Cost-Effectiveness of Bariatric Surgery in Patients Living with Obesity and Type 2 Diabetes.

Aims: The favourable effects of bariatric surgeries on body weight reduction and glucose control have been demonstrated in several studies. Additionally, the cost-effectiveness of bariatric surgeries has been confirmed in several analyses. The aim of the current analysis was to demonstrate the cost-effectiveness of bariatric surgeries in obese patients with type 2 diabetes in Hungary compared to conventional diabetes treatments based on economic modelling of published clinical trial results. Materials and Methods: Patients entered the simulation model at the age of 45 with body mass index (BMI) ≥ 30 kg/m2 and type 2 diabetes. The model was performed from the public payer's perspective, comparing sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) procedures to conventional care of diabetes. The results were provided separately for three BMI categories. Results: The base-case analysis demonstrated that both surgery types were dominant; i.e., they saved 17 064 to 24 384 Euro public payer expenditures and resulted in improved health outcomes (1.36 to 1.50 quality-adjusted life years gain (QALY)) in the three BMI categories. Bariatric surgeries extended the life expectancy and the disease-free survival times of all the investigated diabetes complications. All the scenario analyses confirmed the robustness of the base-case analysis, such that bariatric surgeries remained dominant compared to conventional diabetes treatments. Conclusion: The results of this cost-effectiveness analysis highlight the importance of bariatric surgeries as alternatives to conventional diabetes treatments in the obese population. Therefore, it is strongly recommended that a wider population has access to these surgeries in Hungary.

[From GLP1 receptor agonists to triple hormone receptor activation supplemented with glucagon receptor agonism.] / A GLP1-receptor-agonistáktól a glükagonreceptor-agonizmussal kiegészített hármashormonreceptor-aktiválásig.

Following the introduction of mono- and then dual hormone (incretin) receptor agonists into therapy, attention was turned to multiple receptor stimulation, with the additional activation of the glucagon receptor, as a new option for the pharmaceutical treatment of type 2 diabetes and obesity. In addition to its role in carbohydrate metabolism, the article reviews the other important physiological tasks of glucagon, especially its participation in intrainsular paracrine regulation, energy expenditure and the shaping of appetite and food consumption. It covers the potential benefits of the triple combination and briefly touches data on the efficacy and safety of the first triple receptor agonist drug, retatrutide, in preclinical human studies. Further confirmation of the promising results may represent progress in the treatment of these forms of disease and their accompanying conditions, such as steatosis hepatis. Orv Hetil. 2023; 164(42): 1656-1664.

Mate-guarding success depends on male investment in a butterfly.

Males of many insects, including butterflies, produce mate-guarding devices, such as mating plugs, to prolong guarding and prevent future female matings in the male's absence. In a few butterflies, large external mate-guarding devices, that is, sphragides, occur. Gór et al. (Behaviour, 160, 2023 and 515-557) found conspicuously large size and morphological variation of mate-guarding devices within a single population of the potentially polyandrous Clouded Apollo (Parnassius mnemosyne, L.) butterfly. They termed the externally visible male-produced devices as Copulatory opening APpendices (CAP) consisting of small devices, termed small CAPs and the much larger shield (i.e. sphragis). Our aim was to reveal CAP replacement dynamics within females during their lifetime and to understand how male investment into small CAPs or shields was (i) related to CAP persistence on the female, that is securing paternity, (ii) associated with female quality, measured as size and (iii) with actual adult sex ratio. We investigated a univoltine Clouded Apollo population to estimate CAP replacement risks, using multistate survival models, in an extensive observational study through 6 years based on mark-recapture. Shields were the most frequent mate-guarding devices and were more persistent than small CAPs, often lasting for life, excluding future matings. Thus, most females bearing a shield were deprived of postcopulatory female choice, and the genetic variance in their offspring could be reduced compared to those bearing small CAPs, thus mating more often. The ratio of shields to all CAPs gradually decreased towards the end of the flight period. Males were more prone to produce a shield when mating females with wider thoraces and when the ratio of males (i.e. competition) was higher in the population. To our best knowledge, this is the first quantitative study to investigate potential factors on which male investment in mate-guarding devices may depend, and how the variation in these devices impacts CAP persistence on females.

iGlarLixi (insulin glargine 100 U/ml plus lixisenatide) is effective and well tolerated in people with uncontrolled type 2 diabetes regardless of age: A REALI pooled analysis of prospective real-world data.

