Showing papers on "Insulin published in 2021"
TL;DR: Advances provide a new perspective for the understanding of the β-cell failure that triggers type 2 diabetes, and highlight the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of theβ-cell glucose response.
Abstract: Metabolic homeostasis in mammals is tightly regulated by the complementary actions of insulin and glucagon. The secretion of these hormones from pancreatic β-cells and α-cells, respectively, is controlled by metabolic, endocrine, and paracrine regulatory mechanisms and is essential for the control of blood levels of glucose. The deregulation of these mechanisms leads to various pathologies, most notably type 2 diabetes, which is driven by the combined lesions of impaired insulin action and a loss of the normal insulin secretion response to glucose. Glucose stimulates insulin secretion from β-cells in a bi-modal fashion, and new insights about the underlying mechanisms, particularly relating to the second or amplifying phase of this secretory response, have been recently gained. Other recent work highlights the importance of α-cell-produced proglucagon-derived peptides, incretin hormones from the gastrointestinal tract and other dietary components, including certain amino acids and fatty acids, in priming and potentiation of the β-cell glucose response. These advances provide a new perspective for the understanding of the β-cell failure that triggers type 2 diabetes.
206 citations
TL;DR: Tirzepatide as mentioned in this paper is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist under development for the treatment of type 2 diabetes.
151 citations
TL;DR: In this paper, a 10-week, randomized, placebo-controlled, double-blind trial was conducted to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese.
Abstract: In rodents, obesity and aging impair nicotinamide adenine dinucleotide (NAD+) biosynthesis, which contributes to metabolic dysfunction. Nicotinamide mononucleotide (NMN) availability is a rate-limiting factor in mammalian NAD+ biosynthesis. We conducted a 10-week, randomized, placebo-controlled, double-blind trial to evaluate the effect of NMN supplementation on metabolic function in postmenopausal women with prediabetes who were overweight or obese. Insulin-stimulated glucose disposal, assessed by using the hyperinsulinemic-euglycemic clamp, and skeletal muscle insulin signaling [phosphorylation of protein kinase AKT and mechanistic target of rapamycin (mTOR)] increased after NMN supplementation but did not change after placebo treatment. NMN supplementation up-regulated the expression of platelet-derived growth factor receptor β and other genes related to muscle remodeling. These results demonstrate that NMN increases muscle insulin sensitivity, insulin signaling, and remodeling in women with prediabetes who are overweight or obese (clinicaltrial.gov NCT 03151239).
146 citations
TL;DR: A review of the causes of insulin resistance can be found in this article, which suggests that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway.
Abstract: Insulin resistance, defined as a defect in insulin-mediated control of glucose metabolism in tissues — prominently in muscle, fat and liver — is one of the earliest manifestations of a constellation of human diseases that includes type 2 diabetes and cardiovascular disease. These diseases are typically associated with intertwined metabolic abnormalities, including obesity, hyperinsulinaemia, hyperglycaemia and hyperlipidaemia. Insulin resistance is caused by a combination of genetic and environmental factors. Recent genetic and biochemical studies suggest a key role for adipose tissue in the development of insulin resistance, potentially by releasing lipids and other circulating factors that promote insulin resistance in other organs. These extracellular factors perturb the intracellular concentration of a range of intermediates, including ceramide and other lipids, leading to defects in responsiveness of cells to insulin. Such intermediates may cause insulin resistance by inhibiting one or more of the proximal components in the signalling cascade downstream of insulin (insulin receptor, insulin receptor substrate (IRS) proteins or AKT). However, there is now evidence to support the view that insulin resistance is a heterogeneous disorder that may variably arise in a range of metabolic tissues and that the mechanism for this effect likely involves a unified insulin resistance pathway that affects a distal step in the insulin action pathway that is more closely linked to the terminal biological response. Identifying these targets is of major importance, as it will reveal potential new targets for treatments of diseases associated with insulin resistance. Insulin resistance is one of the earliest manifestations of several human diseases, including type 2 diabetes and cardiovascular disease. This Review discusses the causes of insulin resistance and recent insights into the underlying mechanisms, providing directions for the development of novel therapeutic strategies
133 citations
TL;DR: It is confirmed in a clinical cohort, that lower serum concentrations of HCA species were associated with diabetes and closely related to glycemic markers.
