Glucagon Levels Research Articles

OR12-03 The Pancreatic Islet Alpha Cell Arginine Transporter SLC7A2 Regulates Arginine-induced Glucagon Secretion and Glycemia

Abstract Disclosure: J.E. Stanley: None. A. Reuter: None. K. Sellick: None. A.D. Attie: None. M.P. Keller: None. E. Dean: None. Glucagon secreted from pancreatic islet α cells stimulates both hepatic glycogenolysis and gluconeogenesis resulting in the fractional extraction of amino acids from the blood. Thus, glucagon stimulates hepatic glucose output and raises blood glucose. When liver glucagon signaling is impaired, amino acid accumulation (hyperaminoacidemia) promotes subsequent α cell hyperplasia and hyperglucagonemia via this liver-α-cell axis, an endocrine feedback loop. We show that high levels of both glutamine and recently arginine are required to stimulate α cells to proliferate. Arginine also potently stimulates glucagon secretion, but the mechanisms behind this are not well defined. We find that the cationic amino acid transporter, SLC7A2/CAT2 is the most highly expressed amino acid transporter in human pancreatic α cells and three-fold higher in α cells than it is in β-cells in both mouse and human islets. We also find two SNPs in the human SLC7A2 locus are strongly associated with HbA1c (rs142010226 (A/G) - chr8: 17,367,112; p=9.11e-18; β=0.0113 and rs2517232 - chr8: 17,367,421; p=2.553e-14; β=-0.0283). Both SNPs are in the first intron of SLC7A2 but appear to exert opposite effect on HbA1c and associated with distinct haplotype blocks. ATAC-Seq analyses of human islets show that these SNPs are within 1 kb of binding sites for MAFB and FOXA2 transcription factors, both critical for α cell gene expression. To test if α cell expression of SLC7A2 plays a role in both glycemia and arginine-stimulated glucagon secretion, we generated α cell-specific Slc7a2-/- (α7A2KO) mice. Blood glucose and glucagon levels were not significantly different after a 6-hour fast in α7A2KO and 7A2WTCre+ mice. After a 6-hour fast, mice were administered an arginine bolus (2g/kg) via intraperitoneal injections and their blood glucose and glucagon levels were measured 15 minutes post-injection. α7A2KO mice had a significantly higher blood glucose level than 7A2WTcre+ mice after stimulation with arginine (arginine-stimulated blood glucose - 7A2WTCre+ 124.3 ± 26.7 mg/dl vs. α7A2KO 159.6 ± 32.1 mg/dl n=23-25 p=0.0019). However, glucagon secretion was significantly lower after stimulation with arginine in the α7A2KO mice compared to the 7A2WTCre+ mice (arginine-stimulated glucagon - 7A2WTCre+ 321.8 ± 171.9 pM vs. α7A2KO 74.6 ± 22.8 pM n=4-6; p<0.0001). Together, these data indicate that SLC7A2 mediates arginine’s effects in α cells and plays an important role in regulating glycemia. Presentation: Friday, June 16, 2023

THU536 Pseudoglucagonoma Syndrome: A Rare Complication After Partial Pancreatectomy