AIM: To evaluate the effectiveness and safety in routine clinical practice of insulin glargine/lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) according to age. METHODS: Patient-level data were pooled from 1316 adults with T2D inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi for 24 weeks. Participants were classified into age subgroups of younger than 65 years (N = 806) and 65 years or older (N = 510). RESULTS: Compared with participants aged younger than 65 years, those aged 65 years or older had a numerically lower mean body mass index (31.6 vs. 32.6 kg/m2 ), a longer median diabetes duration (11.0 vs. 8.0 years), were more likely to receive prior basal insulin (48.4% vs. 43.5%) and had a lower mean HbA1c (8.93% [74.10 mmol/mol] vs. 9.22% [77.28 mmol/mol]). Similar and clinically relevant reductions in HbA1c and fasting plasma glucose from baseline to week 24 of iGlarLixi therapy were observed regardless of age. At 24 weeks, least-squares adjusted mean (95% confidence interval [CI]) change in HbA1c from baseline was -1.55% (-1.65% to -1.44%) in those aged 65 years or older and -1.42% (-1.50% to -1.33%) in those aged younger than 65 years (95% CI: -0.26% to 0.00%; P = .058 between subgroups). Low incidences of gastrointestinal adverse events and hypoglycaemic episodes were reported in both age subgroups. iGlarLixi decreased mean body weight from baseline to week 24 in both subgroups (-1.6 kg in those aged ≥ 65 years and -2.0 kg in those aged < 65 years). CONCLUSIONS: iGlarLixi is effective and well tolerated in both younger and older people with uncontrolled T2D.

[The "other" incretin - the therapeutic rediscovery of the glucose-dependent insulinotropic polypeptide]. / A "másik" inkretin ­ a glükózdependens insulinotrop polipeptid terápiás újrafelfedezése.

Among the two incretins that strongly stimulate insulin secretion and are also involved in its physiological regulation in type 2 diabetes, glucagon-like peptide-1 (GLP1) has been the focus of interest for a long time, due to its retained - although reduced - secretagogue nature also in type 2 diabetes. Its receptor agonists were also included in the antidiabetic treatment toolkit. In the light of more recent studies, however, the "other" incretin, the glucose-dependent insulinotropic polypeptide (GIP) has also come into a different light. It turned out that by regulating glucagon and insulin production according to blood sugar levels, it acts as a bifunctional blood sugar stabilizing factor in type 2 diabetes as well. The article reviews new data on the physiology of GIP, its verifiable effects in type 2 diabetes and obesity, the so-called "twincretin" effect as well as the benefits of the double stimulation of the GIP and the GLP1 receptor. It describes the pharmacology of the first dual receptor agonist, tirzepatide, already incorporated in therapeutic recommendations, and the first clinical trials related to its use. In the light of the data so far, the molecule may open new horizons in the treatment of type 2 diabetes and obesity. Orv Hetil. 2023; 164(6): 210-218.

Effectiveness and Safety of iGlarLixi (Insulin Glargine 100 U/mL Plus Lixisenatide) in Type 2 Diabetes According to the Timing of Daily Administration: Data from the REALI Pooled Analysis.

