Emergence Of Insulin Resistance Research Articles

Targeting Stearoyl-CoA Desaturase: A novel approach for diabetes therapy

Diabetes mellitus is an epidemic with serious health and financial consequences. While glycemic control is the primary focus of current diabetic care, new evidence points to the crucial role that lipid metabolism plays in the emergence of insulin resistance, particularly in type 2 diabetes. The enzyme stearoyl-CoA desaturase (SCD), which transforms saturated fatty acids into monounsaturated fatty acids, has drawn interest as a possible therapeutic target for the treatment of diabetes. The complicated connection between SCD, lipid metabolism, and insulin resistance is examined in this research, underlining the therapeutic potential of SCD inhibitors in the management of diabetes.

Remission of type 2 diabetes mellitus in a patient with obesity and hypogonadism

Currently, obesity is the main risk factor for the development of type 2 diabetes mellitus (type 2 diabetes) as a key link in the emergence of insulin resistance. Traditionally, the basic strategy for controlling type 2 diabetes is to normalize blood glucose levels by correcting lifestyle and lifelong use of oral and/or injectable hypoglycemic therapy. However, in recent years, doctors and researchers are increasingly turning to the possibility of remission of type 2 diabetes. Remission of diabetes mellitus is the preservation of normal values of glycemia with the complete abolition of hypoglycemic therapy (tablet or injection). Many studies reflect that lifestyle changes, such as weight loss, dieting and increased physical activity, contribute to the onset of remission of type 2 diabetes in a significant number of people. In this clinical case, we demonstrate the possibility of achieving remission of diabetes mellitus with a multifactorial approach to the treatment of type 2 diabetes mellitus, which causes stabilization of blood glucose levels, prevention of complications and improvement of quality of life, and thus, we exhibit new prospects in the treatment of this disease.

Seizing the Connection: Exploring the Interplay Between Epilepsy and Glycemic Control in Diabetes Management.

Epilepsy, a neurological disorder characterized by recurrent seizures, and diabetes, a metabolic disorder characterized by impaired regulation of glucose levels, are two distinct conditions that may appear unrelated at first glance. Nevertheless, recent scholarly investigations have revealed these entities' intricate and ever-evolving interplay. This review initially delves into the intricate interplay between epilepsy and its potential ramifications on glycemic control. Seizures, particularly those accompanied by convulsive manifestations, have the potential to induce acute perturbations in blood glucose levels via diverse mechanisms, encompassing the liberation of stress hormones, the emergence of insulin resistance, and the dysregulation of the autonomic nervous system. Comprehending these intricate mechanisms is paramount in customizing productive strategies for managing diabetes in individuals with epilepsy. On the contrary, it is worth noting that diabetes can substantially impact the trajectory and control of epilepsy. The correlation between hyperglycemia and an elevated susceptibility to seizures, as well as the potential for exacerbating the intensity of epilepsy, has been established. This narrative review offers a concise exposition of the intricate interplay between epilepsy and glycemic control within diabetes management. The objective of exploring reciprocal influences, underlying mechanisms, and common risk factors is to augment the clinical comprehension of this intricate interconnection. In essence, this acquired knowledge possesses the potential to serve as a guiding compass for healthcare professionals, enabling them to craft bespoke therapeutic approaches that enhance the holistic welfare of individuals grappling with the coexistence of epilepsy and diabetes.

Astaxanthin and DHA supplementation ameliorates the proteomic profile of perinatal undernutrition-induced adipose tissue dysfunction in adult life

Maternal diet is an essential factor that directly and indirectly regulates fetal growth. Exposure to certain environmental conditions substantially impacts an individual's short- and long-term health. Adipose tissue dysfunction is a worldwide chronic disease caused by improper lipid build-up in adipose tissue leading to obesity. Therefore, it is the need of the hour to invent anti-obesity agents. As a keto–carotenoid, Astaxanthin (AsX) has been shown to have preventive effects against problems associated with obesity. A crucial role in the pathogenesis of obesity has been attributed to dietary polyunsaturated fatty acids. Adipose tissue plays a vital role in maintaining overall body homeostasis. Metabolic dysfunction of white adipocytes forms a critical step in the emergence of insulin resistance and related diseases. Here we aim to investigate the effect of AsX and Docosahexaenoic acid (DHA) supplementation on the proteomic profile of perinatal undernutrition-induced adipose tissue dysfunction in adult life using a rat model. The LC–MS/MS quantitative proteomics enabled us to identify differentially expressed proteins in perinatal undernourished but AsX and DHA-supplemented animal models. Data are available via ProteomeXchange with identifier PXD041772.This study explored biological roles, molecular functions of differentially expressed proteins, and pathways related to adipose tissue dysfunction induced by undernutrition and its effective modulation by AsX and DHA.

