Diabetes Insulin Resistance Research Articles

Association of priori-defined DASH dietary pattern with metabolic health status among Iranian adolescents with overweight and obesity

There was no evidence on the relationship of Dietary Approaches to Stop Hypertension (DASH) with metabolic health condition in adolescents with overweight and obesity. The purpose of this research was to investigate the association of priori-defined DASH dietary pattern with metabolic health status among adolescents with overweight and obesity in Iran. A cross-sectional survey performed on a representative sample of adolescents with overweight and obesity (n = 203). Dietary intakes were collected via a validated food frequency questionnaire and DASH score was characterized according to eight components. Data of anthropometric measures, blood pressure, circulating insulin, fasting blood sugar, and lipid profile were collected. Metabolic health status was defined based on criteria of International Diabetes Federation (IDF) and insulin resistance (IR). Based on IDF and IDF/IR criteria, 38.9% and 33.0% of adolescents suffered from metabolically unhealthy overweight/obesity (MUO). After controlling all confounders, subjects in the highest vs. lowest tertile of DASH diet had respectively 92% and 91% lower odds of MUO based on IDF definition (OR = 0.08; 95%CI 0.03–0.22) and IDF/IR criteria (OR = 0.09; 95%CI 0.03–0.29). Subgroup analysis by sex and body mass index determined that this relationship was more powerful in girls and overweight individuals. Also, in fully adjusted model, highest vs. lowest adherence to DASH diet was linked to decreased odds of hyperglycemia (OR = 0.07; 95% CI 0.03–0.21), hypertriglyceridemia (OR = 0.26; 95% CI 0.09–0.73), low HDL cholesterolemia (OR = 0.30; 95% CI 0.12–0.73) and insulin resistance (OR = 0.07; 95% CI 0.02–0.28), as metabolic health components. Greater compliance to DASH dietary pattern was linked to a remarkable lower odd of metabolic unhealthy condition among Iranian adolescents, especially in overweight subjects and girls. More prospective surveys are required to assert these results.

Obesity and Acanthosis Nigricans as the Clinical Markers of Insulin Resistance and Type-2 Diabetes Mellitus in Young Patients; A Case Report of Two Cases

Two young girls, aged 11 and 12 years, presented with obesity and Acanthosis Nigricans. They were found to have severe insulin resistance and type-2 diabetes mellitus. Anti-glutamic acid decarboxylase and anti-islet cell antibodies were negative. Tests for hypothyroidism and Cushing’s syndrome were negative. They were managed with lifestyle modification and metformin.

The prognostic significance of insulin resistance in COVID-19: a review.

Emerging publications indicate that diabetes predisposes patients with COVID-19 to more severe complications, which is partly attributed to inflammatory condition. In the current review, we reviewed recent published literature to provide evidence on the role of insulin resistance (IR) in diabetes, the association between diabetes and COVID-19 severity and mortality, the impact of COVID-19 infection on incident new-onset diabetes, mechanisms responsible for IR in COVID-19 patients, and the predictive value of different surrogates of IR in COVID-19. The literature search performs to find out studies that have assessed the association between IR surrogates and morbidity and mortality in patients with COVID-19. We showed that there is a bulk of evidence in support of the fact that diabetes is a potent risk factor for enhanced morbidity and mortality in COVID-19 patients. COVID-19 patients with diabetes are more prone to remarkable dysglycemia compared to those without diabetes, which is associated with an unfavourable prognosis. Furthermore, SARS-COV2 can make patients predispose to IR and diabetes via activating ISR, affecting RAAS signaling pathway, provoking inflammation, and changing the expression of PPARɣ and SREBP-1. Additionally, higher IR is associated with increased morbidity and mortality in COVID-19 patients and different surrogates of IR can be utilized as a prognostic biomarker for COVID-19 patients. Different surrogates of IR can be utilized as predictors of COVID-19 complications and death.

Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications.

Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.

Extracellular vesicles-Potential link between periodontal disease and diabetic complications.