INTRODUCTION: iGlarLixi (insulin glargine 100 U/mL plus lixisenatide) has demonstrated glycaemic efficacy and safety in adults with inadequately controlled type 2 diabetes mellitus (T2DM). Per the European Medicines Agency's product label, iGlarLixi should be injected once a day within 1 h prior to a meal, preferably the same meal every day when the most convenient meal has been chosen. It is however unknown whether iGlarLixi administration timing affects glycaemic control and safety, as clinical trial evidence is mainly based on pre-breakfast iGlarLixi administration. Therefore, we assessed the effectiveness and safety of iGlarLixi in clinical practice, according to its administration timing. METHODS: Data were pooled from two prospective observational studies including 1303 European participants with T2DM inadequately controlled on oral antidiabetic drugs with or without basal insulin who initiated iGlarLixi therapy for 24 weeks. Participants were classified into four subgroups based on daily timing of iGlarLixi injection: pre-breakfast (N = 436), pre-lunch (N = 262), pre-dinner (N = 399), and those who switched iGlarLixi injection time during the study (N = 206). RESULTS: No meaningful differences in baseline characteristics were observed between the study groups. Least-squares mean reductions in haemoglobin A1c (HbA1c) from baseline to week 24 were substantial in all groups, with the numerically largest decrease observed in the pre-breakfast group (1.57%) compared with the pre-lunch (1.27%), pre-dinner (1.42%), or changed injection time (1.33%) groups. Pre-breakfast iGlarLixi injection also resulted in a numerically greater proportion of participants achieving HbA1c < 7.0% at week 24 (33.7% versus 19.0% for pre-lunch, 25.6% pre-dinner, and 23.2% changed injection time). iGlarLixi was well tolerated across all groups, with low rates of gastrointestinal disorders and hypoglycaemia. Mean body weight decreased similarly in all groups (by 1.3-2.3 kg). CONCLUSION: iGlarLixi was effective and safe regardless of its daily administration time. However, pre-breakfast iGlarLixi injection resulted in a more effective glycaemic control.

[Is there a need for a revised classification in diabetes mellitus?] / Indokolt-e a klasszifikáció módosítása diabetesben?

Diabetes mellitus is a cluster of diseases with heterogeneous etiopathogenesis and clinical nature. The exact classification of certain cases is of decisive importance in terms of the optimal choice of treatment. However, the classification is still not completely resolved, despite the available, ever-expanding tool park and rapidly expanding knowledge. Therefore, new recommendations are made to clarify the grouping. This article reviews the classification guidelines created between 1965 and 2019 based on international consensus, with the coordination of the World Health Organization (WHO), as well as the proposals made based on recent tests and observations. It states that for daily practice, the present WHO guideline is still the most orienting. In addition, in cases of uncertain classification, it is essential to follow up the patients and repeat the examinations as necessary, until the nature of the specific form of the disease is clarified. Orv Hetil. 2022; 163(48): 1909-1916.

Phenotypic senescence in a natural insect population.

Senescence seems to be universal in living organisms and plays a major role in life-history strategies. Phenotypic senescence, the decline of body condition and/or performance with age, is a largely understudied component of senescence in natural insect populations, although it would be important to understand how and why insects age under natural conditions. We aimed (i) to investigate how body mass and thorax width change with age in a natural population of the univoltine Clouded Apollo butterfly (Parnassius mnemosyne, Lepidoptera: Papilionidae) and (ii) to assess the relationship of this change with sex and wing length. We studied a population between 2014 and 2020 using mark-recapture during the whole flight period each year. Repeated measurements of body mass and thorax width and single measurements of wing length were performed on marked individuals. We analyzed body mass and thorax width change with age (days since marking), wing length, and the date of the first capture. Both body mass and thorax width declined nonlinearly with age. Individuals appearing earlier in the flight period had significantly higher initial body mass and thorax width and their body mass declined faster than later ones. Initial body sizes of females were higher, but males' body sizes decreased slower. Initial thorax width showed higher annual variation than body mass. To our best knowledge, this is the first study that revealed phenotypic senescence in a natural butterfly population, using in vivo measurements. We found sexual differences in the rate of phenotypic senescence. Despite the annual variation of initial body sizes, the rate of senescence did not vary considerably across the years.