122 citations
TL;DR: In this article, a randomized clinical trial was conducted at 15 centers in the US (enrollment from July 30, 2018, to October 30, 2019; follow-up completed July 7, 2020) and included adults with type 2 diabetes receiving their diabetes care from a primary care clinician.
Abstract: Importance Continuous glucose monitoring (CGM) has been shown to be beneficial for adults with type 2 diabetes using intensive insulin therapy, but its use in type 2 diabetes treated with basal insulin without prandial insulin has not been well studied. Objective To determine the effectiveness of CGM in adults with type 2 diabetes treated with basal insulin without prandial insulin in primary care practices. Design, Setting, and Participants This randomized clinical trial was conducted at 15 centers in the US (enrollment from July 30, 2018, to October 30, 2019; follow-up completed July 7, 2020) and included adults with type 2 diabetes receiving their diabetes care from a primary care clinician and treated with 1 or 2 daily injections of long- or intermediate-acting basal insulin without prandial insulin, with or without noninsulin glucose-lowering medications. Interventions Random assignment 2:1 to CGM (n = 116) or traditional blood glucose meter (BGM) monitoring (n = 59). Main Outcomes and Measures The primary outcome was hemoglobin A1c(HbA1c) level at 8 months. Key secondary outcomes were CGM-measured time in target glucose range of 70 to 180 mg/dL, time with glucose level at greater than 250 mg/dL, and mean glucose level at 8 months. Results Among 175 randomized participants (mean [SD] age, 57 [9] years; 88 women [50%]; 92 racial/ethnic minority individuals [53%]; mean [SD] baseline HbA1clevel, 9.1% [0.9%]), 165 (94%) completed the trial. Mean HbA1clevel decreased from 9.1% at baseline to 8.0% at 8 months in the CGM group and from 9.0% to 8.4% in the BGM group (adjusted difference, −0.4% [95% CI, −0.8% to −0.1%];P = .02). In the CGM group, compared with the BGM group, the mean percentage of CGM-measured time in the target glucose range of 70 to 180 mg/dL was 59% vs 43% (adjusted difference, 15% [95% CI, 8% to 23%];P Conclusions and Relevance Among adults with poorly controlled type 2 diabetes treated with basal insulin without prandial insulin, continuous glucose monitoring, as compared with blood glucose meter monitoring, resulted in significantly lower HbA1clevels at 8 months. Trial Registration ClinicalTrials.gov Identifier:NCT03566693
120 citations
TL;DR: In this paper, the authors highlight the potential mechanisms behind obesity-associated insulin resistance and suggest that the liver is the most sensitive organ undergoing insulin impairment faster than other organs, and thus, hepatic insulin resistance is the primary event that leads to the subsequent development of peripheral tissue insulin resistance.
119 citations
TL;DR: The role of SGK-1 in the pathogenesis of increased vascular stiffness and impaired vascular relaxation and vascular stiffness in the cardiometabolic syndrome (CMS) and obesity is examined in this paper.
Abstract: The cardiometabolic syndrome (CMS) and obesity are typically characterized by a state of metabolic insulin resistance. As global and US rates of obesity increase there is an acceleration of the incidence and prevalence of insulin resistance along with associated cardiovascular disease (CVD). Under physiological conditions insulin regulates glucose homeostasis by enhancing glucose disposal in insulin sensitive tissues while also regulating delivery of nutrients through its vasodilation actions on small feed arteries. Specifically, insulin-mediated production of nitric oxide (NO) from the vascular endothelium leads to increased blood flow enhancing disposal of glucose. Typically, insulin resistance is considered as a decrease in sensitivity or responsiveness to the metabolic actions of insulin including insulin-mediated glucose disposal. However, a decreased sensitivity to the normal vascular actions of insulin, especially diminished nitric oxide production, plays an additional important role in the development of CVD in states of insulin resistance. One mechanism by which insulin resistance and attendant hyperinsulinemia promote CVD is via increases in vascular stiffness. Although obesity and insulin resistance are known to be associated with substantial increases in the prevalence of vascular fibrosis and stiffness the mechanisms and mediators that underlie vascular stiffening in insulin resistant states are complex and have only recently begun to be addressed. Current evidence supports the role of increased plasma levels of aldosterone and insulin and attendant reductions in bioavailable NO in the pathogenesis of impaired vascular relaxation and vascular stiffness in the CMS and obesity. Aldosterone and insulin both increase the activity of serum and glucocorticoid kinase 1 (SGK-1) which in turn is a major regulator of vascular and renal sodium (Na+) channel activity.The importance of SGK-1 in the pathogenesis of the CMS is highlighted by observations that gain of function mutations in SGK-1 in humans promotes hypertension, insulin resistance and obesity. In endothelial cells, an increase in Na+ flux contributes to remodeling of the cytoskeleton, reduced NO bioavailability and vascular stiffening. Thus, endothelial SGK-1 may represent a point of convergence for insulin and aldosterone signaling in arterial stiffness associated with obesity and the CMS. This review examines our contemporary understanding of the link between insulin resistance and increased vascular stiffness with emphasis placed on a role for enhanced SGK-1 signaling as a key node in this pathological process.
