Beta-cell Activity Research Articles

“Whey Protein Supplements between Bodybuilders” Health, Risk of Diseases and Myth: A Narrative Review 2010-2024

This narrative review evaluates the most recent studies on the health effects of whey protein (WP) supplements, with a focus on potential risks and negative consequences. WP, which is frequently taken by bodybuilders to gain muscle and lose weight, has been linked to a number of health problems. Twenty-four preclinical and human studies that provide a complete overview of the health effects of WP were included in our comprehensive review after a comprehensive search of various databases. The review provides important findings, including a possible link between WP and kidney and liver damage, changes in bowel activity, acne, effects on bone metabolism, and pancreatic beta cell activity. The above findings highlight the complex nature of the impact of weightlifting on human health, revealing both positive and negative consequences in relation to different situations in diverse contexts. Research suggests that individuals with impaired liver and kidney function, as well as those prone to acne, should be cautious when consuming protein, and polycystic ovary syndrome. However, there may be positive effects on gut activity, bone and muscle metabolism, and pancreatic activity in humans and experimental animals, emphasizing the importance of consuming WP in a balanced manner and calling for more comprehensive research to understand its long-term health consequences.

226.5: Targeting the activity of beta cells by membrane surface redox regulation for islet transplantation.

226.5: Targeting the activity of beta cells by membrane surface redox regulation for islet transplantation.

Fluoride-Induced Alterations in the Pancreas of Mammals: A Meta-analysis.

This review explores the diverse effects of fluoride on pancreatic function, encompassing both in vitro and in vivo studies. Fluoride exposure induces notable alterations at the cellular and molecular levels, affecting pancreatic morphology, histology, and enzymatic activity. In vitro studies demonstrate significant inhibition of pancreatic α-amylase activity and apoptosis in pancreatic beta cells. In vivo investigations reveal structural abnormalities in pancreatic cells, including mitochondrial damage, vacuolation, and nuclear damage. Moreover, fluoride exposure disrupts antioxidant enzyme activity, exacerbating oxidative stress and lipid peroxidation. Changes in digestive enzyme activity, such as the inhibition of pancreatic lipase and α-amylase, further contribute to pancreatic dysfunction. Additionally, alterations in hormone secretion, notably insulin levels and disturbed glucose homeostasis, highlight the complex effects of fluoride on the pancreatic endocrine system. These findings underscore fluoride-induced pancreatic toxicity and highlight the need for a comprehensive understanding and mitigation strategies to safeguard pancreatic health.

Dorzagliatin: A Breakthrough Glucokinase Activator Coming on Board to Treat Diabetes Mellitus.

Dorzagliatin, an innovative dual-acting allosteric oral glucokinase activator that targets glucose homeostasis and insulin resistance, has gained approval for treating type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The effectiveness of existing antidiabetic treatments in enhancing beta cell (β-cell) activity is restricted. Currently, there are no satisfactory medications available to address the fundamental deficiency in glucose sensing for glucokinase-maturity-onset diabetes of the young (GCK-MODY), which is caused by mutations in the glucokinase gene; researchers have embarked on glucokinase activators. Dorzagliatin enhances the affinity of glucokinase for glucose and glucose-sensing capacity, improves β-cell function, and reduces insulin resistance. Two phase 3 studies, an adjunct trial of dorzagliatin with metformin for T2DM patients and a monotherapy trial for drug-naïve T2DM patients, are key clinical trials that have shown a favorable safety and tolerability profile. They also demonstrated a rapid, sustained reduction in glycated hemoglobin (HbA1c) and a significant decrease in postprandial blood glucose. This review will summarize the substantial clinical evidence supporting the safety and efficacy of dorzagliatin in treating diabetes mellitus (DM) and clarify the molecular mechanisms underlying its action.

The metabolic consequences of 'yo-yo' dieting are markedly influenced by genetic diversity.

