Psychological First Aid.

In this communication, we discuss the concept of psychological first aid, as relevant to diabetes management. Psychological first aid, in the diabetes care context, is defined as "the empathic support, counselling and education to improve coping skills, and optimize selfcare of persons living with diabetes, so that psychological well-being can be optimized." Various models can help provide structured psychological first aid. We feel that each and every health care provider should be able to provide effective first aid, including psychological first aid.

A sneak peek into chronic glucose exposure and insulin secretion impairment through translatome.

Diabetes is an epidemic caused by a multitude of factors. Despite the studies attempting to unravel its mechanism, there is still more to discover about glucose-insulin dynamics. In a recent issue of the Journal of Clinical Investigation, Cheruiyot et al. uncovered a translational regulatory circuit during ß-cell glucose toxicity that inherently affects the translational makeup and protein expression in functioning ß-cells.Journal of Clinical Investigation, Cheruiyot et al. uncovered a translational regulatory circuit during ß-cell glucose toxicity that inherently affects the translational makeup and protein expression in functioning ß-cells. Their multiomics approach might provide a deeper understanding of high glucose and translational regulation of genes involved in ß-cell insulin impairment caused by prolonged high-glucose exposure.

Fisetin ameliorates polycystic ovary syndrome in rats via a mechanistic modulation of AMP-activated protein kinase and SIRT1 molecular pathway.

Fisetin, a polyphenolic flavonoid, exhibits numerous pharmacological activities against metabolic syndromes. The present research aims to explore the therapeutic efficacy of fisetin in experimental polycystic ovary syndrome (PCOS). Female Sprague-Dawley rats were administered mifepristone (20 mg/kg/day) to induce PCOS. PCOS rats were treated with fisetin (20 mg/kg and 40 mg/kg) and further compared with metformin HCl, the conventional drug for PCOS. The mechanism of fisetin was explored using dorsomorphin (an AMPK inhibitor). Then, rats were sacrificed for further analysis of biochemical and histological parameters. PCOS rats exhibited irregular estrous cycles, increased serum testosterone (4.72 ± 0.139 ng/ml), estradiol (750.2 ± 16.56 pg/ml), LH (30.33 ± 1.563 mIU/ml), HOMA-IR (1.115 ± 0.049), TNF-α (86.59 ± 3.93 pg/ml), IL-6 (55.34 ± 4.432 pg/ml), and TBARS (3.867 ± 0.193 µmol/mg) along with declined progesterone (11.67 ± 1.54 ng/ml), FSH (13.33 ± 1.256 mIU/ml), GSH (33.47 ± 1.348 µmol/mg) levels, and SOD (2.163 ± 0.298 U/mg) activity as compared to normal control group. Fisetin high dose significantly lowers testosterone (3.014 ± 0.234 ng/ml), estradiol (533.7 ± 15.39 pg/ml), LH (16.67 ± 1.62 mIU/ml), HOMA-IR (0.339 ± 0.20), TNF-α (46.02 ± 2.66 pg/ml), IL-6 (31.77 ± 3.47 pg/ml), and TBARS (1.747 ± 0.185 µmol/mg) and enhances progesterone (33.17 ± 1.447 ng/ml), FSH (27.17 ± 1.42 mIU/ml), GSH (60.35 ± 1.1.102 µmol/mg) levels, and SOD (4.513 ± 0.607 U/mg) activity. The histology of ovarian tissues shows a significant increase in cystic follicles in PCOS rats compared with the normal control group. These alterations were attenuated with fisetin treatment. Administration of dorsomorphin with fisetin can reverse the beneficial effects of fisetin in PCOS rats. Altogether, these present findings highlight the potential of fisetin as a promising therapeutic intervention for the management of PCOS by modulating AMPK/SIRT1 signaling in rats.

An automatic deep reinforcement learning bolus calculator for automated insulin delivery systems.

