Insulin Dysregulation Research Articles

Impact of high-fructose diet and metformin on histomorphological and molecular parameters of reproductive organs and vaginal microbiota of female rat

There are limited data on the effects of a high-fructose diet on the female reproductive system. Although metformin has some functional effects on female fertility, its reproductive outcome on high fructose diet-induced metabolic syndrome is unclear. The aim of the present study is to evaluate the impact of a high fructose diet on histomorphological and molecular parameters of the reproductive organs and vaginal microbiota as well as the treatment potential of metformin. Wistar albino rats were used in the study. The metabolic syndrome model was induced by a high-fructose diet in rats for 15 weeks. Metformin was orally administered once a day for the last 6 weeks. The high-fructose diet increased blood glucose, triglycerides, insulin, and ovarian testosterone levels; however, it reduced ovarian aromatase levels and follicle numbers and caused uterine inflammation. The high-fructose diet-induced molecular abnormalities on ovarian tissue were demonstrated by the downregulation of ovarian insulin signaling pathway proteins and dysregulation of ovarian mitogenic and apoptotic pathway proteins. A high-fructose diet caused vaginal dysbiosis, metformin increased probiotic bacteria in the vaginal microbiota. Our results revealed that metformin improves ovarian impairments by modulating hormonal balance, insulin level, mapk, and apoptotic signaling molecules, as well as regulating the vaginal microbiota.

An optimized fractionation method reveals insulin-induced membrane surface localization of GLUT1 to increase glycolysis in LβT2 cells

Insulin is an important regulator of whole-body glucose homeostasis. In insulin sensitive tissues such as muscle and adipose, insulin induces the translocation of glucose transporter 4 (GLUT4) to the cell membrane, thereby increasing glucose uptake. However, insulin also signals in tissues that are not generally associated with glucose homeostasis. In the human reproductive endocrine axis, hyperinsulinemia suppresses the secretion of gonadotropins from gonadotrope cells of the anterior pituitary, thereby linking insulin dysregulation to suboptimal reproductive health. In the mouse, gonadotropes express the insulin receptor which has the canonical signaling response of IRS, AKT, and mTOR activation. However, the functional outcomes of insulin action on gonadotropes are unclear. Here, we demonstrate through use of an optimized cell fractionation protocol that insulin stimulation of the LβT2 gonadotropic cell line results in the unexpected translocation of GLUT1 to the plasma membrane. Using our high purity fractionation protocol, we further demonstrate that though Akt signaling in response to insulin is intact, insulin-induced translocation of GLUT1 occurs independently of Akt activation in LβT2 cells.

Comparison of a customized glycemic pellets challenge with the oral sugar test to measure glycemic and insulinemic responses in horses.

Testing for insulin dysregulation (ID) in horses is commonly performed to guide management and therapeutic strategies. To evaluate a newly developed glycemic pellets challenge (GPC) and compare results to those obtained using the low-dose oral sugar test (OST). Twenty-four adult horses with unknown insulin status. A randomized crossover trial was performed. Horses underwent GPC (0.5 g glycemic carbohydrates/kg body weight) and OST (0.15 mL corn syrup/kg body weight) 7 days apart. Feed was withheld before testing and blood samples were collected at T0, T60, T120, and T180 minutes for GPC and at T0, T60, and T90 minutes for OST. Blood glucose concentration was measured using a point-of-care glucometer and insulin by radioimmunoassay. Comparisons were made using nonparametric tests, linear regression, and Bland-Altman agreement analysis. Eighteen horses consumed >85% of the GPC pellets within 10 minutes and had acceptable OST results. Maximum glucose (P = .02) and insulin (P = .007) concentrations were significantly higher for GPC compared with OST. Time to maximum insulin concentration (Tmax[ins]) varied within and between tests and neither Tmax[ins] (P = .28) nor maximum insulin concentration (P = .46) was correlated with the time horses took to consume pellets. The GPC is well tolerated and may offer another diagnostic testing modality for ID. Blood glucose and insulin concentrations increase during GPC and reach higher concentrations than observed with low-dose OST. The Tmax[ins] varied for GPC and OST, emphasizing the importance of identifying the optimal time range for the collection of samples to capture diagnostically relevant changes in insulin concentration.