Abstract Disclosure: E.P. Monsour: None. S. Badour: None. K.M. Tuna: None. J. Leey: None. M. Lamas: None. Introduction/Background: Necrolytic migratory erythema (NME) is a specific cutaneous eruption associated with glucagonoma, an alpha-cell secreting pancreatic neuroendocrine tumor. Glucagonoma syndrome is a paraneoplastic syndrome characterized by NME, diabetes, stomatitis, anemia, weight loss, and gastrointestinal disturbances. Rarely NME can occur in the absence of an alpha-cell tumor of the pancreas, termed pseudoglucagonoma syndrome, seen in other clinical entities such as hepatic disease and intestinal malabsorption. Here, we describe a rare case of pseudoglucagonoma syndrome as a long-term complication following partial pancreatectomy. Clinical Case: A 45-year-old male with a history of benign pancreatic head cyst s/p partial pancreatectomy, pancreatic exocrine insufficiency, and pancreatogenic diabetes reported a 2-week history of a rash on his bilateral upper and lower extremities that was accompanied with blistering and skin peeling. Associated symptoms included tongue pain, diarrhea, and worsening paresthesias. Medications included subcutaneous insulin aspart, pantoprazole, and pancrelipase. Physical examination revealed a patchy rash with hyperpigmented plaques and shellac-like scales, a smooth red tongue, and symmetric hyperreflexia. Preliminary punch biopsy was concerning for NME; thus, the patient was evaluated for possible glucagonoma. Laboratory evaluation revealed normocytic anemia with hemoglobin of 9.8 mg/dL, plasma glucose of 104 mg/dL, and glucagon level of 103 ng/L (RR: <208 ng/L). MRCP was negative for any pancreatic lesions. The patient was further evaluated for nutritional deficiencies and had strinkingly low vitamin A, D, E, K, B6, serum copper, and zinc levels. Plasma amino acids revealed low phenylalanine and tryptophan levels. He was started on a multivitamin (with minerals) and oral nutritional supplements with resolution of rash and subsequent improvement in symptoms. Final pathology of punch biopsy revealed parakeratosis with dermal edema, most compatible with nutritional deficiency. Discussion and conclusion: The pathogenesis and etiology of NME in glucagonoma and pseudoglucagonoma syndromes are not entirely understood. NME is thought to be multifactorial to multiple (essential) nutrient and vitamin deficiencies, as seen in our patient and other nutrient deficiency dermatoses such as zinc deficiency, necrolytic acral erythema, and pellagra. After further investigation, the patient reported poor adherence to pancrelipase supplementation, likely contributing to his clinical presentation and symptoms. Whereas in glucagonoma, excess glucagon levels cause a state of catabolism and exert its effect on the liver to increase gluconeogenesis via amino acid catabolism leading to deficiency. It is essential for clinicians to be aware of this rare and underrecognized phenomenon. Presentation: Thursday, June 15, 2023

THU526 Long-term Follow-up Of A Functional Gastroenteropancreatic Tumor Secreting Both Somatostatin And Gastrin

Abstract Disclosure: R. Zafar: None. J. Syeda: None. K. Rajamani: None. Introduction: There have been fewer than 200 cases of somatostatinoma reported since 1977. We report a case of a functional Gastroenteropancreatic neuroendocrine tumor (GEP-NET) secreting both somatostatin and gastrin. Clinical Case: A 55-year-old male with diabetes mellitus, chronic diarrhea, gastric ulcer, and cholelithiasis was referred to the endocrinology clinic for poorly controlled diabetes mellitus. He had a history of B-cell lymphoma of the thyroid treated by chemotherapy and radiation. He was found to have two paraduodenal masses by PET CT scan during surveillance for recurrence of lymphoma. Laboratory evaluation revealed elevated levels of insulin, glucagon, gastrin, somatostatin, and chromogranin A on multiple occasions both fasting and random. Ultrasound-guided endoscopic biopsy of the paraduodenal nodules was initially read as a neuroendocrine tumor. Subsequent immunohistochemical staining was positive for both somatostatin and gastrin. The stains were negative for glucagon and insulin. The Ki-67 proliferation index was less than 1%. The patient declined surgical treatment of the paraduodenal tumors. He underwent cholecystectomy for cholelithiasis. Gastric ulcers resolved with the use of proton pump inhibitors. His blood glucose was well controlled with insulin. Sequential CT/PET scans showed no change in the size of paraduodenal masses over a follow-up period of 14 years. Conclusion: GEP-NETs may secrete more than one type of hormone simultaneously. This case highlights a functional GEP-NET with clinical manifestations due to elevated levels of somatostatin and gastrin. Characterization of GEP-NETs by immuno-histochemical staining and hormonal analysis may help direct clinical management. Although many GEP-NETs are managed surgically, this case suggests that the Ki-67 proliferation index and sequential PET or CT scans may guide the nonsurgical management of functional GEP-NETs.

