Consequence Of Insulin Resistance Research Articles

Metformin Monotherapy With and Without Lifestyle Changes Affects Anthropometric Parameters, Blood Pressure, Blood Glucose, and Lipid Profile in Indian Patients With Newly Diagnosed Type 2 Diabetes.

Type 2 diabetes mellitus (T2DM) is a consequence of insulin resistance, insulin deficiency, or both. It is usually seen in adults and is a consequence of genetic (polygenic inheritance), endogenous (obesity and or hormonal factors), and environmental factors (e.g., obesogenic environment, endocrine disrupting chemicals, stress, and medicines). The prevalence of T2DM has increased over the past few decades. South Asians, including Indians, are more prone to central adiposity and develop lifestyle diseases like T2DM at body mass index values lower than those considered normal for the Western population. Generally, the first line of treatment is metformin monotherapy with lifestyle changes in patients with T2DM. Most of the research conducted on this drug is on Western subjects. Since the Indian population has genetic differences in the site of deposition of adipose and is more prone to develop lifestyle diseases, the effect of metformin may be different in Indians. Seventy-one (34 female, non-pregnant, non-lactating) adults with newly diagnosed T2DM were recruited in this short-duration pilot study after obtaining written informed consent. Patients regularly taking any drug were excluded, as were patients with chronic comorbidities. Treatment was initiated with metformin 500 mg OD. Lifestyle changes were recommended according to the age and physical condition of the patients. Anthropometric parameters (age, weight, height, BMI, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)), blood pressure, glycemic status (fasting and 2 h PP glucose and HbA1c), and lipid profile of the subjects were recorded before initiating and six months after initiating metformin monotherapy with lifestyle changes. Small but statistically significant improvements were observed in the WHR,WHtR, blood pressure, blood glucose, and glycated hemoglobin. Although improvement was also observed in weight and lipid profile, these changes were not statistically significant. This study shows that metformin monotherapy with lifestyle changes is suitable for patients of Indian origin and results in improvement in the WHR, WHtR, blood pressure, plasma glucose, and glycated hemoglobin.

Obesity in Prediabetic Patients: Management of Metabolic Complications and Strategies for Prevention of Overt Diabetes.

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent.

Insulin resistance and metabolic diseases - a review

Introduction: This review paper aims to discuss the effects of insulin resistance, and its association with various metabolic diseases. Insulin resistance (IR), characterized by diminished tissue responsiveness to physiological insulin levels, is a key component in various metabolic diseases, including type 2 diabetes, cardiovascular disorders (CVDs), obesity, and non-alcoholic fatty liver disease (NAFLD).
 State of knowledge The consequences of IR are profound; in type 2 diabetes, it hinders glucose utilization by muscle cells, leading to hyperglycemia, muscle damage, and loss of mass and strength. IR also plays a central role in NAFLD, promoting lipid accumulation, hepatic inflammation, fibrosis, and cell death.
 Materials and methods: A review of chosen literature in the PubMed and Google Scholar databases was conducted, using the following key words: „Insulin resistane”, „Insulin resistance in obesity”, „Obesity”, „Insulin resistance NAFLD”, „Diebetes”, „Insulin resistance CVD”
 Summary: The consequences of insulin resistance are far-reaching. In the context of type 2 diabetes, it impedes glucose utilization by muscle cells, resulting in hyperglycemia and subsequent muscle cell damage, contributing to loss of mass and strength. Insulin resistance is also a central player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), fostering lipid accumulation, hepatic inflammation, and, ultimately, fibrosis and cell death.
 Conclusions: In conclusion, understanding insulin resistance is paramount in addressing the rising prevalence of metabolic diseases globally Controlling insulin resistance emerges as a crucial aspect of managing these metabolic disorders and their complications. Further research into the mechanisms of IR formation and effective intervention strategies is imperative for improving public health outcomes.