Nicotinamide Mononucleotide Improves Endometrial Homeostasis in a Rat Model of Polycystic Ovary Syndrome by Decreasing Insulin Resistance and Regulating the Glylytic Pathway.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can lead to insulin resistance (IR) and dysregulation of glucose metabolism, resulting in an imbalance in the endometrial environment, which is unfavorable for embryo implantation of PCOS. This study aims to investigate whether nicotinamide mononucleotide (NMN) improves the stability of the endometrium in a rat model of PCOS and identifies whether it is related to reduce IR and increase glycolysis levels and its potential signaling pathway. Female Sprague-Dawley (SD) rats are fed letrozole and a high-fat diet (HFD) to form the PCOS model, then the model rats are treated with or without NMN. It randomly divided into control, PCOS, and PCOS-NMN groups according to the feeding and treating method. Compared with the PCOS group, the regular estrous cycles are restored, the serum androgen (p<0.01) and fasting insulin levels (p<0.05) are reduced, and endometrial morphology (p<0.05) is improved in NMN-PCOS group. Furthermore, NMN inhibits endometrial cell apoptosis, improves endometrial decidualization transition, reduces IR, restores the expression of glycolysis rate-limiting enzymes, and activates the PI3K/AKT pathway in the uterus. These results suggest that NMN enhances endometrial tissue homeostasis by decreasing uterine IR and regulating the glycolysis through the PI3K/AKT pathway.

Effect of short-term dopamine reduction on insulin sensitivity and post-prandial insulin and glucose responses in Standardbred horses

The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses.

Loss of electrical β-cell to δ-cell coupling underlies impaired hypoglycaemia-induced glucagon secretion in type-1 diabetes.

Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion1. In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D)2, which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D3. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists4-7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, KATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This 'electric brake' is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk8.

Metabolomic Effects of Liraglutide Therapy on the Plasma Metabolomic Profile of Patients with Obesity.

Liraglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP1RA), is a well-established anti-diabetic drug, has also been approved for the treatment of obesity at a dose of 3 mg. There are a limited number of studies in the literature that have looked at changes in metabolite levels before and after liraglutide treatment in patients with obesity. To this end, in the present study we aimed to explore the changes in the plasma metabolomic profile, using liquid chromatography-high resolution mass spectrometry (LC-HRMS) in patients with obesity. A single-center prospective study was undertaken to evaluate the effectiveness of 3 mg liraglutide therapy in twenty-three patients (M/F: 8/15) with obesity, mean BMI 40.81 ± 5.04 kg/m2, and mean age of 36 ± 10.9 years, in two groups: at baseline (pre-treatment) and after 12 weeks of treatment (post-treatment). An untargeted metabolomic profiling was conducted in plasma from the pre-treatment and post-treatment groups using LC-HRMS, along with bioinformatics analysis using ingenuity pathway analysis (IPA). The metabolomics analysis revealed a significant (FDR p-value ≤ 0.05, FC 1.5) dysregulation of 161 endogenous metabolites (97 upregulated and 64 downregulated) with distinct separation between the two groups. Among the significantly dysregulated metabolites, the majority of them were identified as belonging to the class of oxidized lipids (oxylipins) that includes arachidonic acid and its derivatives, phosphorglycerophosphates, N-acylated amino acids, steroid hormones, and bile acids. The biomarker analysis conducted using MetaboAnalyst showed PGP (a21:0/PG/F1alpha), an oxidized lipid, as the first metabolite among the list of the top 15 biomarkers, followed by cysteine and estrone. The IPA analysis showed that the dysregulated metabolites impacted the pathway related to cell signaling, free radical scavenging, and molecular transport, and were focused around the dysregulation of NF-κB, ERK, MAPK, PKc, VEGF, insulin, and pro-inflammatory cytokine signaling pathways. The findings suggest that liraglutide treatment reduces inflammation and modulates lipid metabolism and oxidative stress. Our study contributes to a better understanding of the drug's multifaceted impact on overall metabolism in patients with obesity.

