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.

Redefining ITT cortisol thresholds on Abbott platforms to prevent misdiagnosis of adrenal insufficiency.

BACKGROUND: Adrenal insufficiency (AI) is a life-threatening condition which requires long term glucocorticoid replacement. The insulin tolerance test (ITT) is the current gold standard test for diagnosis of secondary AI, but the widely accepted cut-off value of a peak cortisol of less than 500 nmol/L assumes that anyone who does not reach this value has AI and thus requires full replacement. The cut-off used to diagnose AI is also founded on outdated assays. Use of this cut-off in an era of more specific immunoassays therefore risks misdiagnosis, subsequent unnecessary glucocorticoid exposure and associated adverse effects with increased mortality risk. DESIGN, PATIENTS AND MEASUREMENTS: This retrospective analysis assessed 300 ITT cortisol responses using the Abbott Architect and Alinity analyser platforms in patients with suspected AI over a period of 12 years (August 2010 to January 2022), at a tertiary centre. RESULTS: Patients were classified as having AI or not, based on a comprehensive clinical review of electronic patient records from the point of test to the present day by a panel of pituitary and adrenal specialists. Using the current institutional cut-off value of 500 nmol/L, receiver operating characteristic analysis identified a 100.0% sensitivity and 43.6% specificity (area under the curve 0.979). Using a lower cortisol threshold value of 416 nmol/L on the Abbott analyser platform maintained a sensitivity of 100.0% and improved the specificity to 86.7%. CONCLUSION: This data supports lowering the Abbott analyser ITT peak cortisol threshold to 416 nmol/L. Use of this improved cut-off avoids unnecessary glucocorticoid replacement therapy in 104 (34.7%) of individuals in this study. All patients remained well with at least 1 year longitudinal follow up of glucocorticoid replacement.

The influence of insulin-induced hypoglycemia on copeptin concentrations.

Plasma copeptin is a biomarker that reflects arginine vasopressin (AVP) secretion. In this study we measured copeptin during insulin tolerance test (ITT) in 65 patients referred to our department for evaluation of anterior pituitary function. Plasma for measurements of copeptin were collected at the start of the test and regurarly up to 120 minutes thereafter. Of 60 patients who developed significant hypoglycemia and were included in the analyses, 13 (22%) had corticotropic deficiency, 11 (18%) had thyreotropic deficiency, 33 (55%) had growth hormone deficiency and 4 (6%) had AVP deficieny (AVPD). Thirty-seven (62%) patients had at least one anterior pituitary deficiency. In patients without AVPD, median (range) copeptin increased from 4.5 pmol/L (1.3-33.0) to a maximum of 6.2 pmol/L (2.0-34.4; p<0.001). Baseline copeptin was similar in men and women, but maximal copeptin during ITT was higher in men. Copeptin concentrations were not affected by age, BMI, somatotropic, or corticotropic function. Copeptin concentrations were lower in patients with AVPD than patiets without AVPD, and in patients with thyrotropic deficiency, compared to patients with intact thyrotropic function, both at baseline and during ITT. In conclusion, copeptin increases significantly during insulin induced hypoglycemia but is of limited value in predicting anterior pituitary hormonal function.

Evaluation of growth hormone deficiency in women with unexplained infertility.

PURPOSE: Growth hormone (GH) has been recognized to play a regulatory role in female reproduction. It has been reported that infertile GH deficient patients regained fertility after GH replacement. The frequency of GH deficiency is not established in patients diagnosed with unexplained infertility. Here, we aim to present the prevalence of GH deficieny in this patient group. METHODS: We included patients diagnosed with unexplained infertility throughout 18 months. Insulin tolerance test (ITT) and glucagon stimulation tests (GST) were performed and insufficient response to both tests was required for the diagnosis of GH deficiency. RESULTS: Twenty-five patients were included in the study, the mean age was 27.4 ± 4.5 years and the median duration of infertility was 60 months (min:14, max:120). Two patients were GH deficient according to GST and 14 to ITT. Two patients (8%) showed lack of response on both tests and were diagnosed with GH deficiency. CONCLUSION: The rate of GH deficiency among women with unexplained infertility was 8% in this preliminary study. There is need for further studies with larger patient groups to verify the results.

