Insulin receptors in the kidneys in health and disease

Insulin is an important hormone that affects various metabolic processes,including kidney function.Impairment in insulin's action leads to insulin resistance in the target tissue.Besides defects in post-receptor insulin signaling,impairment at the receptor level could significantly affect insulin sensitivity of the target tissue.The kidney is a known target of insulin;however,whether the kidney develops "insulin resistance" is debatable.Regulation of the insulin receptor(IR) expression and its function is very well studied in major metabolic tissues like liver,skeletal muscles,and adipose tissue.The physiological relevance of IRs in the kidney has recently begun to be clarified.The credit goes to studies that showed a wide distribution of IR throughout the nephron segments and their reduced expression in the insulin resistance state.Moreover,altered renal and systemic metabolism observed in mice with targeted deletion of the IR from various epithelial cells of the kidney has strengthened this proposition.In this review,we recapitulate the crucial findings from literature that have expanded our knowledge regarding the significance of the renal IR in normal-and insulin-resistance states.

Influence of berberine on protein tyrosine kinase of erythrocyte insulin receptors from type 2 diabetes mellitus

Objective： Bererine has been used to treat type 2 diabetes mellitus in Chinese traditional medicine because of its hypoglycemic effect. In this report, we compared the intrinsic tyrosine kinase activities of erythrocyte insulin receptors from type 2 diabetes mellitus with or without stimulation by berberine in vitro. Methods- Preparations containing insulin receptors were obtained from soluble human erythrocytes, and the insulin receptors were partially purified by affinity chromatography. The tyrosine kinase activity was measured by the exogenous substrate phosphorylation. Results： Both the membrane tyrosine kinase activity and the purified receptor tyrosine kinase activity from diabetics decreased significantly compared with those of normal individuals （reduced by 67.4% and 47.2%, respectively）. After incubation with berbefine, there is a statistical difference in the activity of membrane tyrosine kinase for diabetic patients （ a 150% increase）. Berefine had no effect on the tyrosine kinase activity of purified insulin receptors. Conclusion： We concluded from these results that berbefine was able to improve the insulin sensitivity by increasing the protein tyrosine kinase activity of membrane-bound insulin receptors from type 2 diabetes mellitus.

Changes of the binding capacity of insulin receptors and activities of adenylate cyclase in hepatocytes after scalding in rats

In order to investigate the effects of transmembranous conduction of signals on insulin resistance after scalding,the changes of the binding capacity of insulin receptors in the cell membrane of hepatocytes and the activities of adenylate cyclase were observed in rats after they were inflicted with 30% TBSA full thickness scalding. It was found that the maximum binding capacity of insulin receptors was significantly decreased after scalding but the average affinity increased. The sensitivity of insulin inhibition on the activity of adenylate cyclase was significantly reduced but there was no apparent difference of the maximum inhibition activity. These findings suggest that the impairment of transmembranous conduction of insulin signals across the cell membrane of hepatocytes after scalding can result in abnormal metabolism of glucose and consequently insulin resistance.

Olfactory receptors in neural regeneration in the central nervous system

Olfactory receptors are crucial for detecting odors and play a vital role in our sense of smell,influencing behaviors from food choices to emotional memories.These receptors also contribute to our perception of flavor and have potential applications in medical diagnostics and environmental monitoring.The ability of the olfactory system to regenerate its sensory neurons provides a unique model to study neural regeneration,a phenomenon largely absent in the central nervous system.Insights gained from how olfactory neurons continuously replace themselves and reestablish functional connections can provide strategies to promote similar regenerative processes in the central nervous system,where damage often results in permanent deficits.Understanding the molecular and cellular mechanisms underpinning olfactory neuron regeneration could pave the way for developing therapeutic approaches to treat spinal co rd injuries and neurodegenerative diseases like Alzheimer's disease.Olfa ctory receptors are found in almost any cell of eve ry orga n/tissue of the mammalian body.This ectopic expression provides insights into the chemical structures that can activate olfactory receptors.In addition to odors,olfactory receptors in ectopic expression may respond to endogenous compounds and molecules produced by mucosal colonizing microbiota.The analysis of the function of olfactory receptors in ectopic expression provides valuable information on the signaling pathway engaged upon receptor activation and the receptor's role in proliferation and cell differentiation mechanisms.This review explo res the ectopic expression of olfa ctory receptors and the role they may play in neural regeneration within the central nervous system,with particular attention to compounds that can activate these receptors to initiate regenerative processes.Evidence suggests that olfactory receptors could serve as potential therapeutic targets for enhancing neural repair and recovery following central nervous system injuries.

