Serum Glucagon Research Articles

Excitatory Impact of Dental Occlusion on Dorsal Motor Nucleus of Vagus.

Neurons in the trigeminal mesencephalic nucleus (Vme) have axons that branch peripherally to innervate the orofacial region and project centrally to several motor nuclei in brainstem. The dorsal motor nucleus of vagus nerve (DMV) resides in the brainstem and takes a role in visceral motor function such as pancreatic exocrine secretion. The present study aimed to demonstrate the presence of Vme–DMV circuit, activation of which would elicit a trigeminal neuroendocrine response. A masticatory dysfunctional animal model termed unilateral anterior crossbite (UAC) model created by disturbing the dental occlusion was used. Cholera toxin B subunit (CTb) was injected into the inferior alveolar nerve of rats to help identify the central axon terminals of Vme neurons around the choline acetyltransferase (ChAT) positive motor neurons in the DMV. The level of vesicular glutamate transporter 1 (VGLUT1) expressed in DMV, the level of acetylcholinesterase (AChE) expressed in pancreas, the level of glucagon and insulin expression in islets and serum, and the blood glucose level were detected and compared between UAC and the age matched sham-operation control mice. Data indicated that compared with the controls, there were more CTb/VGLUT1 double labeled axon endings around the ChAT positive neurons in the DMV of UAC groups. Mice in UAC group expressed a higher VGLUT1 protein level in DMV, AChE protein level in pancreas, glucagon and insulin level in islet and serum, and higher postprandial blood glucose level, but lower fasting blood glucose level. All these were reversed at 15-weeks when UAC cessation was performed from 11-weeks (all, P < 0.05). Our findings demonstrated Vme–DMV circuit via which the aberrant occlusion elicited a trigeminal neuroendocrine response such as alteration in the postprandial blood glucose level. Dental occlusion is proposed as a potential therapeutic target for reversing the increased postprandial glucose level.

Association between time in range, a novel measurement of glycemic control and islet secretory function in chinese patients with type 2 diabetes mellitus—An observational study

AimsTo explore the association between dynamic islet secretory function and TIR (time in range), a new valuable metric of glycemic control in type 2 diabetes (T2D). MethodsIn this observational study 256 patients with type 2 diabetes were included and continuous glucose monitoring system (CGMS) were applied to monitor blood glucose and also the calculation of TIR [the time spent in an individual’s target glucose range (usually 3.9–10 mmol/L)]. The participants were divided into 3 groups according to the tertiles of TIR, 85 cases with TIR ≥ 65.05% (T1 group), 86 cases with 41.84 < TIR ≤ 65.05% (T2 group) and 85 cases with TIR < 41.84% (T3 group). Serum glucagon (GLA0h, GLA0.5h, GLA1h, GLA2h, GLA3h), C-peptide (Cp0h, Cp0.5h, Cp1h, Cp2h, Cp3h) concentration at different time points were measured after a 100 g standard steamed buns meal test to assess the pancreatic alpha cell and beta cell function. Spearman correlation analysis and multivariate linear stepwise regression analysis were adopted for statistical analysis. ResultsThe average age and diabetes duration of all the participants were separately 56.09 ± 13.8 years and 8.0 (4.0,15.0) years. Compared with patients in T1 group, participants in group T2 and T3 tend to have a lower concentration of C-peptide at all time points, as well as GLA0h, GLA2h and GLA3h (p < 0.05). TIR was positively correlated with C-peptide at different time points, area under the curve of C-peptide in half an hour (AUCCp0.5h), GLA0h, GLA3h, area under the curve of glucagon in half an hour (AUCGLA0.5h)(rs = 0.263, 0.414, 0.510, 0.587, 0.528, 0.360, 0.259, 0.144 and 0.208, respectively, p < 0.05) and was negatively correlated with the increment of serum glucagon from baseline at 0.5 h, 1 h and 2 h after the standard energy loaded(△GLA0.5h, △GLA1h, △GLA2h)(rs = −0.152,-0.172 and −0.203, respectively, p < 0.05). Cp2h, Cp0h and GLA0h were independent factors for TIR (β = 6.558,-6.930, 0.247, respectively, p < 0.01). ConclusionBoth islet alpha cell and beta cell secretory function have important influence on TIR, a novel vital index of glycemic fluctuation.