Explaining Long COVID: A Pioneer Cross-Sectional Study Supporting the Endocrine Hypothesis.

Context: In some patients, symptoms may persist after COVID-19, defined as long COVID. Its pathogenesis is still debated and many hypotheses have been raised. Objective: Our primary objective was to evaluate the corticotroph and somatotroph functions of patients previously infected with SARS-CoV-2 and experiencing post-COVID-19 syndrome to detect any deficiencies that may explain long COVID. Methods: A cross-sectional study was conducted including patients who had previously contracted SARS-CoV-2 with a postinfection period of 3 months or less to 15 months, divided into 2 groups. The first group (G1) comprised fully recovered patients, while the second group (G2) included patients experiencing long COVID. The primary outcome was the comparison of corticotroph and somatotroph functions. Results: A total of 64 patients were divided into 2 groups, each consisting of 32 patients. G2 exhibited more frequently anterior pituitary deficits compared to G1 (P = .045): for the corticotroph axis (G1: 6.3% vs G2: 28.1%) and for the somatotroph axis (G1: 31.3% vs G2: 59.4%). Baseline cortisol level was significantly lower in G2 (G1: 13.37 µg/dL vs G2: 11.59 µg/dL) (P = .045). The peak cortisol level was also lower in G2 (G1: 23.60 µg/dL vs G2: 19.14 µg/dL) (P = .01). For the somatotroph axis, the insulin growth factor-1 level was lower in G2 (G1: 146.03 ng/mL vs G2: 132.25 ng/mL) (P = .369). The peak growth hormone level was also lower in G2 (G1: 4.82 ng/mL vs G2: 2.89 ng/mL) (P = .041). Conclusion: The results showed that long COVID patients in our cohort were more likely to have anterior pituitary deficiencies. The endocrine hypothesis involving anterior pituitary insufficiency can be considered to explain long COVID.

Evaluation of the growth response of children with growth hormone deficiency according to the peak growth hormone levels in provocation tests.

BACKGROUND: We aimed to evaluate the relation between the peak growth hormone (GH) levels in provocation tests and response to recombinant human GH (rhGH) therapy in patients with GH deficiency (GHD). METHODS: This was a cross-sectional, single-center, and retrospective study. A total of 135 patients under the age of 16 years who were diagnosed with GHD through insulin tolerance tests and L-DOPA stimulation tests and who received rhGH therapy for at least 2 years in the Pediatric Endocrinology Clinic of Akdeniz University Hospital between 1997 and 2021 were included in the study. RESULTS: The patients were divided into two groups: idiopathic GHD (group I, n = 119) and multiple pituitary hormone deficiencies or organic pathology on magnetic resonance imaging (group II, n = 16). The patients in group I were classified into three subgroups according to the peak GH values in the provocation tests (group Ia: peak GH <3 µg/L, n = 34; group Ib: peak GH between 3 and 7 µg/L, n = 71; group Ic: peak GH between 7 and 10 µg/L, n = 34). The median age was 11.5 years in group I (8.8 in group Ia, 12.1 in group Ib, 12.3 in group Ib) and 8.8 years in group II. The height standard deviation score (SDS) was -2.93 in group I (-2.85 in group Ia, -2.99 in group Ib, -2.94 in group Ic) and -3.79 in group II. The median Δheight SDS was 0.61 in group I and 1.05 in group II at the end of the first year of treatment and 0.31 in group I and 0.45 in group II at the end of the second year (p = 0.005 and p = 0.074, respectively). When the subgroups of group I were compared, height SDS, Δheight SDS, and height velocity (HV) SDS were all higher in group Ia at the end of the first year of rhGH therapy (p = 0.040, p = 0.029, and p = 0.005, respectively). The height SDS was still significantly higher in group Ia (p = 0.033) while the HV SDS and Δheight SDS were similar between the groups at the end of the second year of therapy (p = 0.164 and p = 0.522, respectively). There was a statistically significant association between the first-year HV SDS and the peak GH value in provocation tests in multiple regression analyses (p<0.001). In addition, the final model revealed that height SDS and weight SDS at the start of the treatment and the first-year HV SDS are the factors with a statistically significant effect on the second-year HV SDS (p = 0.022, p = 0.001, and p<0.001, respectively). CONCLUSION: Our findings show that the lower the GH peak in provocation tests, the better the response to treatment. The best HV was observed in the first year of rhGH therapy, and the diagnosis should be checked in those patients who had a low first-year HV and did not have a severely low GH peak in provocation tests.

