RARE DISEASE
Exercise-induced hyperinsulinism
Exercise-induced hyperinsulinism
Exercise-induced hyperinsulinism
Synonyms: EIHI, Exercise-induced hyperinsulinemic hypoglycemia, Hyperinsulinism due to SLC16A1 deficiency, Hyperinsulinism due to monocarboxylate transporter 1 deficiency
Synonyms: EIHI, Exercise-induced hyperinsulinemic hypoglycemia, Hyperinsulinism due to SLC16A1 deficiency, Hyperinsulinism due to monocarboxylate transporter 1 deficiency
Synonyms: EIHI, Exercise-induced hyperinsulinemic hypoglycemia, Hyperinsulinism due to SLC16A1 deficiency, Hyperinsulinism due to monocarboxylate transporter 1 deficiency
Drug discovery
52
papers
On emerging therapies
Overview
Exercise-induced hyperinsulinism (EIHI) is a rare autosomal dominant genetic disorder characterized by inappropriate insulin secretion triggered by anaerobic exercise or pyruvate exposure, leading to hypoglycemia [1][2][6]. Mutations in the SLC16A1 gene cause overexpression of monocarboxylate transporter 1 (MCT1) in pancreatic β-cells, enabling lactate/pyruvate uptake and insulin release despite low glucose [2][16][19]. Diagnosis involves genetic testing, PET imaging, and elevated insulin during hypoglycemic episodes [1][6]. Management includes diazoxide therapy and activity modification [1][6][12].
Burden
High risk of hypoglycemia-induced seizures, neurodevelopmental impairment, or brain injury without prompt treatment [1][12].
Lifelong medication adherence challenges and lifestyle limitations impact quality of life [1][7].
Financial/psychological strain due to rare disease management and genetic testing barriers [1][12].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
52 drug discovery papers about Exercise-induced hyperinsulinism. Recent publications:
52 drug discovery papers about Exercise-induced hyperinsulinism. Recent publications:
categories:
Small molecules
small molecules
2026-01-26 | [Exercise-induced hyperinsulinism: genetic basis and clinical management].
Exercise-induced hyperinsulinism, also known as monocarboxylate transporter 1 hyperinsulinemia, is a rare subtype of congenital hyperinsulinism caused by gain-of-function variants in the SLC16A1 gene, which encodes monocarboxylate transporter 1. Fewer than 20 cases have been reported in the literature. In this review, the genetic pathogenesis, current diagnosis, and treatment of exercise-induced hyperinsulinism are systematically reviewed to improve clinicians' understanding of the disease.
2024-12-23 | Hypoglycaemia following physical exercise in a patient with novel SLC16A1 variant.
Rare defects in the promoter region of SLC16A1, the gene encoding monocarboxylate transporter 1 (MCT-1), result in exercise-induced hyperinsulinism. In this disorder, inappropriate insulin secretion is triggered by anaerobic exercise with consequent hypoglycaemia. We describe the case of a 41-year-old man presenting with a generalised tonic-clonic seizure and severe hypoglycaemia following strenuous exercise. A subsequent prolonged fast with incorporation of exercise into the protocol demonstrated hyperinsulinaemic hypoglycaemia; genetic testing revealed a variant of unknown significance in the SLC16A1 gene. Administration of subcutaneous octreotide resulted in dose-dependent reduction in hyperinsulinaemia and hypoglycaemia.
2021-05-28 | Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway.
Skeletal muscle is mainly responsible for insulin-stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance. We fed 6-week-old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high-fat-diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis. AX-treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX-treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic-euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA-mediated AMPK-depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK-depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise-induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.
2020-06-09 | Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis
Pancreatic beta-cells are the only cells in the body that can synthesize and secrete insulin. Through the process of glucose-stimulated insulin secretion, beta-cells release insulin into circulation, stimulating GLUT4-dependent glucose uptake into peripheral tissue. Insulin is normally secreted in pulses which allows for robust signaling at the liver. Long before type 2 diabetes is diagnosed, beta-cells become oversensitive to glucose, causing impaired pulsatility and overstimulation in fasting levels of glucose. The resulting hypersecretion of insulin can cause poor insulin signaling and clearance at the liver, leading to hyperinsulinemia and insulin resistance. Continued overactivity can eventually lead to beta-cell exhaustion and failure at which point type 2 diabetes begins. To prevent or reverse the negative effects of overstimulation, beta-cell activity can be reduced. Clinical studies have revealed the potential of beta-cell rest to reverse new cases of diabetes, but treatments lack durable benefits. In this perspective, we propose an intervention that reduces overactive glucokinase activity in the beta-cell. Glucokinase is known as the glucose sensor of the beta-cell due to its high control over insulin secretion. Therefore, glucokinase overactivity may be responsible for hyperinsulinemia early in the disease and can be inhibited to restore normal stimulus-secretion coupling. We have previously reported that reducing glucokinase activity in prediabetic mouse islets can correct glucose sensing and restore pulsatility. Building on this finding, we review the importance of pulsatile insulin secretion in the liver and beta-cell and highlight how restoring pulsatility by targeting early pathological changes in the beta cell may improve glucose homeostasis.