SAT638 Understanding Heritable Metabolic Alterations Upon Paternal Preconception Nicotine Exposure

Abstract Disclosure: S.R. Aguiar: None. R. Chamorro-Garcia: None. Exposure to endocrine-disrupting chemicals (EDCs) found in our environment can increase the risk of susceptibility to metabolic diseases, such as obesity and type 2 diabetes. Tobacco products harbor a cluster of harmful EDCs that are inhaled by smokers and dispersed through the air. Previous research showed that tobacco exposure during pregnancy can lead to developmental alterations that increase the risk of metabolic disease in the offspring later into adulthood. Although global tobacco use is higher among men than women, little is known about how paternal exposure to tobacco products contribute to metabolic disease in future unexposed generations. Paternal preconception exposure to environmental factors have been shown to lead to increased risk of disease in future offspring, though mechanisms of these heritable alterations remain unclear. Our research focuses on determining the mechanisms through which paternal preconception exposure to tobacco-related chemicals, such as nicotine, lead to metabolic disease, and the underlying mechanism of epigenetic inheritance of these metabolic traits. We hypothesize that paternal nicotine exposure elicits alterations in the paternal germline (i.e., sperm) that are transferred to the zygote upon fertilization leading to metabolic alterations in unexposed offspring. We found that paternal preconception exposure to nicotine leads to insulin resistance and increased plasma ghrelin levels in F1 females. In F1 males, we found different metabolic alterations in the form of altered fasting glucose levels and decreased plasma glucagon levels. Taken together, our current data suggest that paternal preconception nicotine exposure may alter ghrelin signaling pathways that lead to metabolic disruption in F1 females, as well as alter glycogen mobilization in F1 males. To determine the mechanism behind these heritable metabolic alterations observed in paternal nicotine-exposed offspring, we will investigate small non-coding RNA populations in the sperm of nicotine-treated sires. We will characterize heritable alterations during early embryogenesis by whole genome transcriptomics. These approaches will identify the mechanisms behind heritable metabolic alterations observed in offspring paternally-exposed to nicotine, as well as indicate what specific transcripts are impacted during early embryogenesis that give rise to these phenotypes. This project will provide insights into the intergenerational metabolically disruptive effects of paternal tobacco use and the mechanism of inheritance that drives these phenotypes, ultimately providing more evidence to change tobacco policies and legislation. Presentation: Saturday, June 17, 2023

SAT610 Multiple Endocrine Neoplasia Type 1 - The First Reported Case In An Indigenous Australian

Abstract Disclosure: E. Mignone: None. K. Neal: None. Background: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare and under recognised syndrome. It has not been previously reported in Indigenous Australians for this reason. Clinical Case: A 48-year-old Indigenous Australian female was consulted on by an inpatient endocrine team in March 2020 for persistent hypercalcaemia on a background of a parathyroidectomy in 2011 for primary hyperparathyroidism (PHPTH). She was admitted to a remote Australian hospital for investigation and management of acute on chronic abdominal pain. Relevant medical history included a parathyroidectomy at age 40, multiple PE/DVT, MI, AF, CTEPH, right heart failure, HTLV-1 and recurrent abdominal pain presumed secondary to GORD. Gastroscopy from 2013 revealed chronic gastritis with hundreds of gastric polyps discovered on subsequent gastroscopy in 2015. The young age of PHPTH combined with her chronic gastritis and polyps prompted neuroendocrine tumour (NET) screening, including MEN1. At time of consult in 2020, laboratory studies were consistent with recurrence of PHPTH with a corrected calcium of 2.9 mmol/L (2.15-2.57mmol/L), serum PTH level 31.5 pmol/L (1-7pmol/L), vitamin D level 30 nmol/L, 24-hour urinary calcium variable between low and high. NET markers were markedly elevated with a gastrin level of 14042 ng/L (<100 ng/L), pancreatic polypeptide 2905 pmol/L (<55 pmol/L), urine 5HIAA ratio 8 mmol/L (<4 mmol/L), vasoactive intestinal peptide and glucagon levels normal. Pituitary studies, serum calcitonin, plasma metanephrines and PTH related protein levels were within normal limits. A CT of the abdomen showed thickened gastric folds, and persistent liver and IVC lesions from 2018. A diagnosis of Zollinger Ellison Syndrome (ZES) was made. Eventually, genetic testing was positive for a rare heterozygous variant of c.207dupC in exon 2 of MEN1 gene. A 68-gallium-DOTATATE PET/CT showed multiple avid pancreatic, gastric, nodal and liver lesions with high somatostatin receptor expression, suggestive of a neuroendocrine malignancy. Treatment was based largely on symptom control due to poor overall prognosis from underlying cardiorespiratory comorbidities. Abdominal pain from ZES was managed with a high dose PPI, H2 receptor antagonist and subcutaneous somatostatin analogue were trialled. Hypercalcaemia was treated with IV bisphosphonate therapy. Calcimimetic analogues were considered however patient declined. Genetic counselling was attempted however many cultural and logistical barriers were identified and family declined further testing. Unfortunately, our patient died in 2021 from presumed multifactorial respiratory failure. Conclusion: High index of suspicion is required to diagnose MEN1. This is particularly true within the Indigenous Australian population, with no prior documented cases reported. Presentation: Saturday, June 17, 2023