Copeptin levels increase in response to both insulin-induced hypoglycemia and arginine but not to clonidine: data from GH-stimulation tests.

Background: The diagnosis of the polyuria-polydipsia syndrome is challenging. Copeptin is a robust biomarker of arginine vasopressin (AVP) secretion. Arginine, which stimulates growth hormone (GH), has been shown also to stimulate copeptin secretion via unknown mechanisms. Aim: The aim was to investigate copeptin levels in response to three different GH stimulation tests in patients suspected of GH deficiency. Methods: In this cross-sectional study, we measured plasma copeptin levels at baseline and at 60, 105, and 150 min in patients undergoing a stimulation test for growth hormone deficiency with either arginine (n = 16), clonidine (n = 8) or the insulin tolerance test (ITT) (n = 10). Results: In patients undergoing the arginine test, the mean age was 9 years, and 10 years for clonidine. The ITT was only performed in adult patients (>18 years) with a mean age of 49 years. Copeptin level increased significantly from baseline to 60 min after arginine (P <0.01) and ITT (P < 0.01). By contrast, copeptin level tended to decrease after clonidine stimulation (P = 0.14). Conclusion: These data support that infusion of arginine increases plasma copeptin levels and reveal a comparable response after an ITT. We hypothesize that the underlying mechanism is abrogation of somatostatin-induced AVP suppression.

Prevalence of refractoriness when testing growth hormone levels in children.

OBJECTIVE: Late night spontaneous growth hormone (GH) pulses may influence the pituitary GH response to provocation tests. We evaluated GH response during arginine-insulin-tolerance test (AITT) after a GH peak during a short spontaneous nocturnal profile (SSNP) in children with short stature or low growth velocity. DESIGN: Using SSNP and subsequent AITT, we examined 257 children 4-18 years old (138 (53.7%) males) recruited from three hospitals. Medical records were reviewed retrospectively. Refractory children were defined as a GH peak ≥7 µg/L during SSNP but no GH peak ≥7 µg/L during AITT. RESULTS: In total, 201/257 children had a GH peak ≥7 µg/L at SSNP and/or AITT. Of these, 21.9% were refractory. The proportion of males (p = 0.033) and body mass index (BMI) standard deviation score (SDS) (p = 0.037) were higher in the refractory group than in children with a GH peak ≥7 µg/L during AITT. The median period between last GH peak ≥7 µg/L during SSNP and GHmax at AITT was 210 (30-390) minutes. The GHmax at AITT occurred 30 min earlier for children without a peak ≥7 µg/L during the SSNP (p = 0.004). The number of refractoriness differed somewhat between the hospitals (p = 0.025). CONCLUSIONS: Many children with short stature were refractory at testing; among them we found few clinical characteristics. Refractoriness might be influenced by some differences in procedure, but needs to be considered when evaluating GH response in children.

Evaluation of field-testing protocols to diagnose insulin dysregulation in ponies using a Bayesian approach.

Field tests and their association with laminitis have not been evaluated in large cohorts. The objectives of this study were to evaluate the performance of basal insulin (BI), the oral sugar test (OST) and the insulin tolerance test (ITT) to diagnose ID and investigate their association with laminitis. Insulin dysregulation status was determined in 146 ponies using BI (insulin concentration >20 µIU/mL), an OST (insulin concentration >65 µIU/mL at 60 or 90 min after oral administration of 0.45 mL/kg corn syrup) and an ITT (< 50% reduction in glucose concentration 30 min after intravenous administration of 0.1 IU/kg insulin). Laminitis was identified using modified-Obel scores. A Bayesian approach was used to define the characteristics of the tests and receiver operating characteristic curves were used to assess their association with laminitis. All tests were well tolerated and laminitis was diagnosed in 9% of ponies. Insulin dysregulation was diagnosed in 15% of ponies using BI, 38% using the OST and 54% using the ITT with 11% of ponies positive for all three tests. The sensitivities and specificities of BI, the OST and the ITT to diagnose ID were 0.52 (95% confidence interval [CI], 0.35-0.79) and 0.97 (95% CI, 0.91 - 1.00), 0.84 (95% CI, 0.70 - 0.94) and 0.60 (95% CI, 0.49 - 0.71), and 0.85 (95% CI, 0.68-0.96) and 0.88 (95% CI, 0.75 - 0.97), respectively. Only BI and the OST were associated with laminitis (P = 0.003 and 0.015, respectively).