Artocarpus lakoocha Roxb. and Oxyresveratrol Inhibits Interleukin 6 Secretion Related with Insulin Resistance in 3T3-L1 Adipocytes

Chronic low-grade inflammation plays an important role in insulin resistance and the development of type 2 diabetes in obese people. Adipocytes, the most abundant cell type in adipose tissue, could produce various types of cytokines responsible for chronic inflammation. The purpose of the present study was to investigate the preventive effect of oxyresveratrol and Puag-Haad, which is the oxyresveratrol-enriched aqueous extract from Artocarpus lakoocha Roxb., on the inflammation and insulin resistance demonstrated by adipocytes. The release of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, were monitored to evaluate the inflammatory status of the adipocyte cells during the 3T3-L1 adipocytes maturation period. Intracellular lipid accumulation and glucose uptake were measured to assess adipogenicity and insulin sensitivity status of mature adipocytes, respectively. The results showed that 3T3-L1 adipocytes substantially secreted IL-6 but not TNF-α, IL-1β. Further, IL-6 secretion was correlated with lipid quantity accumulated in the adipocytes. Oxyresveratrol and Puag-Haad predominantly exhibited anti-inflammatory activity in a dose-dependent manner, inhibiting IL-6 release but showed less effect on lipid accumulation. 3T3-L1 adipocytes treated with Puag-Haad (40 µg/mL) for 15 days showed significant decreases in fat accumulation and IL-6 secretion and promoted the glucose uptake. These outcomes indicate an improvement in insulin sensitivity. Taken all together, the data indicates that Puag-Haad is an interesting natural substance that should be further studied for its preventive effect on obese-mediated inflammation and the consequences of insulin resistance and type 2 diabetes. Keywords: Artocarpus lakoocha Roxb., Oxyresveratrol, Pro-inflammatory cytokine, Insulin resistance, Adipocyte

Two models of insulin resistance development and the strategy to combat age-related diseases: literature review

Insulin resistance (IR) is the root cause of most age-related diseases (ARD), the major challenge for today's health systems. Therefore, adequate understanding of the mechanisms underlying IR is essential to build effective ARD prevention. Analyze the existing models of IR causation and progression in order to justify the most effective ARD prevention strategy. Search and analysis of publications on IR and hyperinsulinemia (HI) from databases elibrary.ru, PubMed, and Google Scholar. Two models of IR development are analyzed along with the relationship between IR, HI, and obesity. The prevailing model considers obesity (imbalance of caloric intake and energy expenditure) as the main factor in the development of IR; HI is seen as a consequence of IR, mostly insignificant for the outcomes of IR. The model contradicts many experimental and clinical findings. The strategy to combat ARDs that follows from the model (hypocaloric diet and pharmacotherapy of IR) has proven mostly ineffective.The alternative model (IR as a consequence of HI, and obesity as one of IR manifestations) is more consistent with the pool of experimental and clinical data. It more precisely predicts ARD development and allows more adequate correction of adverse lifestyle factors. It corresponds to a different strategy for combating ARD: emphasis on low-carb diet and longer fasting window combined with consideration of other factors of IR. If the prevailing model of IR development is revised, this should open up opportunities for more effective early prevention of a wide range of chronic diseases in which the role of IR is significant.

Prickly Pear Cacti (Opuntia spp.) Cladodes as a Functional Ingredient for Hyperglycemia Management: A Brief Narrative Review.

The worldwide prevalence of obesity is increasing along with its comorbidities, including type 2 diabetes mellitus (T2DM). From a pathophysiological perspective, T2DM arises as a consequence of insulin resistance and pancreatic β-cell dysfunction, which together induce chronic hyperglycemia. The pharmacological treatment of T2DM specifically focuses on its management, rather than remission, with a lack of pharmacological agents to prevent the onset of the disease. Considering the role of unhealthy dietary patterns on the development of T2DM, identifying novel food ingredients and bioactive substances may provide new avenues by which to address the T2DM epidemic. In this brief review, we have summarized the latest findings on the consumption of the prickly pear (PP; Opuntia spp.) cladode as a potential nutritional tool for the management of hyperglycemia. The consumption of prickly pear cladodes was reported to exert hypoglycemic effects, making it a potential cost-effective nutritional intervention for the management of T2DM. Several studies have demonstrated that the consumption of prickly pear cladodes and the related products reduced post-prandial glucose levels. The cladodes’ high fiber content may be implicated in improving glycemic control, by affecting glucose absorption and effectively slowing its release into the blood circulation. Given these potential hypoglycemic effects, prickly pear cladodes may represent a potential functional food ingredient to improve glycemic control and counter the negative metabolic effects of the modern Western diet. Nonetheless, in consideration of the lack of evidence on the chronic effects of the prickly pear cladode, future research aimed at evaluating its long-term effects on glycemic control is warranted.

