Insulin Resistance In Peripheral Tissues Research Articles

Preventing Childhood Obesity in Diabetes: A Critical Imperative

: Diabetes mellitus (DM) encompasses a range of chronic metabolic conditions characterized by hyperglycemia, stemming from either insulin deficiency due to pancreatic β-cell damage (T1DM) or peripheral tissue insulin resistance (T2DM). Given the importance of DM and obesity, this narrative review aimed to address the optimal screening and control of childhood obesity as the main strategies for dealing with the comorbidities of T2DM. This review underscores the critical importance of optimal screening and management of childhood obesity as primary strategies for addressing comorbidities associated with T2DM. In many cases, T2DM may remain asymptomatic for several years, leaving patients unaware of their condition or experiencing few symptoms despite having poorly controlled prediabetes or DM. Hence, it is imperative to recognize that screening for prediabetes and childhood obesity presents a crucial opportunity for intervention to avert the future development of DM and its lifelong health repercussions. Moreover, lifestyle modifications stand out as the most effective approach for preventing or delaying the onset of T2DM comorbidities and complications. It is noteworthy that reductions in mortality among people with DM, associated with current antidiabetic medications, will increase the lifetime accumulation of T2DM complications and morbidities worldwide.

Berberine attenuates obesity-induced insulin resistance by inhibiting miR-27a secretion.

Berberine (BBR) is an alkaloid found in plants. It has neuroprotective, anti-inflammatory and lipid-lowering activity. However, the efficacy of treatment with BBR and the mechanisms through which it acts need further study. This study investigated the therapeutic effects and the mechanism of action of BBR on obesity-induced insulin resistance in peripheral tissues. High-fat-fed C57BL/6J mice and low-fat-fed C57BL/6J mice with miR-27a overexpression were given BBR intervention (100 mg/kg, po), and the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) were performed. Palmitic acid-stimulated hypertrophic adipocyte models were treated with BBR (10 μM). Related indicators and protein expression levels were examined. The AUCs of the OGTT and the ITT in the BBR intervention group were reduced significantly (p < 0.01) (p < 0.05), and the serum biochemical parameters, including FBG, TC, TG and LDL-C were significantly reduced after BBR intervention. In the invitro experiments, the triglyceride level and volume of lipid droplets decreased significantly after BBR intervention (p < 0.01) (p < 0.05). Likewise, BBR ameliorates skeletal muscle and pancreas insulin signalling pathways invivo and invitro. The results showed that BBR significantly ameliorated insulin resistance, reduced body weight and percent body fat and improved serum biochemical parameters in mice. Likewise, BBR reduced triglyceride level and lipid droplet volume in hypertrophic adipocytes, BBR improved obesity effectively. Meanwhile, BBR ameliorated the histomorphology of the pancreas, and skeletal muscle and pancreas insulin related signalling pathways of islets in invitro and invivo experiments. The results further demonstrated that BBR inhibited miR-27a levels in serum from obese mice and supernatant of hypertrophic adipocytes. miR-27a overexpression in low-fat fed mice indicated that miR-27a caused insulin resistance, and BBR intervention significantly improved the miR-27a induced insulin resistance status. This study demonstrates the important role of BBR in obesity-induced peripheral insulin resistance and suggest that the mechanism of its effect may be inhibition of miR-27a secretion.

Pioglitazone does not enhance exogenous glucose oxidation or metabolic clearance rate during aerobic exercise in men under acute high-altitude exposure.