AN ANALYTICAL REVIEW-BASED STUDY ON SITAGLIPTIN

Sitagliptin is an oral anti-hyperglycemic agent of the dipeptidyl peptidase-4 (DPP-4) inhibitor magnificence used inside the remedy of type-2 diabetes. It stimulates insulin release and reduces glucagon levels by inhibiting of inactivation of the incretin in a glucose-dependent manner. In 2013 it was the second best- selling drug in the U.S. This evaluation encompasses diverse analytical strategies inclusive of spectrometry, high-overall performance liquid chromatography (HPLC), liquid chromatography-electrospray ionization- mass spectrometry (LC-ESI-MS-MS), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis (CE), ultra-overall performance liquid chromatography (UPLC), high-overall performance skinny layer chromatography (HPTLC) and fuel line chromatography-mass spectrometry (GC-MS) for the estimation of sitagliptin in unmarried and/or in combination. Keywords: Sitagliptin, Analytical methods, Type-2 diabetes.

Pituitary Stalk Interruption Syndrome in a Child: A Rare Case Report with Literature Review

Introduction Pituitary stalk interruption syndrome is an exceedingly rare congenital abnormality affecting the pituitary gland that is still not fully understood. This study presents a 7-year-old child with the disease. Case presentation A 7-year-old male child was presented with short stature, school performance postponement, and an intellectual disability at a mild level. At 6.5 years of age, he had no facial features, was wearing eyeglasses, and had a weight and height of 20 kg (25th percentile) and 101 cm (3rd percentile), respectively. At the age of 7 years, his height was 117 cm (10th percentile) and his weight was 25 kg (50th percentile). Most laboratory tests were normal. However, insulin-like growth factor-1 and glucagon levels were low. A dynamic magnetic resonance imaging of the pituitary gland revealed an ectopic posterior pituitary lobe and the absence of a pituitary stalk. The patient was put on hormone replacement therapy (Norditropin pen) to control the growth hormone deficiency, and he was put under a close follow-up to monitor growth and panhypopituitarism. Conclusion Although hormone replacement therapy is associated with satisfactory outcomes in treating the syndrome, lifelong follow-up is indicated as new hormone deficiencies may arise later in life.

Fluorescein-based sensors to purify human α-cells for functional and transcriptomic analyses.