Potential hemo-biological identification markers to the left displaced abomasum in dairy cows

BackgroundLeft displaced abomasum (LDA) occurs at high frequency in the early postpartum period and can affect production performance of dairy cows. Clinical diagnosis of LDA is usually done by abdominal auscultation and percussion. The purpose of this study was to explore the potential applicability of blood biomarkers for early warning and diagnosis of LDA in dairy cows.ResultsTwenty early postpartum healthy cows and thirty early postpartum LDA cows of similar parity were used. A receiver operating characteristic curve (ROC) method was used to analyze the sensitivity of hematological biomarkers to LDA including energy balance metabolic biomarkers, liver/kidney function biomarkers, and minerals. A cut-off point was defined for each of the selected hematological biomarkers deemed sensitive markers of LDA. Compared with healthy cows, body condition score (BCS), dry matter intake (DMI) and milk production were lower in LDA cows. Among energy metabolism markers, serum non-esterified fatty acid (NEFA), β-hydroxybutyric acid (BHBA), insulin (INS), and revised quantitative insulin sensitivity check index (RQUICKI) levels were lower while serum glucagon (GC) was greater in LDA cows. Among the liver/kidney function biomarkers, activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), the ratio of AST/ALT and levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), albumin (ALB), blood urea nitrogen (BUN), creatinine, and total protein (TP) were greater in LDA cows. Among minerals analyzed, serum Cl, Ca, and K were lower in LDA cows. After ROC analysis, it was determined that serum Ca, INS, RQUICKI, ALT, GGT, and creatinine are potential indicators for early warning and diagnosis of LDA for early postpartum dairy cows.ConclusionsDairy cows with LDA were under severe negative energy balance (NEB), had signs of liver damage and potentially lower insulin sensitivity. A combination of multi-hematological biomarkers including Ca, INS, RQUICKI, ALT, GGT and creatinine has the potential to help identify cows at risk of LDA in the early postpartum period.

Increased alpha and beta cell mass during mouse pregnancy is not dependent on transdifferentiation.

Maternal pancreatic beta-cell mass (BCM) increases during pregnancy to compensate for relative insulin resistance. If BCM expansion is suboptimal, gestational diabetes mellitus can develop. Alpha-cell mass (ACM) also changes during pregnancy, but there is a lack of information about α-cell plasticity in pregnancy and whether α- to β-cell transdifferentiation can occur. To investigate this, we used a mouse model of gestational glucose intolerance induced by feeding low-protein (LP) diet from conception until weaning and compared pregnant female offspring to control diet-fed animals. Control and LP pancreata were collected for immunohistochemical analysis and serum glucagon levels were measured. In order to lineage trace α- to β-cell conversion, we utilized transgenic mice expressing yellow fluorescent protein behind the proglucagon gene promoter (Gcg-Cre/YFP) and collected pancreata for histology at various gestational timepoints. Alpha-cell proliferation increased significantly at gestational day (GD) 9.5 in control pregnancies resulting in an increased ACM at GD18.5, and this was significantly reduced in LP animals. Despite these changes, serum glucagon was higher in LP mice at GD18.5. Pregnant Gcg-Cre/YFP mice showed no increase in the abundance of insulin+YFP+glucagon- cells (phenotypic β-cells). A second population of insulin+YFP+glucagon+ cells was identified which also did not alter during pregnancy. However, there was an altered anatomical distribution within islets with fewer insulin+YFP+glucagon- cells but more insulin+YFP+glucagon+ cells being present in the islet mantle at GD18.5. These findings demonstrate that dynamic changes in ACM occur during normal pregnancy and were altered in glucose-intolerant pregnancies.

An antidiabetic nutraceutical combination of red yeast rice (Monascus purpureus), bitter gourd (Momordica charantia), and chromium alleviates dedifferentiation of pancreatic β cells in db/db mice.

Antidiabetic properties of red yeast rice, bitter gourd, and chromium have gained scientific support. This study aimed to test whether a nutraceutical combination of these 3 materials prevented dedifferentiation of pancreatic β cells. Male db/db mice (8 weeks of age) were allocated into four groups (DB, DB/L, DB/M, and DB/H; n = 8–10) and fed a high‐fat diet containing 0%, 0.2%, 0.4%, or 1% nutraceutical, respectively, whereas wild‐type mice receiving a standard diet served as a healthy control (C; n = 10). The nutraceutical contained 10 mg/g monacolin K, 165 µg/g chromium, and 300 mg/g bitter gourd. After 8‐weeks dietary treatment, diabetic syndromes (including hyperglycemia, hyperphagia, excessive drinking, polyuria, glucosuria, albuminuria, and glucose intolerance), were improved by the nutraceutical in a dose‐dependent fashion. Decreased insulin and increased glucagon in serum and pancreatic islets in db/db mice were abolished in the DB/H group. Furthermore, supplementation curtailed dedifferentiation of β cells, as evidenced by decreasing the dedifferentiation marker (Aldh1a3) and increasing β‐cell‐enriched genes and transcription factors (Ins1, Ins2, FOXO1, and NKX6.1), as well as nuclear localization of NKX6.1 in pancreatic islets when compared to the DB group. We concluded that this nutraceutical, a combination of Monascus purpureus, Momordica charantia, and chromium, could be used as an adjunct for type 2 diabetes treatment and delay disease progression by sustaining β‐cell function.

Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus

ABSTRACT Introduction Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest. Areas covered This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses. In addition, with the findings of recent cardiovascular outcome trials (CVOTs), the authors discuss, herein, the efficacious use of saxagliptin. Expert opinion Saxagliptin exhibits a moderate glucose-lowering effect and is well tolerated by patients with T2D. SAVOR-TIMI 53, a CVOT of saxagliptin, reported neutral effects of saxagliptin in respect of the cardiovascular outcomes, but did raise a concern about the risk of heart failure. Conversely, recent CVOTs on sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown a favorably reduced risk of heart failure with these drugs. Also, DPP-4is decrease the serum glucagon level, whereas the SGLT2is increase it. Given the characteristics of the two classes of drugs, combined therapy with the two might be a promising option.

Effects of carbon dioxide pneumoperitoneum on exocrine and endocrine functions, and oxidative state of rat pancreas

ABSTRACT We investigated the effects of increased intra-abdominal pressure during laparoscopy on the endocrine and exocrine functions, oxidative stress and histopathology of the pancreas in rats. We established three experimental groups of eight animals. Group 1 was the untreated control. Forth other two groups, pneumoperitoneum with CO2 was established for 60 min at 6 mm Hg for group 2 and 12 mm Hg for group 3; groups 2 and 3 animals were allowed to re-perfuse for 30 min. Amylase, glucagon and insulin levels were analyzed in blood samples and insulin:glucagon ratio was calculated. Histopathology and malondialdehyde assay were performed on pancreatic tissue samples. Histological damage scores for vasocongestion were increased significantly in groups 2 and 3 compared to group 1. Histological damage scores for inflammatory cell infiltration were increased significantly in group 3 compared to group 1. Malondialdehyde levels were increased significantly in group 3 compared to group 1. We found no significant differences among groups for serum amylase levels or histological damage scores for hemorrhage. Insulin and glucagon levels, and the insulin:glucagon ratio was increased significantly in group 3 compared to groups 1 and 2. We found that in rats routine laparoscopy caused increased serum insulin and glucagon levels, and histopathological changes that indicated ischemia-reperfusion injury to the pancreas.

Effect of subacute combined oral exposure of titanium dioxide nanoparticles and glucose on blood glucose homeostasis in young SD rats

To explore the effect of combined oral exposure of titanium dioxide nanoparticles(TiO_2 NPs) and glucose on blood glucose homeostasis in young SD rats. Eighty 4-week-old young SD rats were randomly divided into 8 groups(10 rats in each group, half male and half female). The rats were exposed to TiO_2 NPs through intragastric administration at 0, 2, 10 and 50 mg/kg with or without 1. 8 g/kg glucose daily for 30 days. Blood glucose was monitored weekly during the experiment. Oral glucose tolerance test(OGTT) was carried out after subacute exposure(30 days), and the biomarkers related to blood glucose homeostasis were detected, including the contents of glycosylated serum protein(GSP), glycosylated hemoglobin(HbA1 c), insulin, C-peptide and glucagon. At the same time, the pancreatic pathology of rats was observed. TiO_2 NPs were anatase crystals, closely spherical shape, with an average particle size of(24±5)nm. Exposure of TiO_2 NPs alone had little effect on blood glucose homeostasis. Blood glucose decreased on the 16 th exposure day at dose of 10 mg/kg TiO_2 NPs, and postprandial blood glucose(2 h) decreased after 30 days of TiO_2 NPs exposure at doses of 2 and 50 mg/kg in male rats(P&lt;0. 05). The combined effect of oral exposure of TiO_2 NPs and glucose on blood glucose homeostasis was more obvious than that of TiO_2 NPs alone. Blood glucose decreased on the 9 th exposure day at dose of 10 mg/kg TiO_2 NPs+glucose in female rats, and postprandial blood glucose(2 h) decreased at dose of 2 and 50 mg/kg TiO_2 NPs+glucose after 30 days of exposure in male rats(P&lt;0. 05). Blood glucose decreased on the 9 th day after 10 mg/kg TiO_2 NPs+glucose exposure in female rats. The glycosylated serum protein decreased and postprandial blood glucose(30 and 60 min) as well as the area under curve of OGTT increased in male rats after 30 days of exposure(P&lt;0. 05). The changes of blood glucose-regulating hormones were only found after the combined exposure of 10 mg/kg TiO_2 NPs+glucose for 30 days, including the decrease of insulin in female rats, as well as the decrease of insulin and the increase of glucagon in male rats(P&lt;0. 05). The interaction analysis showed that TiO_2 NPs and glucose had significant synergistic effect on postprandial blood glucose(60 min) in male rats(P&lt;0. 05). No abnormality was found in the pathological observation of pancreas in rats of experimental groups. Subacute combined oral exposure of TiO_2 NPs and glucose could affect the blood glucose homeostasis of young SD rats, resultsing in temporary hypoglycemia and impaired glucose tolerance, as well as adaptive changes of blood glucose-regulating hormones. The male rats were more sensitive. Compared with the exposure of TiO_2 NPs alone, the combined exposure of TiO_2 NPs and glucose induced more significant effects. Significant synergistic effect between them occurred on postprandial blood glucose.

