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Indoor‐confined cats are prone to developing obesity due to a sedentary life and an energy intake exceeding energy requirements. As in humans, feline obesity decreases insulin sensitivity and increases the risk of developing feline diabetes mellitus, but the pathophysiological mechanisms are currently poorly understood. Human obesity‐related metabolic alterations seem to relate to changes in the expression of genes involved in glucose metabolism, insulin action and inflammation. The objective of the current study was to investigate changes in the expression of genes relating to obesity, glucose metabolism and inflammation in cats with non‐experimentally induced obesity. Biopsies from the sartorius muscle and subcutaneous adipose tissue were obtained from 73 healthy, neutered, indoor‐confined domestic shorthaired cats ranging from lean to obese. Quantification of obesity‐related gene expression levels relative to glyceraldehyde‐3‐phosphate dehydrogenase was performed by quantitative real‐time polymerase chain reaction. A negative association between obesity and adiponectin expression was observed in the adipose tissue (mean ± SD; normal weight, 27.30 × 10−3 ± 77.14 × 10−3; overweight, 2.89 × 10−3 ± 0.38 × 10−3 and obese, 2.93 × 10−3 ± 4.20 × 10−3, p < 0.05). In muscle, the expression of peroxisome proliferative activated receptor‐γ2 and plasminogen activator inhibitor‐1 was increased in the obese compared to the normal‐weight cats, and resistin was increased in the normal‐weight compared to the overweight cats. There were no detectable obesity‐related changes in the messenger RNA levels of inflammatory cytokines. In conclusion, a possible obesity‐related low‐grade inflammation caused by increased expression of key proinflammatory regulators was not observed. This could imply that the development of feline obesity and ensuing insulin resistance may not be based on tissue‐derived inflammation, but caused by several determining factors, many of which still need further investigation. [ABSTRACT FROM AUTHOR]

Aim: The voltage‐gated potassium channel Kv11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic α‐ and β‐cells. Moxifloxacin blocks the Kv11.1 channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the Kv11.1 channel. Materials and Methods: The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double‐blind, crossover study of young men and women (age 20‐40 years and body mass index 18.5‐27.5 kg/m2) without chronic disease, using 6‐h oral glucose tolerance tests and continuous glucose monitoring. Results: Thirty‐eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasma‐glucose response (AUC0‐30 min) by 7% (95% CI: −9% to −4%, p <.01), and overall insulin response (AUC0‐360 min) decreased by 18% (95% CI: −24% to −11%, p <.01) and plasma glucagon increased by 17% (95% CI: 4%‐33%, p =.03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%. Conclusions: In young men and women, moxifloxacin, a drug known to block the Kv11.1 channel, increased QT interval, decreased glucose levels and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia. [ABSTRACT FROM AUTHOR]

Voltage‐gated potassium (Kv) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss‐of‐function (LoF) mutations in KCNQ1, encoding Kv7.1, and KCNH2 (hERG), encoding Kv11.1, were found to exhibit post‐prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K+ channels in pancreatic beta cell function, with emphasis on Kv7.1 and Kv11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre‐clinical, clinical and genome‐wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes. [ABSTRACT FROM AUTHOR]

In the last decade, there has been an explosion in both the number of and knowledge about miRNAs associated with both type 1 and type 2 diabetes. Even though we are presently in the initial stages of understanding how this novel class of posttranscriptional regulators are involved in diabetes, recent studies have demonstrated that miRNAs are important regulators of the islet transcriptome, controlling apoptosis, differentiation and proliferation, as well as regulating unique islet and beta-cell functions and pathways such as insulin expression, processing and secretion. Furthermore, a large number of miRNAs have been linked to diabetogenic processes induced by elevated levels of glucose, free fatty acids and inflammatory cytokines. Thus, miRNAs are novel therapeutic targets with the potential of protecting the beta-cell, and there is proof of principle that miRNA antagonists, so-called antagomirs, are effective in vivo for other disorders. miRNAs are exported out of cells in exosomes, raising the intriguing possibility of cell-to-cell communication between distant tissues via miRNAs and that miRNAs can be used as biomarkers of beta-cell function, mass and survival. The purpose of this review is to provide a status on how miRNAs control beta-cell function and viability in health and disease. [ABSTRACT FROM AUTHOR]

It was hypothesized that IL-1 antagonism would preserve β-cell function in new onset Type 1 diabetes (T1D). However, the Anti-Interleukin-1 in Diabetes Action (AIDA) and TrialNet Canakinumab (TN-14) trials failed to show efficacy of IL-1 receptor antagonist (IL-1Ra) or canakinumab, as measured by stimulated C-peptide response. Additional measures are needed to define immune state changes associated with therapeutic responses. Here, we studied these trial participants with plasma-induced transcriptional analysis. In blinded analyses, 70.2% of AIDA and 68.9% of TN-14 participants were correctly called to their treatment arm. While the transcriptional signatures from the two trials were distinct, both therapies achieved varying immunomodulation consistent with IL-1 inhibition. On average, IL-1 antagonism resulted in modest normalization relative to healthy controls. At endpoint, signatures were quantified using a gene ontology-based inflammatory index, and an inverse relationship was observed between measured inflammation and stimulated C-peptide response in IL-1Ra- and canakinumab-treated patients. Cytokine neutralization studies showed that IL-1α and IL-1β additively contribute to the T1D inflammatory state. Finally, analyses of baseline signatures were indicative of later therapeutic response. Despite the absence of clinical efficacy by IL-1 antagonist therapy, transcriptional analysis detected immunomodulation and may yield new insight when applied to other clinical trials. [ABSTRACT FROM AUTHOR]

