together, amplifying cardiovascular disease (CVD) risk and emphasizing the need for a multitargeted treatment approach. American ginseng (AG) and Korean Red Ginseng (KRG) species could improve glycemic control via complementary mechanisms. Additionally, a KRG-inherent component, ginsenoside Rg3, may moderate blood pressure (BP). Our objective was to investigate the therapeutic potential of coadministration of Rg3-enriched Korean Red Ginseng (Rg3-KRG) and AG, added to standard of care therapy, in the management of hypertension and cardiometabolic risk factors in type-2 diabetes. METHODS: Within a randomized controlled, parallel design of 80 participants with type-2 diabetes (HbA1c: 6.5-8%) and hypertension (systolic BP: 140-160 mmHg or treated), supplementation with either 2.25 g/day of combined Rg3-KRG + AG or wheat-bran control was assessed over a 12-wk intervention period. The primary endpoint was ambulatory 24-h systolic BP. Additional endpoints included further hemodynamic assessment, glycemic control, plasma lipids and safety monitoring. RESULTS: Combined ginseng intervention generated a mean ± SE decrease in primary endpoint of 24-h systolic BP (-3.98 ± 2.0 mmHg, p = 0.04). Additionally, there was a greater reduction in HbA1c (-0.35 ± 0.1% [-3.8 ± 1.1 mmol/mol], p = 0.02), and change in blood lipids: total cholesterol (-0.50 ± 0.2 mmol/l, p = 0.01), non-HDL-C (-0.54 ± 0.2 mmol/l, p = 0.01), triglycerides (-0.40 ± 0.2 mmol/l, p = 0.02) and LDL-C (-0.35 ± 0.2 mmol/l, p = 0.06) at 12 wks, relative to control. No adverse safety outcomes were observed. CONCLUSION: Coadministration of Rg3-KRG + AG is an effective addon for improving BP along with attaining favorable cardiometabolic outcomes in individuals with type 2 diabetes. Ginseng derivatives may offer clinical utility when included in the polypharmacy and lifestyle treatment of diabetes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier, NCT01578837.

New Drugs on the Block-Emerging Treatments for Nonalcoholic Steatohepatitis.

Patients with nonalcoholic steatohepatitis (NASH) are at higher risk of progression to advanced stages of fibrosis, cirrhosis, hepatocellular carcinoma and other end-stage liver disease complications. When addressing treatment of NASH, we have limited approved options, and the mainstay of therapy is lifestyle intervention. Extensive research and revelation in the field of pathogenesis of NASH has offered new possibilities of treatment and emerging new drugs that are being tested currently in numerous preclinical and clinical trials. These drugs target almost all steps in the pathogenesis of NASH to improve insulin sensitivity, glucose and lipid metabolism, to inhibit de novo lipogenesis and delivery of lipids to the liver, and to influence apoptosis, inflammation and fibrogenesis. Although NASH is a multifactorial disease, in the future we could identify the predominating pathological mechanism and, by choosing the most appropriate specific medication, tailor the treatment for every patient individually.

Co-administration of viscous fiber, Salba-chia and ginseng on glycemic management in type 2 diabetes: a double-blind randomized controlled trial.

