Insulin Action Research Articles

Detection of type-Ⅱ diabetes using graphene-based biosensors

Diabetes is a global pandemic that increases the risk of various health complications, including heart attacks, renal failure, blindness, stroke, and peripheral neuropathy. Type-2 diabetes (T2D) results from an imbalance in lipid and glucose metabolism due to hostility to insulin action and insufficient insulin production response. Valine amino acid has been identified as a potential biomarker for T2D, but there have been no rigorous studies on its interaction with branch chain amino acids. In this study, we investigated the potential of graphene/modified graphene as a valine biosensor using density functional theory to examine the electronic properties and adsorption behaviour of graphene, Si-doped graphene (SiG), and P-doped graphene (PG). The adsorption of valine over the substrates was physisorption in nature, and the adsorption energies were in the order of SiG > G > PG. Density of states (DOS) and partial DOS calculations confirmed the molecule’s adsorption over the monolayers and indicated variations in the electronic properties. We also performed recovery time calculations to examine the reusability of the nano-surfaces as potential biosensors. Ultrafast recovery times were predicted for all three systems, with SiG showing the best results. Our study suggests that SiG could be used as a biosensor for valine, providing a real-time and efficient diagnostic tool for T2D.

The genetic and dietary landscape of the muscle insulin signalling network.

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway's organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.

The genetic and dietary landscape of the muscle insulin signalling network

Metabolic disease is caused by a combination of genetic and environmental factors, yet few studies have examined how these factors influence signal transduction, a key mediator of metabolism. Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway’s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.

Effect of resveratrol on insulin action in primary myotubes from lean individuals and individuals with severe obesity.

Resveratrol, a natural polyphenol compound contained in numerous plants, has been proposed as a treatment for obesity-related disease processes such as insulin resistance. However, in humans there are conflicting results concerning the efficacy of resveratrol in improving insulin action; the purpose of the present study was to determine whether obesity status (lean, severely obese) affects the response to resveratrol in human skeletal muscle. Primary skeletal muscle cells were derived from biopsies obtained from age-matched lean and insulin-resistant women with severe obesity and incubated with resveratrol (1 µM) for 24 h. Insulin-stimulated glucose oxidation and incorporation into glycogen, insulin signal transduction, and energy-sensitive protein targets [AMP-activated protein kinase (AMPK), Sirt1, and PGC1α] were analyzed. Insulin-stimulated glycogen synthesis, glucose oxidation, and AMPK phosphorylation increased with resveratrol incubation compared with the nonresveratrol conditions (main treatment effect for resveratrol). Resveratrol further increased IRS1, Akt, and TBC1D4 insulin-stimulated phosphorylation and SIRT1 content in myotubes from lean women, but not in women with severe obesity. Resveratrol improves insulin action in primary human skeletal myotubes derived from lean women and women with severe obesity. In women with obesity, these improvements may be associated with enhanced AMPK phosphorylation with resveratrol treatment.NEW & NOTEWORTHY A physiologically relevant dose of resveratrol increases insulin-stimulated glucose oxidation and glycogen synthesis in myotubes from individuals with severe obesity. Furthermore, resveratrol improved insulin signal transduction in myotubes from lean individuals but not from individuals with obesity. Activation of AMPK plays a role in resveratrol-induced improvements in glucose metabolism in individuals with severe obesity.

Mechanistic Insight of Innovative Biomarkers for Screening of Type II Diabetes Mellitus

Abstract: Diabetes Mellitus (DM) is a compounded, persistent illness symbolized by an increased range of glucose levels in the blood caused by cellular resistance to insulin action, insufficient insulin production by pancreatic -cells, or both. Type 1 Diabetes Mellitus (T1DM), the extremely widespread form of DM, is recorded for almost 85-90% of worldwide cases. T2DM is mostly common in middle-aged and older people, and its causes are multifaceted. The use of efficient and profitable solutions for DM screening is critical to ensure pre-identification and minimising patients' risk of acquiring the life-compromising illness. Identification of innovative biomarkers with test methods of DM is therefore critical in order to establish vigorous, non-invasive, pain-free, highly sensitive, and precise procedures for screening. The purpose of this review article is to mention and review all the necessary biomarkers that play a vital role in disease diagnosis and to highlight the present-day findings of the latest clinically validated and traditional biomarkers and procedures for determining them, which provide cost-efficient options for T2DM screening with early detection. It is concluded that various biomarkers, both conventional and innovative, go hand in hand to diagnose the DM of any type.