It has long been suggested that a bidirectional impact exists between periodontitis and diabetes. Periodontitis may affect diabetes glycemic control, insulin resistance, and diabetic complications. Diabetes can worsen periodontitis by delaying wound healing and increasing the chance of infection. Extracellular vesicles (EVs) are heterogeneous particles of membrane-enclosed spherical structure secreted by eukaryotes and prokaryotes and play a key role in a variety of diseases. This review will introduce the biogenesis, release, and biological function of EVs from a microbial and host cell perspective, discuss the functional properties of EVs in the development of periodontitis and diabetes, and explore their role in the pathogenesis and clinical application of these two diseases. Their clinical implication and diagnostic value are also discussed.

Diabetic sensory neuropathy and insulin resistance are induced by loss of UCHL1 in Drosophila

Diabetic sensory neuropathy (DSN) is one of the most common complications of type 2 diabetes (T2D), however the molecular mechanistic association between T2D and DSN remains elusive. Here we identify ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinase highly expressed in neurons, as a key molecule underlying T2D and DSN. Genetic ablation of UCHL1 leads to neuronal insulin resistance and T2D-related symptoms in Drosophila. Furthermore, loss of UCHL1 induces DSN-like phenotypes, including numbness to external noxious stimuli and axonal degeneration of sensory neurons in flies’ legs. Conversely, UCHL1 overexpression improves DSN-like defects of T2D model flies. UCHL1 governs insulin signaling by deubiquitinating insulin receptor substrate 1 (IRS1) and antagonizes an E3 ligase of IRS1, Cullin 1 (CUL1). Consistent with these results, genetic and pharmacological suppression of CUL1 activity rescues T2D- and DSN-associated phenotypes. Therefore, our findings suggest a complete set of genetic factors explaining T2D and DSN, together with potential remedies for the diseases.

Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study

Aims/hypothesisType 2 diabetes is a highly heterogeneous disease for which new subgroups (‘clusters’) have been proposed based on disease severity: moderate age-related diabetes (MARD), moderate obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). It is unknown how disease severity is reflected in terms of quality of life in these clusters. Therefore, we aimed to investigate the cluster characteristics and cluster-wise evolution of quality of life in the previously defined clusters of type 2 diabetes.MethodsWe included individuals with type 2 diabetes from the Maastricht Study, who were allocated to clusters based on a nearest centroid approach. We used logistic regression to evaluate the cluster-wise association with diabetes-related complications. We plotted the evolution of HbA1c levels over time and used Kaplan–Meier curves and Cox regression to evaluate the cluster-wise time to reach adequate glycaemic control. Quality of life based on the Short Form 36 (SF-36) was also plotted over time and adjusted for age and sex using generalised estimating equations. The follow-up time was 7 years. Analyses were performed separately for people with newly diagnosed and already diagnosed type 2 diabetes.ResultsWe included 127 newly diagnosed and 585 already diagnosed individuals. Already diagnosed people in the SIDD cluster were less likely to reach glycaemic control than people in the other clusters, with an HR compared with MARD of 0.31 (95% CI 0.22, 0.43). There were few differences in the mental component score of the SF-36 in both newly and already diagnosed individuals. In both groups, the MARD cluster had a higher physical component score of the SF-36 than the other clusters, and the MOD cluster scored similarly to the SIDD and SIRD clusters.Conclusions/interpretationDisease severity suggested by the clusters of type 2 diabetes is not entirely reflected in quality of life. In particular, the MOD cluster does not appear to be moderate in terms of quality of life. Use of the suggested cluster names in practice should be carefully considered, as the non-neutral nomenclature may affect disease perception in individuals with type 2 diabetes and their healthcare providers.Graphical

Association of dietary patterns with diabetes-related comorbidities varies among diabetes endotypes