In hybrid automatic insulin delivery (HAID) systems, meal disturbance is compensated by feedforward control, which requires the announcement of the meal by the patient with type 1 diabetes (DM1) to achieve the desired glycemic control performance. The calculation of insulin bolus in the HAID system is based on the amount of carbohydrates (CHO) in the meal and patient-specific parameters, i.e. carbohydrate-to-insulin ratio (CR) and insulin sensitivity-related correction factor (CF). The estimation of CHO in a meal is prone to errors and is burdensome for patients. This study proposes a fully automatic insulin delivery (FAID) system that eliminates patient intervention by compensating for unannounced meals. This study exploits the deep reinforcement learning (DRL) algorithm to calculate insulin bolus for unannounced meals without utilizing the information on CHO content. The DRL bolus calculator is integrated with a closed-loop controller and a meal detector (both previously developed by our group) to implement the FAID system. An adult cohort of 68 virtual patients based on the modified UVa/Padova simulator was used for in-silico trials. The percentage of the overall duration spent in the target range of 70-180 mg/dL was 71.2 % and 76.2 % , < 70 mg/dL was 0.9 % and 0.1 % , and > 180 mg/dL was 26.7 % and 21.1 % , respectively, for the FAID system and HAID system utilizing a standard bolus calculator (SBC) including CHO misestimation. The proposed algorithm can be exploited to realize FAID systems in the future.

Correlation between bone mineral density and type 2 diabetes mellitus in elderly men and postmenopausal women.

The relationship between bone mineral density and type 2 diabetes is still controversial. The aim of this study is to investigate the relationship between type 2 diabetes mellitus (T2DM) and bone mineral density (BMD) in elderly men and postmenopausal women. The participants in this study included 692 postmenopausal women and older men aged ≥ 50 years, who were divided into the T2DM group and non-T2DM control group according to whether or not they had T2DM. The data of participants in the two groups were collected from the inpatient medical record system and physical examination center systems, respectively, of the Tertiary Class A Hospital. All data analysis is performed in SPSS Software. Compared with all T2DM group, the BMD and T scores of lumbar spines 1-4 (L1-L4), left femoral neck (LFN) and all left hip joints (LHJ) in the non-T2DM group were significantly lower than those in the T2DM group (P < 0.05), and the probability of major osteoporotic fracture in the next 10 years (PMOF) was significantly higher than that in T2DM group (P < 0.001). However, with the prolongation of the course of T2DM, the BMD significantly decreased, while fracture risk and the prevalence of osteoporosis significantly increased (P < 0.05). We also found that the BMD of L1-4, LFN and LHJ were negatively correlated with homeostatic model assessment-insulin resistance (HOMA-IR) (P = 0.028, P = 0.01 and P = 0.047, respectively). The results also showed that the BMD of LHJ was positively correlated with indirect bilirubin (IBIL) (P = 0.018). Although the BMD was lower in the non-T2DM group than in the T2DM group, the prolongation of the course of T2DM associated with the lower BMD. And the higher prevalence of osteoporosis and fracture risk significantly associated with the prolongation of the course of T2DM. In addition, BMD was significantly associated with insulin resistance (IR) and bilirubin levels in T2DM patients.Registration number: China Clinical Trials Registry: MR-51-23-051741; https://www.medicalresearch.org.cn/search/research/researchView?id=c0e5f868-eca9-4c68-af58-d73460c34028 .

Relationships between apolipoprotein E and insulin resistance in patients with obstructive sleep apnoea: a large-scale cross-sectional study.