Insulin insensitivity decreases exogenous glucose oxidation and metabolic clearance rate (MCR) during aerobic exercise in unacclimatized lowlanders at high altitude (HA). Whether use of an oral insulin sensitizer before acute HA exposure enhances exogenous glucose oxidation is unclear. This study investigated the impact of pioglitazone (PIO) on exogenous glucose oxidation and glucose turnover compared with placebo (PLA) during aerobic exercise at HA. With the use of a randomized crossover design, native lowlanders (n = 7 males, means ± SD, age: 23 ± 6 yr, body mass: 84 ± 11 kg) consumed 145 g (1.8 g/min) of glucose while performing 80 min of steady-state (1.43 ± 0.16 V̇o2 L/min) treadmill exercise at HA (460 mmHg; [Formula: see text] 96.6 mmHg) following short-term (5 days) use of PIO (15 mg oral dose per day) or PLA (microcrystalline cellulose pill). Substrate oxidation and glucose turnover were determined using indirect calorimetry and stable isotopes ([13C]glucose and 6,6-[2H2]glucose). Exogenous glucose oxidation was not different between PIO (0.31 ± 0.03 g/min) and PLA (0.32 ± 0.09 g/min). Total carbohydrate oxidation (PIO: 1.65 ± 0.22 g/min, PLA: 1.68 ± 0.32 g/min) or fat oxidation (PIO: 0.10 ± 0.0.08 g/min, PLA: 0.09 ± 0.07 g/min) was not different between treatments. There was no treatment effect on glucose rate of appearance (PIO: 2.46 ± 0.27, PLA: 2.43 ± 0.27 mg/kg/min), disappearance (PIO: 2.19 ± 0.17, PLA: 2.20 ± 0.22 mg/kg/min), or MCR (PIO: 1.63 ± 0.37, PLA: 1.73 ± 0.40 mL/kg/min). Results from this study indicate that PIO is not an effective intervention to enhance exogenous glucose oxidation or MCR during acute HA exposure. Lack of effect with PIO suggests that the etiology of glucose metabolism dysregulation during acute HA exposure may not result from insulin resistance in peripheral tissues.NEW & NOTEWORTHY Short-term (5 days) use of the oral insulin sensitizer pioglitazone does not alter circulating glucose or insulin responses to enhance exogenous glucose oxidation during steady-state aerobic exercise in young healthy men under simulated acute (8 h) high-altitude (460 mmHg) conditions. These results indicate that dysregulations in glucose metabolism in native lowlanders sojourning at high altitude may not be due to insulin resistance at peripheral tissue.

The C5aR1 complement receptor: A novel immunomodulator of insulin action in skeletal muscle.

The complement system constitutes an integral component of the innate immune system and plays a critical role in adaptive immunity. Activation of this system engenders the production of complement peptide fragments, including C5a, which engage G-protein coupled receptors predominantly expressed in immune-associated cells, such as neutrophils, initiating pro-inflammatory responses. Intriguingly, our investigation has unveiled the presence of C5a receptor 1 (C5aR1) expression within skeletal muscle, a key metabolic tissue and primary target of insulin. Herein, we demonstrate that C5aR1 activation by C5a in differentiated human skeletal muscle cells elicits acute suppression of insulin signalling. This suppression manifests as impaired insulin-dependent association between IRS1 and the p85 subunit of PI3-kinase, a 50% reduction in Akt phosphorylation, and a 60% decline in insulin-stimulated glucose uptake. This impairment in insulin signalling is associated with a three-fold elevation in intramyocellular diacylglycerol (DAG) levels and a two-fold increase in cytosolic calcium content, which promote PKC-mediated IRS1 inhibition via enhanced phosphorylation at IRS1 Ser1101. Significantly, our findings demonstrate that structurally diverse C5aR1 antagonists, along with genetic deletion or stable silencing of C5aR1 by 80% using short-hairpin RNA, effectively attenuate repression of insulin signalling by C5a in LHCN-M2 human skeletal myotubes. These results underscore the potential of heightened C5aR1 activation, characteristic of obesity and chronic inflammatory conditions, to detrimentally impact insulin function within skeletal muscle cells. Additionally, the study suggests that agents targeting the C5a-C5aR axis, originally devised for mitigating complement-dependent inflammatory conditions, may offer therapeutic avenues to ameliorate immune-driven insulin resistance in key peripheral metabolic tissues, including skeletal muscle.

What is the relationship between serum uric acid level and insulin resistance?: A case-control study

Diabetes, arises from either an absolute or relative insufficiency of insulin or insulin resistance of peripheral tissues. For assessing long-term blood glucose concentration and insulin resistance, the utilization of glycosylated hemoglobin (HbA1c) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) is widespread. Insulin resistance can lead to hyperuricemia by reducing the kidney ability to excrete urate, thus increasing sodium reabsorption. The aim of this study was to investigate the possible relationship between serum uric acid levels and insulin resistance. This was a retrospective case-control study. A total of 2530 applications in 2-year time were included in the study. Patient, known hypertension status, fasting plasma glucose, insulin, uric acid, HDL, low-density lipoprotein (LDL), triglyceride/Tg, HbA1c laboratory values and Tg/HDL ratio were examined. A statistically significant difference existed in the median uric acid values between the insulin-resistant and insulin-sensitive groups (P &lt; .001). Additionally, a weak positive statistical correlation was identified between uric acid and HOMA-IR values (R = 0.299; P &lt; .001) and uric acid and Tg/HDL values (R = 0.357; P &lt; .001). This study concludes that there is a positive correlation between serum uric acid levels and insulin resistance.

