Targeting Mitochondria in Diabetes.

Type 2 diabetes (T2D), one of the most prevalent noncommunicable diseases, is often preceded by insulin resistance (IR), which underlies the inability of tissues to respond to insulin and leads to disturbed metabolic homeostasis. Mitochondria, as a central player in the cellular energy metabolism, are involved in the mechanisms of IR and T2D. Mitochondrial function is affected by insulin resistance in different tissues, among which skeletal muscle and liver have the highest impact on whole-body glucose homeostasis. This review focuses on human studies that assess mitochondrial function in liver, muscle and blood cells in the context of T2D. Furthermore, different interventions targeting mitochondria in IR and T2D are listed, with a selection of studies using respirometry as a measure of mitochondrial function, for better data comparison. Altogether, mitochondrial respiratory capacity appears to be a metabolic indicator since it decreases as the disease progresses but increases after lifestyle (exercise) and pharmacological interventions, together with the improvement in metabolic health. Finally, novel therapeutics developed to target mitochondria have potential for a more integrative therapeutic approach, treating both causative and secondary defects of diabetes.

Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis.

AIMS/HYPOTHESIS: Experimental studies suggest that the fatty acid palmitoleate may act as an adipocyte-derived lipid hormone (or 'lipokine') to regulate systemic metabolism. We investigated the relationship of circulating palmitoleate with insulin sensitivity, beta cell function and glucose tolerance in humans. METHODS: Plasma NEFA concentration and composition were determined in non-diabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort at baseline (n = 1234) and after a 3 year follow-up (n = 924). Glucose tolerance, insulin secretion and beta cell function were assessed during an OGTT. Whole-body insulin sensitivity was measured by a hyperinsulinaemic-euglycaemic clamp (M/I) and OGTT (oral glucose insulin sensitivity index [OGIS]). The liver insulin resistance index was calculated using clinical and biochemical data. Body composition including fat mass was determined by bioelectrical impedance. RESULTS: Circulating palmitoleate was proportional to fat mass (r = 0.21, p < 0.0001) and total NEFA levels (r = 0.19, p < 0.0001). It correlated with whole-body insulin sensitivity (M/I: standardised regression coefficient [std. ß] = 0.16, p < 0.0001), liver insulin resistance (std. ß = -0.14, p < 0.0001), beta cell function (potentiation: std. ß = 0.08, p = 0.045) and glucose tolerance (2 h glucose: std. ß = -0.24, p < 0.0001) after adjustment for age, sex, BMI, adiposity and other NEFA. High palmitoleate concentrations prevented the decrease in insulin sensitivity associated with excess palmitate (p = 0.0001). In a longitudinal analysis, a positive independent relationship was observed between changes in palmitoleate and insulin sensitivity over time (std. ß = 0.07, p = 0.04). CONCLUSIONS/INTERPRETATION: We demonstrated that plasma palmitoleate is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals. These results support the role of palmitoleate as a beneficial lipokine released by adipose tissue to prevent the negative effects of adiposity and excess NEFA on systemic glucose metabolism.

Issues for the management of people with diabetes and COVID-19 in ICU.

In the pandemic "Corona Virus Disease 2019" (COVID-19) people with diabetes have a high risk to require ICU admission. The management of diabetes in Intensive Care Unit is always challenging, however, when diabetes is present in COVID-19 the situation seems even more complicated. An optimal glycemic control, avoiding acute hyperglycemia, hypoglycemia and glycemic variability may significantly improve the outcome. In this case, intravenous insulin infusion with continuous glucose monitoring should be the choice. No evidence suggests stopping angiotensin-converting-enzyme inhibitors, angiotensin-renin-blockers or statins, even it has been suggested that they may increase the expression of Angiotensin-Converting-Enzyme-2 (ACE2) receptor, which is used by "Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to penetrate into the cells. A real issue is the usefulness of several biomarkers, which have been suggested to be measured during the COVID-19. N-Terminal-pro-Brain Natriuretic-Peptide, D-dimer and hs-Troponin are often increased in diabetes. Their meaning in the case of diabetes and COVID-19 should be therefore very carefully evaluated. Even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act.

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.

The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

Impact of acute hyperglycemia on layer-specific left ventricular strain in asymptomatic diabetic patients: an analysis based on two-dimensional speckle tracking echocardiography.