2019-09-06 | Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia
New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide. Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described. As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.
oligonucleotides
2023-07-18 | Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.
Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.
2012-04-13 | β-Cell–Specific Gene Repression: A Mechanism to Protect Against Inappropriate or Maladjusted Insulin Secretion?
What makes β-cells unique is their continuous responsibility to produce, store and release the required amount of insulin to keep blood glucose normal. This is no trivial task because daily insulin demands fluctuate acutely (as happens during meals) or chronically (e.g., the adaptation to obesity or pregnancy). Moreover, normal blood glucose has two borders that need continuous protection. Insufficient insulin secretion should be avoided as this leads to hyperglycemia. Moreover, insulin excess causes hypoglycemia, a situation that jeopardizes brain function. Therefore, the optimal amount of β-cell activity is needed for normal health and this depends on an adequate plasticity of the functional β-cell mass (1). This Perspective examines the idea that protection of the two borders of blood glucose requires a genetically programmed β-cell phenotype with two unique faces (Fig. 1). The first depends on transcription factors that activate expression of specific proteins that mediate β-cell function. The second face depends on β-cell–specific repression of a small set of genes. We start to understand how expression of the latter genes may impair normal β-cell function. The best examples of expression of such “disallowed” genes in β-cells lead to inappropriate insulin release (2).
FIG. 1.
A balance between two faces of the mature β-cell. The general working hypothesis in this Perspective is that the mature β-cell needs to defend both the upper and lower normal limits of circulating glucose levels, thereby preventing the occurrence of episodes of hyperglycemia and hypoglycemia. A genetically determined β-cell program is responsible for the appropriate expression level of proteins in β-cells that allow a physiological response in terms of sufficient release of insulin when the organism needs the hormone. In parallel, some genes are specifically repressed in β-cells in order to avoid situations where β-cells respond inappropriately (induction by the wrong stimuli) or in a maladjusted manner …
2011-08-01 | miR-29a and miR-29b Contribute to Pancreatic β-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1)
In pancreatic β cells, elevated glucose concentrations stimulate mitochondrial oxidative metabolism to raise intracellular ATP/ADP levels, prompting insulin secretion. Unusually low levels of expression of genes encoding the plasma membrane monocarboxylate transporter, MCT1 (SLC16A1), as well as lactate dehydrogenase A (LDHA) ensure that glucose-derived pyruvate is efficiently metabolized by mitochondria, while exogenous lactate or pyruvate is unable to stimulate metabolism and hence insulin secretion inappropriately. We show here that whereas DNA methylation at the Mct1 promoter is unlikely to be involved in cell-type-specific transcriptional repression, three microRNAs (miRNAs), miR-29a, miR-29b, and miR-124, selectively target both human and mouse MCT1 3' untranslated regions. Mutation of the cognate miR-29 or miR-124 binding sites abolishes the effects of the corresponding miRNAs, demonstrating a direct action of these miRNAs on the MCT1 message. However, despite reports of its expression in the mouse β-cell line MIN6, miR-124 was not detectably expressed in mature mouse islets. In contrast, the three isoforms of miR-29 are highly expressed and enriched in mouse islets. We show that inhibition of miR-29a in primary mouse islets increases Mct1 mRNA levels, demonstrating that miR-29 isoforms contribute to the β-cell-specific silencing of the MCT1 transporter and may thus affect insulin release.
proteins
2026-02-24 | Intramuscular neutrophil-derived immunometabolic niches locally boost insulin-responsive GLUT4 translocation after muscle contraction.