Studies in vitro of equine intestinal glucagon-like peptide-2 secretion

Equine insulin dysregulation (ID) is a significant metabolic problem because the hyperinsulinaemia that develops increases the animal's risk of developing laminitis, a debilitating foot condition. The role of gastrointestinal factors, such as incretin hormones, in the pathogenesis of ID and hyperinsulinaemia in horses is poorly understood, particularly in comparison to other species. Glucagon-like peptide-2 (GLP-2) is an intestinotrophic peptide released from L cells in the gastrointestinal tract and is implicated in metabolic dysfunction in other species. The aim of this study in vitro was to establish basic physiological understanding about intestinal secretion of GLP-2 in horses. Basal and glucose-stimulated GLP-2 secretion was measured in post-mortem tissue samples from the duodenum, jejunum, and ileum. We observed that GLP-2 secretion was minimal in samples from the duodenum compared to the jejunum and ileum (5-9-fold higher; P < 0.05). Furthermore, GLP-2 secretion was not responsive to glucose stimulation in the ileum or duodenum but was responsive to glucose in the jejunum. This effect in the jejunum was inhibited by 30 % (P = 0.02) using phlorizin, a selective sodium-glucose cotransporter-1 (SGLT-1) inhibitor, and by 38 % (P = 0.04) using phloretin, a non-selective SGLT-1/GLUT-2 inhibitor. The localisation of glucose-responsive GLP-2 secretion in the jejunum might be relevant to the development of post-prandial hyperinsulinaemia. This study has provided data on GLP-2 secretion from the equine small intestine that will enable more complex and dynamic studies on the pathogenesis of ID.

Pharmacokinetics and Alterations in Glucose and Insulin Levels After a Single Dose of Canagliflozin in Healthy Icelandic Horses.

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor that has shown promising results as a drug for the treatment of insulin dysregulation in horses. Even though CFZ is used clinically, no pharmacokinetic data has previously been published. In this study, the pharmacokinetics of CFZ after administration of a single oral dose of 1.8 mg/kg in eight healthy Icelandic horses was examined. Additionally, the effect of treatment on glucose and insulin levels in response to a graded glucose infusion was investigated. Plasma samples for CFZ quantification were taken at 0, 0.33, 0.66, 1, 1.33, 1.66, 2, 2.33, 2.66, 3, 3.5, 4, 5, 6, 8, 12, 24, 32, and 48 h post administration. CFZ was quantified using UHPLC coupled to tandem quadrupole mass spectrometry (UHPLC-MS/MS). A non-compartmental analysis revealed key pharmacokinetic parameters, including a median Tmax of 7 h, a Cmax of 2350 ng/mL, and a t1/2Z of 28.5 h. CFZ treatment reduced glucose (AUCGLU, p = 0.001) and insulin (AUCINS, p = 0.04) response to a graded glucose infusion administered 5 h after treatment. This indicates a rapid onset of action following a single dose in healthy Icelandic horses. No obvious adverse effects related to the treatment were observed.

Prevalence of insulin dysregulation in the non-obese stock-type horse and relationship with morphometric neck measurements

Insulin dysregulation (ID), core to equine metabolic syndrome, may present without obesity. Testing for ID risk is commonly based on breed and obese phenotype but might be valuable for non-obese stock-type horses. This study aimed to determine the prevalence of ID in non-obese stock-type horses and evaluate if morphometric neck measurements (MNM) correlate with ID. Sixty-two, non-obese (BCS 5, range 2.5-6/9) stock-type horses were assessed for MNM: neck circumference at 25%, 50% (NC50), and 75% (NC75) length, and crest height. An oral sugar test (OST; 0.15 mL/kg BW corn syrup) was performed with blood taken pre- and 60 min post-OST for insulin (PREI, POSTI) and glucose (PREG, POSTG). Insulin dysregulation was defined as insulin concentration > 45 µIU/mL POSTI. Three of 62 horses were ID (4.8%; 95% CI 1.0%-13.5%). Horses with ID had greater PREG (121.0 ± 7.56 vs. 105.3 ± 1.72 mg/dL; LS means ± SEM; P = 0.04) and PREI (15.7 ± 2.63 vs. 10.5 ± 0.59 µIU/mL; P = 0.05) than normal responders. Mares had greater PREI than geldings (11.7 ± 0.76 vs. 9.4 ± 0.89 µIU/mL; P = 0.04). Stepwise regression indicated a weak relationship with crest height and POSTG (y = 51.27 + (0.88 x NC50); R2 = 0.09; P = 0.02). Post-glucose correlated with NC50 (r = 0.30; P = 0.04) and NC75 (r = 0.29; P = 0.03). This study showed 4.8% of non-obese horses had ID, warranting testing irrespective of phenotype, but only a weak association between MNM and POSTG was found.

Sodium-glucose transport protein 2 inhibitor use in the management of insulin dysregulation in ponies and horses.