Review on Anti-diabetic Research on Two Important Spices: Trachyspermum ammi and Pimpinella anisum

Abstract Diabetes mellitus (DM) arises from a cascade of factors, primarily stemming from defective insulin secretion by the pancreas and emergence of insulin resistance. These alterations disrupt lipid and protein metabolism, which may lay the foundation for hyperglycemia. The efficacy and safety of spice herbs from traditional medicine have long been regarded for the potential to treat this condition. Remarkably, many of the drugs we rely on today have origins, either directly or indirectly, in the realm of plant sources. The exploration of hypoglycemic potential extends beyond the boundaries of herbs and spices, embracing a diverse tapestry of food extracts. Among the spices, Trachyspermum ammi and Pimpinella anisum are plants in the Umbelliferae family, and their fruits are used traditionally as carminatives, aromatics, disinfectants, and galactogogues. In this comprehensive review the published scientific articles related to antidiabetic properties of both seeds are discussed.

Association Between Triglyceride-Glucose Index (TyG Index) and Type 2 Diabetes Mellitus: A Systematic Review


 Background: Insulin Resistance has a major role in the pathogenesis of diabetes mellitus where there is a decrease in sensitivity in peripheral tissues. The emergence of insulin resistance, 1-2 decades precedes before the diagnosis of type 2 diabetes mellitus is established. This theory is supported by the usefulness of insulin resistance as a marker of future diabetes or the prevention of type 2 diabetes by insulin-sensitizing agents. Recently, there is evidence that has been suggested to measure insulin resistance as surrogate marker by calculated the triglyceride and glucose which is so called as “Fasting triglyceride-glucose index” or can be shorten as “TyG index”. This study reported a systematic review of association between TyG index and type 2 diabetes mellitus from various literatures to make a conclusion as a basis for further research.
 Methods: A literature search in EBSCOhost, ProQuest, MEDLINE, and NCBI database was performed to retrieve and review studies reporting the association between TyG index and type 2 diabetes.
 Results: All studies showed that higher TyG index were associated with higher type 2 diabetes (HR 4.36, 10.38, 9.54 for each).
 Conclusion: This systematic review provides further evidence about higher TyG index is related to higher risk of development type 2 diabetes. It represents that TyG index can predicting the risk of incident T2DM.

The emergence of insulin resistance following a chronic high-fat diet regimen coincides with an increase in the reinforcing effects of nicotine in a sex-dependent manner

The present study assessed the sex-dependent effects of insulin resistance on the reinforcing effects of nicotine. Female and male rats received a chronic high-fat diet (HFD) or regular diet (RD) for 8 weeks. A subset of rats then received vehicle or a dose of streptozotocin (STZ; 25 mg/kg) that induces insulin resistance. To assess insulin resistance, glucose levels were measured 15, 30, 60, 120, and 180 min after an insulin injection (0.75 U/kg). Nine days later, the rats were given extended access to intravenous self-administration (IVSA) of nicotine (0.015, 0.03, 0.06 mg/kg) in an operant box where they consumed their respective diet ad libitum and performed responses for water deliveries. Each nicotine dose was delivered for 4 days with 3 intermittent days of abstinence in their home cage. The day after the last IVSA session, physical signs were compared following administration of mecamylamine (3.0 mg/kg) to precipitate nicotine withdrawal. The results revealed that there were no changes in insulin resistance or nicotine intake in HFD alone rats regardless of sex. Insulin resistance was observed in HFD-fed rats that received STZ, and the magnitude of this effect was greater in males versus females. Our major finding was that nicotine intake was greater among HFD + STZ female rats as compared to males. Lastly, the physical signs of withdrawal were similar across all groups. Our results suggest that females diagnosed with disorders that disrupt insulin signaling, such as diabetes may be at risk of greater vulnerability to nicotine use due to enhanced reinforcing effects of this drug.