BACKGROUND: Hyperglycemia has detrimental effect on ischemic myocardium, but the impact of acute hyperglycemia on the myocardium in asymptomatic diabetic patients has not been fully elucidated. Thus, this follow-up study was aimed to investigate the effects and reversibility of acute hyperglycemia on regional contractile function of left ventricle (LV) in diabetic patients without cardiovascular disease. METHODS: The two-dimensional speckle tracking echocardiography (2D-STE), including multilayer strain analysis, was used for evaluation of global and regional LV function in asymptomatic, normotensive patients with uncomplicated diabetes, with acute hyperglycemia ( ≥ 11.1 mmol/l) (Group A, n = 67), or with optimal metabolic control (fasting plasma glucose < 7 mmol/l and HbA1c < 7%) (Group B, n = 20), while 20 healthy individuals served as controls (Group C). In group A, after 72 h of i.v. continuous insulin treatment (at the time euglycemia was achieved) (second examination) and after 3 months following acute hyperglycemia (third examination) 2D-STE was repeated. RESULTS: Global longitudinal strain (GLS) (- 19.6 ± 0.4%) in Group A was significantly lower in comparison to both groups B (- 21.3 ± 0.4%; p < 0.05) and C (- 21.9 ± 0.4%; p < 0.01) at baseline, while we could not detect the differences between groups B and C. Peak systolic longitudinal endocardial (Endo), mid-myocardial (Mid) and epicardial (Epi) layer strain were significantly lower in group A at baseline compared to both groups B and C. Deterioration in peak systolic circumferential strain was observed at basal LV level, in all three layers (Endo, Mid and Epi) and in mid-cavity LV level in Epi layer in group A in comparison to group C. Moreover, in group A, after euglycemia was achieved (at second and third examination) GLS, as well as peak longitudinal and circumferential strain remain the same. CONCLUSION: Acute hyperglycemia in asymptomatic diabetic patients has significant negative effects on systolic LV myocardial mechanics primarily by reducing GLS and multilayer peak systolic longitudinal and circumferential strain which was not reversible after three months of good glycemic control.

The Diabetes Unmet Need with Basal Insulin Evaluation (DUNE) study in type 2 diabetes: Achieving HbA1c targets with basal insulin in a real-world setting.

AIMS: To describe in a real-world setting the achievement of physician-selected individualized HbA1c targets in individuals with type 2 diabetes, newly or recently initiated with basal insulin, and the association of hypoglycaemia with target achievement. MATERIALS AND METHODS: A 12-week, prospective, single-arm, observational study of adults with type 2 diabetes, either newly initiated with any basal insulin or start on basal insulin within the preceding 12 months. At enrollment, eligible participants from 28 countries were treated with or without oral antihyperglycaemic drugs and/or GLP-1 receptor agonists. RESULTS: Individualized targets for almost all of the 3139 evaluable participants (99.7%) had been set by their physicians, with 57% of participants having HbA1c targets between 7.0% and <7.5% (53 and <58 mmol/mol). By week 12, 28% and 27% of newly and previously initiated participants, respectively, achieved individualized HbA1c targets with modest average increases in daily insulin dose of 9 and 5 U (0.10 and 0.06 U/kg), respectively, from baseline (14 and 23 U [0.17 and 0.29 U/kg], respectively). Overall, 16% of participants experienced at least one episode of hypoglycaemia. Both the incidence and frequency of hypoglycaemia, but not the severity, were positively associated with a higher likelihood of achieving individualized HbA1c targets (P < 0.05). CONCLUSIONS: In this prospective real-world study, most participants using basal insulin did not achieve the individualized HbA1c targets set by their physicians. Participants who experienced symptomatic hypoglycaemia were more likely to achieve HbA1c targets than those who did not.

Biological and biochemical characteristics of a Mediterranean population with Gestational Diabetes Mellitus.