The interplay between obesity, immunosenescence, and insulin resistance.

Obesity, which is the accumulation of fat in adipose tissue, has adverse impacts on human health. Obesity-related metabolic dysregulation has similarities to the metabolic alterations observed in aging. It has been shown that the adipocytes of obese individuals undergo cellular aging, known as senescence. Senescence can be transmitted to other normal cells through a series of chemical factors referred to as the senescence-associated secretory phenotype (SASP). Most of these factors are pro-inflammatory compounds. The immune system removes these senescent T-cells, but immunosenescence, which is the senescence of immune cells, disrupts the clearance of senescent T-cells. Immunosenescence occurs as a result of aging or indirectly through transmission from senescent tissues. The significant occurrence of senescence in obesity is expected to cause immunosenescence and impairs the immune response to resolve inflammation. The sustained and chronic inflammation disrupts insulin's metabolic actions in metabolic tissues. Therefore, this review focuses on the role of senescent adipocyte cells in obesity-associated immunosenescence and subsequent metabolic dysregulation. Moreover, the article suggests novel therapeutic approaches to improve metabolic syndrome by targeting senescent T-cells or using senotherapeutics.

The Role of Obesity in Type 2 Diabetes Mellitus-An Overview.

Obesity or excessive weight gain is identified as the most important and significant risk factor in the development and progression of type 2 diabetes mellitus (DM) in all age groups. It has reached pandemic dimensions, making the treatment of obesity crucial in the prevention and management of type 2 DM worldwide. Multiple clinical studies have demonstrated that moderate and sustained weight loss can improve blood glucose levels, insulin action and reduce the need for diabetic medications. A combined approach of diet, exercise and lifestyle modifications can successfully reduce obesity and subsequently ameliorate the ill effects and deadly complications of DM. This approach also helps largely in the prevention, control and remission of DM. Obesity and DM are chronic diseases that are increasing globally, requiring new approaches to manage and prevent diabetes in obese individuals. Therefore, it is essential to understand the mechanistic link between the two and design a comprehensive approach to increase life expectancy and improve the quality of life in patients with type 2 DM and obesity. This literature review provides explicit information on the clinical definitions of obesity and type 2 DM, the incidence and prevalence of type 2 DM in obese individuals, the indispensable role of obesity in the pathophysiology of type 2 DM and their mechanistic link. It also discusses clinical studies and outlines the recent management approaches for the treatment of these associated conditions. Additionally, in vivo studies on obesity and type 2 DM are discussed here as they pave the way for more rigorous development of therapeutic approaches.

Antidiabetic Effectiveness Test of Ethanol Extract of Brown Leaves (Theobroma Cacao L.) Against Mice (Mus Musculus)

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia that occurs due to abnormalities in insulin secretion, insulin action or both. DM sufferers are increasing from year to year, accompanied by increasing costs of therapy, therefore, as an alternative to controlling blood glucose levels, use natural ingredients such as cocoa leaves. The aim of this research was to determine the effectiveness of ethanol extract of cocoa leaves (Theobroma cacao L.) in reducing blood glucose levels in mice that had been induced by Aloxan. The research method used was experimental research. The research stages were sample collection, sample identification, making simpilicia, examining the characteristics of simpilicia, making extracts using maceration using 96% ethanol solvent, and testing the antidiabetic effect of EEDC in mice induced by alloxan at a dose of 175 mg/kg. bb intraperitoneally. Diabetic mice were divided into 5 groups, each group consisting of 5 mice that were given the test material 50 mg/KgBB of ethanol extract of brown leaves; 100 mg/KgBB; and 200 mg/KgBB, Metformin 65 mg/KgBB, and CMC 0.5%. Next, blood glucose levels were measured on days 3, 6, 9, 12, and 15, the percentage reduction in blood glucose levels was calculated, then the data was analyzed using the One-Way ANOVA method and Duncan's test, to see real differences between treatments. The research results showed that simplicia, the ethanol extract of brown leaves contains flavonoids, alkaloids, tannins, steroids/triterpenoids, saponins and glycosides. Cocoa leaf ethanol extract has effectiveness in lowering glucose levels, at the 5th and 6th hours it shows good effectiveness at a dose of 200 mg/KgBW of (72.16 ± 0.1.51)% and (82.80 ± 0.73 )%, not significantly different from metfromin 65 mg/KgBB of (74.45 ± 1.51)% and (83.29 ± 1.01).

