Obesity has dramatically increased in Irish adolescents and young adults and is related to changes in physical activity and diet (1,2). Severe obesity is associated with a much earlier presentation of type 2 diabetes (3—6), as noted in Irish Caucasian patients (7). Most studies of early-onset type 2 diabetes have been in minority populations with higher risk of type 2 diabetes than Caucasians (4—6). The potential for diabetes complications in these young individuals has immediate implications for diagnosis and treatment and longer-term implications for public health. We measured insulin resistance, insulin secretion, and a range of cardiovascular risk markers in an obese group of young Irish subjects with type 2 diabetes and compared them with a matched group of obese nondiabetic subjects and a representative group of older subjects with type 2 diabetes. All of the subjects were from the same clinic, and all were matched for obesity and duration of diabetes.
Eleven subjects with early-onset (age 40 years) type 2 diabetes were recruited, as well as 13 nondiabetic control subjects who were age and obesity matched to the young type 2 diabetic group. The protocol had ethical approval, and written informed consent was obtained. An oral glucose tolerance test was used to confirm glucose tolerance.
### Intravenous glucose tolerance test
An insulin-modified frequently sampled intravenous glucose tolerance test was performed (8,9). Oral hypoglycemic agents were withheld for 7 days before the …
There are conflicting reports on the effect of serum from patients with insulin-dependent diabetes mellitus (IDDM) or normal human serum on beta-cell function and insulin secretion. Here, we report that the sera of newly diagnosed IDDM patients potently suppresses insulin secretion from a clonal rat pancreatic beta-cell line (BRIN-BD11), but do not alter cell viability. Indeed, the viability of the beta-cells was not significantly different between cells cultured in 10% (v/v) IDDM sera, normal human sera, or fetal calf serum after 24, 48 and 72 h. Alanine-stimulated insulin secretion from cells cultured for 24 h in (10% v/v) IDDM patient sera was reduced to 48% of that secreted from cells cultured in (10% v/v) normal human sera. After depletion of the complement components C1q and C3, the inhibition of insulin secretion induced by IDDM patient sera was significantly reversed (no significant difference was observed between cells cultured in complement-depleted IDDM patient sera and cells cultured in normal human sera or complement-depleted normal human sera). The concentration of glutamic acid decarboxylase (GAD) autoantibodies was markedly increased in the sera of six out of nine newly diagnosed IDDM patients in this study, whereas insulin auto-antibodies (IAA) were detected in the sera of three of the nine patients and islet-cell antibodies (ICA) in the sera of five of them. In addition, the concentration of soluble terminal complement complexes (SC5-9) was greater in some of the beta-cell culture media samples after 24 h incubation when the incubation medium was supplemented with IDDM patient sera than when supplementation was with normal human sera. We propose that the mechanism of sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement- and cytokine-stimulated intracellular events that attenuate the metabolite-induced secretory process.
Abstract Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is the most important tissue involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2). GSEA analysis from microarray studies revealed the repression of mitochondrial mt-aaRSs independently of age, which was validated by real-time PCR assays. In agreement with this, a reduced expression of several encoding mt-aaRSs was also detected in skeletal muscle from diabetic (db/db) mice but not in obese ob/ob mice. In addition, the expression of the mt-aaRSs proteins most relevant in the synthesis of mitochondrial proteins, threonyl-tRNA, and leucyl-tRNA synthetases (LARS2 and TARS2) were also repressed in muscle from db/db mice. It is likely that these alterations participate in the reduced expression of proteins synthesized in the mitochondria detected in db/db mice. Because it is known that, nitrosative stress inhibits aminoacylation of TARS2 and LARS2 activities, we noticed an increased protein expression of iNOS in isolated muscle mitochondria in diabetic mice. Our results indicate a reduced expression of mitochondrial mt-aaRSs in skeletal muscle from T2D patients, which may participate in the reduced expression of proteins synthesized in mitochondria. This may be due to an enhanced NO production secondary to enhanced iNOS expression in muscle under diabetic conditions. Highlights Mt-aaRSs are downregulated in the skeletal muscle of type 2 diabetic patients and diabetic mice. The downregulation of mt-aaRSs in the skeletal muscle of diabetic mice is affecting the synthesis of ND2 which is a mitochondrially encoded subunit of complex I. Mitochondrial iNOS could be a target for reduced expression of mt-aaRSs in the skeletal muscle of diabetic mice.