Weight loss can improve the metabolic complications of obesity. However, it is unclear whether insulin resistance persists despite weight loss and whether any protective benefits are preserved following weight regain (weight cycling). The impact of genetic background on weight cycling is undocumented. We aimed to investigate the effects of weight loss and weight cycling on metabolic outcomes and sought to clarify the role of genetics in this relationship. Both C57BL/6 J and genetically heterogeneous Diversity Outbred Australia (DOz) mice were alternately fed high fat Western-style diet (WD) and a chow diet at 8-week intervals. Metabolic measures including body composition, glucose tolerance, pancreatic beta cell activity, liver lipid levels and adipose tissue insulin sensitivity were determined. After diet switch from WD (8-week) to chow (8-week), C57BL/6 J mice displayed a rapid normalisation of body weight, adiposity, hyperinsulinemia, liver lipid levels and glucose uptake into adipose tissue comparable to chow-fed controls. In response to the same dietary intervention, genetically diverse DOz mice conversely maintained significantly higher fat mass and insulin levels compared to chow-fed controls and exhibited much more profound interindividual variability than C57BL/6 J mice. Weight cycled (WC) animals were re-exposed to WD (8-week) and compared to age-matched controls fed 8-week WD for the first time (LOb). In C57BL/6 J but not DOz mice, WC animals had significantly higher blood insulin levels than LOb controls. All WC animals exhibited significantly greater beta cell activity than LOb controls despite similar fat mass, glucose tolerance, liver lipid levels and insulin-stimulated glucose uptake in adipose tissue. Following weight loss, metabolic outcomes return to baseline in C57BL/6 J mice with obesity. However, genetic diversity significantly impacts this response. A period of weight loss does not provide lasting benefits after weight regain, and weight cycling is detrimental and associated with hyperinsulinemia and elevated basal insulin secretion.

340-OR: Transcriptional Activation in Beta-Cells during ER Stress Linking iPLA2beta with NFkB

340-OR: Transcriptional Activation in Beta-Cells during ER Stress Linking iPLA2beta with NFkB

Gestational diabetes mellitus may predispose to metabolic dysfunction-associated steatotic liver disease.

The development of type 2 diabetes mellitus is a major contributing factor to the worldwide health burden of metabolic dysfunction-associated steatotic liver disease (MASLD). Insulin resistance, subclinical inflammation, dyslipidemia, obesity, and hypertension are all factors in this reciprocal interaction that contribute to the development of MASLD, which includes hepatocellular carcinoma, advanced fibrosis/cirrhosis, and non-alcoholic steatohepatitis (NASH). A new risk factor for MASLD/NASH that affects the course of the disease independently throughout life is gestational diabetes mellitus (GDM). Women with a history of GDM had a higher chance of developing NASH, according to a recent study that used a large-scale database. Although the precise etiology is yet unknown, temporary disruption of pancreatic beta cell activity during pregnancy may set off systemic inflammation, affecting distant organs including the liver. Early screening and management strategies are crucial in mitigating MASLD progression and preventing adverse cardiovascular events in affected individuals.

Beta-cell activity and development of Type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease, resulting in diminished islet integrity and destruction of the insulin-secreting beta cells. In this review, we investigate the intrinsic relationship between the development of T1D and the activity of the beta cells. The idea was initially hypothesized in 1982 that an increased beta-cell activity would enhance the surface antigen expression and thereby attract the immune system. Later, other findings support this idea, including increased risk of T1D development during third trimester of pregnancy, and the difference in T1D incidence in Russian and Finnish Karelia due to different lifestyles. Other implications of high beta-cell activity, such as reduced sulfatide levels, formation of non-correct insulin molecules and an increase in IFN-alpha upon virus attack, can contribute to the development of T1D. A possible way to prevent the development of T1D is to diminish beta-cell activity, which has shown promising results in animal models.