Diagnosis and testing for growth hormone deficiency across the ages: a global view of the accuracy, caveats, and cut-offs for diagnosis.

Growth hormone deficiency (GHD) is a clinical syndrome that can manifest either as isolated or associated with additional pituitary hormone deficiencies. Although diminished height velocity and short stature are useful and important clinical markers to consider testing for GHD in children, the signs and symptoms of GHD are not always so apparent in adults. Quality of life and metabolic health are often impacted in patients with GHD; thus, making an accurate diagnosis is important so that appropriate growth hormone (GH) replacement therapy can be offered to these patients. Screening and testing for GHD require sound clinical judgment that follows after obtaining a complete medical history of patients with a hypothalamic-pituitary disorder and a thorough physical examination with specific features for each period of life, while targeted biochemical testing and imaging are required to confirm the diagnosis. Random measurements of serum GH levels are not recommended to screen for GHD (except in neonates) as endogenous GH secretion is episodic and pulsatile throughout the lifespan. One or more GH stimulation tests may be required, but existing methods of testing might be inaccurate, difficult to perform, and can be imprecise. Furthermore, there are multiple caveats when interpreting test results including individual patient factors, differences in peak GH cut-offs (by age and test), testing time points, and heterogeneity of GH and insulin-like growth factor 1 assays. In this article, we provide a global overview of the accuracy and cut-offs for diagnosis of GHD in children and adults and discuss the caveats in conducting and interpreting these tests.

The methanol extract of Ceiba pentandra reverses monosodium glutamate-induced cardiometabolic syndrome in rats via the regulation of dyslipidemia, inflammation, oxidative stress, and insulin sensitization.

The antidiabetic effects of the methanol extract of the stem bark of Ceiba pentandra (Cp) have been demonstrated in various experimental models. Besides, this extract is rich in 8-formyl-7-hydroxy-5-isopropyl-2-methoxy-3-methyl-1,4-naphthaquinone, 2,4,6-Trimethoxyphenol and vavain. However, it remains unknown whether Cp can mitigate cardiometabolic syndrome (CMS). The present study assessed the curative properties of Cp against Monosodium Glutamate (MSG)-induced CMS in rats. Male neonate Wistar rats were intraperitoneally administered with MSG (4 mg/g/day) during the first 5 days of life (postnatal days 2-6). They were kept under standard breeding conditions up to 5 months of age for the development of CMS. Diseased animals were then orally treated with atorvastatin (80 mg/kg/d) or Cp (75 and 150 mg/kg/day) for 28 days during which food intake, body mass, blood pressure, heart rate, glucose, and insulin tolerance were monitored. Plasma and tissues were collected on day 29th to assess the lipid profile, oxidative stress, and inflammatory parameters. The histomorphology of the adipose tissue was also evaluated. Cp significantly (p < 0.001) reduced the obesogenic and lipid profiles, adipocyte size, blood pressure, and oxidative and inflammatory status in MSG-treated rats. Cp also ameliorated glucose (p < 0.05) and insulin sensitivities (p < 0.001) hence, reducing animals' cardiometabolic risk score (p < 0.001). The curative effect of Cp on cardiometabolic syndrome is related to its capacity to reduce oxidative stress, inflammation, dyslipidemia, and increase insulin sensitivity. These results demonstrate the potential of Cp as a good candidate for alternative treatment of CMS.

The Involvement of Endogenous Enkephalins in Glucose Homeostasis.