BACKGROUND: Obstructive sleep apnoea (OSA) is commonly associated with insulin resistance (IR) and dyslipidaemia. Apolipoprotein E (APOE) plays important roles in lipid metabolism. The study aimed to disentangle the multifactorial relationships between IR and APOE based on a large-scale population with OSA. METHODS: A total of 5,591 participants who underwent polysomnography for OSA diagnosis were finally enrolled. We collected anthropometric, fasting biochemical and polysomnographic data for each participant. Linear regression analysis was performed to evaluate the relationships between APOE, IR, and sleep breathing-related parameters. Logistic regression, restricted cubic spline (RCS) and mediation analyses were used to explore relationships between APOE and IR in patients with OSA. RESULTS: Increasing OSA severity was associated with greater obesity, more obvious dyslipidaemia, and higher levels of APOE and IR. APOE was positively correlated with the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and microarousal index (MAI) even after adjusting for age, sex, body mass index, and smoking and drinking levels (ß = 0.107, ß = 0.102, ß = 0.075, respectively, all P < 0.001). The risks of IR increased from the first to fourth quartiles of APOE (odds ratio (OR) = 1.695, 95% CI: 1.425-2.017; OR = 2.371, 95% confidence interval (CI): 2.009-2.816; OR = 3.392, 95% CI: 2.853-4.032, all P < 0.001) after adjustments. RCS analysis indicated non-linear and dose response relationships between APOE, AHI, ODI, MAI and insulin resistance. Mediation analyses showed that HOMA-IR explained 9.1% and 10% of the association between AHI, ODI and APOE. The same trends were observed in men, but not in women. CONCLUSIONS: This study showed that APOE is a risk factor for IR; moreover, IR acts as a mediator between OSA and APOE in men. APOE, IR, and OSA showed non-linear and multistage relationships. Taken together, these observations revealed the complex relationships of metabolic disorders in patients with OSA, which could lead to the development of new treatment modalities and a deeper understanding of the systemic impact of OSA.

Uncovering the function of insulin receptor substrate in termites' immunity through active immunization.

Insulin receptor substrate (IRS) proteins are key mediators in insulin signaling pathway. In social insect lives, IRS proteins played important roles in caste differentiation and foraging, but there function in disease defenses such as active immunization has not been reported yet. To investigate the issue, we successfully suppressed the IRS gene 3 days after dsRNA injection. Suppressing IRS gene increased the contents of glucose, trehalose, glycogen, and triglyceride and decreased the content of pyruvate in termites, and led to the metabolic disorder of glucose and lipids. IRS suppressing significantly enhanced grooming behaviors of nestmates of fungus-contaminated termites and hence increased the conidial load in the guts of the nestmates. Additionally, IRS suppressing led to significant downregulation of the immune genes Gram-negative bacteria-binding protein2 (GNBP2) and termicin and upregulation of the apoptotic gene caspase8, and hence diminished antifungal activity of nestmates of fungus-contaminated termites. The above abnormal behavioral and physiological responses significantly decreased the survival rate of dsIRS-injected nestmates of the fungus-contaminated termites. These findings suggest that IRS is involved in regulation of active immunization in termites, providing a better understanding of the link between insulin signaling and the social immunity of termites.

Expression and biochemical characterization of the putative insulinase enzyme PF11_0189 found in the Plasmodium falciparum genome.

PF11_0189 is a putative insulin degrading enzyme present in Plasmodium falciparum genome. The catalytic domain of PF11_0189 is about 27 kDa. Substrate specificity study shows PF11_0189 acts upon different types of proteins. The substrate specificity is found to be highest when insulin is used as a substrate. Metal dependency study shows highest dependency of PF11_0189 towards zinc metal for its proteolytic activity. Chelation of zinc metal with EDTA shows complete absence of PF11_0189 activity. Peptide inhibitors, P-70 and P-121 from combinatorial peptide library prepared against PF11_0189 show inhibition with an IC50 value of 4.8 µM and 7.5 µM respectively. A proven natural anti-malarial peptide cyclosporin A shows complete inhibition against PF11_0189 with an IC50 value of 0.75 µM suggesting PF11_0189 as a potential target for peptide inhibitors. The study implicates that PF11_0189 is a zinc metalloprotease involved in catalysis of insulin. The study gives a preliminary insight into the mechanism of complications arising from glucose abnormalities during severe malaria.

Postoperative hyperglycemia among adult non-diabetic surgical patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia.