Pancreatic α-cells secrete glucagon, an insulin counter-regulatory peptide hormone critical for the maintenance of glucose homeostasis. Investigation of the function of human α-cells remains a challenge due to the lack of cost-effective purification methods to isolate high-quality α-cells from islets. Here, we use the reaction-based probe diacetylated Zinpyr1 (DA-ZP1) to introduce a novel and simple method for enriching live α-cells from dissociated human islet cells with ~95% purity. The α-cells, confirmed by sorting and immunostaining for glucagon, were cultured up to 10 days to form α-pseudoislets. The α-pseudoislets could be maintained in culture without significant loss of viability, and responded to glucose challenge by secreting appropriate levels of glucagon. RNA-sequencing analyses (RNA-seq) revealed that expression levels of key α-cell identity genes were sustained in culture while some of the genes such as DLK1, GSN, SMIM24 were altered in α-pseudoislets in a time-dependent manner. In conclusion, we report a method to sort human primary α-cells with high purity that can be used for downstream analyses such as functional and transcriptional studies.

Regulation of the Cortisol Axis, Glucagon, and Growth Hormone by Glucose Is Altered in Prediabetes and Type 2 Diabetes.

Insulin-antagonistic, counter-regulatory hormones have been implicated in the development of type 2 diabetes (T2D). In this cross-sectional study, we investigated whether glucose-dependent regulation of such hormones differ in individuals with T2D, prediabetes (PD), and normoglycemia (NG). Fifty-four individuals with or without T2D underwent one hyperinsulinemic-normoglycemic-hypoglycemic and one hyperglycemic clamp with repeated hormonal measurements. Participants with T2D (n = 19) were compared with a group-matched (age, sex, BMI) subset of participants without diabetes (ND, n = 17), and also with participants with PD (n = 18) and NG (n = 17). In T2D vs ND, glucagon levels were higher and less suppressed during the hyperglycemic clamp whereas growth hormone (GH) levels were lower during hypoglycemia (P < .05). Augmented ACTH response to hypoglycemia was present in PD vs NG (P < .05), with no further elevation in T2D. In contrast, glucagon and GH alterations were more marked in T2D vs PD (P < .05).In the full cohort (n = 54), augmented responses of glucagon, cortisol, and ACTH and attenuated responses of GH correlated with adiposity, dysglycemia, and insulin resistance. In multilinear regressions, insulin resistance was the strongest predictor of elevated hypoglycemic responses of glucagon, cortisol, and ACTH. Conversely, fasting glucose and HbA1c were the strongest predictors of low GH levels during hypoglycemia and elevated, i.e. less suppressed glucagon levels during hyperglycemia, respectively. Notably, adiposity measures were also strongly associated with the responses above. Altered counter-regulatory hormonal responses to glucose variations are observed at different stages of T2D development and may contribute to its progression by promoting insulin resistance and dysglycemia.

Effects of dietary chromium supplementation on blood biochemical parameters in dairy cows: A multilevel meta-analytical approach

Chromium (Cr) has been reported to modulate blood biochemistry in dairy cows. However, there is a discrepancy in the literature regarding the effects of dietary Cr supplementation on various blood parameters. This meta-analysis aimed to evaluate the effects of Cr supplementation in dairy cows on blood glucose, insulin, glucagon, nonesterified fatty acid (NEFA), cortisol, and serum total protein (STP) concentrations. Following relevant literature data extraction, a 3-level meta-analytical random effect model was fitted to the data expressed as standardized mean difference (SMD) of outcome measures of control versus Cr-supplemented cows (i.e., difference in mean between control and treatment group or pooled standard deviation). The SMD can be categorized as having a small effect (0.20), a moderate effect (0.50), and a large effect (0.80). The meta-regression identified the potential sources of heterogeneity, including the body weight of cows, experimental duration/duration of Cr supplementation, blood sampling time (3 wk before parturition until 4 wk after parturition categorized as the transition period, else as the nontransition period), and form of Cr complexes. Blood glucose did not differ significantly between control and Cr-supplemented cows with an estimated SMD of μ = 0.0071 (95% confidence interval [CI]: -0.212 to 0.226). The effect of Cr supplementation on blood insulin was also nonsignificant with an SMD of μ = 0.0007 (95% CI: -0.191 to 0.193). Cows receiving Cr supplements had significantly higher levels of glucagon than controls (95% CI: 0.116 to 0.489), with an estimated SMD = 0.303. Combined transition and nontransition data suggest Cr supplementation did not affect the concentration of NEFA. However, in transition cows, Cr supplementation significantly decreased blood NEFA levels as compared with controls (95% CI: -0.522 to -0.0039), with estimated SMD = -0.263. The estimated SMD was μ = -0.1983 (95% CI: -0.734 to 0.337) for cortisol and -0.0923 (95% CI: -0.316 to 0.131) for total protein. In summary, Cr supplementation in the transition cows decreased NEFA concentration. Blood glucose, insulin, cortisol, and STP concentrations were unaffected. However, Cr supplementation increased glucagon concentration.