Mechanisms underlying the pathophysiology of type 2 diabetes: From risk factors to oxidative stress, metabolic dysfunction, and hyperglycemia

Type 2 diabetes (T2D) is a complex multifactorial disease that emerges from the combination of genetic and environmental factors, and obesity, lifestyle, and aging are the most relevant risk factors. Hyperglycemia is the main metabolic feature of T2D as a consequence of insulin resistance and β-cell dysfunction. Among the cellular alterations induced by hyperglycemia, the overproduction of reactive oxygen species (ROS) and consequently oxidative stress, accompanied by a reduced antioxidant response and impaired DNA repair pathways, represent essential mechanisms underlying the pathophysiology of T2D and the development of late complications. Mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammation are also closely correlated with insulin resistance and β-cell dysfunction. This review focus on the mechanisms by which oxidative stress, mitochondrial dysfunction, ER stress, and inflammation are involved in the pathophysiology of T2D, highlighting the importance of the antioxidant response and DNA repair mechanisms counteracting the development of the disease. Moreover, we indicate evidence on how nutritional interventions effectively improve diabetes care. Additionally, we address key molecular characteristics and signaling pathways shared between T2D and Alzheimer’s disease (AD), which might probably be implicated in the risk of T2D patients to develop AD.

CDKN2C expression in adipose tissue is reduced in type II diabetes and central obesity: impact on adipocyte differentiation and lipid storage?

CDKN2C/p18 (Cyclin-Dependent Kinase Inhibitor 2C) is a cell growth regulator that controls cell cycle progression and has previously been associated with increased risk for type II diabetes (T2D) and reduced peripheral adipose tissue (AT) storage capacity. This study explored the role of CDKN2C in AT lipid and glucose metabolism in T2D. Expression of CDKN2C and other genes was analyzed by transcriptomics, or real-time PCR in subcutaneous AT (SAT) samples obtained from T2D and control subjects matched for sex, age and BMI and also in paired SAT and omental AT (OAT) samples. Functional studies included adipocyte glucose uptake and lipolysis rates. CRISPR/Cas9 CDKN2C gene knockdown was performed in human preadipocytes to assess adipogenesis. CDKN2C mRNA expression in SAT and OAT was reduced in T2D and obese subjects compared to controls. CDKN2C expression in SAT was inversely correlated with measures ofhyperglycemia, insulin resistanceandvisceral adiposity and positively correlated with expression of genes in several metabolic pathways, including insulin signaling and fatty acid and carbohydrate metabolism. CDKN2C protein was mainly expressed in adipocytes compared to stromal vascular cells, and its gene and protein expression was up-regulated during adipocyte differentiation. Knockdown of CDKN2C did not affect the percentage of differentiating cells compared to wild type cultures. However, CDKN2C knockdown cultures had significantly lower expression of differentiation markers CEBPA, ADIPOQ and FASN and transiently reduced lipid accumulation per adipocyte during differentiation. Our findings suggest that adipose CDKN2C expression might be reduced as a consequence of insulin resistance and obesity, and this can further contribute to impairment of SAT lipid storage.

An interferon-related signature characterizes the whole blood transcriptome profile of insulin-resistant individuals\u2014the CODAM study

BackgroundWorldwide, the prevalence of obesity and insulin resistance has grown dramatically. Gene expression profiling in blood represents a powerful means to explore disease pathogenesis, but the potential impact of inter-individual differences in a cell-type profile is not always taken into account. The objective of this project was to investigate the whole blood transcriptome profile of insulin-resistant as compared to insulin-sensitive individuals independent of inter-individual differences in white blood cell profile.ResultsWe report a 3% higher relative amount of monocytes in the insulin-resistant individuals. Furthermore, independent of their white blood cell profile, insulin-resistant participants had (i) higher expression of interferon-stimulated genes and (ii) lower expression of genes involved in cellular differentiation and remodeling of the actin cytoskeleton.ConclusionsWe present an approach to investigate the whole blood transcriptome of insulin-resistant individuals, independent of their DNA methylation-derived white blood cell profile. An interferon-related signature characterizes the whole blood transcriptome profile of the insulin-resistant individuals, independent of their white blood cell profile. The observed signature indicates increased systemic inflammation possibly due to an innate immune response and whole-body insulin resistance, which can be a cause or a consequence of insulin resistance. Altered gene expression in specific organs may be reflected in whole blood; hence, our results may reflect obesity and/or insulin resistance-related organ dysfunction in the insulin-resistant individuals.