115 citations
TL;DR: The role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, was discussed in this article.
Abstract: Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target. The cellular consequences of dysfunctional autophagy contribute to numerous diseases. In this Review, Kitada and Koya consider the relationship between impaired autophagy and age-related metabolic derangements, including insulin resistance, type 2 diabetes mellitus and sarcopenic obesity, and discuss candidate autophagy-based therapies.
109 citations
TL;DR: Investigation of patients with COVID-19 and T2D from a cohort of 3,305 cases from Wuhan, China found that insulin treatment was associated with a significant increase in mortality, and insulin treatmentwas associated with enhanced systemic inflammation and aggravated injuries of vital organs.
101 citations
TL;DR: This paper showed that miR-690 is highly expressed in M2 BMDM exosomes and functions as an insulin sensitizer both in vivo and in vitro, which could be a new therapeutic insulin-sensitizing agent for metabolic disease.
TL;DR: Shapiro et al. as discussed by the authors evaluated the safety and efficacy of pancreatic endoderm cells (PECs) implanted in non-immunoprotective macroencapsulation devices for the treatment of type 1 diabetes.
TL;DR: In this article, a screen of glucoregulatory hormones revealed lower levels of adiponectin in patients with acute respiratory distress syndrome (ARDS) and COVID-19 status.
TL;DR: Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide and was only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
Abstract: CONTEXT Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. OBJECTIVE Explore mechanisms of glucose control by tirzepatide. DESIGN Post hoc analyses of fasting biomarkers and multiple linear regression analysis. SETTING Forty-seven sites in 4 countries. PATIENTS OR OTHER PARTICIPANTS Three hundred and sixteen subjects with type 2 diabetes. INTERVENTIONS Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. MAIN OUTCOME MEASURES Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. RESULTS Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. CONCLUSIONS Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.
TL;DR: This review summarizes available evidence on this topic, in order to better understand the complex relationships linking hyperandrogenism and impaired insulin action in women with PCOS.
Abstract: PCOS is a common and heterogeneous endocrine disorder in women of reproductive age, frequently associated with metabolic abnormalities. It was estimated that about 75% of these subjects have an impairment of insulin action, as measured by gold standard methods. While the relationship between insulin resistance and PCOS is consistently shown by a number of studies, the mechanisms underlying its primary origin still remains an unsolved issue. Insulin resistance and the associated hyperinsulinemia can induce both the endocrine and reproductive traits of PCOS. However, androgen excess, in turn, can impair insulin action, directly and/or through several changes occurring in different tissues. Body fat excess, which is another common feature in these women, can contribute to worsening the whole picture. Nevertheless, insulin resistance may also be found in many normal-weight individuals. Endocrine and metabolic abnormalities can develop in different moments, and probably there is fetal programming of these alterations. However, a number of vicious circles, with bidirectional relationships between androgen excess and insulin resistance, and with the contribution of several other factors, make it extremely difficult to understand where this process really originates. This review summarizes available evidence on this topic, in order to better understand the complex relationships linking hyperandrogenism and impaired insulin action in women with PCOS.
TL;DR: A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective GIP-based diabetes drugs as discussed by the authors, which will be helpful tools to shed light on the open questions.
Abstract: The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to "isoglycaemic" intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and-in the long run-body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH2 ) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.