Hasil Kadar HbA1C Penderita Diabetes Melitus Tipe 2 Pada Kelompok Prolanis Di Puskesmas Juhar Tahun 2023

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia that occurs due to abnormalities in insulin secretion, insulin action or both. The International Diabetes Federation (IDF) estimates that the number of diabetes sufferers in Indonesia could reach 28.57 million in 2045. This number is 47% greater than the number of 19.47 million in 2021. This research was conducted on patients who had been diagnosed with type 2 DM who were members of the Prolanis group. Prolanis is a health service system that aims to improve the quality of life of participants with chronic diseases, one of which is Diabetes Mellitus type 2. HbA1c is a substance formed from the reaction between glucose and hemoglobin. HbA1c is one of the parameters for assessing glycemic control (patient compliance). The research entitled Analysis of HbA1c Levels in Type 2 Diabetes Mellitus Sufferers in the Prolanis Group at the Juhar Community Health Center aims to analyze and measure HbA1c levels in Type 2 Diabetes Sufferers. The research method used was Descriptive Cross-sectional. The examination material used is median cubital vein blood with EDTA anticoagulant. From the results of the examination, 25 samples were obtained, of which 12 patients had HbA1c levels >8% with criteria for poor DM control, 6 patients had HbA1c levels of 6.5-8% with criteria for moderate DM control, and there were 7 patients with HbA1c levels <6.5%. with the criteria for good DM control. From the results of this study, it was found that controlling DM at the Juhar Community Health Center there were 14 patients who had HbA1c values above 6.5 and after follow-up for the next 6 months, some had HbA1c levels that decreased and others that increased. To obtain good DM control, it is best for people with diabetes to have an HbA1c check every 3 months as part of diabetes management and this management is very important to carry out in health services, including primary level health services.

Alterations in nonesterified free fatty acid trafficking rather than hyperandrogenism contribute to metabolic health in obese women with polycystic ovary syndrome

To determine whether alterations in nonesterified fatty acid (NEFA) dynamics or degree of hyperandrogenism (HA) contribute to the difference in insulin sensitivity between women with metabolically healthy obese polycystic ovary syndrome (PCOS) (MHO-PCOS) and women with metabolically unhealthy obese PCOS (MUO-PCOS). Prospective cross-sectional study. Tertiary-care academic center. One hundred twenty-five obese women with PCOS. Consecutive obese (body mass index [BMI] ≥ 30 kg/m2) oligo-ovulatory women (n = 125) with PCOS underwent an oral glucose tolerance test and a subgroup of 16 participants underwent a modified frequently sampled intravenous glucose tolerance test to determine insulin-glucose and -NEFA dynamics. Degree of insulin resistance (IR) in adipose tissue (AT) basally (Adipo-IR) and dynamically (the nadir in NEFA levels observed [NEFAnadir], the time it took for NEFA levels to reach nadir [TIMEnadir], and the percent suppression in plasma NEFA levels from baseline to nadir [%NEFAsupp]); peak lipolysis rate (SNEFA) and peak rate of NEFA disposal from plasma pool (KNEFA); whole-body insulin-glucose interaction (acute response of insulin to glucose [AIRg], insulin sensitivity index [Si], glucose effectiveness [Sg], and disposition index [Di]); and HA (hirsutism score, total and free testosterone levels, and dehydroepiandrosterone sulfate levels). A total of 85 (68%) women were MUO-PCOS and 40 (32%) were MHO-PCOS using the homeostasis model of assessment of IR. Subjects with MUO-PCOS and MHO-PCOS did not differ in mean age, BMI, waist-to-hip ratio, HA, and lipoprotein levels. By a modified frequently sampled intravenous glucose tolerance test, eight women with MUO-PCOS had lesser Si, KNEFA, and the percent suppression in plasma NEFA levels from baseline to nadir (%NEFAsupp) and greater TIMEnadir, NEFAnadir, and baseline adipose tissue IR index (Adipo-IR) than eight subjects with MHO-PCOS, but similar fasting NEFA levels and SNEFA. Women with MUO-PCOS had a higher homeostasis model of assessment-β% and fasting insulin levels than women with MHO-PCOS. In bivalent analysis, Si correlated strongly and negatively with Adipo-IR and NEFAnadir, weakly and negatively with TIMEnadir, and positively with KNEFA and %NEFAsupp, in women with MUO-PCOS only. Independent of age and BMI, women with MUO-PCOS have reduced NEFA uptake and altered insulin-mediated NEFA suppression, but no difference in HA, compared with women with MHO-PCOS. Altered insulin-mediated NEFA suppression, rather than HA or lipolysis rate, contributes to variations in insulin sensitivity among obese women with PCOS.