Exercise is well known to enhance insulin sensitivity in skeletal muscle, yet the underlying mechanisms remain incompletely understood. We have previously shown that neutrophil recruitment contributes to contraction-induced GLUT4 translocation and local myokine induction, but whether these immune cells also participate in the post-exercise increase in insulin sensitivity has been unclear. Here using GLUT4-EGFP transgenic mice and sciatic nerve-mediated in situ contraction of the hindlimb, with analyses focused on extensor digitorum longus (EDL) muscle, we demonstrate that neutrophil recruitment and subsequent formation of neutrophil extracellular traps (NETs) are crucial for the well-known post-exercise increase in insulin sensitivity. Two-photon imaging revealed that NET-like cell-free DNA (cfDNA) structures persisted for hours after contraction, forming spatially confined perivascular immunometabolic niches along the capillary meshwork. Strikingly insulin-stimulated GLUT4 translocation was preferentially enriched at these NET-rich sites, whereas DNase-mediated NET degradation eliminated cfDNA signals and abolished the contraction-induced enhancement of GLUT4 translocation, glucose uptake and attenuated AS160 (T642) phosphorylation under low-dose insulin. Our findings demonstrate that neutrophils are essential components of the mechanism underlying enhanced post-exercise insulin sensitivity involving, at least in part, the local formation of NETs. These NET-governed immunometabolic niches constitute a structural and spatial framework underlying the exercise-induced acute improvement of insulin-responsive metabolic efficiency in skeletal muscle. KEY POINTS: Neutrophil extracellular traps (NETs) establish spatially confined immunometabolic niches that are indispensable for the post-exercise increase in insulin sensitivity. High-resolution imaging revealed that insulin-stimulated GLUT4 translocation is markedly enhanced predominantly in NET-rich perivascular regions, indicating a spatially restricted mechanism of post-exercise insulin sensitization. DNase-mediated degradation of NETs abolished this enhancement, establishing their essential role in local insulin-responsive GLUT4 translocation. These NETs are formed by neutrophils rapidly recruited to skeletal muscle after contraction and deposited along the capillary network.
2022-03-24 | The Role of GLP-1 Signaling in Hypoglycemia due to Hyperinsulinism
Incretin hormones play an important role in the regulation of glucose homeostasis through their actions on the beta cells and other tissues. Glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are the two main incretins and are secreted by enteroendocrine L- and K-cells, respectively. New evidence suggests that incretin hormones, particularly GLP-1, play a role in the pathophysiology of hyperinsulinemic hypoglycemia. In individuals with acquired hyperinsulinemic hypoglycemia after gastrointestinal surgery, including Nissen fundoplication and gastric bypass surgery, the incretin response to a meal is markedly increased and antagonism of the GLP-1 receptor prevents the hyperinsulinemic response. In individuals with congenital hyperinsulinism due to inactivating mutations in the genes encoding the beta cell KATP channels, the GLP-1 receptor antagonist, exendin-(9-39), increases fasting plasma glucose and prevents protein-induced hypoglycemia. Studies in human and mouse islets lacking functional KATP channels have demonstrated that the effect on plasma glucose is at least in part mediated by inhibition of insulin secretion resulting from lower cytoplasmic cAMP levels. The understanding of the role of incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia is important for the exploration of the GLP-1 receptor as a therapeutic target for these conditions. In this article, we will review incretin physiology and evidence supporting a role of the incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia, as well as results from proof-of concept studies exploring a therapeutic approach targeting the GLP-1 receptor to treat hyperinsulinemic hypoglycemia.
2018-05-30 | Physical exercise increases Sestrin 2 protein levels and induces autophagy in the skeletal muscle of old mice.
Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model.
2015-02-01 | Suppression of Insulin Production and Secretion by a Decretin Hormone
Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
antibodies
2026-05-13 | Extracellular 70 kDa heat shock protein in blood plasma binds insulin and modulates glycaemic control in vivo.
The 70 kDa heat shock protein family (HSP70) preserves the three-dimensional integrity of intracellular proteins, preventing the formation of cytotoxic aggregates that activate inflammatory pathways. Both constitutive and stress-inducible HSP70 isoforms uphold proteostasis during the heat shock response (HSR), an evolutionarily conserved, anti-inflammatory mechanism that restores cellular homeostasis following proteotoxic stress and metabolic disruption. Under conditions threatening homeostasis-such as heat shock (HS) and physical exertion, in which the sympathetic nervous system is strongly activated-HSP70 may be secreted into the extracellular space, where it functions as an immunomodulator and pro-inflammatory danger signal. Chronic inflammatory conditions, including obesity and type 2 diabetes, are characterized by persistently elevated levels of extracellular HSP70 in the bloodstream, which correlate with insulin resistance and β-cell dysfunction. Notably, glucose ingestion blocks exercise-induced HSP70 secretion, suggesting a previously unrecognized role of extracellular HSP70 in modulating glycaemia via insulin binding. Here we show a novel counterregulatory mechanism in which plasma HSP70 binds insulin with high affinity (Kd ∼3 pM), impairing glucose uptake in insulin-dependent tissues without affecting receptor signaling. In fasted rats subjected to HS, elevated plasma HSP70 raises glycaemia by ∼3 mM during glucose tolerance tests (at 30 min), enhancing glucose availability for non-insulin-dependent tissues. HS-induced glucose intolerance peaks 12 h post-HS in an HSP70-interacting protein (HIP)-dependent manner. However, HS enhances the insulinogenic index (IGI) and insulin sensitivity, peaking at 24 h. This observation challenges the paradigm that HSP70 functions to chaperone proteins solely intracellularly, revealing its role in extracellular glycaemic regulation by HIP-assisted protein-protein interactions in blood plasma, thus offering a novel clinical viewpoint in glycaemic management. These findings suggest that humanized anti-HSP70 monoclonal antibodies could mitigate insulin sequestration and offer a novel therapeutic strategy to restore insulin sensitivity, thereby improving metabolic outcomes in conditions with elevated plasma HSP70, such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and cardiovascular disease.