TL;DR: In this paper, the authors discuss the discoveries that have led to the current understanding of how insulin promotes glucose uptake in muscle, and touch upon insulin access to muscle and insulin signaling toward glycogen, lipid, and protein metabolism.
DOI•
02 Dec 2021
TL;DR: In this article, a first-in-human phase 1/2, open-label study provided proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion.
Abstract: Summary These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3–12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants.
TL;DR: In this paper, the effect of quercetin on the improvement of the signs of MetS, including elevated glucose level, hyperlipidemia, obesity, and blood pressure, is discussed.
Abstract: Metabolic syndrome (MetS) is a complex of diseases that lead to mortality due to the development of cardiovascular problems. Quercetin, as an important flavonoid, has various properties such as decreasing blood pressure, anti-hyperlipidemia, anti-hyperglycemia, anti-oxidant, antiviral, anticancer, anti-inflammatory, anti-microbial, neuroprotective, and cardio-protective effects. In this review article, we collected original articles from different sources such as Google Scholar, Medline, Scopus, and Pubmed, which is related to the effect of quercetin on the improvement of the signs of MetS, including elevated glucose level, hyperlipidemia, obesity, and blood pressure. According to these data, quercetin may also have a role in the management of metabolic disorders via different mechanisms such as increasing adiponectin, decreasing leptin, anti-oxidant activity, reduction of insulin resistance, the elevation of insulin level, and blocking of calcium channel. We have attempted to make some recommendations on the quercetin application in patients. However, it needs to do further clinical trials and more investigations to show the real clinical value of quercetin on metabolic syndrome.
01 Jul 2021
TL;DR: In this paper, the authors examined associations of Gut microbiome composition with insulin resistance and type 2 diabetes in a large population-based setting controlling for various sociodemographic and lifestyle factors and found that higher microbiome α diversity, along with more butyrate-producing gut bacteria, was associated with less Type 2 diabetes and with lower insulin resistance among individuals without diabetes.
Abstract: Importance Previous studies have indicated that gut microbiome may be associated with development of type 2 diabetes. However, these studies are limited by small sample size and insufficient for confounding. Furthermore, which specific taxa play a role in the development of type 2 diabetes remains unclear. Objective To examine associations of gut microbiome composition with insulin resistance and type 2 diabetes in a large population-based setting controlling for various sociodemographic and lifestyle factors. Design, setting, and participants This cross-sectional analysis included 2166 participants from 2 Dutch population-based prospective cohorts: the Rotterdam Study and the LifeLines-DEEP study. Exposures The 16S ribosomal RNA method was used to measure microbiome composition in stool samples collected between January 1, 2012, and December 31, 2013. The α diversity (Shannon, richness, and Inverse Simpson indexes), β diversity (Bray-Curtis dissimilarity matrix), and taxa (from domain to genus level) were identified to reflect gut microbiome composition. Main outcomes and measures Associations among α diversity, β diversity, and taxa with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and with type 2 diabetes were examined. Glucose and insulin were measured to calculate the HOMA-IR. Type 2 diabetes cases were identified based on glucose levels and medical records from January 2012 to December 2013. Analyses were adjusted for technical covariates, lifestyle, sociodemographic, and medical factors. Data analysis was performed from January 1, 2018, to December 31, 2020. Results There were 2166 participants in this study: 1418 from the Rotterdam Study (mean [SD] age, 62.4 [5.9] years; 815 [57.5%] male) and 748 from the LifeLines-DEEP study (mean [SD] age, 44.7 [13.4] years; 431 [57.6%] male); from this total, 193 type 2 diabetes cases were identified. Lower microbiome Shannon index and richness were associated with higher HOMA-IR (eg, Shannon index, -0.06; 95% CI, -0.10 to -0.02), and patients with type 2 diabetes had a lower richness than participants without diabetes (odds ratio [OR], 0.93; 95% CI, 0.88-0.99). The β diversity (Bray-Curtis dissimilarity matrix) was associated with insulin resistance (R2 = 0.004, P = .001 in the Rotterdam Study and R2 = 0.005, P = .002 in the LifeLines-DEEP study). A total of 12 groups of bacteria were associated with HOMA-IR or type 2 diabetes. Specifically, a higher abundance of Christensenellaceae (β = -0.08; 95% CI, -0.12 to -0.03: P Conclusions and relevance In this cross-sectional study, higher microbiome α diversity, along with more butyrate-producing gut bacteria, was associated with less type 2 diabetes and with lower insulin resistance among individuals without diabetes. These findings could help provide insight into the etiology, pathogenesis, and treatment of type 2 diabetes.