Therapeutic Potential of Fingolimod in Diabetes Mellitus and Its Chronic Complications.

Diabetes mellitus is a metabolic disease characterized by elevated blood glucose due to a deficiency of insulin secretion and/or action. Long-term poor blood glucose control may lead to chronic damage and dysfunction of the heart, kidneys, eyes, and other organs. Therefore, it is important to develop treatments for diabetes and its chronic complications. Fingolimod is a structural sphingosine analogue and sphingosine-1-phosphate receptor modulator currently used for the treatment of relapsing-remitting multiple sclerosis. Several studies have shown that it has beneficial effects on the improvement of diabetes and its chronic complications. This paper reviews the therapeutic potential of Fingolimod in diabetes and its chronic complications, aiming to further guide future treatment strategies.

Description of knowledge, attitudes and practices to maintain oral hygiene as well as gingival index and plaque index in children suffering from type 1 diabetes mellitus

Background: Diabetes mellitus is a chronic disease whose incidence continues to increase throughout the world. Periodontal disease is a complication of diabetes. Poor periodontal health can lead to a variety of serious health problems. Therefore, this research is considered important to determine knowledge, attitudes and practices to maintain oral hygiene as well as gingival index and plaque index in children with type 1 diabetes mellitus. Objectives: To determine the description of knowledge, attitudes and practices to maintain oral hygiene as well as gingival index and plaque index in children with type 1 diabetes mellitus. Method: This research is a cross-sectional observational analytical study consisting of 32 respondents from children suffering from T1DM and members of IKADAR Malang. The instrument used was a questionnaire to measure knowledge, attitudes and practices regarding cleaning teeth and mouth; insulin injection compliance, diet, and physical activity. Hba1c to determine DMT-1 status. Gingival and plaque index. Results and discussions: Respondents with controlled diabetes, good knowledge, attitudes and practices all had healthy gingiva and good PI, namely 3 (15.79%). respondents with regular insulin, good diet and low physical activity all had uncontrolled diabetes, namely 2 (7.14%). Conclusion: The majority of respondents have uncontrolled diabetes, knowledge, attitudes, practices to maintain good oral hygiene, healthy gingiva, and good PI in one unit, namely 9. The majority of respondents have regular insulin injection compliance, moderate diet, low physical activity, and uncontrolled diabetes mellitus status in one unit, namely 17.

EDUKASI DAN SKRINING DIABETES MELITUS PADA REMAJA DI RONGTENGAH SAMPANG MADURA

Diabetes mellitus is a heterogeneous group of disorders characterized by hyperglycemia resulting from absolute or relative deficits in insulin production or action. The increase in non-communicable diseases, one of which is diabetes mellitus. Diabetes mellitus in adolescents occurs at age ≥ 15 years. So to reduce the risk of early non-communicable diseases in adolescents, pro-health behavior is needed from adolescence through early detection. The aim of this activity is to increase understanding among teenagers about the dangers of diabetes mellitus so that they can adopt a healthy lifestyle and recognize early detection methods that can be used to prevent the disease. The method used in this community service activity is a presentation and discussion about the dangers of diabetes mellitus. To measure the level of participants' understanding regarding the dangers of diabetes mellitus, a pretest and posttest were carried out at the end of the activity. This activity was attended by 35 participants, namely teenagers aged 17-20 years in Rongtengah Sampang Madura. The average pretest score was 53.7 points, while the average posttest score was 72.3 points. These results indicate that there has been an increase in public knowledge about the meaning, risk factors, symptoms and ways to prevent diabetes mellitus. It is hoped that educational activities can be sustainable so that teenagers can apply ways to prevent diabetes mellitus