2021-04-22 | Non-canonical mitochondrial STAT3 signaling mediates exercise-induced insulin secretion down-regulation
ABSTRACT Chronic exercise protects pancreatic beta cells from diabetogenic stress, reducing insulin secretion through unknown mechanisms. We tested the hypothesis that the IL-6/mitochondrial STAT3 (pS-STAT3) axis plays a role in this protective effect. C57BL/6N mice were subjected to endurance training ahead of pancreatic islet isolation and functional analysis. Similar in vitro experiments were performed using insulin-producing INS-1E cells and islets from untrained mice, cultured with serum from trained animals and treated with or without an IL-6 receptor (IL-6R) inhibitor. Then, IL-6R/pS-STAT3 pathway activation and its effects on mitochondrial function and insulin secretion were assessed. Exercise-induced down-regulation of insulin secretion was prevented by inhibition of IL-6R signaling and following STAT3 knockdown. IL-6R activation promoted STAT3 phosphorylation and translocation to the mitochondria, increasing oxygen consumption. Accordingly, lower H2O2 content was reported in islets from trained mice and beta cells exposed to exercise-conditioned serum, while exposure to exogenous H2O2 blocked the down-regulatory effect of training on insulin secretion. Similar findings were observed in islets from obese-trained mice. Together, these findings suggest that the IL-6R/pS-STAT3 axis mediates exercise-induced down-regulation of insulin secretion through modulation of the mitochondrial redox state.
other
2022-02-23 | Exercise-Induced Improvement in Insulin-Stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wild-Type AS160.
One exercise session can elevate insulin-stimulated glucose uptake (ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic approaches to rigorously test this idea. The initial experiment evaluated the role of AS160 in postexercise increase in ISGU using muscles from male wild-type (WT) and AS160-knockout (KO) rats. The next experiment used AS160-KO rats with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160 deficiency could restore the ability of exercise to improve ISGU. The third experiment tested if eliminating the muscle GLUT4 deficit in AS160-KO rats via AAV-delivered GLUT4 would enable postexercise enhancement of ISGU. The final experiment used AS160-KO rats and AAV delivery of AS160 mutated to prevent phosphorylation of Ser588, Thr642, and Ser704 to evaluate their role in postexercise ISGU. We discovered the following: 1) AS160 expression was essential for postexercise increase in ISGU; 2) rescuing muscle AS160 expression of AS160-KO rats restored postexercise enhancement of ISGU; 3) restoring GLUT4 expression in AS160-KO muscle did not rescue the postexercise increase in ISGU; and 4) although AS160 phosphorylation on three key sites was not required for postexercise elevation in ISGU, it was essential for the full exercise effect.
small molecules
2026-01-26 | [Exercise-induced hyperinsulinism: genetic basis and clinical management].
Exercise-induced hyperinsulinism, also known as monocarboxylate transporter 1 hyperinsulinemia, is a rare subtype of congenital hyperinsulinism caused by gain-of-function variants in the SLC16A1 gene, which encodes monocarboxylate transporter 1. Fewer than 20 cases have been reported in the literature. In this review, the genetic pathogenesis, current diagnosis, and treatment of exercise-induced hyperinsulinism are systematically reviewed to improve clinicians' understanding of the disease.
2024-12-23 | Hypoglycaemia following physical exercise in a patient with novel SLC16A1 variant.
Rare defects in the promoter region of SLC16A1, the gene encoding monocarboxylate transporter 1 (MCT-1), result in exercise-induced hyperinsulinism. In this disorder, inappropriate insulin secretion is triggered by anaerobic exercise with consequent hypoglycaemia. We describe the case of a 41-year-old man presenting with a generalised tonic-clonic seizure and severe hypoglycaemia following strenuous exercise. A subsequent prolonged fast with incorporation of exercise into the protocol demonstrated hyperinsulinaemic hypoglycaemia; genetic testing revealed a variant of unknown significance in the SLC16A1 gene. Administration of subcutaneous octreotide resulted in dose-dependent reduction in hyperinsulinaemia and hypoglycaemia.