Obesity has nearly tripled since 1975 and is predicted to continue to escalate. The surge in obesity is expected to increase the risk of diabetes type 2, hypertension, coronary artery disease, and stroke. Therefore, it is essential to better understand the mechanisms that regulate energy and glucose homeostasis. The opioid system is implicated in regulating both aspects (hedonic and homeostatic) of food intake. Specifically, in the present study, we investigated the role of endogenous enkephalins in changes in food intake and glucose homeostasis. We used preproenkephalin (ppENK) knockout mice and their wildtype littermates/controls to assess changes in body weight, food intake, and plasma glucose levels when mice were fed a high-fat diet for 16 weeks. Body weight and food intake were measured every week (n = 21-23 mice per genotype), and at the end of the 16-week exposure period, mice were tested using the oral glucose tolerance test (OGTT, n = 9 mice per genotype) and insulin tolerance test (n = 5 mice per genotype). Our results revealed no difference in body weight or food intake between mice of the two genotypes. However, HFD-exposed enkephalin-deficient mice demonstrated impaired OGTT associated with reduced insulin sensitivity compared to their wildtype controls. The impaired insulin sensitivity is possibly due to the development of peripheral insulin resistance. Our results reveal a potential role of enkephalins in the regulation of glucose homeostasis and in the pathophysiology of diabetes type 2.

Sex steroid priming for growth hormone stimulation testing in children and adolescents with short stature: A systematic review.

OBJECTIVE: Growth hormone stimulation testing (GHST) is used to diagnose growth hormone deficiency (GHD) in children. As sex steroids impact on anterior pituitary function, there is concern around the efficacy of GHST in peripubertal children, where endogenous sex steroid levels are low. Sex steroid priming before GHST is thought to improve test efficacy in these children, however evidence to support its use in clinical practice is limited. In this systematic review, we addressed the following research questions: Does priming increase GH stimulation test efficacy in peripubertal children? Does priming identify those who would benefit most from treatment in terms of final height? Is there evidence for an optimal sex-steroid priming regimen? DESIGN, PATIENTS, MEASUREMENTS: The study was registered with PROSPERO and conducted according to PRISMA guidelines. We searched Medline, Cochrane-Library, Scopus, EMBASE and Web-of-Science and included all studies that included GHST in both primed and unprimed children. A GH cut-off of 7 µg/L was used as a threshold for GHD. Study quality was assessed using the Risk-Of-Bias in Non- Randomized Studies (ROBINS-I) tool or the revised Cochrane risk-of-bias tool for Randomised trials. RESULTS: Fifteen studies met our inclusion criteria, of which 4/15 (27%) were randomised control trials. The majority (9/15) of the studies indicated that priming increases growth hormone response upon GHST in peripubertal children, increasing test specificity. Two studies investigated final height after treatment based on the results of primed versus unprimed GHST. These results indicate that growth hormone treatment based on results of a primed GHST improve outcomes compared with treatment based on an unprimed test. CONCLUSION: Sex-steroid priming increases the growth hormone response during GHST, resulting in fewer patients meeting the threshold required for a diagnosis of GHD. Unnecessary GH treatment may be avoided in some patients without a detrimental effect on final height. Numerous sex-steroid priming regimens have been used in clinical practice and the majority appear to be effective, but an optimal regimen has not been determined.

Clinical characteristics of patients with unexplainable hypothalamic disorder diagnosed by the corticotropin-releasing hormone challenge test: a retrospective study.

BACKGROUND: The corticotropin-releasing hormone (CRH) challenge test can distinguish the disorders of the hypothalamus from those of the pituitary. However, the pathophysiology of hypothalamic disorder (HD) has not been fully understood. This study aimed to elucidate the clinical characteristics of patients with unexplainable HD, diagnosed by the CRH challenge test. METHODS: We retrospectively reviewed patients who underwent the CRH challenge test. Patients were categorized into four groups as follows: patients with peak serum cortisol ≥18 µg/dL were assigned to the normal response (NR) group (n = 18), among patients with peak serum cortisol < 18 µg/dL and peak adrenocorticotropic hormone (ACTH) increase ≥two-fold, patients without obvious background pathology were assigned to the unexplainable-HD group (n = 18), whereas patients with obvious background pathology were assigned to the explainable-HD group (n = 38), and patients with peak serum cortisol < 18 µg/dL and peak ACTH increase

Consumption of glucose syrup enhances glucose tolerance in mice.