PURPOSE: Viscous dietary fiber, functional seeds and ginseng roots have individually been proposed for the management of diabetes. We explored whether their co-administration would improve glycemic control in type 2 diabetes beyond conventional therapy. METHODS: In a randomized, double-blind, controlled trial conducted at two academic centers (Toronto, Canada and Zagreb, Croatia), individuals with type 2 diabetes were assigned to either an active intervention (10 g viscous fiber, 60 g white chia seeds, 1.5 g American and 0.75 g Korean red ginseng extracts), or energy and fiber-matched control (53 g oat bran, 25 g inulin, 25 g maltodextrose and 2.25 g wheat bran) intervention for 24 weeks, while on conventional standard of care. The prespecified primary endpoint was end difference at week 24 in HbA1c, following an intent-to-treat analysis adjusted for center and baseline. RESULTS: Between January 2016 and April 2018, 104 participants (60M:44F; mean ± SEM age 59 ± 0.8 years; BMI 29.0 ± 0.4 kg/m2; HbA1c 7.0 ± 0.6%) managed with antihyperglycemic agent(s) (n = 98) or lifestyle (n = 6), were randomized (n = 52 test; n = 52 control). At week 24, HbA1c levels were 0.27 ± 0.1% lower on test compared to control (p = 0.03). There was a tendency towards an interaction by baseline HbA1c (p = 0.07), in which a greater reduction was seen in participants with baseline HbA1c > 7% vs ≤ 7% (- 0.56 ± 0.2% vs 0.03 ± 0.2%). Diet and body weight remained unchanged. The interventions were well tolerated with no related adverse events and with high retention rate of 84%. CONCLUSIONS: Co-administration of selected dietary and herbal therapies was well-tolerated and may provide greater glycemic control as add-on therapy in type 2 diabetes. Registration: Clinicaltrials.gov NCT02553382 (registered on September 17, 2015).

Effect of viscous fiber supplementation on obesity indicators in individuals consuming calorie-restricted diets: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Dietary fiber has played a consistent role in weight management, with efficacy potentially attributed to increased viscous fiber consumption. PURPOSE: To summarize the effects of viscous fiber on body weight and other anthropometric parameters, along with a calorie-deficient diet, through a systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, and the Cochrane library were searched through July 24, 2019 for randomized controlled trials that assessed the effect of viscous fiber supplementation as part of a restricted calorie diet for ≥ 4 weeks relative to comparator diets. Data were pooled using the generic inverse-variance method with random-effects models and expressed as mean differences with 95% confidence intervals. Inter-study heterogeneity was assessed using Cochran's Q and quantified with I2. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the overall certainty of evidence. RESULTS: Findings from 15 studies (n = 1347) showed viscous fiber supplementation significantly decreased body weight (- 0.81 kg [- 1.20, - 0.41]; p < 0.0001), BMI (- 0.25 kg/m2 [- 0.46, - 0.05]; p = 0.01), and body fat (- 1.39% [- 2.61, - 0.17]; p = 0.03), compared to control. No effect on waist circumference was found. The certainty of evidence was graded as "moderate" for body weight, BMI, and body fat based on downgrades for imprecision. Waist circumference was graded "low" for downgrades of inconsistency and imprecision. CONCLUSION: Viscous fiber within a calorie-restricted diet significantly improved body weight and other markers of adiposity in overweight adults and those with additional risk factors for cardiovascular disease. This trial is registered at www.clinicaltrials.gov as NCT03257449. REGISTRATION: ClinicalTrials.gov identifier: NCT03257449.

Association between arsenic exposure and biomarkers of type 2 diabetes mellitus in a Croatian population: A comparative observational pilot study.

Chronic exposure to high inorganic As levels in drinking water has been related to many diseases, including type 2 diabetes mellitus (T2D). The association with low and moderate As levels, however, remains controversial and has yet not been studied in European populations. This study aimed to investigate possible association between As exposure and biomarkers of T2D in Croatian population. Observation recruited 86 adults from Eastern Croatia, where groundwater is contaminated with inorganic As, and 116 adults from Western Croatia, where As levels in drinking water are low. Both populations were divided in patient groups (T2D or prediabetes) and healthy controls. Exposure was assessed by determining total As in blood and urine and As metabolites in urine. Eastern Croatian population had a significantly higher content of As in urine than Western, whereas the opposite was true for arsenobetain. Total As and As metabolites in urine positively correlated with hemoglobin A1c (HbA1c) and negatively with albuminuria. This study provides important preliminary data on the levels of As in urine and blood and their association with biomarkers of T2D in Croatian population exposed to low or moderate levels of As through drinking water as a solid basis for further research of the pathophysiological effects of such As exposure on the status and complications of diabetes.