2021-05-28 | Astaxanthin stimulates mitochondrial biogenesis in insulin resistant muscle via activation of AMPK pathway.
Skeletal muscle is mainly responsible for insulin-stimulated glucose disposal. Dysfunction in skeletal muscle metabolism especially during obesity contributes to the insulin resistance. Astaxanthin (AX), a natural antioxidant, has been shown to ameliorate hepatic insulin resistance in obese mice. However, its effects in skeletal muscle are poorly understood. The current study aimed to investigate the molecular target of AX in ameliorating skeletal muscle insulin resistance. We fed 6-week-old male C57BL/6J mice with normal chow (NC) or NC supplemented with AX (NC+AX) and high-fat-diet (HFD) or HFD supplemented with AX for 24 weeks. We determined the effect of AX on various parameters including insulin sensitivity, glucose uptake, inflammation, kinase signaling, gene expression, and mitochondrial function in muscle. We also determined energy metabolism in intact C2C12 cells treated with AX using the Seahorse XFe96 Extracellular Flux Analyzer and assessed the effect of AX on mitochondrial oxidative phosphorylation and mitochondrial biogenesis. AX-treated HFD mice showed improved metabolic status with significant reduction in blood glucose, serum total triglycerides, and cholesterol (p< 0.05). AX-treated HFD mice also showed improved glucose metabolism by enhancing glucose incorporation into peripheral target tissues, such as the skeletal muscle, rather than by suppressing gluconeogenesis in the liver as shown by hyperinsulinemic-euglycemic clamp study. AX activated AMPK in the skeletal muscle of the HFD mice and upregulated the expressions of transcriptional factors and coactivator, thereby inducing mitochondrial remodeling, including increased mitochondrial oxidative phosphorylation component and free fatty acid metabolism. We also assessed the effects of AX on mitochondrial biogenesis in the siRNA-mediated AMPK-depleted C2C12 cells and showed that the effect of AX was lost in the genetically AMPK-depleted C2C12 cells. Collectively, AX treatment (i) significantly ameliorated insulin resistance and glucose intolerance through regulation of AMPK activation in the muscle, (ii) stimulated mitochondrial biogenesis in the muscle, (iii) enhanced exercise tolerance and exercise-induced fatty acid metabolism, and (iv) exerted antiinflammatory effects via its antioxidant activity in adipose tissue. We concluded that AX treatment stimulated mitochondrial biogenesis and significantly ameliorated insulin resistance through activation of AMPK pathway in the skeletal muscle.
2020-06-09 | Reducing Glucokinase Activity to Enhance Insulin Secretion: A Counterintuitive Theory to Preserve Cellular Function and Glucose Homeostasis
Pancreatic beta-cells are the only cells in the body that can synthesize and secrete insulin. Through the process of glucose-stimulated insulin secretion, beta-cells release insulin into circulation, stimulating GLUT4-dependent glucose uptake into peripheral tissue. Insulin is normally secreted in pulses which allows for robust signaling at the liver. Long before type 2 diabetes is diagnosed, beta-cells become oversensitive to glucose, causing impaired pulsatility and overstimulation in fasting levels of glucose. The resulting hypersecretion of insulin can cause poor insulin signaling and clearance at the liver, leading to hyperinsulinemia and insulin resistance. Continued overactivity can eventually lead to beta-cell exhaustion and failure at which point type 2 diabetes begins. To prevent or reverse the negative effects of overstimulation, beta-cell activity can be reduced. Clinical studies have revealed the potential of beta-cell rest to reverse new cases of diabetes, but treatments lack durable benefits. In this perspective, we propose an intervention that reduces overactive glucokinase activity in the beta-cell. Glucokinase is known as the glucose sensor of the beta-cell due to its high control over insulin secretion. Therefore, glucokinase overactivity may be responsible for hyperinsulinemia early in the disease and can be inhibited to restore normal stimulus-secretion coupling. We have previously reported that reducing glucokinase activity in prediabetic mouse islets can correct glucose sensing and restore pulsatility. Building on this finding, we review the importance of pulsatile insulin secretion in the liver and beta-cell and highlight how restoring pulsatility by targeting early pathological changes in the beta cell may improve glucose homeostasis.
2019-09-06 | Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia
New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide. Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described. As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.
oligonucleotides
2023-07-18 | Transthyretin knockdown recapitulates the insulin-sensitizing effects of exercise and promotes skeletal muscle adaptation to exercise endurance.