An Overview of Differential miRNA Profile of Patients with Latent Autoimmune Diabetes in Adults (LADA)

Diabetes mellitus (DM) is a metabolic and chronic disease characterized by hyperglycemia developing with impaired pancreatic beta cell activity, decreased insulin secretion, icreased insulin resistance, and accordingly impaired carbohydrate, protein and lipid metabolism. DM is classified as type 1, type 2, gestational and other forms of diabetes according to the characteristic properties such as age of onset, insulin dependency, micro- and macrovascular complications. Latent autoimmune diabetes in adults (LADA) is an autoimmune diabetes that begins in adulthood without insulin dependency for glycemic control at least in the first six months after diagnosis. Owing to the common genetic, immunologic, and metabolic features LADA is misdiagnosed with type 1 or type 2 diabetes. Therefore, it is need a biomarkers that ease the diagnosis of LADA. MicroRNAs are small non-coding RNAs involved in biological processes and regulate the response of target tissues to insulin as well as insulin production, signaling and release, insulin resistance, and glucose homeostasis. Dysregulation in miRNA expression can lead to impairment of glucose metabolism. Circulating miRNA are associated with different types of diabetes and have a potential to discriminate them. So, we reviewed the miRNAs that gene expressions levels which change in LADA compared to type 1 and type 2 diabetes.

Vernonia amygdalina Del (Bitter leaf) a traditional anti-diabetic gold mine - Mini Review

Diabetes mellitus is a worldwide epidemic that has serious consequences for public health. This in-depth analysis of Vernonia amygdalina, or Bitter Leaf, aims to shed light on the plant's potential anti-diabetic properties by discussing its botanical description, chemical composition, traditional uses, and mechanisms of action, scientific findings, safety concerns, and implications for future study. Vernonia amygdalina, a plant native to various nations in Africa, has gained popularity as a possible treatment for diabetes. Bitter leaf's traditional function in reducing diabetes-related complications is also highlighted, and the review goes deeply into the plant's rich historical and cultural context. The possible anti-diabetic properties of Bitter leaf are discussed, along with the processes that may be at play. These include the effect on insulin sensitivity, glucose homeostasis, and pancreatic beta cell activity. Improving glycemic control and insulin resistance is only two of the positive effects seen in clinical trials and research investigations. There is also discussion of precautions to take, including details on how this treatment could interact with standard drugs. The review continues by stressing the need for more study to fill up the gaps in our understanding and pave the path for the deliberate application of Vernonia amygdalina as an adjunctive method of diabetes care. This analysis of Bitter leaf's diabetes-fighting properties adds to the increasing body of information around diabetes natural treatments, opening up new lines of inquiry and possible therapeutic applications in the field.

Silibinin as a promising treatment for diabetes: Insights into behavioral and metabolic changes in an animal model.

Diabetes mellitus is causing serious health problems in the chronic period. Silibinin is a flavonoid obtained from the milk thistle (Silybum marianum), which is among the herbal ethnopharmacological administrations. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia-reducing effect. However, behavioral parameters have not been evaluated together with insulin levels and liver function tests. Our aim in this study was to examine the effects of silibinin on insulin secretion, anxiety-like behaviors, and learning in a streptozotocin (STZ)-induced rat diabetes model. Wistar albino rats weighing 200-250 g were divided into 4 groups. Control: Saline solution, Diabetes: STZ 45 mg/kg, S 100: STZ 45 mg/kg + Silibinin 100 mg/kg, S 200: STZ 45 mg/kg + Silibinin 200 mg/kg. Administrations were continued for 21 days. On the 21st day, open field and elevated plus maze as unconditional anxiety tests; Barnes maze for learning and memory; and rotarod test for locomotor activity were conducted. Following behavioral tests, blood samples were taken under anesthesia. Blood glucose levels and ALT values were measured. Insulin levels were measured with an ELISA plate reader. Silibinin shortened the time to find the correct hole. Silibinin prevented the decrease in insulin due to STZ, exhibited a hyperglycemia-reducing effect and decreased the elevation of ALT.

Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices.

Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis of energy-rich nutrients. While glucose serves as a primary regulator of this process, incretins augment beta cell function, partly by enhancing cytosolic [Ca2+] dynamics. However, the details of how precisely they affect beta cell recruitment during activation, their active time, and functional connectivity during plateau activity, and how they influence beta cell deactivation remain to be described. Performing functional multicellular Ca2+ imaging in acute mouse pancreas tissue slices enabled us to systematically assess the effects of the GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously in many coupled beta cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able to recruit approximately a quarter of beta cells into an active state. Costimulation with Ex-4 and stimulatory glucose shortened the activation delays and accelerated beta cell activation dynamics. More specifically, active time increased faster, and the time required to reach half-maximal activation was effectively halved in the presence of Ex-4. Moreover, the active time and regularity of [Ca2+]IC oscillations increased, especially during the first part of beta cell response. In contrast, subsequent addition of Ex-4 to already active cells did not significantly enhance beta cell activity. Network analyses further confirmed increased connectivity during activation and activity in the presence of Ex-4, with hub cell roles remaining rather stable in both control experiments and experiments with Ex-4. Interestingly, Ex-4 demonstrated a biphasic effect on deactivation, slightly prolonging beta cell activity at physiological concentrations and shortening deactivation delays at supraphysiological concentrations. In sum, costimulation by Ex-4 and glucose increases [Ca2+]IC during beta cell activation and activity, indicating that the effect of incretins may, to an important extent, be explained by enhanced [Ca2+]IC signals. During deactivation, previous incretin stimulation does not critically prolong cellular activity, which corroborates their low risk of hypoglycemia.

NGF effects promote the maturation of rat pancreatic beta cells by regulating GLUT2 levels and distribution, and glucokinase activity.

The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process in which metabolic events and ionic channel activity are finely coupled. GLUT2 and glucokinase (GK) play central roles in GSIS by regulating the rate of the glycolytic pathway. The biphasic release of insulin upon glucose stimulation characterizes mature adult beta cells. On the other hand, beta cells obtained from neonatal, suckling, and weaning rats are considered immature because they secrete low levels of insulin and do not increase insulin secretion in response to high glucose. The weaning of rats (at postnatal day 20 in laboratory conditions) involves a dietary transition from maternal milk to standard chow. It is characterized by increased basal plasma glucose levels and insulin levels, which we consider physiological insulin resistance. On the other hand, we have observed that incubating rat beta cells with NGF increases GSIS by increasing calcium currents in neonatal cells. In this work, we studied the effects of NGF on the regulation of cellular distribution and activity of GLUT2 and GK to explore its potential role in the maturation of GSIS in beta cells from P20 rats. Pancreatic islet cells from both adult and P20 rats were isolated and incubated with 5.6 mM or 15.6 mM glucose with and without NGF for 4 hours. Specific immunofluorescence assays were conducted following the incubation period to detect insulin and GLUT2. Additionally, we measured glucose uptake, glucokinase activity, and insulin secretion assays at 5.6 mM or 15.6 mM glucose concentrations. We observed an age-dependent variation in the distribution of GLUT2 in pancreatic beta cells and found that glucose plays a regulatory role in GLUT2 distribution independently of age. Moreover, NGF increases GLUT2 abundance, glucose uptake, and GSIS in P20 beta cells and GK activity in adult beta cells. Our results suggest that besides increasing calcium currents, NGF regulates metabolic components of the GSIS, thereby contributing to the maturation process of pancreatic beta cells.

Genetic perspectives on childhood monogenic diabetes: Diagnosis, management, and future directions.