Exogenous insulin autoimmune syndrome:A case report and review of literature

BACKGROUND Insulin autoimmune syndrome(IAS)is a severe manifestation of spontaneous hypoglycemia.It is characterized by elevated levels of immune-reactive insulin and highly potent insulin autoantibodies(IAAs),which are induced by endogenous insulin circulating in the bloodstream.It is distinguished by recurring instances of spontaneous hypoglycemia,the presence of IAA within the body,a substantial elevation in serum insulin levels,and an absence of prior exogenous insulin administration.Nevertheless,recent studies show that both conventional insulin and its analogs can induce IAS episodes,giving rise to the notion of nonclassical IAS.Therefore,more attention should be paid to these diseases.CASE SUMMARY In this case report,we present a rare case of non-classical IAS in an 83-year-old male patient who present with symptoms of a psychiatric disorder.Upon symptom onset,the patient exhibited Whipple's triad(including hypoglycemia,blood glucose level less than 2.8 mmol/L during onset,and rapid relief of hypoglycemic symptoms after glucose administration).Concurrently,his serum insulin level was significantly elevated,which contradicted his C-peptide levels.After a comprehensive examination,the patient was diagnosed with exogenous insulin autoimmune syndrome.Considering that the patient had type 2 diabetes mellitus and a history of exogenous insulin use before disease onset,it was presumed that non classical IAS was induced by this condition.The PubMed database was used to search for previous cases of IAS and non-classical IAS to analyze their characteristics and treatment approaches.CONCLUSION The occurrence of non-classical IAS is associated with exogenous insulin or its analogs,as well as with sulfhydryl drugs.Symptoms can be effectively alleviated through the discontinuation of relevant medications,administration of hormones or immunosuppressants,plasma exchange,and lifestyle adjustments.

Association between glucose-lowering drugs and circulating insulin antibodies induced by insulin therapy in patients with type 2 diabetes

BACKGROUND Insulin antibodies(IAs)affect blood glucose control in patients receiving insulin therapy.AIM To investigate the relationship between different hypoglycemic treatments and IAs in patients with type 2 diabetes mellitus(T2DM).METHODS This cross-sectional,retrospective study included 1863 patients with T2DM who were receiving exogenous insulin therapy.All patients received stable antidiabetic therapy in the last 3 months and IA levels were measured using an iodine-125 array.RESULTS A total of 1863 patients were enrolled.There were 902(48.4%)patients who had positive IAs(IA level>5%),with a mean IA level of 11.06%(10.39%-11.72%).IA levels were positively correlated with high fasting blood glucose(odds ratio=1.069,P<0.001).The proportion of positive IAs was lowest in patients using glargine only(31.9%)and highest in patients using human insulin only(70.3%),P<0.001.The IA levels in patients using sulfonylureas/glinides(8.3%),metformin(9.6%),and dipeptidyl peptidase-4 inhibitors(8.2%)were all lower than in patients without these drugs(all P<0.05).CONCLUSION Nearly half of patients on insulin therapy have positive IA antibodies,and IA antibody levels are associated with blood glucose control.Insulin glargine and a combination of oral glucose-lowering drugs were correlated with lower IA levels.

Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.

Amylase intrapancreatic infusion delays insulin release during an intravenous glucose tolerance test,proof of acini–islet–acinar interactions

BACKGROUND The possible existence of an acini–islet–acinar(AIA)reflex,involving mutual amylase and insulin interactions,was investigated in the current acute experiment on pigs.AIM To confirm the existence of an AIA reflex and justify the placement of the exocrine and endocrine pancreatic components within the same organ.METHODS The study was performed on six pigs under general anesthesia.An intravenous glucose tolerance test was performed,with a bolus infusion of 50%glucose to the jugular vein,while amylase(5000 U/kg)or vehicle intrapancreatic infusions were administered via the pancreaticoduodenalis cranialis artery during 30 min with a 1 mL/min flow rate.RESULTS The amylase infusion to pancreatic arterial circulation inhibited and delayed the insulin release peak which is usually associated with the highest value of blood glucose and is typically observed at 15 min after glucose infusion,for>1 h.The intrapancreatic infusion of the vehicle(saline)did not have any effect on the time frame of insulin release.Infusion of 1%bovine serum albumin changed the insulin release curve dramatically and prolonged the high range of insulin secretion,far beyond the glucose peak.CONCLUSION Intrapancreatic arterial infusion of amylase interrupted the integrated glucose–insulin interactions.This confirms an AIA reflex and justifies placement of the exocrine and endocrine pancreatic components within the same organ.