Fingerprint Dermatoglyphic Patterns among Adults with Type II Diabetes Mellitus in Western Kenya

Background: Dermatoglyphics is the study of epidermal ridges and their configurations on the skin of the palms and soles of the foot. The patterns can be grouped into loops, whorls, and arches each of them having a unique characteristic that appears to be influenced by genetic factors. Diabetes Mellitus is a common metabolic disorder caused by reduced insulin secretion. Type 2 diabetes results from genetic disorders involving multiple genes that control insulin secretion and action. This study aimed to assess the variations in fingerprint patterns among adults with Type II diabetes mellitus which could be used as an early, easy, cheap and painless method of screening diabetes.
 Materials and Methods: A comparative cross-sectional study design was used where 150 diabetic patients were compared with 150 non-diabetics as controls all selected from Kakamega County Teaching Referral Hospital, Western Kenya. Socio- demographic data and family history were recorded, thereafter fingerprints were taken using the Indian ink method. The chi-square test was used to check for a significant association between the pattern variations in diabetics and the control group.
 Results: The study involved 300 respondents where 33.33% were aged above 60 years with females being the majority at 60.67 % while among diabetics 68 % had a family history of diabetes. Whorl (p=0.0003) and ulna loops (p=0.002) patterns were decreased among male diabetics when compared to male non-diabetics while in female diabetics, whorl patterns were increased (p=0.02929) when compared to female non- diabetics. There was an association between whorl patterns and family history among diabetics (p=0.049). Ulna loops were significantly low (p=0.004) while whorls were significantly high (p=0.016) among diabetics when compared to non-diabetics.
 Conclusion: This study showed that dermatoglyphic patterns could be used as a feature for early screening of type II diabetes.

High-Fat, High-Calorie Breast Milk in Women with Overweight or Obesity and Its Association with Maternal Serum Insulin Concentration and Triglycerides Levels.

The childhood obesity epidemic continues to be a challenge. Maternal obesity and excessive infant weight gain are strong predictors of childhood obesity, which itself is a major risk factor for adult obesity. The primary source of nutrition during early life is breast milk, and its composition is impacted by maternal habitus and diet. We thus studied the relationship between maternal BMI, serum lipids and insulin, and breast milk fat and calorie content from foremilk to hindmilk. Women who were exclusively breastfeeding at 7-8 weeks postpartum were BMI classified as Normal (18.5-24.9, n = 9) and women with Overweight/Obese (OW/OB ≥ 25, n = 13). Maternal blood and continuous breast milk samples obtained from foremilk to hindmilk were analyzed, and infant milk intake was assessed. Women with OW/OB had significantly higher milk fat and calorie content in the first foremilk and last hindmilk sample as compared to Normal BMI women. Amongst all women, maternal serum triglycerides, insulin, and HOMA were significantly correlated with foremilk triglyceride concentration, suggesting that maternal serum triglyceride and insulin action contribute to human milk fat content. As the milk fat content of OW/OB women has caloric implications for infant growth and childhood obesity, these results suggest the potential for modulating milk fat content by a reduction in maternal serum lipids or insulin.

Intermediate versus morning chronotype has lower vascular insulin sensitivity in adults with obesity.