Концепция вероятной роли биологически активного хрома в возникновении инсулиновой резистентности и алиментарного ожирения

The conception of probable alimentary chromium role in connection with metabolic reasons emergence of insulin resistance in the alimentary obesity and type 2 diabetes is represented. The violation of insulin receptors structural organization and conformation with these pathological conditions in connection with redox states of chromium is supposed. Based on information from general chemistry and chromium metabolism, higher biological activity of hexavalent chromium when compared to the activity of trivalent chromium is assumed in insulin-resistant conditions. Aim. To analyze the literature data on the a supposed participation of chromium in food and chromium nutraceuticals in connection with insulin resistance at the metabolic level. Material and methods. The analysis of the literature was carried out by the method of manual search and selection of the most important and significant for the analyzed issue monographs and articles up to 60 years in depth. The search criteria were works directly related to the association of food chromium with the insulin-dependent metabolic response of cells and the activity of insulin receptors. No works published over the past 10 years that introduce principled novelty and are of principled importance for the present problem have not been identified. Results and discussion. The concept of the supposed participation of chromium as an essential element in connection with the metabolic reasons for the formation of insulin resistance and the structural organization of insulin receptors depending on the redox state of chromium is presented. Keywords: hexavalent and trivalent chromium, insulin resistance, redox state, insulin receptor, alimentary obesity, diabetes.

Correlation of serum betatrophin levels with disease severity and the emergence of insulin resistance in cirrhotic patients

BackgroundInsulin resistance (IR) is frequently associated with chronic liver disease. There has been an increased interest in betatrophin protein and its involvement in the compensatory response to IR. We aimed to investigate the correlation of serum betatrophin levels with disease severity and the emergence of IR in cirrhotic patients. This study included 27 cirrhotic patients and 30 healthy participants who served as a control group. IR was assessed by the Homeostasis Model Assessment (HOMA-IR). Serum insulin and betatrophin levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA).ResultsIR was existing in 74% of cirrhotic patients (p < 0.001). Subjects with IR had higher serum betatrophin levels than those without IR (p = 0.04). Serum betatrophin levels were significantly higher in cirrhotic patients than controls (p < 0.001). In addition, Child-Pugh class C patients had higher serum betatrophin levels than those with Child-Pugh class B cirrhosis (p = 0.01). Moreover, the highest serum betatrophin levels were detected in patients with tense ascites followed by those with moderate and mild ascites (p = 0.01). In the cirrhosis group, serum betatrophin levels correlated positively with fasting blood glucose levels (p < 0.001), fasting insulin levels (p = 0.006), HOMA-IR (p = 0.006), Child-Pugh score (p = 0.023), MELD score (p < 0.001), and INR (p = 0.005), and correlated negatively with platelets count (p = 0.01).ConclusionCirrhotic patients have higher serum betatrophin levels; moreover, these levels are positively correlated with disease severity as well as the emergence of insulin resistance.

In vivo and in silico dynamics of the development of Metabolic Syndrome.

The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.

Plasma copeptin may not be a sensitive marker of perinatal stress in healthy full-term growth-restricted fetuses

Objective: Intrauterine-growth-restriction-(IUGR) is associated with chronic fetal stress, as well as a phase of enhanced fetal/early postnatal insulin sensitivity, followed by a later emergence of insulin resistance. We aimed to prospectively investigate concentrations of copeptin, a sensitive marker of stress and insulin resistance, in IUGR versus appropriate-for-gestational-age-(AGA) fetuses.Methods: Cord blood copeptin concentrations were determined by ELISA in well-defined, non-distressed at birth, asymmetric IUGR (n = 30) and AGA (n = 20) full-term pregnancies. Doppler studies were indicative of placental insufficiency.Results: Cord blood copeptin concentrations were similar in IUGR cases and AGA controls, after controlling for delivery mode. Copeptin concentrations were markedly elevated in vaginally delivered fetuses (p = 0.001). No association was recorded between fetal copeptin concentrations and maternal age, parity, gestational age, or fetal gender.Conclusions: Cord blood copeptin concentrations are probably not affected by IUGR at term, in the absence of fetal distress, possibly due to a balance between copeptin up-regulation by chronic fetal stress, on one hand, and copeptin down-regulation in the presence of increased insulin sensitivity, on the other hand; thus, copeptin may not be a sensitive marker of chronic perinatal stress in healthy asymmetric IUGR infants. Cord blood copeptin seems to primarily reflect perinatal stress associated with delivery mode.