The Role of NAD+ in Metabolic Regulation of Adipose Tissue: Implications for Obesity-Induced Insulin Resistance.

Obesity-induced insulin resistance is among the key factors in the development of type 2 diabetes, atherogenic dyslipidemia and cardiovascular disease. Adipose tissue plays a key role in the regulation of whole-body metabolism and insulin sensitivity. In obesity, adipose tissue becomes inflamed and dysfunctional, exhibiting a modified biochemical signature and adipokine secretion pattern that promotes insulin resistance in peripheral tissues. An important hallmark of dysfunctional obese adipose tissue is impaired NAD+/sirtuin signaling. In this chapter, we summarize the evidence for impairment of the NAD+/sirtuin pathway in obesity, not only in white adipose tissue but also in brown adipose tissue and during the process of beiging, together with correlative evidence from human studies. We also describe the role of PARPs and CD38 as important NAD+ consumers and discuss findings from experimental studies that investigated potential NAD+ boosting strategies and their efficacy in restoring impaired NAD+ metabolism in dysfunctional obese adipose tissue. In sum, these studies suggest a critical role of NAD+ metabolism in adipose biology and provide a basis for the potential development of strategies to restore metabolic health in obesity.

Метаболический синдром: риски в детско-юношеском спорте

Metabolic syndrome is one of the pre-nosological conditions that implies strain on several systems of the body and disruption of all types of metabolism. The key components of the syndrome are visceral obesity, peripheral tissue insulin resistance, arterial hypertension and non-alcoholic fatty liver disease. There is a number of diseases associated with the syndrome, which makes diagnosing its preclinical manifestations important. Overweight and obesity only continue spreading; moreover, these conditions are registered in people of increasingly younger age. Metabolic syndrome in childhood increases the risk of cardiovascular disease in adulthood. Top tier athletes are no exception. Some sports and playing roles promote body weight growth. A young athlete may have specific constitutional features, and, without proper control, motivating such athletes to grow muscles means they also grow fat. The recommendation is to pay special attention to children under the age of 11 that play rugby, American football as line men, in heavy weight categories. Application of the latest diagnostic criteria with their actualization on a regular basis, as well as search for additional markers and parameters identifiable in laboratory settings, would ensure adjustment of the athlete's condition in a timely manner.

Iron and β-Cell Function: Implications for Diabetes Pathophysiology

Background: The intricate relationship between iron metabolism and diabetes mellitus has become a subject of increasing interest, with a growing body of evidence suggesting that iron plays a significant role in the pathophysiology of diabetes. Spe-cifically, the impact of iron on β-cell function has emerged as a critical area of study. Β cells, located in the pancreatic islets of Langerhans, are responsible for insulin synthesis and secretion. Purpose: Understanding how iron influences these vital cells is crucial for unraveling the complexities of diabetes development and progression. Methods: This review synthesizes current literature on the interaction between iron and β-cell function, exploring the molecular and cellular mechanisms underlying this relationship. We conducted a systematic search of databases, including PubMed and Scopus, to identify relevant studies published up to the present date. Articles were selected based on their focus on iron homeostasis, β-cell function, and their implica-tions for diabetes pathophysiology. Results: Iron is an essential micronutrient that participates in various cellular pro-cesses, including energy metabolism and reactive oxygen species (ROS) regulation. In β cells, iron is intricately involved in insulin synthesis, folding, and maturation. However, an imbalance in iron homeostasis can lead to oxidative stress, mitochon-drial dysfunction, and impaired insulin secretion. The reviewed literature provides compelling evidence that alterations in iron levels can adversely affect β-cell func-tion, contributing to the development and progression of diabetes. Excess iron has been associated with increased oxidative stress within β cells, leading to damage and dysfunction. Furthermore, iron-induced ROS may activate inflammatory pathways, promoting β-cell apoptosis and insulin resistance in peripheral tissues. Conversely, iron deficiency may also impact β-cell health. Insufficient iron availability can com-promise the efficiency of insulin synthesis and secretion, potentially contributing to glucose dysregulation. Iron-deficient conditions may lead to alterations in cellular energy metabolism, further exacerbating the vulnerability of β cells to stressors. Conclusions: Understanding the nuanced interplay between iron and β-cell function has implications for diabetes management. Therapeutic strategies aimed at modulating iron levels, such as iron chelation or dietary interventions, hold promise for preserving β-cell health and improving glycemic control. This review underscores the intricate relationship between iron and β-cell function, providing valuable insights into the pathophysiology of diabetes. Whether through excess or deficiency, iron significantly influences the health and function of β cells, shaping the landscape of diabetes development. Further research is warranted to delineate the precise mecha-nisms involved and to explore targeted interventions that may harness the therapeutic potential of modulating iron levels in diabetes management.