Background and aimsDifferences of dietary pattern adherence across the novel diabetes endotypes are unknown. This study assessed adherence to pre-specified dietary patterns and their associations with cardiovascular risk factors, kidney function, and neuropathy among diabetes endotypes. Methods and resultsThe cross-sectional analysis included 765 individuals with recent-onset (67 %) and prevalent diabetes (33 %) from the German Diabetes Study (GDS) allocated into severe autoimmune diabetes (SAID, 35 %), severe insulin-deficient diabetes (SIDD, 3 %), severe insulin-resistant diabetes (SIRD, 5 %), mild obesity-related diabetes (MOD, 28 %), and mild age-related diabetes (MARD, 29 %). Adherence to a Mediterranean diet score (MDS), Dietary Approaches to Stop Hypertension (DASH) score, overall plant-based diet (PDI), healthful (hPDI) and unhealthful plant-based diet index (uPDI) was derived from a food frequency questionnaire and associated with cardiovascular risk factors, kidney function, and neuropathy using multivariable linear regression analysis. Differences in dietary pattern adherence between endotypes were assessed using generalized mixed models.People with MARD showed the highest, those with SIDD and MOD the lowest adherence to the hPDI. Adherence to the MDS, DASH, overall PDI, and hPDI was inversely associated with high-sensitivity C-reactive protein (hsCRP) among people with MARD (β (95%CI): −9.18 % (−15.61; −2.26); −13.61 % (−24.17; −1.58); −19.15 % (−34.28; −0.53); −16.10 % (−28.81; −1.12), respectively). Adherence to the PDIs was associated with LDL cholesterol among people with SAID, SIRD, and MOD. ConclusionsMinor differences in dietary pattern adherence (in particular for hPDI) and associations with markers of diabetes-related complications (e.g. hsCRP) were observed between endotypes. So far, evidence is insufficient to derive endotype-specific dietary recommendations. Trial registrationClinicaltrials.gov: NCT01055093.

Dietary Epigenetic Modulators: Unravelling the Still-Controversial Benefits of miRNAs in Nutrition and Disease.

In the context of nutrient-driven epigenetic alterations, food-derived miRNAs can be absorbed into the circulatory system and organs of recipients, especially humans, and potentially contribute to modulating health and diseases. Evidence suggests that food uptake, by carrying exogenous miRNAs (xenomiRNAs), regulates the individual miRNA profile, modifying the redox homeostasis and inflammatory conditions underlying pathological processes, such as type 2 diabetes mellitus, insulin resistance, metabolic syndrome, and cancer. The capacity of diet to control miRNA levels and the comprehension of the unique characteristics of dietary miRNAs in terms of gene expression regulation show important perspectives as a strategy to control disease susceptibility via epigenetic modifications and refine the clinical outcomes. However, the absorption, stability, availability, and epigenetic roles of dietary miRNAs are intriguing and currently the subject of intense debate; additionally, there is restricted knowledge of their physiological and potential side effects. Within this framework, we provided up-to-date and comprehensive knowledge on dietary miRNAs' potential, discussing the latest advances and controversial issues related to the role of miRNAs in human health and disease as modulators of chronic syndromes.

Evaluating the relationship between thyroid function and insulin resistance in gestational diabetes

Evaluating the relationship between thyroid function and insulin resistance in gestational diabetes

Otklonjena insulinska rezistencija - hormonske korelacije u gestacijskom dijabetesu

Background: To investigate the correlation between the variations of cortisol and insulin-like growth factor 1 (IGF1) and sex hormone binding globulin (SHBG) levels with insulin resistance and glucolipid metabolism in gestational glucose diabetics. Methods: The study included 110 pregnant women diagnosed with gestational diabetes mellitus in the GDM group, and 130 healthy pregnant women in the control group. Data collection, examination of relevant indexes, and comparison of differences in indexes between groups were conducted. Pearson correlation analysis was utilized to identify risk variables associated with GDM development, while binary logistic regression was employed to determine risk factors for GDM development. Results: The GDM group showed significantly greater levels of FPG, HbA1c, FINS, TG, FFA, Lp-PLA2, HOMA-IR, Cortisol, and IGF-1 compared to the control group (P<0.05), but considerably lower levels of SHBG, and HOMA-b. HOMA-IR was found to be positively correlated with FPG, HbA1c, FINS, TG, FFA, Lp-PLA2, Cortisol and IGF-1, whereas, negatively correlated with SHBG. FINS and SHBG were found to be independent protective factors for GDM (OR=0.463, 0.801, P<0.05), whereas, HbA1c, TG, FFA, and gestational BMI were found to be independent risk factors for GDM (OR=1.992, 4.234, 1.990, 1.629, P<0.05). Conclusions: SHBG, IGF-1, and Cortisol are all linked to glucose-lipid metabolism indices, and aberrant serum hormone expression is a major contributor to insulin resistance.