Laminitis is a common and painful condition of the equine foot and approximately 90% of cases are associated with insulin dysregulation (ID) that is a central feature of the common endocrine disorder equine metabolic syndrome (EMS) and occurs in a subset of animals with pituitary pars intermedia dysfunction. Additional features of EMS include obesity, altered circulating concentrations of adipokines (particularly adiponectin and leptin) and hypertriglyceridaemia. Obesity, ID, hypoadiponectinaemia, hyperleptinaemia and an altered plasma lipid profile are also features of human metabolic syndrome (HMS) alongside hyperglycaemia. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel class of oral hypoglycaemic agents used in combination with lifestyle changes in the management of HMS. SGLT2 receptors are responsible for 90% of the renal glucose reabsorption that occurs in the proximal convoluted tubule. Thus, these drugs increase urinary glucose excretion by suppressing glucose reabsorption from the glomerular filtrate resulting in urinary calorie loss with consequent weight loss and improvements in ID, hyperglycemia, hypoadiponectinaemia and hyperleptinaemia. There are no licenced veterinary drugs available for treating ID and preventing insulin-associated laminitis in horses. Thus, the use of SGLT2i for the control of equine hyperinsulinaemia with the goal of improving recovery from associated active laminitis or preventing future laminitis has recently been advocated. There are a small number of published studies reporting the use of the SGLT2i canagliflozin, ertugliflozin and velagliflozin to aid the management of equine ID. However, the doses used are largely extrapolated from human studies with limited consideration of species-specific variations. In addition, there is limited evaluation of the fundamental differences between ID in horses and humans, particularly the fact that most horses with ID remain hyperinsulinaemic but normoglycaemic such that increased urinary loss of glucose may not explain the beneficial effects of these drugs. Further study of the potential deleterious effects of treatment-associated hypertriglyceridaemia is required together with the effect of SGLT2i therapy on circulating concentrations of adipokines in horses.

Evaluating insulindysregulation in horses: A two-step insulin-tolerance test using porcine zinc insulin

In insulin dysregulation, hyperinsulinemia (HI) can be accompanied by peripheral insulin resistance (IR) in horses, which can be diagnosed with an insulin-tolerance test (ITT). The administration of 0.1 IU/kg body weight of recombinant regular human insulin (RHI) should elicit a 50 % reduction of the initial blood glucose concentration at 30 min after insulin administration in insulin sensitive horses. Compared to RHI, porcine zinc insulin (PZI) is veterinary-approved and therefore easier accessible for many practitioners. The aim of this study was to compare the insulin and glucose dynamics during a standard ITT with RHI to an ITT performed with PZI. Twelve Icelandic horses were subjected to an ITT with RHI (ITT-RHI) and with PZI (ITT-PZI) at same dosages in a randomised crossover design. The insulin and glucose dynamics that resulted from these tests were compared, and the consistency of classification into insulin-sensitive and IR categories was evaluated. No complications were observed with the use of either RHI or PZI in ITT. A good correlation of the test results was observed (r = 0.88; P < 0.001). The blood glucose concentrations and the percentage reduction in glucose concentration did not differ significantly between the two tests (P = 0.053), but four out of twelve horses were classified as IR in the ITT-RHI whereas with the ITT-PZI seven out of twelve horses were classified as IR with the 50 % glucose reduction from baseline. Based on the Youden index, when using the ITT-PZI, an adjusted cut-off value for blood glucose reduction of 40 % at 30 min resulted in better test performance. With consideration for the seemingly weaker effect of PZI and the adjusted cut-off value, PZI can be an appropriate substitute to RHI in an ITT.

Adiposity in mares induces insulin dysregulation and mitochondrial dysfunction which can be mitigated by nutritional intervention

Obesity is a complex disease associated with augmented risk of metabolic disorder development and cellular dysfunction in various species. The goal of the present study was to investigate the impacts of obesity on the metabolic health of old mares as well as test the ability of diet supplementation with either a complex blend of nutrients designed to improve equine metabolism and gastrointestinal health or L-carnitine alone to mitigate negative effects of obesity. Mares (n = 19, 17.9 ± 3.7 years) were placed into one of three group: normal-weight (NW, n = 6), obese (OB, n = 7) or obese fed a complex diet supplement for 12 weeks (OBD, n = 6). After 12 weeks and completion of sample collections, OB mares received L-carnitine alone for an additional 6 weeks. Obesity in mares was significantly associated with insulin dysregulation, reduced muscle mitochondrial function, and decreased skeletal muscle oxidative capacity with greater ROS production when compared to NW. Obese mares fed the complex diet supplement had better insulin sensivity, greater cell lipid metabolism, and higher muscle oxidative capacity with reduced ROS production than OB. L-carnitine supplementation alone did not significantly alter insulin signaling, but improved lipid metabolism and muscle oxidative capacity with reduced ROS. In conclusion, obesity is associated with insulin dysregulation and altered skeletal muscle metabolism in older mares. However, dietary interventions are an effective strategy to improve metabolic status and skeletal muscle mitochondrial function in older mares.