Insights into the development of insulin resistance: Unraveling the interaction of physical inactivity, lipid metabolism and mitochondrial biology.

While impairments in peripheral tissue insulin signalling have a well-characterized role in the development of insulin resistance and type 2 diabetes (T2D), the specific mechanisms that contribute to these impairments remain debatable. Nonetheless, a prominent hypothesis implicates the presence of a high-lipid environment, resulting in both reactive lipid accumulation and increased mitochondrial reactive oxygen species (ROS) production in the induction of peripheral tissue insulin resistance. While the etiology of insulin resistance in a high lipid environment is rapid and well documented, physical inactivity promotes insulin resistance in the absence of redox stress/lipid-mediated mechanisms, suggesting alternative mechanisms-of-action. One possible mechanism is a reduction in protein synthesis and the resultant decrease in key metabolic proteins, including canonical insulin signaling and mitochondrial proteins. While reductions in mitochondrial content associated with physical inactivity are not required for the induction of insulin resistance, this could predispose individuals to the detrimental effects of a high-lipid environment. Conversely, exercise-training induced mitochondrial biogenesis has been implicated in the protective effects of exercise. Given mitochondrial biology may represent a point of convergence linking impaired insulin sensitivity in both scenarios of chronic overfeeding and physical inactivity, this review aims to describe the interaction between mitochondrial biology, physical (in)activity and lipid metabolism within the context of insulin signalling.

Mechanistic insights of soluble uric acid-induced insulin resistance: Insulin signaling and beyond.

Hyperuricemia is a metabolic disease caused by purine nucleotide metabolism disorder. The prevalence of hyperuricemia is increasing worldwide, with a growing trend in the younger populations. Although numerous studies have indicated that hyperuricemia may be an independent risk factor for insulin resistance, the causal relationship between the two is controversial. There are few reviews, however, focusing on the relationship between uric acid (UA) and insulin resistance from experimental studies. In this review, we summarized the experimental models related to soluble UA-induced insulin resistance in pancreas and peripheral tissues, including skeletal muscles, adipose tissue, liver, heart/cardiomyocytes, vascular endothelial cells and macrophages. In addition, we summarized the research advances about the key mechanism of UA-induced insulin resistance. Moreover, we attempt to identify novel targets for the treatment of hyperuricemia-related insulin resistance. Lastly, we hope that the present review will encourage further researches to solve the chicken-and-egg dilemma between UA and insulin resistance, and provide strategies for the pathogenesis and treatment of hyperuricemia related metabolic diseases.

Management of Obesity and Obesity-Related Disorders: From Stem Cells and Epigenetics to Its Treatment.

Obesity is a complex worldwide disease, characterized by an abnormal or excessive fat accumulation. The onset of this pathology is generally linked to a complex network of interactions among genetic and environmental factors, aging, lifestyle, and diets. During adipogenesis, several regulatory mechanisms and transcription factors are involved. As fat cells grow, adipose tissue becomes increasingly large and dysfunctional, losing its endocrine function, secreting pro-inflammatory cytokines, and recruiting infiltrating macrophages. This long-term low-grade systemic inflammation results in insulin resistance in peripheral tissues. In this review we describe the main mechanisms involved in adipogenesis, from a physiological condition to obesity. Current therapeutic strategies for the management of obesity and the related metabolic syndrome are also reported.