Leptin, the product of the ob gene, is a hormone secreted by adipocytes. Animals with mutations in the ob gene are obese and lose weight when given leptin, but little is known about the physiological role of leptin in humans. Obese subjects have higher concentrations of leptin than lean subjects, the strongest correlation being with percentage body fat. Thus, it appears that obese subjects are resistant to the effects of endogenously secreted leptin. We have also shown that insulin stimulates leptin production, chronically but not acutely, presumably through its trophic effect on adipocytes. Troglitazone is an insulinsensitizing thiazolidinedione, which improves hepatic and skeletal muscle insulin resistance in NIDDM and obesity. This study was undertaken to investigate the effects of troglitazone on leptin production in vitro and in vivo. In the presence and absence of 100 nmol/l insulin and 10 umol/L troglitazone, 72-h primary cultures of isolated abdominal adipocytes were studied. Insulin led to an almost twofold increase in leptin in vitro, and this increase was completely abolished by coincubation with troglitazone. Incubation with troglitazone alone led to a 40% decrease in leptin production. In obese patients administered troglitazone 200 mg twice daily for 12 weeks, there was no significant change in fasting plasma leptin concentrations, despite a 40–50% reduction in fasting and postmeal plasma insulin concentrations. Troglitazone treatment led to a significant increase in insulin sensitivity, and there was a positive correlation between the change in insulin sensitivity and the change in plasma leptin concentration in these subjects. In conclusion, troglitazone treatment had no net effect on plasma leptin concentrations, possibly because of improvement in insulin sensitivity and reduction in plasma insulin concentrations.
OBJECTIVE Low-grade chronic inflammation has been hypothesized to underlie the constellation of cardiometabolic risk factors, possibly by inducing insulin resistance. In the present study, we investigated associations between inflammation markers, insulin sensitivity (expressed as the ratio of the M value to the mean plasma insulin concentrations measured during the final 40 min of the clamp [M/I]), and a range of cardiometabolic risk factors in a large, healthy population. RESEARCH DESIGN AND METHODS The Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort includes 1,326 nondiabetic European men and women, aged between 30 and 60 years. We measured cardiometabolic risk factors and performed a hyperinsulinemic-euglycemic clamp. We determined total white blood cell count (WBC) and erythrocyte sedimentation rate (ESR) as markers of chronic inflammation. RESULTS WBC and ESR were both strongly associated with M/I. WBC and ESR were further associated with a range of cardiometabolic risk factors. Associations between WBC and HDL cholesterol, triglycerides, heart rate, fasting C-peptide, and insulin and 2-h insulin in men and women and between WBC and 2-h glucose in women remained significant after adjustment for both M/I and waist circumference. Associations between ESR and HDL cholesterol, heart rate, fasting, and 2-h insulin in men and women and between ESR and fat mass in women remained significant after adjustment for M/I and waist circumference. CONCLUSIONS This study showed that low-grade chronic inflammation is associated with the cardiometabolic risk profile of a healthy population. Insulin resistance, although strongly associated with inflammation, does not seem to play a large intermediary role.
Introduction: One of the medical emergencies worldwide is antibiotic resistance caused by the irrational use of antibiotics. This issue increases the mortality and morbidity rates and challenges in selecting the appropriate therapeutic regimen in bacterial infection cases. Solution inquiry is still being conducted, including the research and development of new antibiotics. However, there is still an imbalance between the pacing rate of new antibiotic discovery and the emergence of the antibiotic resistance problem, so that currently, there are plenty of studies on alternative therapies. Apple cider vinegar (ACV) is a fermented fruit product that has been shown to have antimicrobial effects. Methods: This review article was composed by conducting a journal search with the keywords "antibiotic resistance", "apple cider vinegar", and "antimicrobial". Among 39 journals that have been reviewed, 30 were found to be suitable as references for this article review. Results: ACV can be used as an option in adjuvant therapy for antibiotics in overcoming the problem of antibiotic resistance. ACV works by inhibiting the growth of bacteria, which can be done by eliminating the expression of several proteins and enzymes that are crucial in bacterial growth. ACV can also reduce pro-inflammatory cytokines, increase monocyte activity, and fight free radicals. In the meantime, ACV is easy to obtain at an affordable price. However, the lack of studies on the effects of ACV is still an obstacle to potentiating this adjuvant therapy. Conclusions: ACV can be used as adjuvant therapy in overcoming the problem of antibiotic resistance. Further research is still needed to determine the exact mechanism and effectiveness of ACV in the problem of antibiotic resistance. Keywords: antibiotic resistance, apple cider vinegar, antimicrobial.
The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population.
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