Search

Metabolic tests are vital to determine in vivo insulin sensitivity and glucose metabolism in preclinical models, usually rodents. Such tests include glucose tolerance tests, insulin tolerance tests, and glucose clamps. Although these tests are not standardized, there are general guidelines for their completion and analysis that are constantly being refined. In this review, we describe metabolic tests in rodents as well as factors to consider when designing and performing these tests. [ABSTRACT FROM AUTHOR]

Purpose: The effect of hyperinsulinemia on short-term outcomes after laparoscopic sleeve gastrectomy (LSG) in patients with obesity combined with insulin resistance is unclear. Material and Methods: This was a retrospective analysis of patients who underwent LSG at our center between January 1, 2020, and December 31, 2021. Patients were divided into hyperinsulinemia (HINS) and nonhyperinsulinemia (NHINS) groups based on fasting insulin levels. The primary endpoint was weight change. Metabolic disease outcomes, postoperative complications, and quality of life score changes were secondary endpoints. Results: A total of 92 patients were included in this study, with 59 in the HINS group and 33 in the NHINS group. At 6 months postoperatively, the median (P25, P75) %EWL was 76.01 (64.40, 86.99)% in the HINS group and 92.02 (86.78, 100.88)% in the NHINS group (P< 0.001). The mean %TWL (SD) was 23.26 (7.14)% in the HINS group and 26.80 (6.55)% in the NHINS group (P=0.021). The remission of dyslipidemia and hypertension in the NHINS group and the HINS group were not significantly different (P> 0.05 for all). The differences in QOL between groups were not statistically significant (P=0.788). In terms of postoperative complications, there was no statistically significant difference between the groups (P> 0.05 for all). Conclusion: HINS negatively influences weight change in patients with obesity and insulin resistance, and the NHINS group had better postoperative weight loss. In terms of hypertension, dyslipidemia, and postoperative complications, there was no significant effect of HINS. [ABSTRACT FROM AUTHOR]

Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed. [ABSTRACT FROM AUTHOR]

Background/Aims: In contrast to streptozotocin (STZ)-induced rodent models of diabetes, there are no thorough characterizations of the intestinal phenotype and the underlying changes in the global gene-expression of genetic models of diabetes, such as the Zucker diabetic fatty (ZDF) rat. The aim of the present study was to characterize the intestine in the ZDF rat. Methods: The intestine of ZDF rats and lean controls was examined macroscopically and histologically, and ribonucleic acid sequencing (RNAseq) was performed in samples of jejunal mucosa. Results: We observed an increased mass and length of the small and large intestines in ZDF rats. RNAseq showed an increased expression of Pdk2 and Pdk4, which are involved in the regulation of glucose and fatty acid metabolism, and increased expression of genes involved in gluconeogenesis and peroxisomal beta-oxidation in jejunal mucosa. Conclusion: Intestinal enlargement in ZDF rats is likely driven by increased food intake, since (i) it also occurs in obese and normoglycemic Zucker fatty rats, and (ii) insulin treatment of STZ-induced diabetic rats reduced the food intake and mass of the small intestine. Results from RNAseq indicate that small intestinal epithelial cells in ZDF rats have developed insulin resis tance, and support that a normal physiological effect of insulin in the enterocytes is the regulation of glucose metabolism. [ABSTRACT FROM AUTHOR]

GLP-1 and its based drugs possess extrapancreatic metabolic functions, including that in the liver. These direct hepatic metabolic functions explain their therapeutic efficiency for subjects with insulin resistance. The direct hepatic functions could be mediated by previously assumed "degradation" products of GLP-1 without involving canonic GLP- 1R. Although GLP-1 analogs were created as therapeutic incretins, extrapancreatic functions of these drugs, as well as native GLP-1, have been broadly recognized. Among them, the hepatic functions are particularly important. Postprandial GLP-1 release contributes to insulin secretion, which represses hepatic glucose production. This indirect effect of GLP-1 is known as the gut-pancreas-liver axis. Great efforts have been made to determine whether GLP-1 and its analogs possess direct metabolic effects on the liver, as the determination of the existence of direct hepatic effects may advance the therapeutic theory and clinical practice on subjects with insulin resistance. Furthermore, recent investigations on the metabolic beneficial effects of previously assumed "degradation" products of GLP-1 in the liver and elsewhere, including GLP-128-36 and GLP-132-36, have drawn intensive attention. Such investigations may further improve the development and the usage of GLP-1-based drugs. Here, we have reviewed the current advancement and the existing controversies on the exploration of direct hepatic functions of GLP-1 and presented our perspectives that the direct hepatic metabolic effects of GLP-1 could be a GLP-1 receptor-independent event involving Wnt signaling pathway activation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Epidemiological studies have reported that the prevalence of diabetes in women > 40 years of age, especially those in the postmenopausal phase, was higher than in men in areas with high levels of arsenic in drinking water. The detailed effect of arsenic on glucose metabolism/ homeostasis in the postmenopausal condition is still unclear. OBJECTIVES: We investigated the effects of arsenic at doses relevant to human exposure from drinking water on blood glucose regulation in estrogen-deficient female mice. METHODS: Adult female mice who underwent ovariectomy or sham surgery were exposed to drinking water contaminated with arsenic trioxide (0.05 or 0.5 ppm) in the presence or absence of 17β-estradiol supplementation for 2--6 weeks. Assays related to glucose metabolism were performed. RESULTS: Exposure of sham mice to arsenic significantly increased blood glucose, decreased plasma insulin, and impaired glucose tolerance, but did not induce insulin resistance. Blood glucose and insulin were higher, and glucose intolerance, insulin intolerance, and insulin resistance were increased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Furthermore, liver phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was increased and liver glycogen content was decreased in arsenic-treated ovariectomized mice compared with arsenic-treated sham mice. Glucose-stimulated insulin secretion in islets isolated from arsenic-treated ovariectomized mice was also significantly decreased. Arsenic treatment significantly decreased plasma adiponectin levels in sham and ovariectomized mice. Altered glucose metabolism/ homeostasis in arsenic-treated ovariectomized mice was reversed by 17| β -estradiol supplementation. CONCLUSIONS: Our findings suggest that estrogen deficiency plays an important role in arsenic-altered glucose metabolism/homeostasis in females. [ABSTRACT FROM AUTHOR]

Obesity and type 2 diabetes are associated with an increased risk for development of certain forms of cancer, including colon cancer. The publication of highly controversial epidemiological studies in 2009 raised the possibility that use of the insulin analog glargine increases this risk further. However, it is not clear how mitogenic effects of insulin and insulin analogs measured in vitro correlate with tumor growth-promoting effects in vivo. The aim of this study was to examine possible growth-promoting effects of native human insulin, insulin X10 and IGF-1, which are considered positive controls in vitro, in a short-term animal model of an obesity- and diabetes-relevant cancer. We characterized insulin and IGF-1 receptor expression and the response to treatment with insulin, X10 and IGF-1 in the murine colon cancer cell line (MC38 cells) in vitro and in vivo. Furthermore, we examined pharmacokinetics and pharmacodynamics and monitored growth of MC38 cell allografts in mice with diet-induced obesity treated with human insulin, X10 and IGF-1. Treatment with X10 and IGF-1 significantly increased growth of MC38 cell allografts in mice with diet-induced obesity and we can therefore conclude that supra-pharmacological doses of the insulin analog X10, which is super-mitogenic in vitro and increased the incidence of mammary tumors in female rats in a 12-month toxicity study, also increase growth of tumor allografts in a short-term animal model. [ABSTRACT FROM AUTHOR]