Effectiveness of IGlarLixi, a Fixed-Ratio Combination of Insulin Glargine 100 U/mL and Lixisenatide, in People with Type 2 Diabetes.

INTRODUCTION: The latest Position Statement of the American Diabetes Association/European Association for the Study of Diabetes proposes the use of a fixed-ratio combination (FRC) of a long-acting basal insulin and a glucagon-like peptide-1 receptor agonist as part of treatment intensification. This study aimed to assess the effectiveness of the insulin glargine + lixisenatide (iGlarLixi) FRC on glycaemic control and hypoglycaemia in real-life settings. METHODS: This non-interventional, 26-week study included participants aged 18-80 years with suboptimally controlled type 2 diabetes (T2D) using oral antidiabetics (OADs) ± basal insulin therapy. The primary efficacy endpoint was the proportion of participants who achieved at least a 1% decrease in glycated haemoblobin (HbA1c) level from baseline to week 26. RESULTS: Of the 441 participants eligible for entry into the study, 353 were included in the efficacy analyses. These individuals were switched from OADs without (282 [79.9%]) or with (71 [20.1%]) insulin-based treatment. A reduction in HbA1c of at least 1.0% (primary endpoint) was achieved by 215 subjects (60.9%). All glycaemic variables (mean ± standard deviation) improved significantly during follow-up (HbA1c, from 8.9 ± 1.31 to 7.4 ± 0.97%; fasting blood glucose, from 9.0 ± 2.18 to 6.9 ± 1.23 mmol/L; postprandial blood glucose, from 11.3 ± 2.33 to 8.5 ± 1.46 mmol/L; p < 0.001 for all). Body weight also decreased during follow-up, from 90.5 ± 18.03 to 88.2 ± 17.75 kg (p < 0.001). Overall, 41 participants (9.3% of the safety population) self-reported 101 non-severe hypoglycaemic episodes (incidence rate 0.498 events/person-year). There were no severe hypoglycaemic episodes reported. Gastrointestinal adverse events were reported by five participants (1.1% of the safety population). The vast majority (96.6%) of the study population continued iGlarLixi treatment after the final visit. CONCLUSION: The results of this non-interventional study confirmed the efficacy results of the randomized controlled trial programme of the iGlarLixi FRC in a real-life setting. iGlarLixi significantly improved glycaemic control in association with a low frequency of hypoglycaemia and gastrointestinal adverse events in a heterogeneous population of participants with T2D suboptimally controlled with OADs ± basal insulin.

Network analysis of neurotransmitter related human kinase genes: possible role of SRC, RAF1, PTK2B?

Previous co-expression analysis of human kinase genes highlighted 119 genes in neurotransmitter-related activity (based on Go:Terms). Using a merged interactome dataset, we analyzed the network of these Neurotransmitter Related Human Kinase Genes. Using the full interactome dataset we extended the network and calculating degrees and closeness centralities we identified SRC, MAPK1, RAF1, PTK2B and AKT1 kinase genes as potentially relevant nodes which did not show relevant activity in the original experimental study. As AKT1 and MAPK1 have already been indicated in various neuronal functions, we hypothesize a potential direct or indirect role for SRC, RAF1, PTK2B genes in neurotransmission and in central nervous system signaling processes.

Characterization of human invariant natural killer T cells expressing FoxP3.