METS-IR, a Novel Simple Insulin Resistance Index, is Associated with NAFLD in Patients with Type 2 Diabetes Mellitus.

Substantial evidence has established a strong association between non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM) and insulin resistance (IR). Insulin resistance metabolic score (METS-IR) is a new and more effective comprehensive indicator for measuring IR. Our aim was to investigate the relationship between METS-IR and NAFLD in T2DM population. This cross-sectional study included 1097 adult patients with T2DM. Anthropometric measurements and biochemical indicators were collected, and the NAFLD was diagnosed by ultrasound. The METS-IR was calculated. Based on the presence of NAFLD, the population was divided into non-NAFLD and NAFLD groups. The relationship between METS-IR and NAFLD was evaluated. Compared with the non-NAFLD group, the METS-IR was higher in the NAFLD group (P < 0.001). The incidence rate of NAFLD increased across the quartiles of the METS-IR (P < 0.001). Spearman correlation analysis showed that METS-IR was positively correlated with NAFLD (Correlation Coefficient: 0.441, P < 0.001). The binary logistic regression analysis indicated that METS-IR was independently associated with NAFLD (OR: 1.120, 95% CI 1.080-1.161). Furthermore, the area under the receiver operating characteristic curve of the METS-IR was 0.781 (95% CI 0.746-0.817) and relatively higher than other evaluation variables. In patients with T2DM, METS-IR is closely associated with NAFLD, and might be a valuable predictor of NAFLD. Further research is needed to verify this association.

Nonalcoholic Fatty Liver Disease and Staging of Hepatic Fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is in parallel with the obesity epidemic, and it is the most common cause of liver diseases. The patients with severe insulin-resistant diabetes having high body mass index (BMI), high-grade adipose tissue insulin resistance, and high hepatocellular triacylglycerols (triglycerides; TAG) content develop hepatic fibrosis within a 5-year follow-up. Insulin resistance with the deficiency of insulin receptor substrate-2 (IRS-2)-associated phosphatidylinositol 3-kinase (PI3K) activity causes an increase in intracellular fatty acid-derived metabolites such as diacylglycerol(DAG), fatty acyl CoA, or ceramides. Lipotoxicity-related mechanism of NAFLD could be explained still best by the "double-hit" hypothesis. Insulin resistance is the major mechanism in the development and progression of NAFLD/nonalcoholic steatohepatitis (NASH). Metabolic oxidative stress, autophagy, and inflammation induce NASH progression. In the "first hit" the hepatic concentrations of diacylglycerol increase with an increase in saturated liver fat content in human NAFLD. Activities of mitochondrial respiratory chain complexes are decreased in the liver tissue of patients with NASH. Hepatocyte lipoapoptosis is a critical feature of NASH. In the "second hit," reduced glutathione levels due to oxidative stress lead to the overactivation of c-Jun N-terminal kinase (JNK)/c-Jun signaling that induces cell death in the steatotic liver. Accumulation of toxic levels of reactive oxygen species (ROS) is caused at least by two ineffectual cyclical pathways. First is the endoplasmic reticulum (ER) oxidoreductin (Ero1)-protein disulfide isomerase oxidation cycle through the downstream of the inner membrane mitochondrial oxidative metabolism and the second is the Kelch like-ECH-associated protein 1 (Keap1)-nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. In clinical practice, on ultrasonographic examination, the elevation of transaminases, γ-glutamyltransferase, and the aspartate transaminase to platelet ratio index indicates NAFLD. Fibrosis-4 index, NAFLD fibrosis score, and cytokeratin18 are used for grading steatosis, staging fibrosis, and discriminating the NASH from simple steatosis, respectively. In addition to ultrasonography, "controlled attenuation parameter," "magnetic resonance imaging proton-density fat fraction," "ultrasound-based elastography," "magnetic resonance elastography," "acoustic radiation force impulse elastography imaging," "two-dimensional shear-wave elastography with supersonic imagine," and "vibration-controlled transient elastography" are recommended as combined tests with serum markers in the clinical evaluation of NAFLD. However, to confirm the diagnosis of NAFLD, a liver biopsy is the gold standard. Insulin resistance-associated hyperinsulinemia directly accelerates fibrogenesis during NAFLD development. Although hepatocyte lipoapoptosis is a key driving force of fibrosis progression, hepatic stellate cells and extracellular matrix cells are major fibrogenic effectors. Thereby, these are pharmacological targets of therapies in developing hepatic fibrosis. Nonpharmacological management of NAFLD mainly consists of two alternatives: lifestyle modification and metabolic surgery. Many pharmacological agents that are thought to be effective in the treatment of NAFLD have been tried, but due to lack of ability to attenuate NAFLD, or adverse effects during the phase trials, the vast majority could not be licensed.