There is debate about the metabolic impact of sugar-sweetened beverages. Here, we tested the hypothesis that ad lib consumption of glucose (Gluc) or high-fructose (HiFruc) syrups improves glucose tolerance in mice. We provided C57BL/6 mice with a control (chow and water) or experimental (chow, water and sugar solution) diet across two consecutive 28-day exposure periods, and monitored changes in body composition, glucose tolerance, cephalic-phase insulin release (CPIR) and insulin sensitivity. The sugar solutions contained 11% concentrations of Gluc or HiFruc syrup; these syrups were derived from either corn starch or cellulose. In Experiment 1, consumption of the Gluc diets reliably enhanced glucose tolerance, while consumption of the HiFruc diets did not. Mice on the Gluc diets exhibited higher CPIR (relative to baseline) by the end of exposure period 1, whereas mice on the control and HiFruc diets did not do so until the end of exposure period 2. Mice on the Gluc diets also exhibited higher insulin sensitivity than control mice at the end of exposure period 2, while mice on the HiFruc diets did not. In Experiment 2, we repeated the previous experiment, but limited testing to the corn-based Gluc and HiFruc syrups. We found, once again, that consumption of the Gluc (but not the HiFruc) diet enhanced glucose tolerance, in part by increasing CPIR and insulin sensitivity. These results show that mice can adapt metabolically to high glucose diets, and that this adaptation process involves upregulating at least two components of the insulin response system.

Thymus serpyllum Exhibits Anti-Diabetic Potential in Streptozotocin-Induced Diabetes Mellitus Type 2 Mice: A Combined Biochemical and In Vivo Study.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder that is characterized by hyperglycemia, insulin resistance, and lack of insulin production. It has been previously reported that Thymus serpyllum has therapeutic potential against many diseases. To investigate the antidiabetic action of Thymus serpyllum, this study aimed to analyze its restorative impact in diabetic mice, in which it was administered in diet. Diabetes was induced in BALB/c mice fed with a high-fat diet and two intraperitoneal injections of streptozotocin. With the onset of diabetes, the mice were administered daily with aqueous extract of Thymus serpyllum (500 mg/kg/d and 800 mg/kg/d) for 4 weeks. Body weight and fasting blood glucose levels were measured after every 1 week of the treatment. Subsequently, intraperitoneal glucose tolerance and insulin tolerance tests were conducted. In addition, liver tissue was isolated for assessment in terms of levels of gene expression of the AMPK, IRS1, and GLUT2 gene. Treatment with the aqueous extract of Thymus serpyllum was found to be significantly effective in controlling hyperglycemia and improving glucose and insulin tolerance. Predictable with these impacts, the extract of Thymus serpyllum upregulated the AMPK expression at the mRNA level, as well as upregulating the expression of IRS1 and GLUT2 gene. Histopathological examination of the liver, kidney, and pancreas also revealed the restorative impact in terms of cellular morphology. The results hence demonstrated that oral administration of aqueous extract of Thymus serpyllum can potentially attenuate hyperglycemia in the liver muscle of streptozotocin (STZ)-induced diabetic mice via AMPK and IRS1 upregulation.

Differential Responses to Sigma-1 or Sigma-2 Receptor Ablation in Adiposity, Fat Oxidation, and Sexual Dimorphism.

Obesity is increasing at epidemic rates across the US and worldwide, as are its co-morbidities, including type-2 diabetes and cardiovascular disease. Thus, targeted interventions to reduce the prevalence of obesity are of the utmost importance. The sigma-1 receptor (S1R) and sigma-2 receptor (S2R; encoded by Tmem97) belong to the same class of drug-binding sites, yet they are genetically distinct. There are multiple ongoing clinical trials focused on sigma receptors, targeting diseases ranging from Alzheimer's disease through chronic pain to COVID-19. However, little is known regarding their gene-specific role in obesity. In this study, we measured body composition, used a comprehensive laboratory-animal monitoring system, and determined the glucose and insulin tolerance in mice fed a high-fat diet. Compared to Sigmar1+/+ mice of the same sex, the male and female Sigmar1-/- mice had lower fat mass (17% and 12% lower, respectively), and elevated lean mass (16% and 10% higher, respectively), but S1R ablation had no effect on their metabolism. The male Tmem97-/- mice exhibited 7% lower fat mass, 8% higher lean mass, increased volumes of O2 and CO2, a decreased respiratory exchange ratio indicating elevated fatty-acid oxidation, and improved insulin tolerance, compared to the male Tmem97+/+ mice. There were no changes in any of these parameters in the female Tmem97-/- mice. Together, these data indicate that the S1R ablation in male and female mice or the S2R ablation in male mice protects against diet-induced adiposity, and that S2R ablation, but not S1R deletion, improves insulin tolerance and enhances fatty-acid oxidation in male mice. Further mechanistic investigations may lead to translational strategies to target differential S1R/S2R regulations and sexual dimorphism for precision treatments of obesity.