Thyroid Hormone Levels Correlate With the Maturation of Implanted Pancreatic Endoderm Cells in Patients With Type 1 Diabetes.

Macroencapsulated pancreatic endoderm cells (PECs) can reverse diabetes in rodents and preclinical studies revealed that thyroid hormones in vitro and in vivo bias PECs to differentiate into insulin-producing cells. In an ongoing clinical trial, PECs implanted in macroencapsulation devices into patients with type 1 diabetes were safe but yielded heterogeneous outcomes. Though most patients developed meal responsive C-peptide, levels were heterogeneous and explanted grafts had variable numbers of surviving cells with variable distribution of endocrine cells. We measured circulating triiodothyronine and thyroxine levels in all patients treated at 1 of the 7 sites of the ongoing clinical trial and determined if thyroid hormone levels were associated with the C-peptide or glucagon levels and cell fate of implanted PECs. Both triiodothyronine and thyroxine levels were significantly associated with the proportion of cells that adopted an insulin-producing fate with a mature phenotype. Thyroid hormone levels were inversely correlated to circulating glucagon levels after implantation, suggesting that thyroid hormones lead PECs to favor an insulin-producing fate over a glucagon-producing fate. In mice, hyperthyroidism led to more rapid maturation of PECs into insulin-producing cells similar in phenotype to PECs in euthyroid mice. These data highlight the relevance of thyroid hormones in the context of PEC therapy in patients with type 1 diabetes and suggest that a thyroid hormone adjuvant therapy may optimize cell outcomes in some PEC recipients.

Association of Glucagon to Insulin Ratio and Metabolic Syndrome in Patients with Type 2 Diabetes.

There is a growing interest in the role of glucagon in type 2 diabetes mellitus (T2DM). Glucagon and insulin regulate glucose and lipid metabolism. Metabolic syndrome is an important risk factor for cardiovascular disease in patients with T2DM. We investigated the association between glucagon to insulin ratio and metabolic syndrome in patients with T2DM. This is a cross-sectional study involving 317 people with type 2 diabetes. Glucagon and insulin levels were measured in a fasted state and 30 min after ingesting a standard mixed meal. The Criteria of the International Diabetes Federation defined metabolic syndrome. Two hundred nineteen (69%) of the subjects had metabolic syndrome. The fasting glucagon to insulin ratio was significantly lower in patients with metabolic syndrome (14.0 ± 9.7 vs. 17.3 ± 10.3, p < 0.05). The fasting glucagon to insulin ratio was significantly lowered as the number of metabolic syndrome components increased. In hierarchical logistic regression analysis, the fasting glucagon to insulin ratio significantly contributed to metabolic syndrome even after adjusting for other covariates. The fasting glucagon to insulin ratio is inversely associated with metabolic syndrome in patients with type 2 diabetes. This suggests that glucagon-targeted therapeutics may reduce cardiovascular risk by improving metabolic syndrome.

Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.

Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion. The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription. Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion. This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.

Characterization of impaired beta and alpha cell function in response to an oral glucose challenge in cystic fibrosis: a cross-sectional study.