AACE2021-A-1048: Effect of Dietary Intake of Branched Chain Amino Acids on Type 2 Diabetic Patients Control

BCAAs up regulate glucose transporters and activate insulin secretion has been widely demonstrated. However, several researchers have suggested that excessive intake of amino acids could lead to inhibition of insulin signalling. BCAAs may induce insulin resistance through m TOR activation. insulin resistance may be linked with high intake of BCAAs, Controversies remain on whether an increase in plasma BCAA levels is a cause or consequence of insulin resistance. The aim of the study is to measure the effect of consumption of BCCAs on lipid profile and glucose level in type 2 obese diabetic patients. Participants enrolled in the study 280 patients (139 male,141 female) with type 2 diabetes for more than 5 years Attending Endocrinology out patient clinic. Written consent was obtained from all participants Anthropometric measurement (height, weight, waist circumference, body mass index Dietary assessment participants had to complete food frequency questionnaire (24 hour recall)for 5 days and analysis for branched chain amino acid intake was performed using food composition table, life style ,socio-demographic level, laboratory investigations including, fasting glucose, HbA1c, cholesterol, triglyceride, LDL, HDL. Mean Age 38.24±4.28 ,male 49.6%, female 50.4%, diabetes duration 8.86±2.26 years, BMI; 29.89 ±3.02, protein intake 77.75±14.76 g, Leucine 4.75±1.01g, valine 4.04±0.89 g, Isoleucine 4.09±0.92 g, fasting glucose 206.60 ±51.01mg A1C 9.33±1.18, cholesterol 238.79±40.37 mg/dl, triglycerides 103.47±14.01mg/dl LDL178.20 ±43.32 mg/dl/ HDL 44.03±9.55mg/dl. All of our patients took higher load for age and ideal weight of (leucine,valine, and isoleucine is likely to be 0.04,0.017-0.02 ,and 0.019 g /kg respective) mainly from plant source protein Regarding correlation with A1C (Valine p 0.01,r 0.02/isoliosine p 0.08 r 0.156) Regarding correlation with LDL (liosine p 0.07 r 0.156). High BCCAs intake mainly from plant source is associated with dyslipidaemia and poor glycaemic control .proper dietary counselling is important in diabetic.

Communication Between Autophagy and Insulin Action: At the Crux of Insulin Action-Insulin Resistance?

Insulin is a paramount anabolic hormone that promotes energy-storage in adipose tissue, skeletal muscle and liver, and these responses are significantly attenuated in insulin resistance leading to type 2 diabetes. Contrasting with insulin’s function, macroautophagy/autophagy is a physiological mechanism geared to the degradation of intracellular components for the purpose of energy production, building-block recycling or tissue remodeling. Given that both insulin action and autophagy are dynamic phenomena susceptible to the influence of nutrient availability, it is perhaps not surprising that there is significant interaction between these two major regulatory mechanisms. This review examines the crosstalk between autophagy and insulin action, with specific focus on dysregulated autophagy as a cause or consequence of insulin resistance.