FEATURES OF CYTOKINE PROFILE OF BLOOD IN RATS WITH STREPTOZOTOCIN-INDUCED DIABETES

In the pathogenesis of many diseases, including diabetes mellitus, cytokines play a crucial role. It is known that cytokines are the regulators of intercellular and intersystem interactions, ensuring the consistency of the actions of the endocrine, immune, and nervous systems under standard conditions and in response to pathogenetic factors, and are involved in the development of autoimmune processes. It was established that proinflammatory cytokines, namely tumor necrosis factor-alpha, interleukin-1β, and interleukin-6 play a significant role in the loss of insulin-producing function by beta cells of the islets of Langerhans, as well as are implicated in the formation of insulin resistance in peripheral tissues.&#x0D; The aim is to study the dynamics of the content of tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) in the blood serum of rats with streptozotocin-induced diabetes.&#x0D; Materials and methods The experiments were performed on 88 white male Wistar rats weighing 170–210 g, which were kept on a standard diet with free access to water. Animals were divided into three groups: 1 – intact (n=10); 2 – control (n=40); 3 – experimental (n=38) with a model of diabetes mellitus, which was reproduced by intraperitoneal injection of streptozotocin by "Sigma" company (USA), diluted in 0.1 M citrate buffer with a pH of 4.5, at a rate of 60 mg/kg body weight. The control group of animals received an intraperitoneal injection with an equivalent dose of 0.1 M citrate buffer solution with a pH of 4.5. Serum levels of TNF-α, IL-1β, and IL-6 were determined by rat enzyme-linked immunosorbent assay Rat ELISA Kits (Elabscience, USA) according to the manufacturer's instructions 14, 28, 42 and 70 days after streptozotocin injection. To assess the reliability of data changes in dynamics (14, 28, 42, 70 days) within each of the comparison groups, a non-parametric method was used (for three or more comparison groups) - Friedman's analysis of variance and Kendall's coefficient of concordance (Friedman ANOVA and Kendall's W).&#x0D; Results Conducted biochemical studies of blood serum showed that in animals with streptozotocin-induced diabetes, there was an increase in the content of proinflammatory cytokines at all stages of the experiment. In particular, TNF-α increased by 11.8% in 14 days, 34.4% in 28 days, 59.1% in 42 days and 80.1% in 70 days after the start of the experiment. An increase in the level of IL-1β was observed in the blood serum at the same time. In 14 days, the content of this cytokine increased by 22.5%, in 28 days increased by 40.2%, in 42 days increased by 72.8%, in 70 days increased by 107.2%. Along with this, we also observed an increase in the activity of IL-6 levels. In 14 days, in the blood serum, the IL-6 level was increased by 17.5%, in 28 days by 33.2%, in 42 days by 60.6% and after 70 days by 94.9% compared to the control group of animals. The analysis of the dynamics of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in blood serum under conditions of experimental diabetes indicates their unidirectional changes.&#x0D; Conclusions The conducted studies showed that pro-inflammatory cytokines play a leading role in the pathogenesis of diabetes mellitus: TNF-α, IL-1β, and IL-6, which is indicated by a significant increase in the levels of such cytokines in blood serum at all stages of the experiment. The most pronounced changes in pro-inflammatory cytokines levels are observed at 70-day.

Association of serum leptin and insulin levels among type 2 diabetes mellitus patients: A case-control study.