Effect of soluble-viscous dietary fibre on coronary heart disease risk score across 3 population health categories: data from randomized, double-blind, placebo-controlled trials.

We applied the Framingham risk equation in healthy, metabolic syndrome, and diabetes populations, following treatment with viscous fibre from konjac-based blend (KBB). KBB yielded reduction in estimated risk score by 16% (1.04 ± 0.03 vs. 0.87 ± 0.04, p < 0.01) in type 2 diabetes, 24% (1.08 ± 0.01 vs. 0.82 ± 0.02, p < 0.01) in metabolic syndrome, and 25% (1.09 ± 0.05 vs. 0.82 ± 0.06, p < 0.01) in healthy individuals. Drivers for decreased risk were improvements in blood cholesterol and systolic blood pressure. The composite coronary heart disease risk across populations was reduced 22% (p < 0.01). Novelty Viscous fibre from konjac-xanthan reduced 10-year relative coronary heart disease using Framingham Risk Score across the glycemic status spectrum.

Insulin Therapy in Adults with Type 1 Diabetes Mellitus: a Narrative Review.

Here, we review insulin management options and strategies in nonpregnant adult patients with type 1 diabetes mellitus (T1DM). Most patients with T1DM should follow a regimen of multiple daily injections of basal/bolus insulin, but those not meeting individual glycemic targets or those with frequent or severe hypoglycemia or pronounced dawn phenomenon should consider continuous subcutaneous insulin infusion. The latter treatment modality could also be an alternative based on patient preferences and availability of reimbursement. Continuous glucose monitoring may improve glycemic control irrespective of treatment regimen. A glycemic target of glycated hemoglobin < 7% (53 mmol/mol) is appropriate for most nonpregnant adults. Basal insulin analogues with a reduced peak profile and an extended duration of action with lower intraindividual variability relative to neutral protamine Hagedorn insulin are preferred. The clinical advantages of basal analogues compared with older basal insulins include reduced injection burden, better efficacy, lower risk of hypoglycemic episodes (especially nocturnal), and reduced weight gain. For prandial glycemic control, any rapid-acting prandial analogue (aspart, glulisine, lispro) is preferred over regular human insulin. Faster-acting insulin aspart is a relatively new option with the advantage of better postprandial glucose coverage. Frequent blood glucose measurements along with patient education on insulin dosing based on carbohydrate counting, premeal blood glucose, and anticipated physical activity is paramount, as is education on the management of blood glucose under different circumstances.Plain Language Summary: Plain language summary is available for this article.

Can dietary viscous fiber affect body weight independently of an energy-restrictive diet? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: The role of dietary fiber in obesity management remains debatable. Evidence suggests that intake of viscous fiber may have the potential to facilitate weight loss. OBJECTIVE: We aimed to summarize and quantify the effects of viscous fiber on body weight, BMI, waist circumference, and body fat, independent of calorie restriction, through a systematic review and meta-analysis of randomized controlled trials. METHODS: Trials ≥4 wk in duration that assessed the effect of viscous fiber supplemented to an ad libitum diet along with comparator diets were included. MEDLINE, EMBASE, and the Cochrane library were searched through 24 July, 2019. Two independent reviewers extracted relevant data. Data were pooled using the generic inverse variance method and random-effects models and expressed as mean differences with 95% CIs. Interstudy heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). The overall certainty of evidence was explored using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Findings from 62 trials (n = 3877) showed that viscous fiber reduced mean body weight (-0.33 kg; 95% CI: -0.51, -0.14 kg; P = 0.004), BMI (in kg/m2) (-0.28; 95% CI: -0.42, -0.14; P = 0.0001), and waist circumference (-0.63 cm; 95% CI: -1.11, -0.16 cm; P = 0.008), with no change in body fat (-0.78%; 95% CI: -1.56%, 0.00%; P = 0.05) when consumed with an ad libitum diet. Greater reductions in body weight were observed in overweight individuals and those with diabetes and metabolic syndrome. The certainty of evidence was graded moderate for body weight, high for waist circumference and body fat, and low for BMI. CONCLUSIONS: Dietary viscous fiber modestly yet significantly improved body weight and other parameters of adiposity independently of calorie restriction. Future trials are warranted to address the inconsistency and imprecision identified through GRADE and to determine long-term weight-loss sustainability.This systematic review and meta-analysis was registered at clinicaltrials.gov as NCT03257449.