The interplay of various nutrients provided to the developing foetus determines the growth potential of the conceptus. This study assessed the inter-relationship between these nutrients in a Mediterranean population including 1062 pregnant, previously non-diabetic women. These underwent an oral glucose tolerance test (oGTT) and were accordingly classified into gestational hyperglycaemic and normoglycaemic groups. Fasting insulin, HbA1c, and lipid profiles were further assessed, and the anthropomorphic characteristics of the mother and child at birth were measured. Lipid profiles were compared between the two groups and related to the biological characteristics of the mother and child at birth. Gestational hyperglycaemia was significantly associated with elevated triglycerides (P<0.0001) and decreased low density lipoprotein cholesterol (LDL-C) (P=0.02). There were no significant changes in total cholesterol and high density lipoprotein cholesterol (HDL-C) levels. Maternal BMI correlated positively with the various glycaemic indices (P<0.0001) and triglycerides (P<0.0001), but inversely with cholesterol (P<0.0001), HDL-C (P<0.0001) and LDL-C (P<0.0001). The infant birth weight correlated positively with maternal body weight (P<0.0001), LDL-C (P<0.0001) and the glycaemic indices (P<0.0001), but negatively with cholesterol (P<0.0001), triglycerides (P<0.0001), HDL-C (P<0.0001) and FBG (P<0.0001). This study confirms that the maternal body mass index (BMI), insulin resistance, and LDL-C levels positively contribute towards foetal growth, whereas a negative correlation was noted with cholesterol, triglycerides, and HDL-C.

Influence of endogenous NEFA on beta cell function in humans.

AIMS/HYPOTHESIS: It is a commonly held view that chronically elevated NEFA levels adversely affect insulin secretion and insulin action (lipotoxicity). However, the effect of NEFA on beta cell function has only been explored using acute NEFA elevations. Our aim was to analyse the relationship between endogenous NEFA levels and beta cell function. METHODS: In 1,267 individuals followed-up for 3 years, we measured insulin sensitivity (by clamp) and beta cell function (by C-peptide modelling during OGTT and as the acute insulin response [AIR] to IVGTT). RESULTS: At baseline, both fasting and insulin-suppressed NEFA levels were higher across glucose tolerance groups, while insulin sensitivity was lower, insulin output was higher, and beta cell glucose sensitivity and AIR were lower (all p < 0.0001). In multiple logistic analyses adjusting for age, BMI, WHR and glucose tolerance, both fasting and insulin-suppressed NEFA levels were inversely related to insulin sensitivity, as expected (both p < 0.0001). Furthermore, after adjusting for insulin sensitivity, insulin-suppressed NEFA were positively associated with total insulin output (p = 0.0042). In contrast, neither fasting nor insulin-suppressed NEFA were related to beta cell glucose sensitivity or AIR. At follow-up, worsening of glucose tolerance (n = 126) was predicted by lower insulin and beta cell glucose sensitivity. In this model, baseline NEFA were not significant predictors of progression. CONCLUSIONS/INTERPRETATION: In the non-diabetic state and in subjects with impaired glucose tolerance, circulating endogenous NEFA are not independently associated measures of beta cell function, and do not predict deterioration of glucose tolerance. Thus, in the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort there is no evidence for beta cell lipotoxicity of endogenous total NEFA concentrations.

Structural myocardial alterations in diabetes and hypertension: the role of galectin-3.

BACKGROUND: Galectin-3 is a protein widely distributed in the heart, brain and blood vessels, and has a regulatory role in inflammation, immunology and cancer. Many studies demonstrated that the increased level of galectin-3 is associated with progressive fibrosis and stiffening of the myocardium. The aim of this study was to investigate the role of galectin-3 in patients with type 2 diabetes (T2D) and/or arterial hypertension (HT). METHODS: Study population included 189 patients, with no coronary artery disease, divided into three groups: group 1 (T2D), group 2 (T2D+HT), and group 3 (HT). All subjects underwent routine laboratory tests, as well as specific biomarkers assessment [galectin-3, glycosylated hemoglobin (HbA1c), N- terminal fragment B-type natriuretic peptide (NT-proBNP)]. Cardiological evaluation included physical examination, transthoracic tissue Doppler echocardiography and stress echocardiography. RESULTS: The results of this study demonstrated significantly increased levels of galectin-3, blood glucose, and HbA1c in group 2. Also, echocardiographicaly, left ventricular (LV) diameters and IVS thickness were increased in this group of patients. Furthermore, in the same cohort a positive correlation between galectin-3 and NT-pro BNP, and galectin-3 and LV mass were demonstrated. In addition, a negative correlation between galectin-3 and LV end-diastolic diameter was revealed. CONCLUSIONS: This study revealed that levels of galectin-3 were higher in patients with both T2D and HT, and correlated with LV mass, indicating the potential role of this biomarker for early detection of myocardial structural and functional alterations.