Monogenic diabetes is caused by one or even more genetic variations, which may be uncommon yet have a significant influence and cause diabetes at an early age. Monogenic diabetes affects 1 to 5% of children, and early detection and gene-tically focused treatment of neonatal diabetes and maturity-onset diabetes of the young can significantly improve long-term health and well-being. The etiology of monogenic diabetes in childhood is primarily attributed to genetic variations affecting the regulatory genes responsible for beta-cell activity. In rare instances, mutations leading to severe insulin resistance can also result in the development of diabetes. Individuals diagnosed with specific types of monogenic diabetes, which are commonly found, can transition from insulin therapy to sulfonylureas, provided they maintain consistent regulation of their blood glucose levels. Scientists have successfully devised materials and methodologies to distinguish individuals with type 1 or 2 diabetes from those more prone to monogenic diabetes. Genetic screening with appropriate findings and interpretations is essential to establish a prognosis and to guide the choice of therapies and management of these interrelated ailments. This review aims to design a comprehensive literature summarizing genetic insights into monogenetic diabetes in children and adolescents as well as summarizing their diagnosis and mana-gement.

Genetic predisposition of LEPR (rs1137101) gene polymorphism related to type 2 diabetes mellitus – a meta-analysis

Background: Type 2 diabetes mellitus (T2DM) is a multifaceted disease appropriate to elevated blood glucose levels resulting from decreased insulin and beta-cell activity. Using a case–control methodology, researchers have examined the relationship between polymorphisms in LEPR and T2DM in a population from south India. Materials and Methods: We conducted a genetic analysis of 311 participants, and results were accomplished using a case-control study, a meta-analysis of previous studies on LEPR was conducted, and type 2 diabetes genotype distribution across various geographical regions Malaysians, Chinese Han, Kuwait, Iran, Mongolia, and Han Chinese, Greece, Saudi, India (North India, Punjabi), (South India, Tamilnadu). The study involved 254 prospective investigations, and nine association studies were preferred according to preset criteria. Studies were assessed for quality using the Hardy-Weinberg equilibrium (HWE) and the Newcastle–Ottawa Scale (NOS). An analysis of the genetic models was conducted to determine their relationship, statistical analysis was utilized to calculate odds ratios (ORs) and matching 95% confidence intervals (CIs). Results: The LEPR-rs1137101 polymorphism in the case-control study was associated with a significant increase in the risk of type 2 diabetes. A meta-analysis revealed a connection between LEPR gene polymorphism (rs1137101) and type 2 diabetes risk. Investigators might gain a more profound thought on the significance of the identified genetic variation and its impact on the chance of developing type 2 diabetes by verifying and strengthening previously reported findings. The model of fixed effects was chosen due to the low heterogeneity, and significant associations were observed in the allelic (OR = 0.79, 95% CI [0.70–0.87]), homozygote (OR = 0.58, 95% CI [0.46–0.72]), dominant (OR = 0.66, 95% CI [0.56–0.79]), and recessive (OR = 0.83, 95% CI [0.71–0.96]) genetic models. A Begg’s funnel plot and Egger’s test indicated no publication bias. These findings suggest that the rs1137101 variant in the LEPR gene has been linked to a higher risk of T2DM. Conclusions: A larger sample size, however, is required for further research, and consideration of potential confounding factors is needed to validate these associations. Understanding the implications of LEPR gene polymorphisms in T2DM susceptibility may contribute to personalized treatment strategies for patients with T2DM.

Simvastatin, but not Pravastatin, Blocks L-Type Ca2+ Channels In Rat Islet -Cells, Inhibiting Glucose-Induced Cytosolic Ca2+ Signaling and Insulin Release