Recently described forkhead box protein 3 (FoxP3) transcription factor is a key molecule in CD4+ CD25hi+ T-cell characterization. Invariant NK T (iNKT) cells are also characterized as regulatory cells modulating the immune response by rapidly producing T(h)1 and T(h)2 cytokines. We aimed to analyze cellular markers important in regulatory features of human iNKT cells and to study their role in functional assays. iNKT cells were single cell sorted from peripheral mononuclear cells of healthy individuals after immunostaining of invariant TCR α-chain. We found FoxP3 expression in human iNKT clones. Randomly selected iNKT cell clones (CD4+, double negative, CD8+) expressed FoxP3 mRNA and protein at different levels upon stimulation as supported by various approaches. FoxP3 mRNA and protein expression was detected in unstimulated iNKT cells as well. Furthermore, different stimulations changed the FoxP3 expression in iNKT cells over time and the most dramatic changes were observed upon anti-CD3 stimulation. Both the supernatant of iNKT cells and iNKT cells themselves exerted similar stimulation effects on PBMC proliferation in functional assays and these stimulations showed a negative correlation with FoxP3 expression. Our data indicate that the FoxP3 expression in iNKT cells may be a key transcriptional factor in controlling the regulatory function of the iNKT cells.

Studies of sex pheromone production under neuroendocrine control by analytical and morphological means in the oriental armyworm, Pseudaletia separata, Walker (Lepidoptera: Noctuidae).

Most female moths produce species-specific sex pheromone blends in the modified epidermal pheromone gland (PG) cells generally located between the 8 and 9th abdominal segments. The biosynthesis is often regulated by pheromone biosynthesis activating neuropeptide (PBAN) either in or prior to de novo fatty acid synthesis or at the formation of oxygenated functional group. In Pseudaletia separata, information about life span, calling, PG morphology, daily fluctuation of pheromone production and its hormonal regulation is limited. We measured pheromone titer daily (16:8; L:D) at 2h intervals in scotophase. Blend ratio stabilized during the 2nd day (till 4-5th) at 6th hour of scotophase, with the ratio of 27.5:12.8:44.4:15.3 for Z-11-16OH:16OH:Z-11-16Ac:16Ac, respectively. Females showed calling behavior from this time. We found with light and fluorescence microscopy that PG consisted of intersegmental membrane (A part), and dorso-lateral region of 9th abdominal segment (B part), encountering for ∼ 35% of total production revealed by gas chromatography. Ratios did not reveal difference. We did not find precursor (triacylglycerols) accumulation in form of lipid droplets, implying that PBAN stimulates de novo biosynthesis of 16:acyl precursors. In vivoHez-PBAN injections (1-3 × 5 pmol, 2h intervals) into 3 days old 16-18 h decapitated females stimulated pheromone production, both in A and B parts. Blend analyses including ratios suggest stimulation of the initial phase of synthesis, but desaturation of fatty acyl intermediates do not follow proportionally. More saturated fatty acid is converted from the available pool to the final OH and Ac, compared to females kept intact in scotophase. In vitro studies (PGs incubated 4-6h in the presence of 0.25 or 0.5 µM Hez-PBAN, especially with surplus 2mM malonyl-CoA) revealed higher saturated component ratio than the unsaturated, compared to natural blend or in vivo injections.

Prevention of Type 1 Diabetes Mellitus using a Novel Vaccine.

Type 1 diabetes mellitus (T1DM) affects 1 in 300 people and the incidence of the disease is rising worldwide. T1DM is caused by chronic autoimmune destruction of the insulin-producing ß-cells. The exact etiology and primary auto-antigen are not yet known. The autoimmune, chronic, and progressive nature of the disease raises the possibility of intervention, preferably by slowing down or stopping the destruction of the ß-cells as early as the prediabetic stage. Since the 1980s, several attempts have been made to maintain ß-cell function using immunosuppressive agents, immune modulation such as plasmapheresis, cytokine therapy, or antibody treatment. These agents were not diabetes specific; the occasionally observed beneficial effect did not compensate for the often very severe side effects. According to the latest assumption, the administration of diabetes-specific auto-antigens can elicit tolerance, which can prevent the destruction of the ß-cells, hopefully without serious side effects. The authors summarize current understanding of the immunology of T1DM, review the trials on prevention, and discuss their vaccination study.