BACKGROUND: Postoperative hyperglycemia is associated with morbidity and mortality in non-diabetic surgical patients. However, there is limited information on the extent and factors associated with postoperative hyperglycemia. This study assessed the magnitude and associated factors of postoperative hyperglycemia among non-diabetic adult patients who underwent elective surgery at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. METHODS: A facility-based cross-sectional study was conducted among 412 adult patients who underwent elective surgery at University of Gondar Comprehensive Specialized Hospital from April 14 to June 30, 2022 All consecutive postoperative non-diabetic elective surgical patients who were admitted to PACU during the data collection period and who fulfilled inclusion criteria were included in the study until the intended minimum sample size was achieved. And data were collected through interviews using a pretested semi-structured questionnaire. Postoperative hyperglycemia was defined as a blood glucose level of ≥ 140 mg/dl. Multivariable logistic regression was performed to identify the association between postoperative hyperglycemia and independent variables. Variables with a p-value less than 0.05 and a 95% confidence interval (CI) were considered statistically significant. RESULTS: A total of 405 patients' data were evaluated with a response rate of 98.3%. The median (IQR) age was 40 (28-52) years. The prevalence of postoperative hyperglycemia was 34.1% (95% CI: 29.4-39.0). Factors significantly associated with postoperative hyperglycemia included being overweight (AOR = 5.45, 95% CI: 2.46-12.0), American Society of Anesthesiologists (ASA) classification II and III (AOR = 2.37, 95% CI: 1.17-4.79), postoperative low body temperature (AOR = 0.18, 95% CI: 0.069-0.48), blood loss ≥ 500 ml (AOR = 2.33, 95% CI: 1.27-4.27), long duration of surgery, mild pain (AOR = 5.17, 95% CI: 1.32-20.4), and moderate pain (AOR = 7.63, 95% CI: 1.811-32.20). CONCLUSION AND RECOMMENDATION: One-third of the study participants had postoperative hyperglycemia. Weight, ASA classification, postoperative body temperature, duration of surgery, intraoperative blood loss, and postoperative pain were identified as a modifiable risk factors. Maintaining normal body temperature throughout the procedure, treating postoperative pain, and monitoring and controlling blood glucose level in patients at risk of hyperglycemia is crucial.

Cu(II) Specifically Disassembles Insulin Amyloid Nanostructures via Direct Interaction with Cross-ß Fibrils.

In this work, we demonstrate direct evidence of the antiamyloid potential of Cu(II) ions against amyloid formation of insulin. The Cu(II) ions were found to efficiently disassemble the preformed amyloid nanostructures into soluble species and suppress monomer fibrillation under aggregation-prone conditions. The direct interaction of Cu(II) ions with the cross-ß structure of amyloid fibrils causes substantial disruption of both the interchain and intrachain interactions, predominantly the H-bonds and hydrophobic contacts. Further, the Cu(II) ions show a strong affinity for the aggregation-prone conformers of the protein and inhibit their spontaneous self-assembly. These results reveal the possible molecular mechanism for the antiamyloidogenic potential of Cu(II) which could be important for the development of metal-ion specific therapeutic strategies against amyloid linked complications.

The SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle insulin resistance in old male rat offspring.

Maternal hypoxia is strongly linked to insulin resistance (IR) in adult offspring, and altered insulin signaling for muscle glucose uptake is thought to play a central role. However, whether the SIRT3/GSK-3ß/GLUT4 axis is involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring has not been investigated. Maternal hypoxia was established from Days 5 to 21 of pregnancy by continuous infusion of nitrogen and air. The biochemical parameters and levels of key insulin signaling molecules of old male rat offspring were determined through a series of experiments. Compared to the control (Ctrl) old male rat offspring group, the hypoxic (HY) group exhibited elevated fasting blood glucose (FBG) (∼30%), fasting blood insulin (FBI) (∼35%), total triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), as well as results showing impairment in the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) revealed impaired cellular structures and mitochondria in the longitudinal sections of skeletal muscle from HY group mice, which might be associated with decreased SIRT3 expression. Furthermore, the expression of insulin signaling molecules, such as GSK-3ß and GLUT4, was also altered. In conclusion, the present results indicate that the SIRT3/GSK-3ß/GLUT4 axis might be involved in maternal hypoxia-induced skeletal muscle IR in old male rat offspring.

Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice.

Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas, and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.

Multireceptor Analysis for Evaluating the Antidiabetic Efficacy of Karanjin: A Computational Approach.