Evidence from routine clinical practice: EMPRISE provides a new perspective on CVOTs.

EMPA-REG OUTCOME is recognised by international guidelines as a landmark study that showed a significant cardioprotective benefit with empagliflozin in patients with type 2 diabetes (T2D) and cardiovascular disease. To assess the impact of empagliflozin in routine clinical practice, the ongoing EMPRISE study is collecting real-world evidence to compare effectiveness, safety and health economic outcomes between empagliflozin and DPP-4 inhibitors. A planned interim analysis of EMPRISE was recently published, confirming a substantial reduction in hospitalisation for heart failure with empagliflozin across a diverse patient population. In this commentary article, we discuss the new data in the context of current evidence and clinical guidelines, as clinicians experienced in managing cardiovascular risk in patients with T2D. We also look forward to what future insights EMPRISE may offer, as evidence is accumulated over the next years to complement the important findings of EMPA-REG OUTCOME.

SGLT2 inhibitors in T2D and associated comorbidities - differentiating within the class.

BACKGROUND: For patients with type 2 diabetes (T2D), cardiovascular disease (CVD) is the single most common cause of mortality. In 2008 and 2012, the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) respectively mandated cardiovascular outcomes trials (CVOTs) on all new anti-diabetic agents, as prospective trials statistically powered to rule out excess cardiovascular risk in patients with T2D. Unexpectedly, some of these CVOTs have demonstrated not only cardiovascular safety, but also cardioprotective effects, as was first shown for the SGLT2 inhibitor empagliflozin in EMPA-REG OUTCOME. EXPERT OPINION: To debate newly available CVOT data and to put them into context, we convened as a group of medical experts from the Central and Eastern European Region. Here we describe our discussions, focusing on the conclusions we can draw from EMPA-REG OUTCOME and other SGLT2 inhibitor CVOTs, including when considered alongside real-world evidence. CONCLUSION: CVOTs investigating SGLT2 inhibitors have suggested benefits beyond glucose lowering that have been confirmed in real-world evidence studies.

High level of clinical inertia in insulin initiation in type 2 diabetes across Central and South-Eastern Europe: insights from SITIP study.

AIMS: Little is known regarding initiation of insulin therapy in type 2 diabetes (T2D) in Central and South-Eastern European countries. Therefore, we conducted a survey to characterise the prescribing practices of specialist diabetes healthcare professionals in this region and assessed factors that influence clinical decision-making regarding insulin initiation in T2D. METHODS: A cross-sectional survey sampled 211 specialist diabetes healthcare prescribers from five Central and South-Eastern European countries (Bulgaria, Croatia, Greece, Hungary, and Slovenia). A structured questionnaire was developed which surveyed current clinical practices and influencing factors, barriers to insulin initiation, and combination therapy prescribing preferences. RESULT: Only 9.4% (20 of out of 211 respondents) of healthcare professionals would initiate insulin therapy in T2D patients at the recommended HbA1c threshold of 7-7.9% [53-63 mmol/mol]. Large regional differences were evident in insulin initiation thresholds (≥ 9.0% [≥ 75 mmol/mol]: Bulgaria 80.8% vs. Slovenia 13.3%). Psychological distress was recorded as the major barrier to insulin initiation. Health insurance regulations were ranked more important than personal clinical experience and clinical guidelines in clinical decision-making. Information from peers was more influential than manufacturer information, clinical experience, and continuous medical education, respectively, for insulin initiation. CONCLUSIONS: Despite large regional variation, there is widespread delay of insulin initiation from specialist diabetes healthcare professionals in Central and South-Eastern Europe.