Liver transthyretin (TTR) synthesis and release are exacerbated in insulin-resistant states but are decreased by exercise training, in relation to the insulin-sensitizing effects of exercise. We hypothesized that TTR knockdown (TTR-KD) may mimic this exercise-induced metabolic improvement and skeletal muscle remodeling. Adeno-associated virus-mediated TTR-KD and control mice were trained for 8 weeks on treadmills. Their metabolism status and exercise capacity were investigated and then compared with sedentary controls. After treadmill training, the mice showed improved glucose and insulin tolerance, hepatic steatosis, and exercise endurance. Sedentary TTR-KD mice displayed metabolic improvements comparable to the improvements in trained mice. Both exercise training and TTR-KD promoted the oxidative myofiber compositions of MyHC I and MyHC IIa in the quadriceps and gastrocnemius skeletal muscles. Furthermore, training and TTR-KD had an additive effect on running performance, accompanied by substantial increases in oxidative myofiber composition, Ca2+-dependent Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, and the downstream expression of PGC1α as well as the unfolded protein response (UPR) segment of PERK-p-eIF2a pathway activity. Consistent with these findings, electrical pulse stimulation of an in vitro model of chronic exercise (with differentiated C2C12 myoblasts) showed that exogenous TTR protein was internalized and localized in the endoplasmic reticulum, where it disrupted Ca2+ dynamics; this led to decreases in intracellular Ca2+ concentration and downstream pathway activity. TTR-KD may function as an exercise/Ca2+-dependent CaMKII-PGC1α-UPR regulator that upregulates the oxidative myofiber composition of fast-type muscles; it appears to mimic the effect of exercise training on insulin sensitivity-related metabolic improvement and endurance capacity.
2012-04-13 | β-Cell–Specific Gene Repression: A Mechanism to Protect Against Inappropriate or Maladjusted Insulin Secretion?
What makes β-cells unique is their continuous responsibility to produce, store and release the required amount of insulin to keep blood glucose normal. This is no trivial task because daily insulin demands fluctuate acutely (as happens during meals) or chronically (e.g., the adaptation to obesity or pregnancy). Moreover, normal blood glucose has two borders that need continuous protection. Insufficient insulin secretion should be avoided as this leads to hyperglycemia. Moreover, insulin excess causes hypoglycemia, a situation that jeopardizes brain function. Therefore, the optimal amount of β-cell activity is needed for normal health and this depends on an adequate plasticity of the functional β-cell mass (1). This Perspective examines the idea that protection of the two borders of blood glucose requires a genetically programmed β-cell phenotype with two unique faces (Fig. 1). The first depends on transcription factors that activate expression of specific proteins that mediate β-cell function. The second face depends on β-cell–specific repression of a small set of genes. We start to understand how expression of the latter genes may impair normal β-cell function. The best examples of expression of such “disallowed” genes in β-cells lead to inappropriate insulin release (2).
FIG. 1.
A balance between two faces of the mature β-cell. The general working hypothesis in this Perspective is that the mature β-cell needs to defend both the upper and lower normal limits of circulating glucose levels, thereby preventing the occurrence of episodes of hyperglycemia and hypoglycemia. A genetically determined β-cell program is responsible for the appropriate expression level of proteins in β-cells that allow a physiological response in terms of sufficient release of insulin when the organism needs the hormone. In parallel, some genes are specifically repressed in β-cells in order to avoid situations where β-cells respond inappropriately (induction by the wrong stimuli) or in a maladjusted manner …
2011-08-01 | miR-29a and miR-29b Contribute to Pancreatic β-Cell-Specific Silencing of Monocarboxylate Transporter 1 (Mct1)
In pancreatic β cells, elevated glucose concentrations stimulate mitochondrial oxidative metabolism to raise intracellular ATP/ADP levels, prompting insulin secretion. Unusually low levels of expression of genes encoding the plasma membrane monocarboxylate transporter, MCT1 (SLC16A1), as well as lactate dehydrogenase A (LDHA) ensure that glucose-derived pyruvate is efficiently metabolized by mitochondria, while exogenous lactate or pyruvate is unable to stimulate metabolism and hence insulin secretion inappropriately. We show here that whereas DNA methylation at the Mct1 promoter is unlikely to be involved in cell-type-specific transcriptional repression, three microRNAs (miRNAs), miR-29a, miR-29b, and miR-124, selectively target both human and mouse MCT1 3' untranslated regions. Mutation of the cognate miR-29 or miR-124 binding sites abolishes the effects of the corresponding miRNAs, demonstrating a direct action of these miRNAs on the MCT1 message. However, despite reports of its expression in the mouse β-cell line MIN6, miR-124 was not detectably expressed in mature mouse islets. In contrast, the three isoforms of miR-29 are highly expressed and enriched in mouse islets. We show that inhibition of miR-29a in primary mouse islets increases Mct1 mRNA levels, demonstrating that miR-29 isoforms contribute to the β-cell-specific silencing of the MCT1 transporter and may thus affect insulin release.
proteins
2026-02-24 | Intramuscular neutrophil-derived immunometabolic niches locally boost insulin-responsive GLUT4 translocation after muscle contraction.