Mild behavioral impairment domains are longitudinally associated with pTAU and metabolic biomarkers in dementia-free older adults.

The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed-effects models. The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p. pTau could be a pharmacological target to treat agitation and psychosis symptoms. MBI domains were linked to metabolic dysregulation involving insulin and homocysteine.

Equine metabolic syndrome: part 1

Both obesity and equine metabolic syndrome are being increasingly recognised. The underlying endocrine abnormality, insulin dysregulation, represents a high risk for endocrinopathic (hyperinsulinaemia-associated) laminitis. Early recognition and prompt treatment of the condition is crucial for the prevention of laminitis, a potentially severe disease that can have a fatal outcome. This article summarises current understanding of metabolic syndrome and its relationship to obesity. Current guidelines regarding early clinical recognition and corroborating diagnostic tests have been provided.

Insulin:Glucagon Bipolar Axis in Obesity With a Glimpse Into Its Association With Insulin Resistance in Different Glucose Tolerance States.

Dysregulation of insulin and glucagon secretion alters the normal insulin:glucagon ratio (IGR) in type 2 diabetes mellitus, obesity, and metabolic syndrome. This study explores the scope of construing the role of these two diametrically opposing hormones on the glucose level not just in obesity but in different glucose tolerance states by looking at the hormone levels and at the insulin glucagon bipolar axis itself. This is an analytical cross-sectional study of 60 healthy adults consisting of an equal number of adults who are lean and adults who are obese. It was conducted at North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences (NEIGRIHMS), located in Shillong City, Meghalaya, India. Fasting glucose, insulin, glucagon, and lipids were estimated. Postprandial estimation of glucose was done two hours after oral administration of 75 grams of glucose solution. The study demonstrated a state of hyperinsulinemia and hyperglucagonemia prevailing in obesity and all sub-categories of the group of persons who are obese. The study showed a higher fasting IGRin the group consisting of adults who were obese (with a mean of 4.11) when compared with the group of adults who are lean (with a mean of 2.24). Fasting IGRwas seen to increase with increasing levels of insulin resistance and increasing impairment in glucose tolerance. IGR showed a positive correlation with the homeostatic model assessment for insulin resistance (HOMA-IR) in the impaired fasting glucose (IFG) category and strongly in the impaired glucose tolerance (IGT) category. Hyperglucagonemia in the group of adult persons who are obese indicates a decreased sensitivity of alpha cells to insulin failing insulin to adequately suppress the secretion of glucagon. The study also demonstrated a positive correlation between IGR and HOMA-IR in obesity and all glucose tolerance states of the group of adults who are obese. It is telltale that the sturdier the insulin resistance, the higher the IGR.

Investigation of glucagon-like peptide-1 response to six oral carbohydrates in ponies

Glucagon-like peptide-1 (GLP-1), the principal incretin in horses, may play a role in the pathophysiology of insulin dysregulation (ID). This study aimed to describe its concentration in response to three preserved forages and four dynamic tests for ID in ponies. Twelve adult ponies of mixed ID status were given a meal of hay, soaked hay or haylage, an in-feed oral glucose test (OGT), oral sugar test (OST), an oral test using a proprietary breakfast cereal (WEET) or a combined glucose-insulin tolerance test (CGIT) weekly in a randomised cross-over study. Glucose, insulin and GLP-1 concentrations were measured before and following each intervention. Ponies were designated ID or non-ID and insulin resistant (IR) or non-IR according to OGT and CGIT results, respectively.All interventions apart from the CGIT provoked a GLP-1 response within 30 min. The OGT and WEET interventions, (containing the greatest dose of non-structural carbohydrate, 1.06 and 1 g/kg BW, respectively), resulted in a greater area under the curve (AUC) for GLP-1 compared to all other interventions (P < 0.001). No difference in GLP-1 response was detected according to ID or IR status, despite there being strong positive correlations (rs [95 % CI]) between GLP-1 and insulin concentrations measured at individual time points (0.67 [0.62 – 0.71]; P < 0.001) and as AUC (0.66 [0.49–0.79], P < 0.001). These data do not support of the use of GLP-1 as an adjunctive diagnostic test for ID or IR, as defined by conventional intravenous or oral dynamic tests.