Plasma betatrophin levels in patients with liver cirrhosis

To investigate the plasma levels of betatrophin in patients with cirrhosis. Forty patients diagnosed at the clinic with liver cirrhosis according to biological, ultrasonographic, or histological criteria were included. The severity of cirrhosis was classified according to Pugh's modification of Child's classification and MELD score. Insulin resistance (IR) was assessed by the Homeostasis Model Assessment. A total of 20 patients showed a MELD score higher than 14. The control group consisted in 15 sex-and aged-matched subjects. Fasting blood samples were obtained for subsequent analysis. Serum insulin was determined by Liaison automated immune chemiluminiscence assay (DiaSorin S.p.A.) using a sandwich assay. The sensitivity of the assay was 0.2 μU/mL. The intra and interassay variation coefficients were < 4% and < 10%, respectively. The normal values were between 2 and 17 μU/mL. Human active betatrophin was analyzed by specific quantitative sandwich ELISA (Aviscera Bioscience). The sensitivity of the assay was 0.4 ng/mL, and the intra and interassay reproducibility were < 6% and < 10%, respectively. Plasma betatrophin levels were significantly increased in patients with cirrhosis compared with those in healthy subjects (P = 0.0001). Betatrophin levels were also associated with disease severity, being higher in Child-Pugh C patients compared to Child-Pugh B (P < 0.0005) and in patients who displayed a MELD score higher than 14 points compared to patients with lower punctuation (P = 0.01). In addition, we found a positive correlation between plasma betatrophin levels and the severity of cirrhosis according to Child-Pugh classification (r = 0.53; P < 0.01) or MELD score (r = 0.45; P < 0.01). In the overall cohort, a moderate correlation between serum betatrophin and plasmatic bilirrubin (r = 0.39; P < 0.01) has been observed, as well as an inverse correlation between betatrophin and albumin (r = -0.41; P < 0.01) or prothrombin time (r = -0.44; P <0.01). Moreover, insulin resistance was observed in 82.5% of the cirrhotic patients. In this group of patients, betatrophin levels were significantly higher than those in the group of patients without IR (P < 0.05). Plasma betatrophin is increased in patients with cirrhosis. This increase is related to the severity of cirrhosis, as well as with the emergence of insulin resistance.

Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2

The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.

Emergence of insulin resistance in juvenile baboon offspring of mothers exposed to moderate maternal nutrient reduction

Developmental programming of postnatal pancreatic β-cell and peripheral insulin function by maternal nutrient reduction (MNR) has been extensively investigated in rodents and sheep, but no data exist from nonhuman primate offspring of MNR mothers. We hypothesized that moderate levels of MNR would result in developmental programming of postnatal β-cell function and peripheral insulin sensitivity that lead to emergence of a prediabetic state prior to puberty. Prepregnancy phenotype of 18 nonpregnant baboons was matched. During pregnancy and lactation 12 mothers ate chow ad libitum (controls), while six ate 70% of chow consumed by controls (weight-adjusted MNR). Weaned offspring ate normal chow. At 3.5 ± 0.18 yr (mean ± SE) in an intravenous glucose tolerance test, conscious, tethered MNR juvenile offspring (2 females and 4 males) showed increased fasting glucose (P < 0.04), fasting insulin (P < 0.04), and insulin area under the curve (AUC; P < 0.01) compared with controls (8 females and 4 males). Insulin AUC also increased following an arginine challenge (P < 0.02). Baseline homeostatic model assessment insulin β-cell sensitivity was greater in MNR offspring than controls (P < 0.03). In a hyperinsulinemic, euglycemic clamp, the glucose disposal rate decreased 26% in MNR offspring. Changes observed were not sex dependent. MNR in pregnancy and lactation programs offspring metabolic responses, increasing insulin resistance and β-cell responsiveness, resulting in emergence of an overall phenotype that would predispose to later life type-2 diabetes, especially, should other dietary challenges such as a Westernized diet be experienced.