504-P: Association between Serum Fatty Acid Metabolism Profile and Type 2 Diabetes with Worse Glycemic Control: A Study in Northeastern China

Background: Type 2 diabetes (T2DM) is a disease characterized by persistent insulin resistance and progressive decline of β-cell function. It has been demonstrated that the changes of free fatty acid (FFA) levels and its metabolism in patients with T2DM could not only act as the cause but also as the consequence of insulin resistance. It is particularly important to analyze the relationship between the changes in FFA metabolism profile and glucose level in patients with T2DM.Method: 606 subjects were enrolled in the study in Dalian, a city in Northeastern China. According to the Glycemic Targets Guideline: Subjects were divided into 3 groups. Group A (T2DM with worse glycemic control):112 patients with HbA1c≥7.0%; Group B : 53 T2DM patients with HbA1c<7.0% ; Group C : 411 healthy subjects. 23 kinds of serum FFAs including arachidonic acid (C20:4), nervonic acid (C24:1) were measured by LC-MS.Result: The levels of nervonic acid (C24:1) were significantly different among the three groups (OR 95%CI:0.99[0.98~1.00], p<0.05). Compared with healthy people in group C, the levels of nervonic acid in group A and B were significantly lower.Conclusion: The decreased level of neuronic acid is associated with worse glycemic control in T2DM patients, which may provide new ideas for clinical intervention and treatment of T2DM patients with worse glycemic control to supplement exogenous FFAs.View largeDownload slideView largeDownload slide DisclosureY. Li: None. M. Zhou: None. X. Xia: None. H. Shen: None. Y. Li: None. Y. Xu: None. C. Han: None. Y. Liu: None.

Metabolic and Energy Imbalance in Dysglycemia-Based Chronic Disease.

Metabolic flexibility is the ability to efficiently adapt metabolism based on nutrient availability and requirement that is essential to maintain homeostasis in times of either caloric excess or restriction and during the energy-demanding state. This regulation is orchestrated in multiple organ systems by the alliance of numerous metabolic pathways under the master control of the insulin-glucagon-sympathetic neuro-endocrine axis. This, in turn, regulates key metabolic enzymes and transcription factors, many of which interact closely with and culminate in the mitochondrial energy generation machinery. Metabolic flexibility is compromised due to the continuous mismatch between availability and intake of calorie-dense foods and reduced metabolic demand due to sedentary lifestyle and age-related metabolic slowdown. The resultant nutrient overload leads to mitochondrial trafficking of substrates manifesting as mitochondrial dysfunction characterized by ineffective substrate switching and incomplete substrate utilization. At the systemic level, the manifestation of metabolic inflexibility comprises reduced skeletal muscle glucose disposal rate, impaired suppression of hepatic gluconeogenesis and adipose tissue lipolysis manifesting as insulin resistance. This is compounded by impaired β-cell function and progressively reduced β-cell mass. A consequence of insulin resistance is the upregulation of the mitogen-activated protein kinase pathway leading to a pro-hypertensive, atherogenic, and thrombogenic environment. This is further aggravated by oxidative stress, advanced glycation end products, and inflammation, which potentiates the risk of micro- and macro-vascular complications. This review aims to elucidate underlying mechanisms mediating the onset of metabolic inflexibility operating at the main target organs and to understand the progression of metabolic diseases. This could potentially translate into a pharmacological tool that can manage multiple interlinked conditions of dysglycemia, hypertension, and dyslipidemia by restoring metabolic flexibility. We discuss the breadth and depth of metabolic flexibility and its impact on health and disease.

Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge.

Mitochondrial dysfunction is frequently associated with impairment in metabolic homeostasis and insulin action, and is thought to underlie cellular aging. However, it is unclear whether mitochondrial dysfunction is a cause or consequence of insulin resistance in humans. To determine the impact of intrinsic mitochondrial dysfunction on metabolism and insulin action, we performed comprehensive metabolic phenotyping of the polymerase gamma (PolG) D257A “mutator” mouse, a model known to accumulate supraphysiological mitochondrial DNA (mtDNA) point mutations. We utilized the heterozygous PolG mutator mouse (PolG+/mut) because it accumulates mtDNA point mutations ~ 500‐fold > wild‐type mice (WT), but fails to develop an overt progeria phenotype, unlike PolGmut/mut animals. To determine whether mtDNA point mutations induce metabolic dysfunction, we examined male PolG+/mut mice at 6 and 12 months of age during normal chow feeding, after 24‐hr starvation, and following high‐fat diet (HFD) feeding. No marked differences were observed in glucose homeostasis, adiposity, protein/gene markers of metabolism, or oxygen consumption in muscle between WT and PolG+/mut mice during any of the conditions or ages studied. However, proteomic analyses performed on isolated mitochondria from 12‐month‐old PolG+/mut mouse muscle revealed alterations in the expression of mitochondrial ribosomal proteins, electron transport chain components, and oxidative stress‐related factors compared with WT. These findings suggest that mtDNA point mutations at levels observed in mammalian aging are insufficient to disrupt metabolic homeostasis and insulin action in male mice.

Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview.

Insulin resistance changes over time during pregnancy, and in the last half of the pregnancy, insulin resistance increases considerably and can become severe, especially in women with gestational diabetes and type 2 diabetes. Numerous factors such as placental hormones, obesity, inactivity, an unhealthy diet, and genetic and epigenetic contributions influence insulin resistance in pregnancy, but the causal mechanisms are complex and still not completely elucidated. In this review, we strive to give an overview of the many components that have been ascribed to contribute to the insulin resistance in pregnancy. Knowledge about the causes and consequences of insulin resistance is of extreme importance in order to establish the best possible treatment during pregnancy as severe insulin resistance can result in metabolic dysfunction in both mother and offspring on a short as well as long-term basis.

Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity

Aims/hypothesisIn the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.MethodsWe studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant’s effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.ResultsAcute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.Conclusions/interpretationWe conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.

SIRT1 mediates the role of RNA-binding protein QKI 5 in the synthesis of triglycerides in non-alcoholic fatty liver disease mice via the PPARα/FoxO1 signaling pathway.

Non-alcoholic fatty liver disease (NAFLD) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress and lipotoxicity. The present study aimed to elucidate the effect of Quaking 5 (QKI 5) as mediated by Sirtuin 1 (SIRT1) on triglyceride (TG) synthesis in the liver of an NAFLD mouse model. A high-fat diet-induced NAFLD model was established in mice, and mouse hepatocytes were isolated to characterize the effects of QKI 5 mediated by SIRT1 on TG synthesis in the liver. Body weight and liver wet weight were recorded. In addition, serum levels of total cholesterol, TG, alanine aminotransferase and aspartate aminotransferase were assessed using an automatic biochemistry analyzer. Hematoxylin and eosin staining was performed to observe the histological morphological alterations of the liver tissues. The concentration of SIRT1 in the serum was also detected. The NAFLD activity score (NAS) was used to evaluate disease severity. The synthesis of TGs in cells or tissues was determined, and the protein levels of SIRT1, QKI 5, peroxisome proliferator-activated receptor (PPAR)α and Forkhead box protein O1 (FoxO1) were examined. The expression levels of SIRT1 or QKI 5, and the acetylation level of QKI 5 were decreased in the mouse model of NAFLD. QKI 5 was deacetylated by SIRT1, which contributed in suppressing the progression of NAFLD in the mice, and inhibiting TG synthesis in vivo and in vitro via the PPARα/FoxO1 signaling pathway. Taken together, the results of the present study demonstrated that SIRT1 deacetylated QKI 5, an RNA-binding protein significantly affecting the synthesis of TG in the liver of the NAFLD mouse model. Furthermore, it activated transcription factor FOXO1 through post-transcriptional regulation of the expression of PPARα and further inhibited the synthesis of TGs, thereby restraining the progression of NAFLD.

Possible dysmetabolic hyperferritinemia in hyperinsulinemic horses.

Background:Hyperinsulinemia associated with equine metabolic syndrome and pituitary pars intermedia dysfunction is a risk factor for laminitis. Research in other species has shown elevated body iron levels as both a predictor and consequence of insulin resistance. In humans, this is known as dysmetabolic hyperferritinemia. Aim:To explore the relationship between equine hyperinsulinemia and body iron levels.Methods:We reviewed case histories and laboratory results from an open access database maintained by the Equine Cushing’s and Insulin Resistance Group Inc. (ECIR). We identified 33 horses with confirmed hyperinsulinemia and laboratory results for serum iron, total iron binding capacity, and ferritin. Pearson correlation was used to test the relationship between insulin and iron indices. Additionally, we performed a secondary analysis of a previously reported controlled trial that was originally designed to test the correlation between iron status and the insulin response in horses. Here, we used a t-test to compare the mean values of insulin and ferritin between horses we categorized as normal or hyperinsulinemic based on their response to an oral challenge.Results:Serum ferritin exceeded published reference range in 100% of the horses identified from the ECIR database. There were no statistically significant associations between insulin indices (RISQI, log insulin) and iron indices (log serum iron, log TSI%, log ferritin). There were trends for a negative association between RISQI and log iron [r(31) = −0.33, p = 0.058] and a positive association between age and ferritin [r(30) = 0.34, p = 0.054]. From the secondary data analysis of published data, we found significantly elevated ferritin (p = 0.05) in horses considered hyperinsulinemic by dynamic insulin testing compared to horses with a normal response.Conclusion:These results suggest the potential for iron overload in hyperinsulinemic horses, a feature documented in other species and should stimulate further study into the relationship between insulin and iron dysregulation in the horse.