Exercise is well known to enhance insulin sensitivity in skeletal muscle, yet the underlying mechanisms remain incompletely understood. We have previously shown that neutrophil recruitment contributes to contraction-induced GLUT4 translocation and local myokine induction, but whether these immune cells also participate in the post-exercise increase in insulin sensitivity has been unclear. Here using GLUT4-EGFP transgenic mice and sciatic nerve-mediated in situ contraction of the hindlimb, with analyses focused on extensor digitorum longus (EDL) muscle, we demonstrate that neutrophil recruitment and subsequent formation of neutrophil extracellular traps (NETs) are crucial for the well-known post-exercise increase in insulin sensitivity. Two-photon imaging revealed that NET-like cell-free DNA (cfDNA) structures persisted for hours after contraction, forming spatially confined perivascular immunometabolic niches along the capillary meshwork. Strikingly insulin-stimulated GLUT4 translocation was preferentially enriched at these NET-rich sites, whereas DNase-mediated NET degradation eliminated cfDNA signals and abolished the contraction-induced enhancement of GLUT4 translocation, glucose uptake and attenuated AS160 (T642) phosphorylation under low-dose insulin. Our findings demonstrate that neutrophils are essential components of the mechanism underlying enhanced post-exercise insulin sensitivity involving, at least in part, the local formation of NETs. These NET-governed immunometabolic niches constitute a structural and spatial framework underlying the exercise-induced acute improvement of insulin-responsive metabolic efficiency in skeletal muscle. KEY POINTS: Neutrophil extracellular traps (NETs) establish spatially confined immunometabolic niches that are indispensable for the post-exercise increase in insulin sensitivity. High-resolution imaging revealed that insulin-stimulated GLUT4 translocation is markedly enhanced predominantly in NET-rich perivascular regions, indicating a spatially restricted mechanism of post-exercise insulin sensitization. DNase-mediated degradation of NETs abolished this enhancement, establishing their essential role in local insulin-responsive GLUT4 translocation. These NETs are formed by neutrophils rapidly recruited to skeletal muscle after contraction and deposited along the capillary network.
2022-03-24 | The Role of GLP-1 Signaling in Hypoglycemia due to Hyperinsulinism
Incretin hormones play an important role in the regulation of glucose homeostasis through their actions on the beta cells and other tissues. Glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are the two main incretins and are secreted by enteroendocrine L- and K-cells, respectively. New evidence suggests that incretin hormones, particularly GLP-1, play a role in the pathophysiology of hyperinsulinemic hypoglycemia. In individuals with acquired hyperinsulinemic hypoglycemia after gastrointestinal surgery, including Nissen fundoplication and gastric bypass surgery, the incretin response to a meal is markedly increased and antagonism of the GLP-1 receptor prevents the hyperinsulinemic response. In individuals with congenital hyperinsulinism due to inactivating mutations in the genes encoding the beta cell KATP channels, the GLP-1 receptor antagonist, exendin-(9-39), increases fasting plasma glucose and prevents protein-induced hypoglycemia. Studies in human and mouse islets lacking functional KATP channels have demonstrated that the effect on plasma glucose is at least in part mediated by inhibition of insulin secretion resulting from lower cytoplasmic cAMP levels. The understanding of the role of incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia is important for the exploration of the GLP-1 receptor as a therapeutic target for these conditions. In this article, we will review incretin physiology and evidence supporting a role of the incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia, as well as results from proof-of concept studies exploring a therapeutic approach targeting the GLP-1 receptor to treat hyperinsulinemic hypoglycemia.
2018-05-30 | Physical exercise increases Sestrin 2 protein levels and induces autophagy in the skeletal muscle of old mice.
Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model.
2015-02-01 | Suppression of Insulin Production and Secretion by a Decretin Hormone
Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output.
antibodies
2026-05-13 | Extracellular 70 kDa heat shock protein in blood plasma binds insulin and modulates glycaemic control in vivo.