Sitagliptin Increases Beta-Cell Function and Decreases Insulin Resistance in Newly Diagnosed Vietnamese Patients with Type 2 Diabetes Mellitus.

IntroductionTo investigate effects of Sitagliptin on the enhancement of beta-cell function, reducing insulin resistance, serum glucagon like peptide-1 (GLP-1) concentrations and blood glucose in patients with type 2 diabetes mellitus (T2D) and suggest one of the underlying mechanisms on beta-cell function and insulin resistance.Patients and MethodsThis was a cross-sectional and observational study in comparison to the control group. A study population of 44 newly diagnosed patients with T2D treated with Sitagliptin with a dose of 100 mg/day for 3 months was analyzed to compare 52 healthy participants. Indices for beta-cell function, peripheral insulin sensitivity, and insulin resistance were calculated with homeostasis model assessment 2 (HOMA2) calculator and compared. Serum GLP-1 concentrations were analyzed, and regression analysis was conducted to find the correlations between GLP-1 and beta-cell function and insulin resistance.ResultsNewly diagnosed patients with T2D witnessed a significant reduction in beta-cell function, serum GLP-1 concentrations at the time of diagnosis. After treatment with Sitagliptin 100 mg/day, they achieved significant improvements in beta-cell function, peripheral insulin sensitivity and insulin resistance. Serum GLP-1 concentrations were increased significantly to those levels in the control group and correlated with peripheral insulin sensitivity and insulin resistance in patients whose beta-cell functions improved.ConclusionSitagliptin improved beta-cell function, insulin resistance and blood glucose in newly diagnosed patients with T2D. Meanwhile, Sitagliptin ameliorated serum GLP-1 concentrations, which contributed to the enhancement of beta-cell.

Maternal Metabolic Alterations in Monosodium Glutamate Fed Rats during Gestation and Lactation Period

Background: Monosodium glutamate (MSG), an extensively used food additive, is claimed to cause many health problems, its use is still under debate. Aim: to explore the metabolic and hypertensive effect of MSG dietary administration in pregnant and lactating female rats, and its possible underlying mechanism. Methods: 16 adult female albino Wister rats were divided into 2 groups, control group; were fed standard rat chow, and MSG group; were fed 2% MSG supplemented rat chow throughout gestation and lactation period. Oral glucose tolerance test (OGTT) and arterial blood pressure (ABP) were measured at mid and late gestation, mid and late lactation periods. At mid lactation period, a retroorbital samples were analyzed for fasting glucose, lipid profile; triglycerides (TGs), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C), hormonal assays; insulin, glucagon, prolactin, corticosterone and ACTH, as well as pancreatic lipase, amylase and malondialdehyde (MDA). By the end of lactation, adipose tissue was assessed for glucose transporter-4 (GLUT-4) and hormone sensitive lipase (HSL) relative expression. Results: MSG rats showed elevated ABP during pregnancy and lactation, with impaired OGTT at mid and late lactation period. Fasting serum glucose, TGs, TC, LDL-C, glucagon, corticosterone, pancreatic lipase and amylase, MDA as well as adipose tissue HSL expression were significantly elevated, while, fasting serum insulin, ACTH and adipose tissue GLUT-4 expression were significantly declined in MSG fed rats as compared to control group. Conclusion: MSG feeding during pregnancy and lactation induced hypertension and metabolic alterations that could be due to pancreatic and adrenal affection secondary oxidative stress.

4447 Leptin supplementation prevents the loss of hypoglycemia-induced glucagon release following exposure to six days of severe caloric restriction in mice