Glucose lowering drug or strategy dependent impact of weight reduction on the prevention of CVD outcomes in Type 2 diabetes: a systematic review of CVOTs.

AIMS: This systematic review was aimed to assess the association between magnitude of body weight loss (BWL) in type 2 diabetes (T2D) patients and cardiovascular (CV) risk in CV outcome trials (CVOTs). METHODS: We searched electronic databases (PubMed, Cochrane and Scopus) for available CVOTs, observational cohort studies or post hoc analyses of clinical trials of adult T2D patients investigated the association of BWL with CV outcomes and/or all-cause mortality. RESULTS: 19 RCTs of novel glucose-lowering drugs (GLP-1RA, DPP-4i and SGLT2i) and 6 RCT or observational trial of different strategies (intensive treatment or standard care) were included (379.904 T2D patients). Higher BWL during GLP-1RA treatment, in comaprison to lower BWL, was associated with higher decrease in risk of MACE, while DPP-4i had not that effect. With SGLT2i the higher decrease in risk of MACE was associated with lower BWL. In contrast, in other different strategies, higher BWL lead to increase in risk for MACE and all-cause mortality. CONCLUSIONS: In CVOTs, treatment of T2D patients resulted in BWL, which correlated with reduction in risk for CV outcomes, particularly with GLP-1 RAs. However, interventional non-CVOTs are warning that in the absence of structured behavioral intervention and relevant medication, the large BWL might be harmful for CV outcomes.

Practicalities and importance of assessing urine albumin excretion in type 2 diabetes: A cutting-edge update.

Type 2 diabetes (T2D) is associated with increased risk for chronic kidney disease (CKD). It is estimated that 40 % of people with diabetes have CKD, which consequently leads to increase in morbidity and mortality from cardiovascular diseases (CVDs). Diabetic kidney disease (DKD) is leading cause of CKD and end-stage renal disease (ESRD) globally. On the other hand, DKD is independent risk factor for CVDs, stroke and overall mortality. According to the guidelines, using spot urine sample and assessing urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) are both mandatory methods for screening of CKD in T2D at diagnosis and at least annually thereafter. Diagnosis of CKD is confirmed by persistent albuminuria followed by a progressive decline in eGFR in two urine samples at an interval of 3 to 6 months. However, many patients with T2D remain underdiagnosed and undertreated, so there is an urgent need to improve the screening by detection of albuminuria at all levels of health care. This review discusses the importance of albuminuria as a marker of CKD and cardiorenal risk and provides insights into the practical aspects of methods for determination of albuminuria in routine clinical care of patients with T2D.

Development of ALOHa-G Risk Score for Detecting Postpartum Dyslipidemia Among Normoglycemic Women with Previous Gestational Diabetes: Observational Cohort Study.