Novel insights into D-Pinitol based therapies:a link between tau hyperphosphorylation and insulin resistance

Alzheimer’s disease is a neurodegenerative disorder characterized by the amyloid accumulation in the brains of patients with Alzheimer’s disease.The pathogenesis of Alzheimer’s disease is mainly mediated by the phosphorylation and aggregation of tau protein.Among the multiple causes of tau hyperphosphorylation,brain insulin resistance has generated much attention,and inositols as insulin sensitizers,are currently considered candidates for drug development.The present narrative review revises the interactions between these three elements:Alzheimer’s disease-tau-inositols,which can eventually identify targets for new disease modifiers capable of bringing hope to the millions of people affected by this devastating disease.

Insulin resistance as the molecular link between diabetes and Alzheimer's disease

Diabetes mellitus(DM)and Alzheimer's disease(AD)are two major health concerns that have seen a rising prevalence worldwide.Recent studies have indicated a possible link between DM and an increased risk of developing AD.Insulin,while primarily known for its role in regulating blood sugar,also plays a vital role in protecting brain functions.Insulin resistance(IR),especially prevalent in type 2 diabetes,is believed to play a significant role in AD's development.When insulin signalling becomes dysfunctional,it can negatively affect various brain functions,making individuals more susceptible to AD's defining features,such as the buildup of beta-amyloid plaques and tau protein tangles.Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD.This review aims to explore the relationship between DM and AD,with a focus on the role of IR.It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR.Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.

Dynamics in the Prevalence of Insulin Resistance between 2005 and 2023 in Type 2 Diabetics in South Kivu in the East of the Democratic Republic of Congo: Cross-Sectional Studies

Aim: Sub-Saharan Africa is undergoing an epidemiological transition responsible for a change in the metabolic profile in favour of insulin resistance. The aim of this study was to assess the dynamics of the prevalence of insulin resistance and associated risk factors in diabetic patients in the Democratic Republic of Congo between 2005 and 2023. Method: We measured fasting blood glucose and insulin levels and looked for metabolic syndrome parameters (2009 criteria) in type 2 diabetes patients in 2005-2008 (n = 176) and in 2018-2023 (n = 303). The HOMA model was used to measure insulin sensitivity and islet β-cell secretory function. Results: Between 2005 and 2013, the trend was towards an increase in the prevalence of insulin resistance (from 13.1% to 50.8%;p Conclusion: This present study shows an increase in insulin resistance in Congolese urban areas and a persistence of atypical diabetes mellitus in Congolese rural areas, confirming the particularity of the pathophysiology of the disease in African areas currently influenced by the epidemiological transition. Further studies using an appropriate methodology are required.

Vitamin D, Parathyroid Hormone, Insulin Sensitivity and Islet β-Cell Secretory Function in Diabetic Patients from South Kivu in the Democratic Republic of Congo: Cross-Sectional Study

Background: The role of vitamin D and parathyroid hormone in the metabolic profile of type 2 diabetes mellitus in sub-Saharan Africa has not been adequately assessed. The aim of this study was to determine the prevalence of low vitamin D level and secondary hyperparathyroidism and their association with insulin sensitivity and β-cell secretory function among Congolese type 2 diabetics. Methodology: Fasting glycaemia, fasting insulin, 25OH D3 and human parathyroid hormone (hPTH) were measured in one hundred and eighty-four type 2 diabetic patients followed as outpatients in South Kivu. Levels of 25OH D3 65 pg/ml defined low vitamin D and elevated parathyroid hormone levels, respectively. The HOMA model was used to measure insulin sensitivity and β-cell secretory function. Results: Medians (IQR) were 25.3 (20.4 - 32.4) ng/ml for 25OH D3 and 53.7 (38.4 - 115.7) pg/ml for hPTH. 58.7% of diabetics had insulin resistance, 126 (68.5%) had low vitamin D and 80 (43.5%) had hyperparathyroidism. In multivariate analysis, hPTH (partial r = −0.28;p = 0.0002) and 25OH D3 (partial r = 0.16;p = 0.03) showed an independent association with insulin sensitivity after adjustment for body mass index and waist circumference. Finally, hPTH (partial r = 0.27;p = 0.0002) was the sole determinant of β-cell secretory function. Conclusions: This study confirms the high prevalence of low vitamin D level and secondary hyperparathyroidism and their association with insulin resistance and impaired islet β-cell secretory function among Congolese with type 2 diabetes mellitus. Vitamin D and calcium supplementation should be envisaged for cases of deficiency in this region.