Secretion of insulin is compromised in type 2 diabetes (T2DM) individuals and inadequate to accommodate for insulin resistance (IR) in peripheral tissue. Hyperleptinemia reflects leptin resistance, which is a key factor in the production of IR in T2DM patients, making leptin a potential biomarker for evaluating IR levels. The objective of the study was to assess the association of serum leptin and insulin levels among T2DM patients. This case-control research was carried out on T2DM patients. A total of 73 patients diagnosed with T2DM (the case group) and 40 healthy participants (control; group 3) were enrolled according to the American Diabetes Association (ADA) criteria. In the case group, T2DM patients were enrolled with metabolic syndrome (group 1, n = 38) or without metabolic syndrome (group 2, n = 35) according to the WHO criteria. Metabolic profiles of T2DM patients with or without metabolic syndrome were evaluated, and compare these two groups with healthy controls. The subjects of all groups were age- and gender-matched. Body mass index (BMI, P < .01), fasting (P = .0133) and postprandial (P < .01) blood sugar levels, % glycated hemoglobin (HbA1c, P < .01), and lipid profile (P < .01) were found significantly different and higher in group 1 as compared to groups 2 and 3. Serum leptin and insulin levels were found higher and significant in patients with metabolic syndrome (P < .01 for both). The values of serum leptin levels were 10.01 ± 2.7 ng/mL, 6.9 ± 2.4 ng/mL, and 4.11 ± 1.8 ng/mL, and those of serum insulin 120 ± 40.7 µIU/mL, 20.43 ± 5.2 µIU/mL, and 11.4 ± 2.5 µIU/mL in groups 1, 2, and 3, respectively. There was a positive linear correlation between BMI, blood sugar, HbA1c, serum cholesterol (TC), and triglycerides (TG) with serum insulin and leptin levels in the case group. An extremely significant correlation (R = 0.74, P < .001) was found in BMI and serum leptin level in the case group. Serum leptin and insulin levels have a positive association, with serum leptin being a significant predictor of IR syndrome (Evidence Level: 5; Technical Efficacy: Stage 3).

Roles of long noncoding RNAs and small extracellular vesicle-long noncoding RNAs in type 2 diabetes.

The prevalence of a high-energy diet and a sedentary lifestyle has increased the incidence of type 2 diabetes (T2D). T2D is a chronic disease characterized by high blood glucose levels and insulin resistance in peripheral tissues. The pathological mechanism of this disease is not fully clear. Accumulated evidence has shown that noncoding RNAs have an essential regulatory role in the progression of diabetes and its complications. The roles of small noncoding RNAs, such as miRNAs, in T2D, have been extensively investigated, while the function of long noncoding RNAs (lncRNAs) in T2D has been unstudied. It has been reported that lncRNAs in T2D play roles in the regulation of pancreatic function, peripheral glucose homeostasis and vascular inflammation. In addition, lncRNAs carried by small extracellular vesicles (sEV) were shown to mediate communication between organs and participate in diabetes progression. Some sEV lncRNAs derived from stem cells are being developed as potential therapeutic agents for diabetic complications. In this review, we summarize the current knowledge relating to lncRNA biogenesis, the mechanisms of lncRNA sorting into sEV and the regulatory roles of lncRNAs and sEV lncRNAs in diabetes. Knowledge of lncRNAs and sEV lncRNAs in diabetes will aid in the development of new therapeutic drugs for T2D in the future.

Reduction in Insulin Mediated ERK Phosphorylation by Palmitate in Liver Cells Is Independent of Fatty Acid Induced ER Stress.

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38–45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress.

The Emerging Roles of IL-36, IL-37, and IL-38 in Diabetes Mellitus and its Complications.

Diabetes mellitus is a metabolic disease caused by a combination of genetic and environmental factors. The importance of the inflammatory response occurring in the pancreas and adipose tissue in the occurrence and progression of diabetes has been gradually accepted. Excess blood glucose and free fatty acids produce large amounts of inflammatory cytokines and chemokines through oxidative stress and endoplasmic reticulum stress. There is sufficient evidence that proinflammatory mediators, such as interleukin (IL)-1β, IL-6, macrophage chemotactic protein-1, and tumor necrosis factor-α, are engaged in insulin resistance in peripheral adipose tissue and the apoptosis of pancreatic β-cells. IL-36, IL-37, and IL-38, as new members of the IL-1 family, play an indispensable role in the regulation of immune system homeostasis and are involved in the pathogenesis of inflammatory and autoimmune diseases. Recently, the abnormal expression of IL-36, IL-37, and IL-38 in diabetes has been reported. In this review, we discuss the emerging functions, potential mechanisms, and future research directions on the role of IL-36, IL-37, and IL-38 in diabetes mellitus and its complications.

Insulin Resistance in Peripheral Tissues and the Brain: A Tale of Two Sites.