OBJECTIVES/GOALS: We have recently shown that mice exposed to six days of 60% caloric restriction acutely display reduced hypoglycemia-induced glucagon release following refeeding, and that this effect is concurrent with low leptin levels. The current study was conducted to ascertain if leptin treatment during caloric restriction would reverse this effect. METHODS/STUDY POPULATION: Three groups of mice were used, an ad libitum (Ad-lib) fed group and two caloric restriction (CR) groups, one of which received twice daily leptin injection (0.5-1μg/g; IP) and the other vehicle (saline) during their caloric restriction. CR mice were placed on 60% caloric restriction for 6 consecutive days. Ad lib mice were housed in an identical manner but fed ad libitum during this same period. Following 6 days of restriction, CR mice were given ad lib access to food for 16 h. After the 16 h period of refeeding, both CR and ad lib mice began a 6 h fast which was immediately followed by a hypoglycemic insulin tolerance test (ITT). ITTs consisted of a variable dose of insulin intended to achieve a blood glucose of ~45 mg/dL within 60 minutes, at which time blood was collected for glucagon and corticosterone assays. RESULTS/ANTICIPATED RESULTS: The mean blood glucose levels during the ITT at 45 and 60 minutes post injection across all three groups were 46.8 + 3.1 and 37.0 + 2.4, respectively. There were no significant differences in glucose levels between the three groups at these two time points. As expected, saline treated CR mice displayed significantly reduced serum glucagon levels in response to the ITT relative to Ad-lib mice (23.5 + 10.9 vs. 91.7 + 20.8 pg/mL, p = 0.009). In contrast, leptin-treated CR mice maintained their hypoglycemia-induced glucagon response to the ITT (78.0 + 16.8 pg/mL, p&gt;0.99 vs. Ad-lib group). In addition, although corticosterone levels in saline treated CR mice were numerically lower than in Ad-lib mice, this difference was not statistically significance (3928 + 277 vs. 4571 + 178 pg/mL, p = 0.179). DISCUSSION/SIGNIFICANCE OF IMPACT: Diabetes patients on insulin therapy often develop impaired hypoglycemic counter-regulation which can lead to life-threatening hypoglycemic complications. Our results suggest that leptin may hold promise as a therapeutic intervention for the prevention of impaired hypoglycemic counter-regulation in persons with diabetes.

216-OR: O-GlcNAc Transferase in the Ventromedial Hypothalamus Regulates Lipid Metabolism through Fat Depot–Specific Sympathetic Innervation

The ventromedial hypothalamus (VMH) is a primary site that initiates counter-regulatory response and regulates food intake, maintaining glucose and lipid homeostasis. Known as a nutrient sensor and metabolic regulator, O-linked β-D-N-acetylglucosamine modification (O-GlcNAcylation) of intracellular proteins is catalyzed by O-GlcNAc transferase (OGT). How O-GlcNAc signaling in the VMH regulates whole-body metabolism remains unknown. Here, using the mouse model with VMH neuron-specific OGT deletion (VOK), we report that OGT is a nutrient sensor in VMH neurons that primarily regulates lipid metabolism. VOK mice show increased body weight and adiposity as well as reduced energy expenditure. OGT deletion in VMH neurons has no significant effects on food intake, physical activity, substrate utilization, glucose tolerance or insulin sensitivity. Lipolysis in subcutaneous and visceral white adipose tissues (WATs) is reduced in VOK mice, indicated by reduced activation of hormone-sensitive lipase (HSL) via cAMP-dependent protein kinase (PKA). In addition, VOK mice have lower serum glucagon and norepinephrine levels and show impaired depot-specific sympathetic innervation to WATs. These data reveal that O-GlcNAc signaling in VMH neurons specifically controls lipid metabolism through depot-specific sympathetic innervation. Disclosure Q. Wang: None. B. Zhang: None. Y. Yang: None. J. Mi: None. G. Tian: None. Q. Ong: None. X. Yang: None. Funding American Diabetes Association (1-19-IBS-119 to X.Y.); National Institutes of Health (R01DK089098, R01DK102648)

In utero exposure to dexamethasone programs the development of the pancreatic β- and α-cells during early postnatal life

AimsThe aim of the present study was to clarify if in utero exposure to DEX would affect the development of different types of pancreatic endocrine cells during postnatal life. Main methodsWe investigated morphological and transcriptional features of both pancreatic β- and α-cell populations within the pancreatic islets during the early postnatal life of rats born to mothers treated with DEX (0.1 mg/kg) from day 14 to 19 of pregnancy. Untreated pregnant Wistar rats of the same age (12-week-old) were used as control (CTL). Pups were euthanized on the 1st, 3rd and 21st (PND1, PND3 and PND21, respectively) days of life, regardless of sex. Serum insulin and glucagon levels were also evaluated. Key findingsRats born to DEX-treated mothers exhibited increased pancreatic α-cell mass, circulating glucagon levels and Gcg, Pax6, MafB and Nkx2.2 expression. Rats born to DEX-treated mothers also presented a rise in serum insulin levels on the PND3 that was paralleled by reduced β-cell mass. Such increase in serum insulin levels, instead, was associated with increased expression of genes associated to insulin secretion such as Gck and Slc2a2. SignificanceAltogether, the present data reveals yet unknown changes in endocrine pancreas during early postnatal life of rats exposed to DEX in utero. Such data may contribute to the understanding of the metabolic features of rats born to DEX-treated mothers.