INTRODUCTION: Previous gestational diabetes (pGD) is associated with a high risk of postpartum dyslipidemia (pD). Our study was aimed at investigating the prevalence of pD and estimating the risk for pD based on metabolic pregnancy parameters in normoglycemic women with pGD. METHODS: 147 women with pGD and normoglycemia after delivery were divided into groups: A (n = 63) with pD and B (n = 84) with normal lipids, defined by the National Cholesterol Education Program's Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report (NCEP ATP III). We recorded age, body mass index (BMI) at conception, fasting glucose (FG), HbA1c, total cholesterol (TC), triglycerides (Tg), low-density lipoprotein (LDL-c), and high-density lipoprotein cholesterol (HDL-c) measured mid-pregnancy and 1-6 months after delivery. GD was diagnosed by 2 h oral glucose tolerance test (OGTT) between the 24th and the 28th week of gestation, which was repeated after delivery to confirm normoglycemia. RESULTS: 42.8% had pD (group A) while 57.2% had normal lipids (group B). Group A was older (36.8 ± 2.7) than B (33.0 ± 4.2 years, p < 0.001) and had a higher BMI (A 31.2 ± 6.4 vs. B 25.5 ± 2.4 kg/m2, p < 0.001). Simultaneously, HbA1c and FG were higher in group A (5.4 ± 0.3, 5.1 ± 0.4) than B (5.2 ± 0.0%, p = 0.001; 4.8 ± 0.0 mmol/L, p < 0.001). Also, group A had higher TC, LDL-c, and Tg [6.6 (6.1-6.9); 4.2 ± 0.4; 2.9 ± 0.8] compared to B [6.2 (5.4-6.9), p < 0.001; 3.4 ± 0.9, p = 0.001; 2.5 ± 0.6, p < 0.001], while the two groups had comparable HDL-c (A: 1.2 ± 0.3 vs. B: 1.2 ± 0.2 mmol/L, p = 0.998). Calculating the cutoff for age, BMI, HbA1c, FG, LDL-c, and Tg (> 35 years, 26.4 kg/m2, 5.2%, 4.8, 3.9 and 2.7 mmol/L, respectively), univariate regression analysis showed a difference for each (p < 0.001). Allocating 1 point to each predictor, we developed ALOHa G score, which showed high accuracy (AUC 0.931, p < 0.001) for risk of pD in normoglycemic women with pGD. According to the ALOHa-G score, more women in group A were at high risk (≥ 4) and medium risk (= 3) (61.9; 34.9) for pD than in group B (4.8; 14.3), with a lower percentage at low risk for PD (≤ 2) in group A than in group B (3.2 vs. 81.0%). CONCLUSION: Our results implied a remarkable occurrence of pD in normoglycemic women with pGD. Also, the ALOHa-G score was developed based on pregnancy metabolic predictors and could be used to identify normoglycemic women with pGD who are at high risk for pD.

Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.

Metformin is an oral antidiabetic agent that has been widely used in clinical practice for over 60 years, and is currently the most prescribed antidiabetic drug worldwide. However, the molecular mechanisms of metformin action in different tissues are still not completely understood. Although metformin-induced inhibition of mitochondrial respiratory chain Complex I and activation of AMP-activated protein kinase have been observed in many studies, published data is inconsistent. Furthermore, metformin concentrations used for in vitro studies and their pharmacological relevance are a common point of debate. The aim of this study was to explore the effects of different metformin concentrations on energy metabolism and activity of relevant signaling pathways in C2C12 muscle cells in vitro. In order to determine if therapeutic metformin concentrations have an effect on skeletal muscle cells, we used micromolar metformin concentrations (50 µM), and compared the effects with those of higher, millimolar concentrations (5 mM), that have already been established to affect mitochondrial function and AMPK activity. We conducted all experiments in conditions of high (25 mM) and low glucose (5.5 mM) concentration, in order to discern the role of glucose availability on metformin action. According to our results, micromolar metformin treatment did not cause Complex I inhibition nor AMPK activation. Also, cells cultured in low glucose medium were more sensitive to Complex I inhibition, mitochondrial membrane depolarization and AMPK activation by millimolar metformin, but cells cultured in high glucose medium were more prone to induction of ROS production. In conclusion, even though suprapharmacological metformin concentrations cause Complex I inhibition and AMPK activation in skeletal muscle cells in vitro, therapeutic concentrations cause no such effect. This raises the question if these mechanisms are relevant for therapeutic effects of metformin in skeletal muscle.

Predictors of Clinical Inertia and Type 2 Diabetes: Assessment of Primary Care Physicians and Their Patients.

With the growing prevalence and complex pathophysiology of type 2 diabetes, many patients fail to achieve treatment goals despite guidelines and possibilities for treatment individualization. One of the identified root causes of this failure is clinical inertia. We explored this phenomenon, its possible predictors, and groups of patients affected the most, together with offering potential paths for intervention. Our research was a cross-sectional study conducted during 2021 involving 52 physicians and 543 patients of primary healthcare institutions in Belgrade, Serbia. The research instruments were questionnaires based on similar studies, used to collect information related to the factors that contribute to developing clinical inertia originating in both physicians and patients. In 224 patients (41.3%), clinical inertia was identified in patients with poor overall health condition, long diabetes duration, and comorbidities. Studying the changes made to the treatment, most patients (53%) had their treatment adjustment more than a year ago, with 19.3% of patients changing over the previous six months. Moreover, we found significant inertia in the treatment of patients using modern insulin analogues. Referral to secondary healthcare institutions reduced the emergence of inertia. This assessment of primary care physicians and their patients pointed to the high presence of clinical inertia, with an overall health condition, comorbidities, diabetes duration, current treatment, last treatment change, glycosylated hemoglobin and fasting glucose measuring frequency, BMI, patient referral, diet adjustment, and physician education being significant predictors.