The 70 kDa heat shock protein family (HSP70) preserves the three-dimensional integrity of intracellular proteins, preventing the formation of cytotoxic aggregates that activate inflammatory pathways. Both constitutive and stress-inducible HSP70 isoforms uphold proteostasis during the heat shock response (HSR), an evolutionarily conserved, anti-inflammatory mechanism that restores cellular homeostasis following proteotoxic stress and metabolic disruption. Under conditions threatening homeostasis-such as heat shock (HS) and physical exertion, in which the sympathetic nervous system is strongly activated-HSP70 may be secreted into the extracellular space, where it functions as an immunomodulator and pro-inflammatory danger signal. Chronic inflammatory conditions, including obesity and type 2 diabetes, are characterized by persistently elevated levels of extracellular HSP70 in the bloodstream, which correlate with insulin resistance and β-cell dysfunction. Notably, glucose ingestion blocks exercise-induced HSP70 secretion, suggesting a previously unrecognized role of extracellular HSP70 in modulating glycaemia via insulin binding. Here we show a novel counterregulatory mechanism in which plasma HSP70 binds insulin with high affinity (Kd ∼3 pM), impairing glucose uptake in insulin-dependent tissues without affecting receptor signaling. In fasted rats subjected to HS, elevated plasma HSP70 raises glycaemia by ∼3 mM during glucose tolerance tests (at 30 min), enhancing glucose availability for non-insulin-dependent tissues. HS-induced glucose intolerance peaks 12 h post-HS in an HSP70-interacting protein (HIP)-dependent manner. However, HS enhances the insulinogenic index (IGI) and insulin sensitivity, peaking at 24 h. This observation challenges the paradigm that HSP70 functions to chaperone proteins solely intracellularly, revealing its role in extracellular glycaemic regulation by HIP-assisted protein-protein interactions in blood plasma, thus offering a novel clinical viewpoint in glycaemic management. These findings suggest that humanized anti-HSP70 monoclonal antibodies could mitigate insulin sequestration and offer a novel therapeutic strategy to restore insulin sensitivity, thereby improving metabolic outcomes in conditions with elevated plasma HSP70, such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and cardiovascular disease.
2021-04-22 | Non-canonical mitochondrial STAT3 signaling mediates exercise-induced insulin secretion down-regulation
ABSTRACT Chronic exercise protects pancreatic beta cells from diabetogenic stress, reducing insulin secretion through unknown mechanisms. We tested the hypothesis that the IL-6/mitochondrial STAT3 (pS-STAT3) axis plays a role in this protective effect. C57BL/6N mice were subjected to endurance training ahead of pancreatic islet isolation and functional analysis. Similar in vitro experiments were performed using insulin-producing INS-1E cells and islets from untrained mice, cultured with serum from trained animals and treated with or without an IL-6 receptor (IL-6R) inhibitor. Then, IL-6R/pS-STAT3 pathway activation and its effects on mitochondrial function and insulin secretion were assessed. Exercise-induced down-regulation of insulin secretion was prevented by inhibition of IL-6R signaling and following STAT3 knockdown. IL-6R activation promoted STAT3 phosphorylation and translocation to the mitochondria, increasing oxygen consumption. Accordingly, lower H2O2 content was reported in islets from trained mice and beta cells exposed to exercise-conditioned serum, while exposure to exogenous H2O2 blocked the down-regulatory effect of training on insulin secretion. Similar findings were observed in islets from obese-trained mice. Together, these findings suggest that the IL-6R/pS-STAT3 axis mediates exercise-induced down-regulation of insulin secretion through modulation of the mitochondrial redox state.
other
2022-02-23 | Exercise-Induced Improvement in Insulin-Stimulated Glucose Uptake by Rat Skeletal Muscle Is Absent in Male AS160-Knockout Rats, Partially Restored by Muscle Expression of Phosphomutated AS160, and Fully Restored by Muscle Expression of Wild-Type AS160.
One exercise session can elevate insulin-stimulated glucose uptake (ISGU) in skeletal muscle, but the mechanisms remain elusive. Circumstantial evidence suggests a role for Akt substrate of 160 kDa (AS160 or TBC1D4). We used genetic approaches to rigorously test this idea. The initial experiment evaluated the role of AS160 in postexercise increase in ISGU using muscles from male wild-type (WT) and AS160-knockout (KO) rats. The next experiment used AS160-KO rats with an adeno-associated virus (AAV) approach to determine if rescuing muscle AS160 deficiency could restore the ability of exercise to improve ISGU. The third experiment tested if eliminating the muscle GLUT4 deficit in AS160-KO rats via AAV-delivered GLUT4 would enable postexercise enhancement of ISGU. The final experiment used AS160-KO rats and AAV delivery of AS160 mutated to prevent phosphorylation of Ser588, Thr642, and Ser704 to evaluate their role in postexercise ISGU. We discovered the following: 1) AS160 expression was essential for postexercise increase in ISGU; 2) rescuing muscle AS160 expression of AS160-KO rats restored postexercise enhancement of ISGU; 3) restoring GLUT4 expression in AS160-KO muscle did not rescue the postexercise increase in ISGU; and 4) although AS160 phosphorylation on three key sites was not required for postexercise elevation in ISGU, it was essential for the full exercise effect.
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