Epinephrine also acts on beta cells and insulin secretion

In a recent review examining neurotransmitter modulation of insulin secretion,the significant impact of epinephrine was not addressed.Its primary action involves inhibiting insulin release via alpha-adrenergic receptors,thereby reducing the response to insulin secretion stimulators,through the activation of K+channels and resulting in membrane hyperpolarization in beta cells.

Insulin therapy in type 2 diabetes: Insights into clinical efficacy, patient-reported outcomes, and adherence challenges

Insulin therapy plays a crucial role in the management of type 2 diabetes as the disease progresses.Over the past century,insulin formulations have undergone significant modifications and bioengineering,resulting in a diverse range of available insulin products.These products show distinct pharmacokinetic and pharmacodynamic profiles.Consequently,various insulin regimens have em-erged for the management of type 2 diabetes,including premixed formulations and combinations of basal and bolus insulins.The utilization of different insulin regimens yields disparate clinical outcomes,adverse events,and,notably,patient-reported outcomes(PROs).PROs provide valuable insights from the patient’s perspective,serving as a valuable mine of information for enhancing healthcare and informing clinical decisions.Adherence to insulin therapy,a critical patient-reported outcome,significantly affects clinical outcomes and is influenced by multiple factors.This review provides insights into the clinical effectiveness of various insulin preparations,PROs,and factors impacting insulin therapy adherence,with the aim of enhancing healthcare practices and informing clinical decisions for individuals with type 2 diabetes.

Individualized intensive insulin therapy of diabetes: Not only thegoal, but also the time

Intensive insulin therapy has been extensively used to control blood glucose levels because of its ability to reduce the risk of chronic complications of diabetes.According to current guidelines,intensive glycemic control requires individu-alized glucose goals rather than as low as possible.During intensive therapy,rapid blood glucose reduction can aggravate microvascular and macrovascular complications,and prolonged overuse of insulin can lead to treatment-induced neuropathy and retinopathy,hypoglycemia,obesity,lipodystrophy,and insulin antibody syndrome.Therefore,we need to develop individualized hypoglycemic plans for patients with diabetes,including the time required for blood glucose normalization and the duration of intensive insulin therapy,which deserves further study.

Effects of vitamin family members on insulin resistance and diabetes complications

The following letter to the editor highlights the article“Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance”in World J Diabetes 2023 Oct 15;14(10):1514-1523.It is necessary to explore the role of vitamin family members in insulin resistance and diabetes complications.

Palmitoleic acid on top of HFD ameliorates insulin resistance independent of diacylglycerols and alters gut microbiota in C57BL/6J mice

With the prevalence of obesity and obesity-related metabolic syndrome,such as insulin resistance in recent years,it is urgent to explore effective interventions to prevent the progression of obesity-related metabolic syndrome.Palmitoleic acid is a monounsaturated fatty acid that is available from dietary sources,mainly derived from marine products.P almitoleic acid plays a positive role in maintaining glucose homeostasis and reducing inflammation.However,it is still unknow the mechanism of palmitoleic acid in ameliorating insulin resistance.Here,we investigated the effects of palmitoleic acid on chow diet(CD)-fed and high-fat diet(HFD)-fed mice,which were fed CD or HFD for 12 weeks before administration.We administrated mice with BSA(control),oleic acid,or palmitoleic acid for 6 weeks on top of CD or HFD feeding.We found that palmitoleic acid only improved glucose homeostasis in HFD-fed obese mice by increasing glucose clearance and reducing HOMA-IR.Further study explored that palmitoleic acid changed the composition of gut microbiota by decreasing Firmicutes population and increasing Bacteroidetes population.In colon,palmitoleic acid increased intestinal tight junction integrity and reduced inflammation.Moreover,palmitoleic acid decreased macrophage infiltration in liver and adipose tissue and increase glucose uptake in adipose tissue.Diacylglycerol(DAG)in tissue(for example,liver)is found to positively correlated with HOMA-IR.HFD enhanced the levels of DAGs in liver but not in adipose tissue in this study.Palmitoleic acid did not reverse the high DAG levels induced by HFD in liver.Therefore,in HFD-fed mice,palmitoleic acid reduced insulin resistance by an independent-manner of DAGs.It might be associated with the beneficial effects of palmitoleic acid on altering the gut microbiota composition,improving of intestinal barrier function,and downregulating the inflammation in colon,liver,and adipose tissue.