Chronotype reflects a circadian rhythmicity that regulates endothelial function. While the morning chronotype (MORN) usually has low cardiovascular disease risk, no study has examined insulin action on endothelial function between chronotypes. We hypothesized intermediate chronotypes (INT) would have lower vascular insulin sensitivity than morning chronotype (MORN). Adults with obesity were classified per Morningness-Eveningness Questionnaire (MEQ) as either MORN (n = 27, 22 female, MEQ = 63.7 ± 4.7, 53.8 ± 6.7 years, 35.3 ± 4.9 kg/m2) or INT (n = 29, 23 female, MEQ = 48.8 ± 6.7, 56.6 ± 9.0 years, 35.7 ± 6.1 kg/m2). A 120 min euglycaemic-hyperinsulinaemic clamp (40 mU/m2/min, 90 mg/dl) was conducted to assess macrovascular insulin sensitivity via brachial artery flow-mediated dilation (%FMD; conduit artery), post-ischaemic flow velocity (resistance arteriole), as well as microvascular insulin sensitivity via contrast-enhanced ultrasound [e.g. microvascular blood volume (perfusion)]. Fasting plasma arginine and citrulline, as well as fasting and clamp-derived plasma endothelin-1 and nitrate/nitrite, were assessed as surrogates of vasoconstriction and nitric oxide-mediated vasodilation. Aerobic fitness (VO2max) and body composition (dual-energy X-ray absorptiometry) were also collected. MORN had a higher VO2max compared with INT (p < .01), although there was no difference in fat mass. While fasting FMD was similar between groups, insulin lowered FMD corrected to shear stress and microvascular blood volume in INT compared with MORN after co-varying for VO2max (both p ≤ .02). INT also had a lower fasting nitrate (p = .03) and arginine (p = .07). Higher MEQ correlated with elevated FMD (r = 0.33, p = .03) and lower post-ischaemic flow velocity (r = -0.33, p = .03) as well as shear rate (r = -0.36, p = .02) at 120 min. When measured during the morning, INT had a lower vascular insulin sensitivity than MORN. Additional work is needed to understand endothelial function differences among chronotypes to optimize cardiovascular disease risk reduction.

Resistin in endocrine pancreas of sheep: Presence and expression related to different diets

Resistin (RETN), a recently discovered adipokine, is a cysteine-rich and secretory protein produced by adipocytes. RETN has been detected in several tissues, including human and laboratory animals' pancreas, wherein impairs glucose tolerance and insulin (INS) action and causes INS resistance. This study aims to evaluate the presence and expression of RETN in the pancreas of 15 adult female sheep reared on Apennine pastures, which show a decrease in their nutritional value due to the drought stress linked to the increasing summer aridity. The sheep were divided into 3 groups according to the diet they were subjected to: maximum pasture flowering (MxF) group, maximum pasture dryness (MxD) group, and experimental (Exp) group which received a feed supplementation in addition to the MxD group feeding. Immunohistochemistry and immunofluorescence were performed on formalin-fixed and paraffin-embedded sections of the pancreas to detect the RETN presence and to evaluate the co-localization of RETN with both glucagon (GCG)- and INS-producing cells. In addition, the expression of the three molecules was evaluated also in relation to different diets.RETN was observed only in the endocrine pancreas, showing a wide distribution throughout the pancreatic islets with few negative cells and the RETN producing cells colocalized with both α cells and ß cells. No differences in distribution and immunostaining intensity of RETN, GCG and INS were observed among the three groups. Quantitative PCR showed the expression of RETN, GCG and INS in all tested samples. No significant differences were observed for RETN and GCG among all three groups of sheep. Instead, a high statistically significant expression of INS was detected in the MxF group with respect to the Exp and MxD groups.These results highlight the localization of RETN in GCG- and INS-secreting cells involved in glucose homeostasis suggesting a modulatory role for RETN. Furthermore, the RETN expression is not influenced by food supplementation and thus is not affected by diet.

Genetic Investigation of the Trail Mechanism in Diabetic and Non-diabetic Obese Patients.

Obesity is an important healthcare issue caused by abnormally increased adipose tissue because of energy-intake overcoming energy expenditure. Disturbances in the physiological function of adipose tissue mediate the development of diabetes. It is a metabolic disease that results from decreased insulin-levels and/or changes in the insulin action mechanism. Tumor Necrosis Factor-Associated Apoptosis-Inducing Ligand(TRAIL), which is a member of the Tumor Necrosis Factor(TNF)-family with an important role in adipose tissue biology, is included in many studies with its ability to induce apoptosis in cancer cells, but the number of human-studies conducted on the gene related to its protective-role against diabetes and obesity at this level is insufficient. Our study was carried out as a case and control and included three groups (80 diabetic obese, 80 non-diabetic obese, and 80 healthy individuals as the control group). The Real-Time-PZR(RT-qPZR), and DNA Sanger-Sequencing Methods were used for gene expression and gene squences. As a result of the analyses, TRAIL gene expression level was found to be higher in the controls than in the diabetic-obese and non-diabetic-obese group. This change in TRAIL gene expression suggests that TRAIL maybe a protective factor against diabetes. The presence of rs781673405, rs143353036, rs1244378045, rs767450259, rs759369504, rs750556128, and rs369143448 mutations, which was determined with the Sequencing-Method, was shown for the first time in the present study. In addition, it is the first study in which human TRAIL gene-expression and sequencing were performed together. We believe that these data will make an important contribution to the literature.