Effects of leptin supplementation to lactating Brandt’s voles (Lasiopodomys brandtii) on the developmental responses of their offspring to a high-fat diet

Maternal serum leptin concentrations have been suggested as a key factor in programming growth patterns and protecting against adult metabolic disease in human offspring. However, the role of maternal leptin in the development of wild rodent offspring is not clear. We tested the hypothesis that maternal hyperleptinemia in lactating Brandt's voles (Lasiopodomys brandtii) can protect their offspring from the risks of high-fat-diet-induced-obesity and insulin resistance. Lactating voles were supplemented with murine leptin (0.64 μg g(-1 ) day(-1)) or phosphate-buffered saline (control) on days 10-17 of lactation (peak lactation). At 12 weeks of age, the female and male offspring of the two maternal groups were randomly assigned to two groups each and fed either a high-fat diet (41% of gross energy as fat) or a control diet (14% of gross energy as fat) until the age of 23 weeks. Body mass, food intake, glucose tolerance and resting metabolic rate were determined in the four offspring groups. After animals were sacrificed, organ masses and adipose tissue distribution, and serum leptin and insulin concentrations were measured. Offspring of leptin-treated mothers showed no significant differences in body mass, energy intake or energy expenditure, body composition, glucose tolerance or serum leptin and insulin concentrations from offspring of control mothers. The high-fat diet induced increases in body mass (by 23% in female and 17% in male offspring) and reduced glucose tolerance in both female and male offspring, indicative of the emergence of insulin resistance, even though digestible energy intake of the male offspring decreased on the high-fat diet. These results indicate that maternal hyperleptinemia during peak lactation in Brandt's voles did not protect against diet-induced obesity or glucose intolerance in their offspring.

Fetal growth restriction, catch-up growth and the early origins of insulin resistance and visceral obesity

There is an association between growing slowly before birth, accelerated growth in early postnatal life and the emergence of insulin resistance, visceral obesity and glucose intolerance in adult life. In this review we consider the pathway through which intrauterine growth restriction (IUGR) leads to the initial increase in insulin sensitivity and to catch-up growth. We also discuss the importance of the early insulin environment in determining later visceral adiposity and the intrahepatic mechanisms that may result in the emergence of glucose intolerance in a subset of IUGR infants. We present evidence that a key fetal adaptation to poor fetal nutrition is an upregulation of the abundance of the insulin receptor in the absence of an upregulation of insulin signalling in fetal skeletal muscle. After birth, however, there is an upregulation in the abundance of the insulin receptor and the insulin signalling pathway in the IUGR offspring. Thus, the origins of the accelerated postnatal growth rate experienced by IUGR infants lie in the fetal adaptations to a poor nutrient supply. We also discuss how the intracellular availability of free fatty acids and glucose within the visceral adipocyte and hepatocyte in fetal and neonatal life are critical in determining the subsequent metabolic phenotype of the IUGR offspring. It is clear that a better understanding of the relative contributions of the fetal and neonatal nutrient environment to the regulation of key insulin signalling pathways in muscle, visceral adipose tissue and the liver is required to support the development of evidence-based intervention strategies and better outcomes for the IUGR infant.

The transition from fetal growth restriction to accelerated postnatal growth: a potential role for insulin signalling in skeletal muscle

A world-wide series of epidemiological and experimental studies have demonstrated that there is an association between being small at birth, accelerated growth in early postnatal life and the emergence of insulin resistance in adult life. The aim of this study was to investigate why accelerated growth occurs in postnatal life after in utero growth restriction. Samples of quadriceps muscle were collected at approximately 140 days gestation (term approximately 150 days gestation) from normally grown fetal lambs (Control, n = 7) and from growth restricted fetal lambs (placentally restricted: PR, n = 8) and from Control (n = 14) and PR (n = 9) lambs at 21 days after birth. The abundance of the insulin and IGF1 receptor protein was higher in the quadriceps muscle of the PR fetus, but there was a lower abundance of the insulin signalling molecule PKC, and GLUT4 protein in the PR group. At 21 days of postnatal age, insulin receptor abundance remained higher in the muscle of the PR lamb, and there was also an up-regulation of the insulin signalling molecules, PI3Kinase p85, Akt1 and Akt2 and of the GLUT4 protein in the PR group. Fetal growth restriction therefore results in an increased abundance of the insulin receptor in skeletal muscle, which persists after birth when it is associated with an upregulation of insulin signalling molecules and the glucose transporter, GLUT4. These data provide evidence that the origins of the accelerated growth experienced by the small baby after birth lie in the adaptive response of the growth restricted fetus to its low placental substrate supply.