Randomized open-label trial of semaglutide and dapagliflozin in patients with type 2 diabetes of different pathophysiology

The limited understanding of the heterogeneity in the treatment response to antidiabetic drugs contributes to metabolic deterioration and cardiovascular complications1,2, stressing the need for more personalized treatment1. Although recent attempts have been made to classify diabetes into subgroups, the utility of such stratification in predicting treatment response is unknown3. We enrolled participants with type 2 diabetes (n = 239, 74 women and 165 men) and features of severe insulin-deficient diabetes (SIDD) or severe insulin-resistant diabetes (SIRD). Participants were randomly assigned to treatment with the glucagon-like peptide 1 receptor agonist semaglutide or the sodium–glucose cotransporter 2 inhibitor dapagliflozin for 6 months (open label). The primary endpoint was the change in glycated haemoglobin (HbA1c). Semaglutide induced a larger reduction in HbA1c levels than dapagliflozin (mean difference, 8.2 mmol mol−1; 95% confidence interval, −10.0 to −6.3 mmol mol−1), with a pronounced effect in those with SIDD. No difference in adverse events was observed between participants with SIDD and those with SIRD. Analysis of secondary endpoints showed greater reductions in fasting and postprandial glucose concentrations in response to semaglutide in participants with SIDD than in those with SIRD and a more pronounced effect on postprandial glucose by dapagliflozin in participants with SIDD than in those with SIRD. However, no significant interaction was found between drug assignment and the SIDD or SIRD subgroup. In contrast, continuous measures of body mass index, blood pressure, insulin secretion and insulin resistance were useful in identifying those likely to have the largest improvements in glycaemic control and cardiovascular risk factors by adding semaglutide or dapagliflozin. Thus, systematic evaluation of continuous pathophysiological variables can guide the prediction of the treatment response to these drugs and provide more information than stratified subgroups (NCT04451837).

Diabetes Status, c-Reactive Protein, and Insulin Resistance in Community-Acquired Pneumonia-A Prospective Cohort Study.

C-reactive protein (CRP) is commonly used to guide community-acquired pneumonia (CAP) treatment. A positive association between admission glucose and CRP levels has been observed in patients with CAP. The associations between prediabetes, unknown diabetes, acute-on-chronic hyperglycaemia, and CRP levels, and between admission CRP levels and insulin resistance (IR) in CAP, remain unexplored. This study investigated the associations firstly between chronic, acute, and acute-on-chronic hyperglycaemia and CRP levels, and secondly between admission CRP levels and IR in CAP. In a prospective cohort study of adults with CAP, the associations between chronic, acute, and acute-on-chronic hyperglycaemia (admission glucose minus HbA1c-derived average glucose) and CRP levels until admission day 3 were modelled with repeated-measures linear mixed models. IR was estimated with the homeostasis model assessment of IR (HOMA-IR). The association between admission CRP levels and HOMA-IR was modelled with linear regression. In 540 patients, no association between chronic, acute, or acute-on-chronic hyperglycaemia and CRP levels was found. In 266 patients, every 50 mg/L increase in admission CRP was associated with a 7% (95% CI 1-14%) higher HOMA-IR. In conclusion, our findings imply that hyperglycaemia does not influence CRP levels in patients with CAP, although admission CRP levels were positively associated with IR.