BACKGROUND: Diabetes mellitus, notably type 2, is a rising global health challenge, prompting the need for effective management strategies. Common medications such as metformin, insulin, repaglinide and sitagliptin can induce side effects like gastrointestinal disturbances, hypoglycemia, weight gain and specific organ risks. Plant-derived therapies like Karanjin from Pongamia pinnata present promising alternatives due to their historical use, holistic health benefits and potentially fewer adverse effects. This study employs in silico analysis to explore Karanjin's interactions with diabetes-associated receptors, aiming to unveil its therapeutic potential while addressing the limitations and side effects associated with conventional medications. METHODOLOGY: The research encompassed the selection of proteins from the Protein Data Bank (PDB), followed by structural refinement processes and optimization. Ligands such as Karanjin and standard drugs were retrieved from PubChem, followed by a comprehensive analysis of their ADMET profiling and pharmacokinetic properties. Protein-ligand interactions were evaluated through molecular docking using AutoDockTools 1.5.7, followed by the analysis of structural stability using coarse-grained simulations with CABS Flex 2.0. Molecular dynamics simulations were performed using Desmond 7.2 and the OPLS4 force field to explore how Karanjin interacts with proteins over 100 nanoseconds, focusing on the dynamics and structural stability. RESULTS: Karanjin, a phytochemical from Pongamia pinnata, shows superior drug candidate potential compared to common medications, offering advantages in efficacy and reduced side effects. It adheres to drug-likeness criteria and exhibits optimal ADMET properties, including moderate solubility, high gastrointestinal absorption and blood-brain barrier penetration. Molecular docking revealed Karanjin's highest binding energy against receptor 3L2M (Pig pancreatic alpha-amylase) at -9.1 kcal/mol, indicating strong efficacy potential. Molecular dynamics simulations confirmed stable ligand-protein complexes with minor fluctuations in RMSD and RMSF, suggesting robust interactions with receptors 3L2M. CONCLUSION: Karanjin demonstrates potential in pharmaceutical expansion for treating metabolic disorders such as diabetes, as supported by computational analysis. Prospects for Karanjin in pharmaceutical development include structural modifications for enhanced efficacy and safety. Nanoencapsulation may improve bioavailability and targeted delivery to pancreatic cells, while combination therapies could optimize treatment outcomes in diabetes management. Clinical trials and experimental studies are crucial to validate its potential as a novel therapeutic agent.

Comparative effects of insulin pump and injection on gestational diabetes mellitus pregnancy outcomes and serum biomarkers.

BACKGROUND: Insulin injection is the basic daily drug treatment for diabetic patients. AIM: To evaluate the comparative impacts of continuous subcutaneous insulin infusion (CSII). METHODS: Based on the treatment modality received, the patients were allocated into two cohorts: The CSII group and the multiple daily injections (MDI) group, with each cohort comprising 210 patients. Comparative assessments were made regarding serum levels of serum-secreted frizzled-related protein 5, homocysteine, and C1q/TNF-related protein 9. Furthermore, outcomes such as fasting plasma glucose, 2-hour postprandial glucose levels, pain assessment scores, and the incidence of complications were evaluated post-treatment. RESULTS: The CSII group displayed notably lower fasting plasma glucose and 2-h postprandial glucose levels in comparison to the MDI group (P < 0.05). Subsequent analysis post-treatment unveiled a significantly higher percentage of patients reporting no pain in the CSII group (60.00%) in contrast to the MDI group (36.19%) (P < 0.05). Additionally, the CSII group exhibited a markedly reduced occurrence of fetal distress and premature rupture of membranes compared to the MDI group (P < 0.05). However, there were no significant variances observed in other pregnancy outcomes between the two groups (P > 0.05). A statistical analysis revealed a significant difference in the incidence of complications between the groups (χ 2 = 11.631, P = 0.001). CONCLUSION: The utilization of CSII via an insulin pump, as opposed to MDI, can significantly enhance the management of insulin administration in patients with GDM by diversifying the sites of insulin delivery. This approach not only promotes optimal glycemic control but also regulates metabolic factors linked to blood sugar, reducing the likelihood of adverse pregnancy outcomes and complications. The clinical relevance and importance of CSII in GDM management highlight its wide-ranging clinical usefulness.