Effects of axylitol-casein complex on insulin resistance and gut microbiota composition in high-fat-diet+streptozotocin-induced type 2 diabetes mellitus mice

This study investigated the effects of a xylitol-casein non-covalent complex(XC)on parameters related to type 2 diabetes mellitus(T2DM),in addition to related changes in gut microbiome composition and functions.High-fat-diet(HFD)+streptozotocin(STZ)-induced T2DM mice were treated with xylitol(XY),casein(CN),and XC,after which fecal samples were collected for gut microbiota composition and diversity analyses based on 16S rRNA high-throughput sequencing and multivariate statistics.XC decreased body weight and improved glucose tolerance,insulin sensitivity,pancreas impairment,blood lipid levels,and liver function in T2DM mice compared to XY-and CN-treated mice.Furthermore,XC modulated theα-diversity,β-diversity and gut microbiota composition.Based on Spearman’s correlation analysis,the relative abundances of Alistipes,Bacteroides,and Faecalibaculum were positively correlated and those of Akkermansia,Lactobacillus,Bifidobacterium,and Turicibacter were negatively correlated with the phenotypes related to the improvement of T2DM.In conclusion,we found that XC alleviated insulin resistance by restoring the gut microbiota of T2DM mice.Our results provide strong evidence for the beneficial effects of XC on T2DM and motivation for further investigation in animal models and,eventually,human trials.

Autoantibodies against beta cells to predict early insulin requirements in pediatric patients with clinically diagnosed type 2 diabetes

BACKGROUND Autoimmunity has emerged as a probable disease modifier in patients with clinically diagnosed type 2 diabetes mellitus(T2DM),that is,patients who have insulin resistance,obesity,and other cardiovascular risk factors,suggesting that the presence of glutamic acid decarboxylase(anti-GAD65),islet antigen 2(anti-IA2),and zinc transporter 8(anti-Zn8T)antibodies could have deleterious effects on beta cell function,causing failure and earlier requirement for insulin treatment.AIM To evaluate anti-GAD65,anti-IA2 and anti-Zn8T as predictors of early insulin requirement in adolescents with a clinical diagnosis of T2DM.METHODS This was a case–control study in patients with clinically diagnosed with T2DM(68 cases and 64 controls with and without early insulin dependence respectively),male and female,aged 12–18 years.Somatometry,blood pressure,glucose,insulin,C-peptide,glycated hemoglobin A1c,and lipid profiles were assessed.ELISA was used to measure anti-GAD65,anti-IA2,and anti-Zn8T antibodies.Descriptive statistics,Pearson'sχ2 test,Student's t test,and logistic regression was performed.P<0.05 was considered statistically significant.RESULTS There were 132 patients(53.8%female),with a mean age was 15.9±1.3 years,and there was a disease evolution time of 4.49±0.88 years.The presence of anti-GAD65,anti-IA2,and anti-Zn8T positivity was found in 29.5%,18.2%,and 15.9%,respectively.Dividing the groups by early or no insulin dependence showed that the group with insulin had a higher frequency of antibody positivity:anti-GAD65 odds ratio(OR):2.42(1.112–5.303,P=0.026);anti-IA2:OR:1.55(0.859–2.818,P=0.105);and anti-Zn8T:OR:7.32(2.039–26.279,P=0.002).CONCLUSION Anti-GAD65 positivity was high in our study.Anti-GAD65 and anti-Zn8T positivity showed a significantly depleted beta cell reserve phenotype,leading to an increased risk of early insulin dependence.

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.