Interdisciplinary assessment and diagnostic algorithm: The role of the diabetologist.

In recent years, many studies have revealed the importance of heart failure (HF) development in type 2 diabetes (T2D), which increases the morbidity and mortality during the course of diabetes. In this context, it became important to emphasize the role of both cardiologists and diabetologists in the early diagnosis and further adequate treatment of HF in T2D. While HF appears in two major forms, with reduced or preserved ejection fraction (EF), namely HFrEF and HFpEF, it became important to define the optimal approach to the diagnostics. Regarding HFrEF, the role of cardiological methods remained dominant, while the complexity of early diagnosis requires nowadays more active participation of diabetologists. The absence of abundant symptoms and echocardiographic findings imposed the need for the use of risk markers based on metabolic variables and low-grade inflammation parameters. Following that unmet need, numerous studies have defined the possible relationship between metabolic variables in diabetes and the risk for HF. Moreover, attempts have been made to integrate biochemical and clinical parameters into risk score engines and some of them gave promising results. However, the follow-up studies in T2D subjects are needed to determine the clinical relevance of these new approaches.

Contrast-induced nephropathy in a patient with type 2 diabetes and coronary artery disease: a case report.

Contrast-induced nephropathy (CIN) is the impairment of kidney function defined as a serum creatinine increase of 25% or 44 µmol/L compared with baseline, usually occurring 24 to 48 hours after the use of intravenous contrast. Important risk factors for CIN include female sex, advanced age (>65 years), type 2 diabetes (T2D), kidney disease, advanced heart failure, and intravascular volume depletion. We herein present a male patient with T2D, moderately reduced renal function, no albuminuria, and a positive echocardiography stress test. He underwent percutaneous coronary intervention (PCI), and two drug-eluting stents (in the left anterior descending coronary artery) and three bare-metal stents (in the right coronary artery) were implanted. Despite adequate rehydration (0.9% intravenous NaCl with 8.4% sodium bicarbonate) before and after the procedures, he developed irreversible kidney injury after coronary angiography and PCI. This case report demonstrates the unpredictable clinical course of CIN. Patients with T2D are at high risk for the occurrence of CIN, so careful clinical assessment is recommended with global renal functional reserve evaluation.

In vitro models of insulin resistance: Mitochondrial coupling is differently affected in liver and muscle cells.

Mitochondrial dysfunction in diabetes is a widely studied topic, but inconsistency in literature data suggests a need for valid and reproducible models that will help to clarify this interaction. We aimed to establish insulin resistance models using chronic high insulin treatment in two cell types: myocytes and hepatocytes, characterise them in terms of mitochondrial function and compare them to the widely used palmitate-induced model of insulin resistance. We found that insulin lowered phosphorylation of Akt while not affecting cell viability, ROS production, mitochondrial morphology or respiration, and caused decrease in mitochondrial coupling only in muscle but not in liver cells.

Redesigning diabetes care delivery in Serbia, using JA CHRODIS Recommendations and criteria.

INTRODUCTION: Managing non-communicable diseases (NCDs) requires redesigning health care delivery to achieve better coordination of services at all levels of health care. The aim of this study was improving prevention and strengthening high quality of care for NCDs by using type 2 diabetes as a model disease. METHODS: The mix method approach served to analyse the impact of the intervention processes. Source of information were routine health statistics, interviews and observation. Key Performance Indicators in defined Improvement Areas assisted in the quality of diabetes care assessment. RESULTS AND DISCUSSION: During the study the National Diabetes Centre (NDC) was established. The NDC experts organized numerous educational events, 316 physicians and nurses have participated. New electronic data base was implemented in 20 pilot Primary Health Care Centres (PHCCs) with 38,833 electronic diabetes records. CONCLUSIONS: The intervention led to establishment of the NDC, strengthening competences of health care professionals and to the renewal of the Diabetes Care Units in PHCCs included in the study.

NDUFB6 Polymorphism Is Associated With Physical Activity-Mediated Metabolic Changes in Type 2 Diabetes.