Perspectives of Patients with Insulin-Treated Type 1 and Type 2 Diabetes on Hypoglycemia: Results of the HAT Observational Study in Central and Eastern European Countries.

INTRODUCTION: The aim of this study was to determine the level of awareness of hypoglycemia, the level of fear for hypoglycemia, and the response to hypoglycemic events among insulin-treated diabetes patients from Central and Eastern Europe (CEE). The impact of hypoglycemia on the use of healthcare resources and patient productivity was also assessed. METHODS: This was a multicenter, non-interventional, two-part, patient self-reported questionnaire study that comprised both a retrospective cross-sectional evaluation and a prospective observational evaluation. Study participants were insulin-treated adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) from CEE. RESULTS: Most patients (85.4% T1DM and 83.6% T2DM) reported normal hypoglycemia awareness. The median hypoglycemia fear score was 5 out of 10 for T1DM and 4 out of 10 for T2DM patients. Patients increased glucose monitoring, consulted a doctor/nurse, and/or reduced the insulin dose in response to hypoglycemia. As a consequence of hypoglycemia, patients took leave from work/studies or arrived late and/or left early. Hospitalization was required for 31 (1.2%) patients with T1DM and 66 (2.1%) patients with T2DM. CONCLUSION: Hypoglycemia impacts patients' personal and social functioning, reduces productivity, and results in additional costs, both direct (related to increased use of healthcare resources) and indirect (related to absenteeism. FUNDING: Novo Nordisk.

The influence of dopamine-beta-hydroxylase and catechol O-methyltransferase gene polymorphism on the efficacy of insulin detemir therapy in patients with type 2 diabetes mellitus.

BACKGROUND: Type II diabetes is an important health problem with a complex connection to obesity, leading to a broad range of cardiovascular complications. Insulin therapy often results in weight gain and does not always ensure adequate glycemic control. However, previous studies reported that insulin detemir is an efficient long-acting insulin with a weight sparing effect. The aim of this study was to determine the association of catechol O-methyltransferase (COMT) Val108/158Met and dopamine-beta-hydroxylase (DBH) 1021C/T polymorphisms with the effectiveness of insulin detemir in achieving glucose control and body weight control. Participants and methods: This 52-week observational study included 185 patients with inadequate glycemic control treated with premix insulin analogues, which were replaced with insulin aspart and insulin detemir, and 156 healthy controls. After DNA isolation from blood samples, genotyping of DBH-1021C/T polymorphism (rs1611115) and COMT Val108/158Met polymorphism (rs4680) was performed. RESULTS: Our results confirmed that insulin detemir did not lead to weight gain. The most significant finding was that A carriers (the combined AG and AA genotype) of the COMT Val108/158Met achieved significantly better hemoglobin A1c (HbA1c) values compared to patients carrying GG genotype. No association between DBH-1021C/T genotypes and weight and/or glucose control was detected in diabetes patients or in healthy control subjects. CONCLUSIONS: This study showed that the presence of one or two A allele of the COMT Val108/158Met was associated with improved glycemic response, and with a better response to insulin detemir therapy in patients with type II diabetes, separating them as best candidates for detemir therapy.

Basal and postprandial change in serum fibroblast growth factor-21 concentration in type 1 diabetic mellitus and in healthy controls.