Ameliorative Effect of Enhydra fluctuans on Liver Damage in Diabetic Rats

Diabetes mellitus and insulin resistance cause harm to the liver. In this study, ameliorative effect of Enhydra fluctuans on liver damage in alloxan-induced diabetic rats were examined.&#x0D; Thirty acclimatized male albino rats divided into six groups (n = 5). Normal rats were fed a standard diet (Group 1); diabetic rats were provided standard feed (Group 2); diabetic rats were fed standard feed and glibenclamide (Group 3); and diabetic rats were fed standard food and fractions of n-hexane E. fluctuans 57.03, 114.06, and 171.09 mg/kg, respectively (Group 4, 5 and 6). For 21 days, rats were fed the n-hexane fraction orally. On day 1 and day 21 of treatments, blood sugar levels were measured. The histophatology of the liver, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) level were estimated.&#x0D; At a dosage of 57.03 mg/kg was substantially (p &lt; 0.05) beneficial in decreasing blood sugar and SGOT. The n-hexane fraction of E. fluctuans ameliorated liver damage in diabetic rats and avoided diabetes complications, according to our findings. As a result, E. fluctuans has a considerable amount of potential as a novel diabetic therapy.&#x0D; &#x0D; Keywords: Diabetes, Enhydra fluctuans, Insulin resistance, Liver cells regeneration.

Secondary analysis of newly diagnosed type 2 diabetes subgroups and treatment responses in the MARCH cohort

ObjectiveTo incorporate new clusters in the MARCH (Metformin and AcaRbose in Chinese patients as the initial Hypoglycemic treatment) cohort of newly diagnosed type 2 diabetes (T2D) patients and compare the anti-glycemic effects of metformin and acarbose across different clusters. MethodsK-means cluster analysis was performed based on six clinical indicators. The diabetic clusters in the MARCH cohort were retrospectively associated with the response to metformin and acarbose. ResultsA total of 590 newly diagnosed T2D patients were classified by data-driven clusters into the MARD (mild obesity-related diabetes) (34.1 %), MOD (mild obesity-related diabetes) (34.1 %), SIDD (severe insulin-deficient diabetes) (20.3 %) and SIRD (severe insulin-resistant diabetes) (11.5 %) subgroups at baseline. At 24 and 48 weeks, 346 participants had finished the follow-up. After the adjustment of age, gender, weight, baseline HbA1c, baseline fasting glucose and 2-h postprandial blood glucose (2hPG), metformin mainly decreased the fasting glucose (0.07 ± 0.89 vs −0.26 ± 0.83, P = 0.043) in the MARD subgroup presented with OGTT (oral glucose tolerance test) results compared with acarbose group at 24 weeks. Acarbose led to a greater decrease in 2hPG in the MOD subgroup compared with metformin group (0.08 ± 0.86 vs −0.24 ± 0.92, P = 0.037) at 24 weeks. There was a also significant interaction between cluster and treatment efficacy in HbA1c (glycated hemoglobin) reduction in metformin and acarbose groups at 24 and 48 weeks (pinteraction<0.001). ConclusionsMetformin and acarbose affected different metabolic variables depending on the diabetes subtype.

NK cell-activating receptor NKp46 does not participate in the development of obesity-induced inflammation and insulin resistance

Recent evidence establishes a pivotal role for obesity-induced inflammation in precipitating insulin resistance and type-2 diabetes. Central to this process is the proinflammatory M1 adipose-tissue macrophages (ATMs) in epididymal white adipose tissue (eWAT). Notably, natural killer (NK) cells are a crucial regulator of ATMs since their cytokines induce ATM recruitment and M1 polarization. The importance of NK cells is shown by the strong increase in NK-cell numbers in eWAT, and by studies showing that removing and expanding NK cells respectively improve and worsen obesity-induced insulin resistance. It has been suggested that NK cells are activated by unknown ligands on obesity-stressed adipocytes that bind to NKp46 (encoded by Ncr1), which is an activating NK-cell receptor. This was supported by a study showing that NKp46-knockout mice have improved obesity-induced inflammation/insulin resistance. We therefore planned to use the NKp46-knockout mice to further elucidate the molecular mechanism by which NKp46 mediates eWAT NK-cell activation in obesity. We confirmed that obesity increased eWAT NKp46+ NK-cell numbers and NKp46 expression in wild-type mice and that NKp46-knockout ablated these responses. Unexpectedly, however, NKp46-knockout mice demonstrated insulin resistance similar to wild-type mice, as shown by fasting blood glucose/insulin levels and glucose/insulin tolerance tests.Obesity-induced increases in eWAT ATM numbers and proinflammatory gene expression were also similar. Thus, contrary to previously published results, NKp46 does not regulate obesity-induced insulin resistance. It is therefore unclear whether NKp46 participates in the development of obesity-induced inflammation and insulin resistance. This should be considered when elucidating the obesity-mediated molecular mechanisms that activate NK cells.

