Libor Vítek and Martin Haluzík
Bile acids (BA), long believed to only have lipid-digestive functions, have emerged as novel metabolic modulators. They have important endocrine effects through multiple cytoplasmic as well as nuclear receptors in various organs and tissues. BA affect multiple functions to control energy homeostasis, as well as glucose and lipid metabolism, predominantly by activating the nuclear farnesoid X receptor and the cytoplasmic G protein-coupled BA receptor TGR5 in a variety of tissues. However, BA also are aimed at many other cellular targets in a wide array of organs and cell compartments. Their role in the pathogenesis of diabetes, obesity and other ‘diseases of civilization’ becomes even more clear. They also interact with the gut microbiome, with important clinical implications, further extending the complexity of their biological functions. Therefore, it is not surprising that BA metabolism is substantially modulated by bariatric surgery, a phenomenon contributing favorably to the therapeutic effects of these surgical procedures. Based on these data, several therapeutic approaches to ameliorate obesity and diabetes have been proposed to affect the cellular targets of BA.
Milos Mraz and Martin Haluzik
Adipose tissue (AT) lies at the crossroad of nutrition, metabolism, and immunity; AT inflammation was proposed as a central mechanism connecting obesity with its metabolic and vascular complications. Resident immune cells constitute the second largest AT cellular component after adipocytes and as such play important roles in the maintenance of AT homeostasis. Obesity-induced changes in their number and activity result in the activation of local and later systemic inflammatory response, marking the transition from simple adiposity to diseases such as type 2 diabetes mellitus, arterial hypertension, and ischemic heart disease. This review has focused on the various subsets of immune cells in AT and their role in the development of AT inflammation and obesity-induced insulin resistance.
Martin Haluzík, Helena Kratochvílová, Denisa Haluzíková and Miloš Mráz
Increasing worldwide prevalence of type 2 diabetes mellitus and its accompanying pathologies such as obesity, arterial hypertension and dyslipidemia represents one of the most important challenges of current medicine. Despite intensive efforts, high percentage of patients with type 2 diabetes does not achieve treatment goals and struggle with increasing body weight and poor glucose control. While novel classes of antidiabetic medications such as incretin-based therapies and gliflozins have some favorable characteristics compared to older antidiabetics, the only therapeutic option shown to substantially modify the progression of diabetes or to achieve its remission is bariatric surgery. Its efficacy in the treatment of diabetes is well established, but the exact underlying modes of action are still only partially described. They include restriction of food amount, enhanced passage of chymus into distal part of small intestine with subsequent modification of gastrointestinal hormones and bile acids secretion, neural mechanisms, changes in gut microbiota and many other possible mechanisms underscoring the importance of the gut in the regulation of glucose metabolism. In addition to bariatric surgery, less-invasive endoscopic methods based on the principles of bariatric surgery were introduced and showed promising results. This review highlights the role of the intestine in the regulation of glucose homeostasis focusing on the mechanisms of action of bariatric and especially endoscopic methods of the treatment of diabetes. A better understanding of these mechanisms may lead to less invasive endoscopic treatments of diabetes and obesity that may complement and widen current therapeutic options.
Patrik Šimják, Anna Cinkajzlová, Kateřina Anderlová, Antonín Pařízek, Miloš Mráz, Michal Kršek and Martin Haluzík
Gestational diabetes mellitus is defined as diabetes diagnosed in the second or third trimester of pregnancy in patients with no history of diabetes prior to gestation. It is the most common complication of pregnancy. The underlying pathophysiology shares some common features with type 2 diabetes mellitus (T2DM) combining relatively insufficient insulin secretion with increased peripheral insulin resistance. While a certain degree of insulin resistance is the physiological characteristics of the second half of pregnancy, it is significantly more pronounced in patients with gestational diabetes. Adipose tissue dysfunction and subclinical inflammation in obesity are well-described causes of increased insulin resistance in non-pregnant subjects and are often observed in individuals with T2DM. Emerging evidence of altered adipokine expression and local inflammation in adipose tissue in patients with gestational diabetes suggests an important involvement of adipose tissue in its etiopathogenesis. This review aims to summarize current knowledge of adipose tissue dysfunction and its role in the development of gestational diabetes. We specifically focus on the significance of alterations of adipokines and immunocompetent cells number and phenotype in fat. Detailed understanding of the role of adipose tissue in gestational diabetes may provide new insights into its pathophysiology and open new possibilities of its prevention and treatment.