Fibroblast growth factor-21 (FGF-21) appears to have an important role in glucose and lipid metabolism. FGF-21 secretion is mainly determined by nutritional status. The aim of this study was to measure basal and postprandial FGF-21 and postprandial change of FGF-21 concentration in type 1 diabetes mellitus (T1DM) patients and in healthy controls, and to investigate the differences between the groups. The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), disease duration 22 years (3-45), and nine healthy controls, median age 30 years (27-47). Basal and postprandial FGF-21 concentrations were measured by ELISA. The associations of FGF-21 with glucose, lipids, and insulin were analyzed. Individuals with T1DM showed significantly lower basal FGF-21 concentration (P=0.046) when compared with healthy controls (median value 28.2 vs 104 pg/mL) and had significantly different postprandial change (∆ 30'-0') of FGF-21 (P=0.006) in comparison with healthy controls (median value -1.1 vs -20.5 pg/mL). The glucose and lipid status did not correlate with FGF-21. In healthy controls, postprandial insulin level correlated with basal FGF-21 (ρ=0.7, P=0.036). Multiple regression analysis showed that they are independently associated after adjustment for confounding factors (ß=1.824, P=0.04). We describe the pathological pattern of basal and postprandial change of FGF-21 secretion not associated with glucose, lipid levels, or insulin therapy in patients with T1DM. Since FGF-21 has numerous protective metabolic effects in the experimental model, the lower basal FGF-21 concentration in T1DM patients opens the question about the potential role of recombinant FGF-21 therapy.

[HEMOGLOBIN A1c AND THE QUALITY OF DIABETES CARE]. / HEMOGLOBIN A1c I KVALITETA SKRBI ZA OBOLJELE OD SECERNE BOLESTI.

Global diabetes epidemics is currently representing one of the most prominent medical and societal challenges. Hemoglobin A1c (HbA1c), a biochemical marker of an average blood glucose concentration has been used for more than 30 years as a clinical indicator of both diabetes treatment efficacy and the risk for development of complications. Recently, HbA1C was proposed as a diabetes diagnostic test as well. Regular monitoring of glycemic control and adjustment of therapy towards the recommended HbA1c-based treatment-goals is a pivotal request of contemporary diabetes care guidelines, as well as a quality indicator proclaimed by numerous national health-care-delivery systems. Standardized and attainable analytical methodology of high-quality and a good knowledge on determinants of biological variability, able to influence test results, are crucial elements for the confident clinical use of HbA1c. In this review, essential analytical and clinical aspects necessary for the reliable use of HbA1c results in diabetes care are concisely presented, together with the degree of Croatian laboratory and clinical practice harmonization with the relevant international standards.

Difference in glucagon-like peptide-1 concentrations between C-peptide negative type 1 diabetes mellitus patients and healthy controls.

BACKGROUND: The role of glucagon-like peptide-1 (GLP-1) has become a new scientific interest in the field of pathophysiology of type 1 diabetes mellitus (T1DM), but the results of the published studies were contradictory. The aim of our study was therefore to measure fasting and postprandial GLP-1 concentrations in T1DM patients and in healthy controls and to examine the difference in those concentrations between the two groups of subjects. METHODS: The cross-sectional study included 30 C-peptide negative T1DM patients, median age 37 years (20-59), with disease duration 22 years (3-45), and 10 healthy controls, median age 30 years (27-47). Fasting and postprandial total and active GLP-1 concentrations were measured by ELISA (ALPCO, USA). The data were statistically analysed by SPSS, and significance level was accepted at P < 0.05. RESULTS: Both fasting total and active GLP-1 concentrations were significantly lower in T1DM patients (total 0.4 pmol/L, 0-6.4 and active 0.2 pmol/L, 0-1.9) compared with healthy controls (total 3.23 pmol/L, 0.2-5.5 and active 0.8 pmol/L, 0.2-3.6), P = 0.008 for total GLP-1 and P = 0.001 for active GLP-1. After adjustment for age, sex and body mass index, binary logistic regression showed that both fasting total and active GLP-1 remained significantly independently lower in T1DM patients (total GLP-1: OR 2.43, 95% CI 1.203-4.909 and active GLP-1: OR 8.73, 95% CI 1.472-51.787). CONCLUSIONS: T1DM patients had independently lower total and active GLP-1 fasting concentrations in comparison with healthy people, which supports the potential therapeutic role of incretin therapy, along with insulin therapy, in T1DM patients.

Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.