Abstract B055: Hyperinsulinemia acts via acinar cell insulin receptors to drive obesity-associated pancreatic cancer initiation

Abstract The rising incidence of pancreatic cancer is largely driven by increased prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of obesity and T2D, and is associated with increased cancer incidence and mortality. Whether insulin alone plays a causal role in increasing cancer risk by directly affecting the tumor cell of origin remains unclear. Our previous studies demonstrated that genetically reducing production of insulin suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, consistent with a role for insulin in modulating the immune system, we saw changes in fibrosis, as well as changes in the transcriptomes of immune cells in the pancreas in mice with reduced insulin. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment. Here, we tested whether insulin receptor (Insr) in KrasG12D-expressing pancreatic acinar cells was necessary for the effects of diet-induced hyperinsulinemia on pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not halt the development of hyperinsulinemia or weight gain associated with high fat diet consumption in mice. However, solely reducing Insr expression in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors. Mechanistically, proteomic analyses suggested that insulin and Insr coordinately regulate the production of digestive enzymes, the main function of acinar cells, by modulating the activity of the spliceosome, ribosome, and secretory machinery. Consistent with this adding insulin to TGF-alpha treated wild-type acini ex vivo increased their conversion into ductal structures and this was blocked by treatment with trypsin inhibitor. Additionally, loss of Insr also reduced the formation of duct-like structures in acinar explants after TGF-alpha stimulation and made them insensitive to insulin. Collectively, these data demonstrated that insulin action on the insulin receptor in acinar cells promotes conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer especially in the context of hyperinsulinemia and obesity. Citation Format: Anni M.Y. Zhang, Yi Han Xia, Jeffrey S.H. Lin, Ken H. Chu, Wei Chuan K. Wang, Titine J.J. Ruiter, Jenny C.C. Yang, Nan Chen, Justin Chhuor, Shilpa Patil, Haoning H. Cen, Elizabeth J. Rideout, Vincent R. Richard, David F. Schaeffer, Rene P. Zahedi, Christoph H. Borchers, James D. Johnson, Janel L. Kopp. Hyperinsulinemia acts via acinar cell insulin receptors to drive obesity-associated pancreatic cancer initiation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B055.

Characteristics of Normal Weight Insulin-Resistant Adults with Unfavorable Health Outcomes.

Background: Insulin resistance can be present in otherwise healthy, normal weight adults. Whether there are phenotype/sex-differences between normal weight insulin-resistant (NWIR) and normal weight insulin-sensitive (NWIS) Caucasians and whether there are differences in adverse health outcomes are unknown. Our goal was to define phenotypes and intermediate-term health outcomes of NWIR versus NWIS Caucasian adults. Methods: We analyzed data from 227 healthy volunteers body mass index 18 to <25.0 kg/m2 who underwent insulin clamp studies between January 1987 and January 2017 at Mayo Clinic to identify those in the top (NWIS, n = 56) and bottom (NWIR, n = 56) quartiles of insulin action. We compared the phenotypical characteristics and were able to collect medical records data for 80% of NWIS and 88% of NWIR to identify time to onset of hypertension, hyperglycemia, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and all cause death; the follow-up averaged 11 (4, 20) years. Results: Body fat was significantly greater and peak VO2 was significantly less in both NWIS than NWIR males and females. Only in females was abdominal subcutaneous fat by computed tomography significantly greater in NWIR than NWIS. In NWIR males high-density lipoprotein-cholesterol and fat free mass were significantly less, and fasting insulin was greater than NWIS males. For the entire NWIS population, Kaplan-Meier disease-free survival analysis showed longer times free of hypertension, hyperglycemia, and some cardiovascular diseases than for NWIR. Conclusions: There are sex-specific phenotypes of NWIR in Caucasian adults. NWIR may be associated with accelerated onset of some adverse medical outcomes.