Patients with type 2 diabetes who have hypercholesterolemia frequently need to take HMG-CoA reductase inhibitors. A key factor in the pathophysiology of type 2 diabetes is altered pancreatic beta-cell activity, which results in a reduced ability of the pancreas to secrete insulin in response to glucose. The impact of HMG-CoA reductase inhibitors on -cell function must therefore be investigated. The regulation of -cell function is greatly influenced by the cytosolic Ca2+ concentration ([Ca2+]i). The current work looked at how HMG-CoA reductase inhibitors affected the [Ca2+]i signaling and insulin release that glucose-induced in rat islet -cells. Simvastatin, a lipophilic HMG-CoA reductase inhibitor, suppressed the initial phase increase and oscillation of [Ca2+]i caused by 8.3 mM glucose in single -cells at concentrations ranging from 0.1 to 3 g ml—1. The fewer Simvastatin-acid, a lipophilic inhibitor, decreased the first [Ca2+]i rise but was two orders of magnitude less effective. Pravastatin (100g ml—1), a hydrophilic inhibitor, has little impact on [Ca2+]. Simvastatin (0.3g ml–1) reduced glucose-induced insulin production from islets more effectively than simvastatin-acid (30g ml–1), whereas pravastatin (100g ml–1) had no effect. Simvastatin, but not pravastatin, showed a reversible blockage of the L-type Ca2+ channels in -cells in whole-cell patch clamp recordings. Simvastatin also prevented the opening of L-type Ca2+ channels, which is how L-arginine and HCl enhance [Ca2+] Conclusion: By blocking L-type Ca2+ channels in -cells, lipophilic HMG-CoA reductase inhibitors can prevent glucose-induced [Ca2+]i signaling and insulin secretion, and their inhibitory potencies are inversely correlated with their lipophilicities. Precaution must be takenWhen HMG-CoA reductase inhibitors are utilized in clinical settings, attention should be given to these findings, especially in type 2 diabetic patients.

KATP channel activity and slow oscillations in pancreatic beta cells are regulated by mitochondrial ATP production.

Pancreatic beta cells secrete insulin in response to plasma glucose. The ATP-sensitive potassium channel (KATP ) links glucose metabolism to islet electrical activity in these cells by responding to increased cytosolic [ATP]/[ADP]. It was recently proposed that pyruvate kinase (PK) in close proximity to beta cell KATP locally produces the ATP that inhibits KATP activity. This proposal was largely based on the observation that applying phosphoenolpyruvate (PEP) and ADP to the cytoplasmic side of excised inside-out patches inhibited KATP . To test the relative contributions of local vs. mitochondrial ATP production, we recorded KATP activity using mouse beta cells and INS-1 832/13 cells. In contrast to prior reports, we could not replicate inhibition of KATP activity by PEP+ADP. However, when the pH of the PEP solutions was not corrected for the addition of PEP, strong channel inhibition was observed as a result of the well-known action of protons to inhibit KATP . In cell-attached recordings, perifusing either a PK activator or an inhibitor had little or no effect on KATP channel closure by glucose, further suggesting that PK is not an important regulator of KATP . In contrast, addition of mitochondrial inhibitors robustly increased KATP activity. Finally, by measuring the [ATP]/[ADP] responses to imposed calcium oscillations in mouse beta cells, we found that oxidative phosphorylation could raise [ATP]/[ADP] even when ADP was at its nadir during the burst silent phase, in agreement with our mathematical model. These results indicate that ATP produced by mitochondrial oxidative phosphorylation is the primary controller of KATP in pancreatic beta cells. KEY POINTS: Phosphoenolpyruvate (PEP) plus adenosine diphosphate does not inhibit KATP activity in excised patches. PEP solutions only inhibit KATP activity if the pH is unbalanced. Modulating pyruvate kinase has minimal effects on KATP activity. Mitochondrial inhibition, in contrast, robustly potentiates KATP activity in cell-attached patches. Although the ADP level falls during the silent phase of calcium oscillations, mitochondria can still produce enough ATP via oxidative phosphorylation to close KATP . Mitochondrial oxidative phosphorylation is therefore the main source of the ATP that inhibits the KATP activity of pancreatic beta cells.