The rs540467 SNP in the NDUFB6 gene, encoding a mitochondrial complex I subunit, has been shown to modulate adaptations to exercise training. Interaction effects with diabetes mellitus remain unclear. We assessed associations of habitual physical activity (PA) levels with metabolic variables and examined a possible modifying effect of the rs540467 SNP. Volunteers with type 2 (n=242), type 1 diabetes (n=250) or normal glucose tolerance (control; n=139) were studied at diagnosis and subgroups with type 1 (n=96) and type 2 diabetes (n=95) after 5 years. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamps, oxygen uptake at the ventilator threshold (VO2AT) by spiroergometry and PA by questionnaires. Translational studies investigated insulin signaling and mitochondrial function in Ndufb6 siRNA-treated C2C12 myotubes, with electronic pulse stimulation (EPS) to simulate exercising. PA levels were 10 and 6%, VO2AT was 31% and 8% lower in type 2 and type 1 diabetes compared to control. Within 5 years, 36% of people with type 2 diabetes did not improve their insulin sensitivity despite increasing PA levels. The NDUFB6 rs540467 SNP modifies PA-mediated changes in insulin sensitivity, body composition and liver fat estimates in type 2 diabetes. Silencing Ndufb6 in myotubes reduced mitochondrial respiration and prevented rescue from palmitate-induced insulin resistance after EPS. A substantial proportion of humans with type 2 diabetes fails to respond to rising PA with increasing insulin sensitivity. This may at least partly relate to a polymorphism of the NDUFB6 gene, which may contribute to modulating mitochondrial function. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT01055093. The trial was retrospectively registered on 25th of January 2010.

Prevalence and Metabolic Predictors for Early Diagnosed Prediabetes in Women with Previous Gestational Diabetes: Observational Cohort Study.

INTRODUCTION: Women with previous gestational diabetes (pGD) are at higher risk of prediabetes (PD) after delivery. The aim of this study was to determine the prevalence of and predictors for PD among women with pGD. METHODS: The study included 186 women with pGD treated by lifestyle modification. After delivery, the women were divided into group A (n = 80) with PD and group B (n = 106) with normal glucose tolerance (NGT), defined by the results of the 2-h oral glucose tolerance test at 4-12 weeks after delivery. We recorded age, body mass index (BMI) at conception and after delivery, fasting glucose (FG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (Tg), low density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c) and the Tg/HDL-c ratio measured in the third trimester of pregnancy. RESULTS: Of the 186 women with pGD enrolled in the study, 43% showed prediabetes at 4-12 weeks after delivery, with 13.9% of these women showing impaired FG (IFG), 12.9% showing impaired glucose tolerance (IGT) and 16.2% with IFG/IGT. The groups differed in terms of age and BMI at conception and after delivery. In the third trimester of pregnancy, HbA1c was higher in women in group A than in those in group B (mean ± standard deviation: 5.6 ± 0.4 vs. 5.2 ± 0.3%; p < 0.001), while FG was comparable. Compared to women in group B, women in group A had higher TC (7.1 ± 0.8 vs. 6.6 ± 1.0 mmol/L), Tg (2.7 ± 0.9 vs. 2.1 ± 0.6 mmol/L) and LDL-c (4.7 ± 0.8 vs. 4.3 ± 1.0 mmol/L) (all p < 0.001), lower HDL-c (1.0 ± 0.2 vs. 1.4 ± 1.0; p < 0.001) and higher median Tg/HDL-c (5.4 [range 4.6-14.3] vs. 4.9 [range 1.1-11.5]; p < 0.001). Univariate analysis found an association between prediabetes and age, BMI at conception and after delivery, HbA1c, TC, LDL-c, HDL-c, Tg and Tg/HDL-c ratio. Of these variables, the multivariate analysis showed age (odds ratio [OR] 1.19; p < 0.001), HbA1c (OR 31.06; p < 0.001), Tg (OR 4.09; p < 0.001) and LDL-c (OR 2.00; p = 0.005) as predictors for prediabetes. CONCLUSION: High prevalence of early diagnosed PD in women with pGD was accompanied by advanced age and higher BMI at conception and after delivery. Moreover, age, HbA1c, Tg and LDL-c were predictors for PD.