Autoantigen-specific regulatory T cells induced in patients with type 1 diabetes mellitus by insulin B-chain immunotherapy.

There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled, phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. Our primary objective was to test its safety. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cell responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4+ T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cells provides strong justification for further testing of this therapy in type 1 diabetes. (clinicaltrials.gov identifier NCT00057499).

Reduced CD4+ T-cell-specific gene expression in human type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) in humans is characterized by the T-cell-dependent destruction of the insulin producing pancreatic beta cells; however, the precise pathogenesis of the disease, especially the initiation of pathologic immune response, is still largely unknown. We hypothesized that the function of human CD4+ T cells is altered in T1DM and analyzed unstimulated human peripheral blood CD4+ T-cell gene expression. We used a novel three-way comparison of DNA microarray data of CD4+ T cells isolated from patients with new onset T1DM, patients with long-term Type 2 diabetes (T2DM), and from healthy control subjects in order to eliminate any possible influence of glucose homeostasis on our findings. We analyzed the T1DM specific gene-expression changes and their functional relevance to T1DM autoimmunity. Our genetic and functional data show that T1DM CD4+ T cells are down-regulated specifically affecting key immune functions and cell cycle. Histone deacetylase gene expression, a key regulator of epigenetic modification is also reduced. The CD4+ T cells showed impaired function, including an abnormal immune response, which may be a key element that leads to the breakdown of self-tolerance.

Reduced CD4+ subset and Th1 bias of the human iNKT cells in Type 1 diabetes mellitus.

Invariant NKT (iNKT) cells are considered to be important in some autoimmune diseases including Type 1 diabetes mellitus (T1DM). So far, the published data are contradictory in regard to the role of iNKT cells in T1DM. We aimed to study iNKT cell frequency and the function of different iNKT cell subgroups in T1DM. We compared the results of four subject groups: healthy (H), long-term T2DM (ltT2DM; more than 1 year), newly diagnosed T1DM (ndT1DM; less than 3 months), and ltT1DM (more than 1 year) individuals. We measured the iNKT cell frequencies by costaining for the invariant TCR alpha-chain with 6B11-FITC and Valpha24-PE. After sorting the Valpha24+6B11+ cells, the generated iNKT clones were characterized. We tested CD4, CD8, and CD161 expression and IL-4 and IFN-gamma production on TCR stimulation. The CD4+ population among the iNKT cells was decreased significantly in ltT1DM versus ndT1DM, ltT2DM, or H individuals. The T1DM iNKT cell cytokine profile markedly shifted to the Th1 direction. There was no difference in the frequency of iNKT cells in PBMC among the different patient groups. The decrease in the CD4+ population among the iNKT cells and their Th1 shift indicates dysfunction of these potentially important regulatory cells in T1DM.

Melanin-based plumage coloration and flight displays in plovers and allies.

Plovers and their allies exhibit an impressive diversity of melanin-based plumage patterns ranging from non-melanized to completely melanized species. We use phylogenetic comparative methods to test whether melanization has evolved in relation to sexual selection for attracting mates, to selection for signalling territory defence, or to natural selection for camouflage. First, according to sexual-selection theory, melanized plumage has evolved to amplify the courtship displays of males. As predicted by this hypothesis, we found that males with aerial displays had more melanized plumage than males of ground-displaying species. In addition, sexual dimorphism in melanization was greater in species with display flights than in species with ground displays. Second, melanization may have evolved through social interactions to signal competitive ability in territory defence. We did not find evidence for this hypothesis, since breeding density was unrelated to the melanization of either sex. Finally, melanized plumage may camouflage the incubating parent. The latter hypothesis was not supported, since melanization was unrelated either to the darkness of nest substrate or the extent of vegetation cover. Taken together, our results are most consistent with the sexual-selection hypothesis, and suggest that melanized plumage has evolved to enhance the aerial displays of male plovers.