Association between hemoglobin and non-alcoholic fatty liver disease (NAFLD) in United States adults: Results from NHANES 2017-2020.

Background: Non-alcoholic fatty liver disease (NAFLD), a chronic liver condition of increasing prevalence, is closely related to various metabolic disorders. Hemoglobin, a protein that transports oxygen in red blood cells, is the focus of this study, which seeks to investigate its potential association with NAFLD. Methods: We selected 6,516 eligible adult participants from the United States using the 2017-2020 National Health and Nutrition Examination Survey database for cross-sectional analyses. We analyzed the association of hemoglobin with NAFLD using weighted logistic regression models. Results: The study performed a weighted logistic regression modeling analysis, which verified that hemoglobin levels were positively associated with NAFLD, especially in the higher hemoglobin quartile groups. Subgroup analyses revealed no significant interactions, demonstrating the robustness of the model. The analysis of mediation effects showed that Gamma-Glutamyl Transferase, Alanine Aminotransferase, and triglycerides were important mediating variables in the relationship between hemoglobin and NAFLD. Conclusion: Increased hemoglobin levels were found to be significantly and independently associated with an increased NAFLD risk. This insight is crucial for the risk assessment and early detection of NAFLD, underscoring the need for heightened vigilance in individuals with higher hemoglobin levels.

Growth hormone improves insulin resistance in visceral adipose tissue after duodenal-jejunal bypass by regulating adiponectin secretion.

BACKGROUND: The mechanism of improvement of type 2 diabetes after duodenal-jejunal bypass (DJB) surgery is not clear. AIM: To study the morphological and functional changes in adipose tissue after DJB and explore the potential mechanisms contributing to postoperative insulin sensitivity improvement of adipose tissue in a diabetic male rat model. METHODS: DJB and sham surgery was performed in a-high-fat-diet/streptozotocin-induced diabetic rat model. All adipose tissue was weighed and observed under microscope. Use inguinal fat to represent subcutaneous adipose tissue (SAT) and mesangial fat to represent visceral adipose tissue. RNA-sequencing was utilized to evaluate gene expression alterations adipocytes. The hematoxylin and eosin staining, reverse transcription-quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay were used to study the changes. Insulin resistance was evaluated by immunofluorescence. RESULTS: After DJB, whole body blood glucose metabolism and insulin sensitivity in adipose tissue improved. Fat cell volume in both visceral adipose tissue (VAT) and SAT increased. Compared to SAT, VAT showed more significantly functional alterations after DJB and KEGG analysis indicated growth hormone (GH) pathway and downstream adiponectin secretion were involved in metabolic regulation. The circulating GH and adiponectin levels and GH receptor and adiponectin levels in VAT increased. Cytological experiment showed that GH stimulated adiponectin secretion and improve insulin sensitivity. CONCLUSION: GH improves insulin resistance in VAT in male diabetic rats after receiving DJB, possibly by increasing adiponectin secretion.

Therapeutic effects of Lingguizhugan decoction in a rat model of high-fat diet-induced insulin resistance.

BACKGROUND: Lingguizhugan (LGZG) decoction is a widely used classic Chinese medicine formula that was recently shown to improve high-fat diet (HFD)-induced insulin resistance (IR) in animal studies. AIM: To assess the therapeutic effect of LGZG decoction on HFD-induced IR and explore the potential underlying mechanism. METHODS: To establish an IR rat model, a 12-wk HFD was administered, followed by a 4-wk treatment with LGZG. The determination of IR status was achieved through the use of biochemical tests and oral glucose tolerance tests. Using a targeted meta-bolomics platform to analyze changes in serum metabolites, quantitative real-time PCR (qRT-PCR) was used to assess the gene expression of the ribosomal protein S6 kinase beta 1 (S6K1). RESULTS: In IR rats, LGZG decreased body weight and indices of hepatic steatosis. It effectively controlled blood glucose and food intake while protecting islet cells. Metabolite analysis revealed significant differences between the HFD and HFD-LGZG groups. LGZG intervention reduced branched-chain amino acid levels. Levels of IR-related metabolites such as tryptophan, alanine, taurine, and asparagine decreased significantly. IR may be linked to amino acids due to the contemporaneous increase in S6K1 expression, as shown by qRT-PCR. CONCLUSIONS: Our study strongly suggests that LGZG decoction reduces HFD-induced IR. LGZG may activate S6K1 via metabolic pathways. These findings lay the groundwork for the potential of LGZG as an IR treatment.

Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma.

Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

Deletion of miPEP in adipocytes protects against obesity and insulin resistance by boosting muscle metabolism.

Mitochondria facilitate thousands of biochemical reactions, covering a broad spectrum of anabolic and catabolic processes. Here we demonstrate that the adipocyte mitochondrial proteome is markedly altered across multiple models of insulin resistance and reveal a consistent decrease in the level of the mitochondrial processing peptidase miPEP. OBJECTIVE: To determine the role of miPEP in insulin resistance. METHODS: To experimentally test this observation, we generated adipocyte-specific miPEP knockout mice to interrogate its role in the aetiology of insulin resistance. RESULTS: We observed a strong phenotype characterised by enhanced insulin sensitivity and reduced adiposity, despite normal food intake and physical activity. Strikingly, these phenotypes vanished when mice were housed at thermoneutrality, suggesting that metabolic protection conferred by miPEP deletion hinges upon a thermoregulatory process. Tissue specific analysis of miPEP deficient mice revealed an increment in muscle metabolism, and upregulation of the protein FBP2 that is involved in ATP hydrolysis in the gluconeogenic pathway. CONCLUSION: These findings suggest that miPEP deletion initiates a compensatory increase in skeletal muscle metabolism acting as a protective mechanism against diet-induced obesity and insulin resistance.

The impact of a culturally adapted lifestyle intervention on the glycaemic profile of mothers with GDM one year after delivery - a community-based, cluster randomized trial in Sri Lanka.

BACKGROUND: A woman with a history of GDM has a high risk of developing type two diabetes (T2DM) in her future life. Lifestyle modifications are known to attenuate the progression of GDM to T2DM. Therefore, the aim of this study was to assess the impact of a simple, cost effective, culturally acceptable lifestyle intervention programme on the trajectory towards T2DM in women with a history of GDM. METHODS: This cluster randomized trial was conducted in 100 postpartum women in three selected districts of Sri Lanka. The subjects were divided into intervention (n = 50) and control groups (n = 50) by cluster randomization method. A culturally adapted protocol (comprised of dietary and physical activity modifications) was administered to the intervention group. The glycemic profile was assessed using fasting and 2-hour post-OGTT plasma glucose and HbA1c, and insulin resistance by HOMA-IR at baseline and after one year of intervention. RESULTS: The mean age (SD) of the subjects in the intervention and control groups were 33.0 (5.1) and 34.3 (6.5) years respectively. All glycemic and insulin resistance parameters (i.e. Fasting plasma glucose- FPG, 2-hour post-OGTT plasma glucose, HbA1c and HOMA-ir) were comparable (p > 0.05) between the two groups at baseline. FPG, 2 h post OGTT, HbA1c and HOMA-ir values between intervention vs. control (p) at 12 months were 87.3 vs. 123.2 (< 0.01); 106.5 vs. 156.1 (0.01); 5.3 vs. 6.8 (< 0.01) and 0.9 vs. 2.3 (< 0.01) respectively. All glycemic parameters showed a significant reduction in the intervention group at 12 months compared to baseline. In contrast, the control group showed a significant increase in FPG, 2-hour post-OGTT plasma glucose and HbA1c at 12 months compared to baseline. In multiple linear regression model adjusted for age, parity and family history, the control group showed an approximately 33 times risk of developing insulin resistance compared to the intervention group. CONCLUSION: The culturally acceptable and individualized lifestyle intervention was able to produce remarkable reductions in glycaemic and insulin resistance parameters among postpartum women with a history of GDM. TRIAL REGISTRATION: Ethical clearance was obtained from the Ethics Review Committee of the University of Sri Jayewardenepura, Sri Lanka (ERC 52/14), Sri Lanka Clinical trial registration number Sri Lanka Clinical Trials Registry (SLCTR/2015/021 date 25.09.2015).