MON-912 Undiagnosed Chronic Eczema as a Presentation of Glucagonoma in MEN 1 Syndrome

Background: Glucagonomas are pancreatic tumors arising from the islets cell of Langerhans that over secrete glucagon. Necrolytic migratory erythema (NME) is an important feature for the recognition of glucagonomas. Glucagonomas occurring in MEN1 is infrequent and seen in less than 3% of all glucagonomas. Clinical Case: A 51-year-old male presented to the clinic multiple visits for rash affecting the legs and genital area of two months. His medical history include type 2 DM and HT. The rash was attributed to subacute eczema and treated with topical steroids but showed no improvement. The skin eruption initially appeared on lower extremities progressed to trunk, and face. The skin lesions were associated with weight loss and stomatitis. On physical examination, skin showed ill-defined erythematous plaque exhibiting annular pattern, scale, and erosion on all extremities and perioral area. When the skin lesions healed, the new cutaneous eruptions occurred. Laboratory testing revealed plasma glucose of 185 mg/dL. The skin biopsy reported vacuolated keratinocytes in the epidermis with eosinophil cytoplasm, compatible with NME leading to further workup for pancreatic tumor. CT abdomen revealed tumor mass 9.6x6 cm at the pancreatic tail and multiple nodules in the liver. Somatostatin receptor scintigraphy showed an area of increased radiotracer uptake at the tail of the pancreas and multiple liver nodules corresponding to the previous CT scan. Serum glucagon was 923 pg/mL, confirming the diagnosis for glucagonoma. The patient was treated with distal pancreatectomy, and enucleation of liver metastases. Histopathological reported grade 2 well-differentiated NET. During the admission, the patient was found to have a parathyroid level of 79.3 pg/mL and increased uptake in the left and right lower regions of the thyroid gland from parathyroid MIBI scan, indicating hyperfunctioning parathyroid glands. All pituitary hormones were within normal ranges and no pituitary tumor was detected by the MRI brain. BMD showed osteoporosis at the lumbar spine and left femoral neck. The patient was referred to general surgery for subtotal parathyroidectomy. Pathological of resected parathyroid glands reported parathyroid hyperplasia. Postoperative PTH level and calcium were returned to normal range. Genetic testing focused on MEN1 gene, and the mutation was identified. After four months follow up plasma glucagon decreased to 425 pg/dL, patient had complete resolution of the cutaneous lesions. Conclusion: Glucagonomas are a rare pancreatic tumors and often difficult to recognize. Chronic eczema may misdiagnose for NME and delay diagnosis. NME can be challenging for physicians to recognize NME which is an important key to diagnose glucagonoma. Even though MEN1 association with glucagonoma is infrequent, awareness of such is important to allow appropriate testing for MEN1 in patients with glucagonoma.

SUN-926 Malignant Transformation of a Benign Glucagonoma After 13 Years

Glucagonoma are rare neuroendocrine tumors arising solely in the pancreas and approximately 25 % of glucagonoma cases start in a benign form. We hereby report a 76 -year-old male who was initially diagnosed with asymptomatic benign glucagonoma. Follow-up surveillance 13 years later shows that the tumor has undergone differentiation into a malignant form. Case Report: A 63-year-old man was referred for evaluation of an enhancing lesion (2.7 cm) at the pancreatic tail. He was completely asymptomatic with normal physical exam. Initial labs: normal except for elevated serum glucagon level (206 pg/mL, ref 0–60). A 2-hour oral GTT confirmed the autonomy of glucagon secretion by the tumor. Somatostatin and other tumor markers were normal. PET scan showed abnormal uptake at the distal pancreatic tail, correlating with the CT scan findings. The patient underwent laparoscopic distal pancreatectomy, with removal of a 2.8cm mass which predominantly expressed glucagon. Plasma glucagon level in the peripheral venous blood and intraoperative splenic vein dropped to <50 pg/mL immediately after the surgical resection. Following surgery patient remained completely asymptomatic for the next 13 years with normal blood glucose, glucagon, insulin, chromogranin levels, complete blood count and liver functions. Additionally patient continued to have normal surveillance MRIs of the abdomen. 13 years following removal of pancreatic mass, an elevated glucagon serum level (230 pg/mL) was noted on routine surveillance screening. At this time patient also remained asymptomatic. Abdominal MRI and PET scan revealed a 4-cm pancreatic mass with hepatic metastases. Biopsy of the hepatic lesion confirmed glucagonoma. Patient was treated with Lanreotide which has normalized the serum glucagon levels and the tumor size remained stable for the 12 months of follow up. Discussion: In our patient the glucagon secreting tumor without any classic presenting symptoms was found incidentally and the asymptomatic glucagonoma treated surgically presumably at an earlier stage. It is known that some glucagonomas are associated with serum levels of the peptide in the “physiologically elevated” range, even in the presence of necrolytic migratory erythema. The complete remission without any treatment lasting for more than 13 years confirmed the benign nature of the tumor. It is also reported that gluconomas less than 2 cm in size has less potential for metastasis. The usual recommendation is to monitor these patients post-resection to a maximum of 10 years although in our patient the malignant nature of the tumor was expressed 13 years after initial resection. The reason for malignant transformation after this prolonged period remains unknown. This case highlights the importance of continuous monitoring neuroendocrine tumors even beyond 10 years after surgery.

Effect of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy in Japanese Subjects with Type 2 Diabetes Mellitus: A Retrospective Study.

Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been very often used in subjects with type 2 diabetes mellitus (T2DM). In addition, combination drugs of both inhibitors have attracted much attention in aspects of its cost-effectiveness and improvement of patients' adherence. However, it is still poorly understood which factors are related to the efficacy of SGLT2 inhibitors as add-on therapy to DPP-4 inhibitors. Therefore, we aimed to elucidate in which type of individuals and/or under which conditions canagliflozin as add-on therapy to teneligliptin could exert more beneficial effects on glycemic control and/or renal protection. We retrospectively analyzed 56 Japanese subjects with T2DM in the real-world clinical practice. Three months after starting the combination therapy, the change of HbA1c (ΔHbA1c) was strongly related to HbA1c levels at baseline. As expected, serum glucagon level was increased after starting the combination therapy. Interestingly, however, the change of glucagon levels (Δglucagon) was not related to HbA1c levels at baseline, ΔHbA1c, and other parameters, which indicated that the increase of glucagon did not clinically affect the effectiveness of combination therapy. In addition, the change of urinary albumin excretion (ΔUAE) was negatively correlated with systolic blood pressure and HbA1c levels at baseline and positively correlated with the change of systolic blood pressure (ΔsBP) in univariate analysis. Furthermore, in multivariate analysis, only ΔsBP was the independent factor associated with ΔUAE. Taken together, canagliflozin as add-on therapy to teneligliptin improves glycemic control in a Δglucagon-independent manner and reduces UAE in a ΔsBP-dependent manner in Japanese subjects with T2DM.

Analysis of Astragalus Polysaccharide Intervention in Heat-Stressed Dairy Cows’ Serum Metabolomics

Simple SummaryHeat stress reduces cow growth, milk yield and reproductive performance, and results in a significant economic loss for the dairy industry. Astragalus polysaccharides (APS), one major active ingredient of astragalus, have a wide range of biological activities. The results of the study revealed that APS has a significant effect on the levels of cortisol (COR), triiodothyronine (T3) and thyroxine (T4) in dairy cows’ serum under heat stress. Moreover, twenty metabolites were identified as potential biomarkers for the diagnosis of APS in heat-stressed dairy cows, and APS regulates the energy metabolism of heat stressed dairy cows through glucose metabolism and amino acid metabolism.This experiment was conducted to investigate the effects of astragalus polysaccharides (APS) on serum metabolism of dairy cows under heat stress. Thirty healthy Holstein dairy cows were randomly divided into three groups (10 cows in each group). In the experimental group, 30 mL/d (Treatment I) and 50 mL/d (Treatment II) of APS injection were injected into the neck muscle respectively. Each stage was injected with APS for 4 days (8:00 a.m. every day) and stopped for 3 days. Serum hormone and antioxidant indexes of dairy cows were investigated. Through repeated measurement analysis of variance, the results have shown that cortisol (COR) (F = 6.982, p = 0.026), triiodothyronine (T3) (F = 10.005, p = 0.012) and thyroxine (T4) (F = 22.530, p = 0.002) at different time points were significantly different. COR showed a downward trend, T3 and T4 showed an upward trend. At each time point, different concentrations of APS have significant effects on COR (F = 30.298, p = 0.000 < 0.05), T3 (F = 18.122, p = 0.001), and T4 (F = 44.067, p = 0.000 < 0.05). However, there were no significant differences in serum insulin (INS), glucagon (GC) and heat shock protein 70 (HSP70) between different time points (p > 0.05) and at each time point (p > 0.05). Additionally, the results have also shown that there were also no significant differences in serum Superoxide dismutase (SOD), malondialdehyde (MDA) and lactate dehydrogenase (LDH) between different time points (p > 0.05) and at each time point (p > 0.05). However, the injection of APS had a significant impact on glutathione peroxidase (GSH-Px) (F = 9.421, p = 0.014) at different times, and showed a trend of rising first and then falling. At each time point, APS of different concentrations had no significant effect on GSH-Px (p > 0.05). Furthermore, we used gas chromatography–mass spectrometry (GC-MS) non-targeted metabolomics to determine the potential markers of APS for heat-stressed dairy cows. Twenty metabolites were identified as potential biomarkers for the diagnosis of APS in heat-stressed dairy cows. These substances are involved in protein digestion and absorption, glutathione metabolism, prolactin signaling pathway, aminoacyl-tRNA biosynthesis, pentose and glucuronate interconversions, and so on. Our findings suggest that APS have an effect on the serum hormones of heat-stressed dairy cows, and regulate the metabolism of heat-stressed dairy cows through glucose metabolism and amino acid metabolism pathways.