Background We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes. Methods One hundred and eighteen patients with type 1 diabetes (20.3 ± 7.5 years) diagnosed <5 years underwent standardized mixed meal test (MMTT) for 2 h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis. Results Patients were divided by their adipokine levels in subgroups above or below the median level ('high versus low'). High adiponectin levels (>10.6 µg/mL) were associated with lower C-peptide compared to the low adiponectin subgroup ( p < 0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders ( p < 0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests ( p < 0.05). Serum adipokines fell during MMTT ( p < 0.05). Conclusions Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Biological activity of the neural cell adhesion molecule (NCAM) depends on both adhesion and activation of intra-cellular signaling. Based on in vitro experiments with truncated extra-cellular domains, several models describing homophilic NCAM trans- and cis-interactions have been proposed. However, cis-dimerization in living cells has not been shown directly and the role of the cytoplasmic part in NCAM dimerization is poorly understood. Here, we used the bioluminescence resonance energy transfer (BRET2) technique to directly demonstrate that full-length NCAM cis-homodimerizes in living cells. Based on BRET250 values we suggest that the intra-cellular part of NCAM inhibits cis-dimerization, an effect mainly dependent on the palmitoylation sites. Structured summary: MINT-8071463: NCAM140 (uniprotkb:P13591-1) physically interacts (MI:0915) with NCAM140 (uniprotkb:P13591-1) by bioluminescence resonance energy transfer (MI:0012) MINT-8071506: NCAM180 (genbank_protein_gi:119587605) physically interacts (MI:0915) with NCAM-180 (genbank_protein_gi:119587605) by bioluminescence resonance energy transfer (MI:0012) MINT-8071483: NCAM140 (uniprotkb:P13591-1) physically interacts (MI:0915) with NCAM140 (uniprotkb:P13591-1) by competition binding (MI:0405) [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is caused by an inflammatory destruction of pancreatic beta-cells. Pro-inflammatory cytokines, in particular interleukin-1 (IL-1), have been suggested to be effector molecules based on the observations that pro-inflammatory cytokines cause beta-cell apoptosis in vitro and aggravate diabetes in vivo, and that inhibition of the action of these cytokines reduce diabetes incidence in animal models of type 1 diabetes and islet graft destruction. This review presents the rationale for and design of a recently launched double-blind, multicenter, randomized clinical trial that investigates the effect of interleukin-1 antagonism on beta-cell function in subjects with T1D of recent-onset. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Differences in breastfeeding, other milk feeding and complementary feeding patterns were evaluated in infants at increased genetic risk with and without maternal type 1 diabetes (T1D). The Trial to Reduce IDDM in the Genetically at Risk is an international nutritional primary prevention double-blinded randomized trial to test whether weaning to extensively hydrolyzed vs. intact cow's milk protein formula will decrease the development of T1D-associated autoantibodies and T1D. Infant diet was prospectively assessed at two visits and seven telephone interviews between birth and 8 months. Countries were grouped into seven regions: Australia, Canada, Northern Europe, Southern Europe, Central Europe I, Central Europe II and the United States. Newborn infants with a first-degree relative with T1D and increased human leukocyte antigen-conferred susceptibility to T1D were recruited. A lower proportion of infants born to mothers with than without T1D were breastfed until 6 months of age in all regions (range, 51% to 60% vs. 70% to 80%). Complementary feeding patterns differed more by region than by maternal T1D. In Northern Europe, a higher proportion of infants consumed vegetables and fruits daily compared with other regions. Consumption of meat was more frequent in all European regions, whereas cereal consumption was most frequent in Southern Europe, Canada and the United States. Maternal T1D status was associated with breastfeeding and other milk feeding patterns similarly across regions but was unrelated to the introduction of complementary foods. Infant feeding patterns differed significantly among regions and were largely inconsistent with current recommended guidelines. [ABSTRACT FROM AUTHOR]

Voltage-gated potassium (K v ) channels play an important role in the repolarization of a variety of excitable tissues, including in the cardiomyocyte and the pancreatic beta cell. Recently, individuals carrying loss-of-function (LoF) mutations in KCNQ1, encoding K v 7.1, and KCNH2 (hERG), encoding K v 11.1, were found to exhibit post-prandial hyperinsulinaemia and episodes of hypoglycaemia. These LoF mutations also cause the cardiac disorder long QT syndrome (LQTS), which can be aggravated by hypoglycaemia. Interestingly, patients with LQTS also have a higher burden of diabetes compared to the background population, an apparent paradox in relation to the hyperinsulinaemic phenotype, and KCNQ1 has been identified as a type 2 diabetes risk gene. This review article summarizes the involvement of delayed rectifier K + channels in pancreatic beta cell function, with emphasis on K v 7.1 and K v 11.1, using the cardiomyocyte for context. The functional and clinical consequences of LoF mutations and polymorphisms in these channels on blood glucose homeostasis are explored using evidence from pre-clinical, clinical and genome-wide association studies, thereby evaluating the link between LQTS, hyperinsulinaemia and type 2 diabetes., (© 2022 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)