Long-acting Porcine Sequence ACTH (Acton Prolongatum) Stimulation Test is a Reliable Alternative Test as Compared to the Gold Standard Insulin Tolerance Test for the Diagnosis of Adrenal Insufficiency.

Context: As synacthen use is not licensed in India and there are concerns about the safety of the insulin tolerance test (ITT), an alternative dynamic test to diagnose adrenal insufficiency (AI) is required. Objective: The study aimed to evaluate the diagnostic performance of the Acton Prolongatum stimulation test (APST) with a standard ITT for the diagnosis of AI. Design: Prospective study comparing two diagnostic tests. Participants: Six healthy volunteers and 53 suspected or known AI patients. Measurements: Serum cortisol response to ITT and APST. Results: The median (95% confidence interval [CI]) peak cortisol levels among healthy volunteers in ITT and APST were 17 (14.58-19.08) and 30.5 (22.57-34.5) µg/dL. Of the 53 patients (age: 39.6 ± 9.38 years; females: 38 [71.1%]), 34 had AI (peak ITT serum cortisol < 14.5 µg/dL) whereas 19 had a normal hypothalamic-pituitary-adrenocortical (HPA) axis. In the receiver operator characteristic curve analysis, 60-min APST cortisol had an area under the curve of 0.984 (95% CI: 0.904-1.00, P < 0.0001). The best accuracy was obtained at a cut-off of 16.42 µg/dL (sensitivity: 97.7% [95% CI: 87.7-99.9%]; specificity: 100% [69.2-100%]). Forty-three of the 53 patients with suspected AI had hypoglycemic symptoms during ITT and two of them required intravenous dextrose, whereas, none had adverse events during APST. The ITT was incomplete in two patients whereas all completed APST. Conclusions: APST is a simple, safe, and reliable alternative to ITT for the diagnosis of AI; 60-min serum cortisol of 16.42 µg/dL in APST best distinguishes the AI patients from those with adequate cortisol response.

Switching to a Standard Chow Diet at Weaning Improves the Effects of Maternal and Postnatal High-Fat and High-Sucrose Diet on Cardiometabolic Health in Adult Male Mouse Offspring.

Cardiac mitochondrial dysfunction contributes to obesity-associated heart disease. Maternal and postnatal diet plays an important role in cardiac function, yet the impacts of a mismatch between prenatal and postweaning diet on cardiometabolic function are not well understood. We tested the hypothesis that switching to a standard chow diet after weaning would attenuate systemic metabolic disorders and cardiac and mitochondrial dysfunction associated with maternal and postnatal high-fat/high-sucrose (HFHS) diet in mice. Six-month-old male CD1 offspring from dams fed a HFHS diet and weaned to the same HFHS diet (HH) or switched to a standard chow diet (HC) were compared to offspring from dams fed a low-fat/low-sucrose diet and maintained on the same diet (LL). HC did not decrease body weight (BW) but normalized glucose tolerance, plasma cholesterol, LDL, and insulin levels compared to the HH. Systolic function indicated by the percent fractional shortening was not altered by diet. In freshly isolated cardiac mitochondria, maximal oxidative phosphorylation-linked respiratory capacity and coupling efficiency were significantly higher in the HC in the presence of fatty acid substrate compared to LL and HH, with modification of genes associated with metabolism and mitochondrial function. Switching to a standard chow diet at weaning can attenuate the deleterious effects of long-term HFHS in adult male mouse offspring.