The concept of insulin resistance has been around since a few decades after the discovery of insulin itself. To allude to the classic Charles Dicken’s novel published 62 years before the discovery of insulin, in some ways, this is the best of times, as the concept of insulin resistance has expanded to include the brain, with the realization that insulin has a life beyond the regulation of glucose. In other ways, it is the worst of times as insulin resistance is implicated in devastating diseases, including diabetes mellitus, obesity, and Alzheimer’s disease (AD) that affect the brain. Peripheral insulin resistance affects nearly a quarter of the United States population in adults over age 20. More recently, it has been implicated in AD, with the degree of brain insulin resistance correlating with cognitive decline. This has led to the investigation of brain or central nervous system (CNS) insulin resistance and the question of the relation between CNS and peripheral insulin resistance. While both may involve dysregulated insulin signaling, the two conditions are not identical and not always interlinked. In this review, we compare and contrast the similarities and differences between peripheral and CNS insulin resistance. We also discuss how an apolipoprotein involved in insulin signaling and related to AD, apolipoprotein E (apoE), has distinct pools in the periphery and CNS and can indirectly affect each system. As these systems are both separated but also linked via the blood–brain barrier (BBB), we discuss the role of the BBB in mediating some of the connections between insulin resistance in the brain and in the peripheral tissues.

Stem Cell-Derived Islets for Type 2 Diabetes.

Since the discovery of insulin a century ago, insulin injection has been a primary treatment for both type 1 (T1D) and type 2 diabetes (T2D). T2D is a complicated disea se that is triggered by the dysfunction of insulin-producing β cells and insulin resistance in peripheral tissues. Insulin injection partially compensates for the role of endogenous insulin which promotes glucose uptake, lipid synthesis and organ growth. However, lacking the continuous, rapid, and accurate glucose regulation by endogenous functional β cells, the current insulin injection therapy is unable to treat the root causes of the disease. Thus, new technologies such as human pluripotent stem cell (hPSC)-derived islets are needed for both identifying the key molecular and genetic causes of T2D and for achieving a long-term treatment. This perspective review will provide insight into the efficacy of hPSC-derived human islets for treating and understanding T2D. We discuss the evidence that β cells should be the primary target for T2D treatment, the use of stem cells for the modeling of T2D and the potential use of hPSC-derived islet transplantation for treating T2D.

Abnormal gut microbiota and impaired incretin effect as a cause of type 2 diabetes mellitus

It has now been established that the intestinal microbiota (CM) is one of the 11 links in the pathogenesis of type 2 diabetes mellitus (DM2). Th e fact is that when the composition of BM is disrupted and the concentration of its active metabolites changes, the processes of synthesis and secretion of incretin hormones are disrupted, the homeostasis of carbohydrates and fats in the body is disrupted, the processes of central regulation of appetite change, chronic infl ammation and insulin resistance of peripheral tissues develop. Th is review discusses possible ways of impairing the synthesis of incretin hormones and the incretin eff ect in patients with T2DM through the prism of BM and its active metabolites, and discusses possible ways of correcting the altered composition of BM with incretin drugs.A systematic literature search was carried out using the Scopus, PubMed, Web of Science databases.

Lactate Is a Key Mediator That Links Obesity to Insulin Resistance via Modulating Cytokine Production From Adipose Tissue.

Numerous evidence indicates that inflammation in adipose tissue is the primary cause of systemic insulin resistance induced by obesity. Obesity-associated changes in circulating LPS level and hypoxia/HIF-1α activation have been proposed to be involved in boosting obesity-induced inflammation. However, there is poor understanding of what triggers obesity-induced inflammation. In this study, we pinpoint lactate as a key trigger to mediate obesity-induced inflammation and systemic insulin resistance. Specific deletion of Slc16a1 that encodes MCT1, the primary lactate transporter in adipose tissues, robustly elevates blood levels of proinflammatory cytokines and aggravates systemic insulin resistance without alteration of adiposity in mice fed high-fat diet. Slc16a1 deletion in adipocytes elevates intracellular lactate level while reducing circulating lactate concentration. Mechanistically, lactate retention due to Slc16a1 deletion initiates adipocyte apoptosis and cytokine release. The locally recruited macrophages amplify the inflammation by release of proinflammatory cytokines to the circulation, leading to insulin resistance in peripheral tissues. This study, therefore, indicates that lactate within adipocytes has a key biological function linking obesity to insulin resistance, and harnessing lactate in adipocytes can be a promising strategy to break this link.