Diabete mellito dopo trattamento con ocrelizumab per sclerosi multipla primariamente progressiva

Objectives: immune reconstitution therapies, which include antibody-based cell-depleting therapies targeting CD20+ (ocrelizumab, ofatumumab) or CD52+ (alemtuzumab) leukocytes, are approved for the treatment of multiple sclerosis. Autoimmune thyroid disease is the most common adverse effect of treatment with alemtuzumab, but some cases of autoimmune diabetes have been reported. To date, diabetes mellitus has not been reported after CD20-targeting monoclonal antibodies therapy. Case Report: a 41-year-old man with primary progressive multiple sclerosis was diagnosed with diabetes mellitus six months following the first ocrelizumab infusion. He experienced polyuria and polydipsia, but not other symptoms as visual loss or weight loss. We started a basal-bolus insulin therapy, with progressive and relatively rapid improvement of glycemic control. To note, C-peptide resulted indicative of a preserved beta-cell activity and autoantibodies were negative. To present date, the patient reached an excellent control with metformin. Conclusions: this is the first case of diabetes mellitus reported after ocrelizumab administration. The timing of onset and course are similar to alemtuzumab-induced autoimmune diseases, usually interpreted as an “immune reconstitution syndrome”; however, ocrelizumab cell count depletion appears inferior in duration and cell population affected. This case suggests the need for screening and follow-up of glycemic status in patients treated with ocrelizumab. As a novel therapeutic antibody, further investigation is required to elucidate the correlation between hyperglycemia and ocrelizumab.

Adjudin improves beta cell maturation, hepatic glucose uptake and glucose homeostasis

Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398).Graphical

THU367 Hyperosmolar Hyperglycemic State In A Middle-old Male With Primary Hyperparathyroidism

Abstract Disclosure: D.M. Dimayuga: None. M.C. Isidro: None. A 79-year-old male was brought to our hospital for drowsiness. He had low-grade fever with associated cough and anorexia 1 week prior. He had a previous history of hypertension and primary hyperparathyroidism (PHPT) maintained on cinacalcet. He did not have a history of diabetes and a family history of diabetes, and his HbA1c was 5.4% three months before. On admission, the results of his physical examination and vital signs were as follows: height, 152cm; weight, 56.0 kg; BMI, 24.2 kg/m2; temperature, 36.5C; heart rate, 85 beats/min; SpO2, 98% (on room air); respiratory rate, 22 breaths/min; and blood pressure, 115/60 mm Hg. His blood glucose level was 966 mg/dL, HbA1c 13.4%, and serum osmolality 324 mOsm/kg. Serum ketones were 15 mg/dL and blood gas analysis was normal. He was diagnosed with hyperglycemic hyperosmolar state (HHS) and infusion of insulin and saline was subsequently initiated. With clinical suspicion of chronic pancreatitis given the patient’s history of PHPT, serum lipase was checked, 105 U/L (NV: 12-53 U/L). Ionized calcium was 1.36 mmol/L. On CT scan of abdomen, there was no evidence of duct dilatation and calcification, and instead, “features of diffuse fatty atrophy of the pancreas” were seen. His endogenous insulin secretory capacity was sufficient (serum C-peptide: 2.76 ng/mL, NV: 0.78-5.19 ng/mL). Eventually, the patient’s level of consciousness improved and glycemic control was achieved. Soon after, insulin was shifted to basal-bolus regimen. On the 7th day of hospitalization, patient was discharged with minimal insulin requirements. Two weeks later, on follow up, his blood glucose levels were found to be stable. It was not clear whether our patient had new-onset autoimmune or type 2 diabetes. Although autoimmune diabetes generally occurs when about 90% of the pancreatic beta cells have been destroyed, the patient could have been in the honeymoon period wherein beta cell activity was transiently regained after commencement of insulin therapy. Our plan is to monitor his C-peptide titers and test his insulin antibodies. Evidence suggests that PHPT may cause insulin resistance and glucose intolerance. The rise in free intracellular calcium may reduce glucose transport in insulin-stimulated glucose transporters, increasing the need for insulin. This could be the case in our patient hence we diagnosed him with type 2 diabetes. To the best of our knowledge, this is the first case demonstrating the co-occurrence of HHS and PHPT. Presentation: Thursday, June 15, 2023