TL;DR: This review provides an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discusses Alzheimer's disease, one of the neurologic diseases most closely associated withbrain insulin resistance.
Abstract: Background The brain was once thought of as an insulin-insensitive organ. We now know that the insulin receptor is present throughout the brain and serves important functions in whole-body metabolism and brain function. Brain insulin signaling is involved not only in brain homeostatic processes but also neuropathological processes such as cognitive decline and Alzheimer's disease. Scope of review In this review, we provide an overview of insulin signaling within the brain and the metabolic impact of brain insulin resistance and discuss Alzheimer's disease, one of the neurologic diseases most closely associated with brain insulin resistance. Major conclusions While brain insulin signaling plays only a small role in central nervous system glucose regulation, it has a significant impact on the brain's metabolic health. Normal insulin signaling is important for mitochondrial functioning and normal food intake. Brain insulin resistance contributes to obesity and may also play an important role in neurodegeneration.
TL;DR: In this paper, the authors assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses.
Abstract: Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
TL;DR: Tirzepatide (LY3298176) is a dual GIP and GLP 1 receptor (GLP-1R) agonist, which delivered superior glycemic control and weight loss compared with GLP- 1R agonism in patients with type 2 diabetes.
Abstract: Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
TL;DR: In this article, the authors investigated the role of branched-chain amino acids (BCAA) in the development of type 2 diabetes (T2D) and other cardiometabolic diseases.
Abstract: Background A strong association of obesity and insulin resistance with increased circulating levels of branched-chain and aromatic amino acids and decreased glycine levels has been recognized in human subjects for decades. Scope of review More recently, human metabolomics and genetic studies have confirmed and expanded upon these observations, accompanied by a surge in preclinical studies that have identified mechanisms involved in the perturbation of amino acid homeostasis— how these events are connected to dysregulated glucose and lipid metabolism, and how elevations in branched-chain amino acids (BCAA) may participate in the development of insulin resistance, type 2 diabetes (T2D), and other cardiometabolic diseases and conditions. Major conclusions In human cohorts, BCAA and related metabolites are now well established as among the strongest biomarkers of obesity, insulin resistance, T2D, and cardiovascular diseases. Lowering of BCAA and branched-chain ketoacid (BCKA) levels by feeding BCAA-restricted diet or by the activation of the rate-limiting enzyme in BCAA catabolism, branched-chain ketoacid dehydrogenase (BCKDH), in rodent models of obesity have clear salutary effects on glucose and lipid homeostasis, but BCAA restriction has more modest effects in short-term studies in human T2D subjects. Feeding of rats with diets enriched in sucrose or fructose result in the induction of the ChREBP transcription factor in the liver to increase expression of the BCKDH kinase (BDK) and suppress the expression of its phosphatase (PPM1K) resulting in the inactivation of BCKDH and activation of the key lipogenic enzyme ATP-citrate lyase (ACLY). These and other emergent links between BCAA, glucose, and lipid metabolism motivate ongoing studies of possible causal actions of BCAA and related metabolites in the development of cardiometabolic diseases.
TL;DR: Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism.
Abstract: Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD+ ) via the 'salvage pathway'. In addition to playing a key role as a mitochondrial co-factor, NAD+ metabolites may contribute to the increase in GSIS (via enhanced Ca++ mobilization). Imeglimin has also been shown to preserve β-cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon-like peptide-1 receptor agonists.
TL;DR: Wang et al. as discussed by the authors provided an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy.