Martina Holubová, Jana Zemenová, Barbora Mikulášková, Vladimíra Panajotova, Jiří Stöhr, Martin Haluzík, Jaroslav Kuneš, Blanka Železná and Lenka Maletínská
Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood–brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of both Prrp-knockout and Prrp receptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague–Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.
Martina Bugáňová, Helena Pelantová, Martina Holubová, Blanka Šedivá, Lenka Maletínská, Blanka Železná, Jaroslav Kuneš, Petr Kačer, Marek Kuzma and Martin Haluzík
Liraglutide is the glucagon-like peptide-1 receptor agonist widely used for the treatment of type 2 diabetes mellitus. Recently, it has been demonstrated to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes and high cardiovascular risk. Although the major modes of liraglutide action are well-known, its detailed action at the metabolic level has not been studied. To this end, we explored the effect of 2-week liraglutide treatment in C57BL/6 male mice with obesity and diabetes induced by 13 weeks of high-fat diet using NMR spectroscopy to capture the changes in urine metabolic profile induced by the therapy. The liraglutide treatment decreased body and fat pads weight along with blood glucose and triglyceride levels. NMR spectroscopy identified 11 metabolites significantly affected by liraglutide treatment as compared to high-fat diet-fed control group. These metabolites included ones involved in nicotinamide adenine dinucleotide metabolism, β-oxidation of fatty acids and microbiome changes. Although majority of the metabolites changed after liraglutide treatment were similar as the ones previously identified after vildagliptin administration in a similar mouse model, the changes in creatinine, taurine and trigonelline were specific for liraglutide administration. The significance of these changes and its possible use in the personalization of antidiabetic therapy in humans requires further research.
Petra Kaválková, Miloš Mráz, Pavel Trachta, Jana Kloučková, Anna Cinkajzlová, Zdeňka Lacinová, Denisa Haluzíková, Marek Beneš, Zuzana Vlasáková, Václav Burda, Daniel Novák, Tomáš Petr, Libor Vítek, Terezie Pelikánová and Martin Haluzík
Duodenal–jejunal bypass liner (DJBL) is an endoscopically implantable device designed to noninvasively mimic the effects of gastrointestinal bypass operations by excluding the duodenum and proximal jejunum from the contact with ingested food. The aim of our study was to assess the influence of DJBL on anthropometric parameters, glucose regulation, metabolic and hormonal profile in obese patients with type 2 diabetes mellitus (T2DM) and to characterize both the magnitude and the possible mechanisms of its effect. Thirty obese patients with poorly controlled T2DM underwent the implantation of DJBL and were assessed before and 1, 6 and 10months after the implantation, and 3months after the removal of DJBL. The implantation decreased body weight, and improved lipid levels and glucose regulation along with reduced glycemic variability. Serum concentrations of fibroblast growth factor 19 (FGF19) and bile acids markedly increased together with a tendency to restoration of postprandial peak of GLP1. White blood cell count slightly increased and red blood cell count decreased throughout the DJBL implantation period along with decreased ferritin, iron and vitamin B12 concentrations. Blood count returned to baseline values 3months after DJBL removal. Decreased body weight and improved glucose control persisted with only slight deterioration 3months after DJBL removal while the effect on lipids was lost. We conclude that the implantation of DJBL induced a sustained reduction in body weight and improvement in regulation of lipid and glucose. The increase in FGF19 and bile acids levels could be at least partially responsible for these effects.