A Study on the Effect of Glucagon Like Peptide 1 Agonist on Glycemic State, Renal Functions and Some Hemodynamic Parameters in Diabetic Male Albino Rats

Abstract Background: Vascular and renal complications are com-mon associations to diabetes mellites despite current therapies. Glucagon like peptide 1 may present a recent solution to these complications and provide a better control. Aim of Study: This investigation aimed to study the effects of glucagon like peptide 1 receptor agonist on induced type 2 diabetes mellitus and the possible underlying mechanisms. Methods: Fifty male albino rats classified into five groups, 10 rats each: Non diabetic, diabetic non treated, diabetic metformin-treated, exendin-4 treated diabetic and combined metformin & exendine-4 treated diabetic groups. After 7 weeks, systolic blood pressure, renal blood flow and renal resistance were measured. Urine volume per minute, urine creatinine, creatinine clearance, fasting blood glucose, glyc-osylated hemoglobin (HbA1c %), serum insulin, serum glu-cagon, blood urea nitrogen, total anti-oxidant capacity, serum malondialdehyde (MDA) and serum tumor necrosis factor alpha (TNFa) were assessed. Results: The diabetic metformin, exendine-4-and combined metformin & exendine-4-treated groups revealed significant improvement in glycemic state, oxidative stress, inflammatory state, hemodynamic parameters and renal functions compared to the corresponding values of diabetic non-treated group. Exendin-treated group significantly decreased the previously mentioned parameters plus glucagon level compared to diabetic non-treated and diabetic metformin-treated groups. Combined metformin & exendine-4-treated group showed improvement of all previously mentioned parameters more than each treat-ment alone. Conclusion: Exendine-4 treatment improved diabetic parameters and associated hemodynamic and renal complica-tions more effective than that of the specific agents as met-formin. Combined metformin treatment with exendine-4 showed significant improvement than that of using each of them alone.

Hormonal and molecular alterations induced by sub-lethal toxicity of zinc oxide nanoparticles on Oreochromis niloticus.

This study was carried out to determine the biochemical and molecular potential effects of Zn-ONPs sub-lethal toxicity on the hormonal profile of Oreochromis niloticus (O. niloticus). One hundred and fifty O. niloticus juvenile female were used in this experiment; Ninety for determination of LC50 and other 60 fish were divided into 3 groups with 20 fish each (two replicate in each group). Group I used as control group whereas other groups treated with 1/20 and 1/30 of LC50 respectively for 4 days. Serum, pituitary gland, hepatic, pancreatic and muscular tissues were obtained for hormonal and molecular evaluation. Serum growth hormone (GH), thyroid stimulating hormone (TSH), triiodothyronine (T3), tetraiodothyronine (T4), follicular stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone and insulin hormones were significantly decreased with a significant increase in both Adrenocorticosteroid hormone (ACTH) and cortisol levels with no change in serum glucagon levels. On molecular levels there were a significant down regulation in transcriptional levels of GH, Insulin like growth factor I (IGF-I), insulin and Insulin receptor-A (IRA genes. These results suggested that, hormonal and molecular alterations can be used as an early biomarkers for Zn-ONPs toxicity in fish.

Osmotic stimulation of vasopressin acutely impairs glucose regulation: a counterbalanced, crossover trial

Epidemiological studies in humans show increased concentrations of copeptin, a surrogate marker of arginine vasopressin (AVP), to be associated with increased risk for type 2 diabetes. To examine the acute and independent effect of osmotically stimulated AVP, measured via the surrogate marker copeptin, on glucose regulation in healthy adults. Sixty subjects (30 females) participated in this crossover design study. On 2 trial days, separated by ≥7 d (males) or 1 menstrual cycle (females), subjects were infused for 120 min with either 0.9% NaCl [isotonic (ISO)] or 3.0% NaCl [hypertonic (HYPER)]. Postinfusion, a 240-min oral-glucose-tolerance test (OGTT; 75 g) was administered. During HYPER, plasma osmolality and copeptin increased (P<0.05) and remained elevated during the entire 6-h protocol, whereas renin-angiotensin-aldosterone system hormones were within the lower normal physiological range at the beginning of the protocol and declined following infusion. Fasting plasma glucose did not differ between trials (P>0.05) at baseline and during the 120 min of infusion. During the OGTT the incremental AUC for glucose from postinfusion baseline (positive integer) was greater during HYPER (401.5±190.5 mmol/L·min) compared with the ISO trial (354.0±205.8 mmol/L·min; P<0.05). The positive integer of the AUC for insulin during OGTT did not differ between trials (HYPER 55,850±36,488 pmol/L·min compared with ISO 57,205±31,119 pmol/L·min). Baseline values of serum glucagon were not different between the 2 trials; however, the AUC of glucagon during the OGTT was also significantly greater in HYPER (19,303±3939 ng/L·min) compared with the ISO trial (18,600±3755 ng/L·min; P<0.05). The present data indicate that acute osmotic stimulation of copeptin induced greater hyperglycemic responses during the oral glucose challenge, possibly due to greater glucagon concentrations.This study was registered at clinicaltrials.gov as NCT02761434.