Abstract: Coronavirus disease 2019 (COVID-19), triggered by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), may lead to extrapulmonary manifestations like diabetes mellitus (DM) and hyperglycemia, both predicting a poor prognosis and an increased risk of death. SARS-CoV-2 infects the pancreas through angiotensin-converting enzyme 2 (ACE2), where it is highly expressed compared to other organs, leading to pancreatic damage with subsequent impairment of insulin secretion and development of hyperglycemia even in non-DM patients. Thus, this review aims to provide an overview of the potential link between COVID-19 and hyperglycemia as a risk factor for DM development in relation to DM pharmacotherapy. For that, a systematic search was done in the database of MEDLINE through Scopus, Web of Science, PubMed, Embase, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), and Wanfang Data. Data obtained underline that SARS-CoV-2 infection in DM patients is more severe and associated with poor clinical outcomes due to preexistence of comorbidities and inflammation disorders. SARS-CoV-2 infection impairs glucose homeostasis and metabolism in DM and non-DM patients due to cytokine storm (CS) development, downregulation of ACE2, and direct injury of pancreatic β-cells. Therefore, the potent anti-inflammatory effect of diabetic pharmacotherapies such as metformin, pioglitazone, sodium-glucose co-transporter-2 inhibitors (SGLT2Is), and dipeptidyl peptidase-4 (DPP4) inhibitors may mitigate COVID-19 severity. In addition, some antidiabetic agents and also insulin may reduce SARS-CoV-2 infectivity and severity through the modulation of the ACE2 receptor expression. The findings presented here illustrate that insulin therapy might seem as more appropriate than other anti-DM pharmacotherapies in the management of COVID-19 patients with DM due to low risk of uncontrolled hyperglycemia and diabetic ketoacidosis (DKA). From these findings, we could not give the final conclusion about the efficacy of diabetic pharmacotherapy in COVID-19; thus, clinical trial and prospective studies are warranted to confirm this finding and concern.
TL;DR: It is demonstrated that reductive TCA cycle flux also produces stimulus-secretion coupling factors that regulate insulin secretion, including in non-dividing cells.
TL;DR: The KD regulates the level of glucose sugar and insulin and can thus claim to be an effective diabetes approach, and a stopgap between obesity and diabetes treatment can also be evidenced by KD.
TL;DR: In this article, the authors used human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway.
Abstract: Insulin resistance is one of the earliest defects in the pathogenesis of type 2 diabetes. Over the past 50 years, elucidation of the insulin signalling network has provided important mechanistic insights into the abnormalities of glucose, lipid and protein metabolism that underlie insulin resistance. In classical target tissues (liver, muscle and adipose tissue), insulin binding to its receptor initiates a broad signalling cascade mediated by changes in phosphorylation, gene expression and vesicular trafficking that result in increased nutrient utilisation and storage, and suppression of catabolic processes. Insulin receptors are also expressed in non-classical targets, such as the brain and endothelial cells, where it helps regulate appetite, energy expenditure, reproductive hormones, mood/behaviour and vascular function. Recent progress in cell biology and unbiased molecular profiling by mass spectrometry and DNA/RNA-sequencing has provided a unique opportunity to dissect the determinants of insulin resistance in type 2 diabetes and the metabolic syndrome; best studied are extrinsic factors, such as circulating lipids, amino acids and other metabolites and exosomal microRNAs. More challenging has been defining the cell-intrinsic factors programmed by genetics and epigenetics that underlie insulin resistance. In this regard, studies using human induced pluripotent stem cells and tissues point to cell-autonomous alterations in signalling super-networks, involving changes in phosphorylation and gene expression both inside and outside the canonical insulin signalling pathway. Understanding how these multi-layered molecular networks modulate insulin action and metabolism in different tissues will open new avenues for therapy and prevention of type 2 diabetes and its associated pathologies.
TL;DR: In the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes.
Abstract: The discovery of insulin 100 years ago and its application to the treatment of human disease in the years since have marked a major turning point in the history of medicine. The availability of purified insulin allowed for the establishment of its physiological role in the regulation of blood glucose and ketones, the determination of its amino acid sequence, and the solving of its structure. Over the last 50 years, the function of insulin has been applied into the discovery of the insulin receptor and its signaling cascade to reveal the role of impaired insulin signaling-or resistance-in the progression of type 2 diabetes. It has also become clear that insulin signaling can impact not only classical insulin-sensitive tissues, but all tissues of the body, and that in many of these tissues the insulin signaling cascade regulates unexpected physiological functions. Despite these remarkable advances, much remains to be learned about both insulin signaling and how to use this molecular knowledge to advance the treatment of type 2 diabetes and other insulin-resistant states.