Glycated haemoglobin, HOMA2-B, C-peptide to glucose ratio and type 2 diabetes clusters as predictors for therapy failure in individuals with type 2 diabetes without insulin therapy: A registry analysis.

Some people with type 2 diabetes mellitus (T2D) and declining β-cell function do require insulin over time. Various laboratory parameters, indices of glucose metabolism or phenotypes of T2D (clusters) have been suggested, which might predict future therapy failure (TF), indicating the need for insulin therapy initiation. This analysis evaluated glycated haemoglobin (HbA1c), homeostatic model assessment (HOMA)2-B, C-peptide to glucose ratio (CGR) and diabetes clusters as predictive parameters for the occurrence of glycaemic TF in individuals diagnosed with T2D without previous insulin therapy. In total, 159 individuals with T2D [41% female, median age 50 (IQR: 53-69) years, diabetes duration 9 (5-15) years], without insulin therapy were prospectively evaluated for the occurrence of a composite primary endpoint, including HbA1c increasing or remaining >8.0% (64 mmol/mol) 3 months after baseline on non-insulin glucose-lowering agents, insulin initiation or hospital admissions because of acute hyperglycaemic events. Diabetes clusters were formed according to previously described characteristics. Only severe autoimmune diabetes clusters were excluded because of a small amount of glutamate decarboxylase antibody-positive participants. The other clusters were distributed as mild age-related diabetes 33%; severe insulin-deficient diabetes 31%; mild obesity-related diabetes 20%; and severe insulin-resistant diabetes 15%. During a median observation of 57 months, higher tertiles of HbA1c at baseline, HOMA2-B, as well as a lower CGR were significantly predictive for the occurrence of the primary endpoint. The probability of meeting the primary endpoint was the highest for mild obesity-related diabetes [hazard ratio 3.28 (95% confidence interval 1.75-6.2)], followed by severe insulin-deficient diabetes [hazard ratio 2.03 (95% confidence interval 1.1-3.7)], mild age-related diabetes and the lowest for severe insulin-resistant diabetes. The best performance to predict TF with an area under the curve (AUC) of 0.77 was HbA1c at baseline, followed by HOMA2-B (AUC 0.69) and CGR (AUC 0.64). HbA1c, indices of insulin secretion capacity (HOMA2-B and CGR) and T2D clusters might be applicable tools to guide practitioners in the decision of whether insulin is required in people already diagnosed with T2D. These findings need to be validated in prospective studies.

Atrial Septal Defect Device Closure in Patients with Metabolic or Genetic Diseases

Background: The coexistence of a metabolic or genetic disease can complicate the course of an atrial septal defect device closure. Methods: The database of our hospital was searched for patients who had undergone atrial septal defect (ASD) device closure and had concurrent metabolic and genetic diseases. Out of 188 such patients, 11 were identified. Results: This cohort study included 11 patients with type 1 diabetes mellitus, insulin resistance, mitochondrial diseases, rickets, Seckel syndrome, Alagille syndrome, cystic fibrosis, Down syndrome, and Crigler-Najjar syndrome type II. The patients were followed for a median of 4 years. Two patients experienced thromboembolic events. One procedure failed as the device was embolized. Large devices with a waist circumference greater than 1.5 times the body weight were used in 3 patients. One patient died 19 days after the procedure due to multi-organ failure, which was not related to device closure. Conclusions: In patients with metabolic or genetic diseases, this procedure may be complicated by factors such as small patient size, hypercoagulation, organ failure (cardiac, renal, or hepatic), vascular abnormalities, and issues with anesthesia or transesophageal echocardiography. It is recommended that careful attention be given to the specific challenges associated with each disease. The utilization of large devices can be considered safe, particularly in patients beyond 4 years of age.