Focus on the epidemiology, pathophysiology, diagnosis, and management of insulin dysregulation in horses

Because there are various inter-related disorders of insulin metabolism that all may contribute to the final result of hyperinsulinaemia, the phrase "insulin dysregulation" has become the most acceptable term to use when describing equine metabolic syndrome (EMS). Insulin dysregulation is widespread in horses, and it appears to be more prevalent in physically sedentary horses. Laminitis and hyperinsulinaemia have been linked, as have other components of insulin dysregulation. Diagnosis of insulin dysregulation should be done in stages, beginning with basal testing, which includes baseline values of insulin and glucose, and concluding with dynamic tests, which detect tissue insulin resistance and hyperinsulinaemia. Dietary adjustments are the key to weight loss in the majority of EMS horses. To encourage weight loss, the horse should be given around 1.25% of its body weight every day. Exercise not only aids equid weight loss but also improves insulin sensitivity. The exercise should be tailored to the specific horse, taking into account its breed, fitness level, and owner's resources. When an obese horse is unable to exercise owing to laminitis or when obesity persists after extensive exercise and dietary management, levothyroxine sodium and metformin hydrochloride can be given to help accelerate weight loss and increase insulin sensitivity. Insulin dysregulation is a defining feature of equine metabolic syndrome and has garnered attention due to its direct link to laminitis. There is need for an in-depth understanding of ID in order to prevent the development of clinical laminitis. The current study discusses the epidemiology, pathophysiology, diagnosis, and management of insulin dysregulation in horses.

Evidence for dopamine production and distribution of dopamine D2 receptors in the equine gastrointestinal mucosa and pancreas.

Insulin dysregulation in horses is characterised by hyperinsulinaemia and/or tissue insulin resistance and is associated with increased risk of laminitis. There is growing evidence in other species that dopamine attenuates insulin release from the pancreas; however, this has yet to be examined in horses. The present study aimed to identify whether there are cells capable of producing or responding to dopamine within the equine gastrointestinal mucosa and pancreas. Tissue samples were collected from the stomach, small and large intestines, and pancreas of six mature horses following euthanasia. Samples of stomach contents and faeces were also collected. Immunohistochemistry was performed to identify tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine production, and dopamine D2 receptors in tissue sections. Additional immunostaining for glucagon, insulin and chromogranin A was performed to identify α cells, β cells and enteroendocrine cells, respectively. Gastric parietal cells expressed both TH and D2 receptors, indicating that they are capable of both producing and responding to dopamine. Dopamine was quantified in stomach contents and faeces by high-performance liquid chromatography with electrochemical detection, with similar concentrations found at both sites. Dopamine D2 receptors were expressed in duodenal epithelial cells but not more distally. A subset of enteroendocrine cells, located sporadically along the gastrointestinal tract, were found to be immunopositive for the D2 receptor. In pancreatic islets, TH was present in α cells, while D2 receptors were strongly expressed in β cells and variably expressed in α cells. These findings are consistent with studies of other species; however, dynamic studies are required to further elucidate the role of dopamine in the modulation of insulin and glucagon secretion in horses. This descriptive study provides preliminary evidence for a potential role of dopamine to act as a paracrine messenger in the gastrointestinal mucosa and endocrine pancreas of horses.

Effect of Exercise Conditioning on Countering the Effects of Obesity and Insulin Resistance in Horses-A Review.

Obesity is an important health concern in horses, along with humans and companion animals. Adipose tissue is an inflammatory organ that alters the insulin-signaling cascade, ultimately causing insulin dysregulation and impaired glucose metabolism. These disruptions can increase the risk of metabolic disease and laminitis in horses and may also impact energy metabolism during exercise. A single bout of exercise, along with chronic exercise conditioning, increases insulin sensitivity and glucose disposal via both contraction- and insulin-mediated glucose uptake pathways. Regular exercise also increases calorie expenditure, which can facilitate weight (as body fat) loss. This paper explores the metabolic pathways affected by adiposity, as well as discusses the impact of exercise on insulin metabolism in horses.