Neural and Endocrine Correlates of Early Life Abuse in Youth With Depression and Obesity.

Depression and insulin resistance are becoming increasingly prevalent in younger populations. The origin and consequence of insulin resistance in depressed youth may, in part, be rooted in exposure to environmental stressors, such as early life abuse, that may lead to aberrant brain motivational networks mediating maladaptive food-seeking behaviors and insipient insulin resistance. In this paper, we aimed to investigate the impact of early life abuse on the development of insulin resistance in depressed and overweight youth aged 9 to 17 years. We hypothesized that youth with the greatest burden of early life abuse would have the highest levels of insulin resistance and corresponding aberrant reward network connectivities. To test this hypothesis, we evaluated sixty-nine depressed and overweight youth aged 9 to 17, using multimodal assessments of early life abuse, food-seeking behavior, and insulin resistance. Based on results of the Childhood Trauma Questionnaire (CTQ), we separated our study participants into two groups: 35 youth who reported high levels of the sum of emotional, physical, or sexual abuse and 34 youth who reported insignificant or no levels of any abuse. Results of an oral glucose tolerance test (OGTT) and resting state functional connectivity (RSFC), using the amygdala, insula, and nucleus accumbens (NAcc) as seed-based reward network regions of interest, were analyzed for group differences between high abuse and low abuse groups. High abuse youth exhibited differences from low abuse youth in amygdala-precuneus, NAcc-paracingulate gyrus, and NAcc-prefrontal cortex connectivities, that correlated with levels of abuse experienced. The more different their connectivity from of that of low abuse youth, the higher were their fasting glucose and glucose at OGTT endpoint. Importantly, level of abuse moderated the relation between reward network connectivity and OGTT glucose response. In contrast, low abuse youth showed hyperinsulinemia and more insulin resistance than high abuse youth, and their higher OGTT insulin areas under the curve correlated with more negative insula-precuneus connectivity. Our findings suggest distinct neural and endocrine profiles of youth with depression and obesity based on their histories of early life abuse.

Mitochondrial ADP Sensitivity and Transport: New Insights Into Diet-Induced Mitochondrial Impairments.

In the quest to understand the etiology and pathophysiology of insulin resistance and type 2 diabetes (T2DM), a body of evidence representing nearly two decades of research points a finger at mitochondria as organelles of great interest (1–3). The term “mitochondrial dysfunction” was born following early reports that these organelles exhibited altered abundance and morphology (1), attenuated oxidative phosphorylation capacity (4), and an altered redox environment (5) in insulin-resistant individuals. Today, despite great efforts to understand the relationship between mitochondria and metabolic disease, there is little accord to conclusively determine if impairments in skeletal muscle mitochondrial biology are cause or consequence of insulin resistance or simply paraphenomena. High-fat feeding interventions are used extensively in the quest to understand the etiology and pathophysiology of insulin resistance and T2DM. Such feeding models recapitulate many of the metabolic features along the spectrum of insulin resistance and diabetes (e.g., adiposity, glucose intolerance, metabolic inflexibility) (6). Painstaking efforts have been made to understand the role of mitochondria in the progression of insulin resistance during high-fat feeding, but ambiguity remains. For example, Sparks et al. (7) reported a ∼90% decline in genes associated with oxidative phosphorylation and mitochondrial biogenesis in skeletal muscle of C57BL/6J mice fed a high-fat diet, which aligns with decreased oxidative enzyme activity observed in patients …