The purpose of the study was to further elucidate the pathophysiology of cystic fibrosis (CF)-related diabetes (CFRD) and potential drivers of hypoglycaemia. Hence, we aimed to describe and compare beta cell function (insulin and proinsulin) and alpha cell function (glucagon) in relation to glucose tolerance in adults with CF and to study whether hypoglycaemia following oral glucose challenge may represent an early sign of islet cell impairment. Adults with CF (≥18 years) were included in a cross-sectional study using an extended (-10, -1, 10, 20, 30, 45, 60, 90, 120, 150, and 180 min) or a standard (-1, 30, 60, and 120 min) oral glucose tolerance test (OGTT). Participants were classified according to glucose tolerance status and hypoglycaemia was defined as 3-hour glucose <3.9 mmol/L in those with normal glucose tolerance (NGT) and early glucose intolerance (EGI). Among 93 participants, 67 underwent an extended OGTT. In addition to worsening in insulin secretion, the progression to CFRD was associated with signs of beta cell stress, as the fasting proinsulin-to-insulin ratio incrementally increased (p-value for trend=0.013). The maximum proinsulin level (pmol/L) was positively associated with the nadir glucagon, as nadir glucagon increased 6.2% (95% confidence interval: 1.4-11.3%) for each unit increase in proinsulin. Those with hypoglycaemia had higher 60-min glucose, 120-min C-peptide, and 180-min glucagon levels (27.8% [11.3-46.7%], 42.9% [5.9-92.85%], and 80.3% [14.9-182.9%], respectively) and unaltered proinsulin-to-insulin ratio compared to those without hypoglycaemia. The maximum proinsulin concentration was positively associated with nadir glucagon during the OGTT, suggesting that beta cell stress is associated with abnormal alpha cell function in adults with CF. In addition, hypoglycaemia seemed to be explained by a temporal mismatch between glucose and insulin levels rather than by an impaired glucagon response.

Synergistic effects of GABA and hypoglycemic drugs

Diabetes mellitus (DM) is the leading cause of premature death and disability. Despite a significant number of drugs, the effectiveness of therapy aimed at normalizing the level of glycemia and preventing complications does not fully satisfy doctors and patients. Therefore, the search for new approaches for the prevention and treatment of DM and its complications continues. Significant resources are used to develop new drugs, but recently the possibility of using «old» widely available drugs with newly discovered pleiotropic properties has been substantiated. These may include preparations of gammaaminobutyric acid (GABA) and agents that directly or indirectly activate GABAergic transmission, which have a pronounced pancreatic protective effect, which has been widely discussed in foreign literature over the past 10-15 years. However, there are few such publications in the domestic literature.It has been established that the content of GABA in β-cells in patients with type 1 and type 2 diabetes is reduced and this correlates with the severity of the disease. Genetic suppression of GABA receptors causes a significant decrease in the mass of β-cells and glucose-stimulated insulin secretion, which confirms the importance of GABA in ensuring glucose homeostasis and the advisability of replenishing the GABA deficiency in DM with its additional administration. It has been established that in animals with DM, GABA suppresses apoptosis and stimulates the regeneration of β-cells, increases β-cell mass and insulin production.Experimental data have been obtained indicating a synergistic effect of GABA when combined with glucagon-like peptide-1 (GLP-1) receptor agonists, DPP-4 inhibitors and sodium-glucose cotransporter 2 (SGLT-2) inhibitors, when a more pronounced pancreoprotective effect is observed, due to decrease in oxidative and nitrosative stress, inflammation, increase in the level of Klotho protein, Nrf-2 activity and antioxidant defense enzymes, suppression of NF-kB activity and expression of pro-inflammatory cytokines. As a result, all this leads to a decrease in apoptosis and death of β-cells, an increase in β-cell mass, insulin production and, at the same time, a decrease in glucagon levels and insulin resistance.The review substantiates the feasibility of using GABA and drugs with a positive GABAeric effect in combination with new generation antidiabetic agents: GLP-1 receptor agonists, DPP-4 inhibitors and SGLT-2 inhibitors in order to increase their antidiabetic potential.The search was carried out in the databases Pubmed, eLibrary, Medline. Keywords: diabetes mellitus, gamma-aminobutyric acid, glucagon-like peptide-1, GLP-1 receptor agonists, glucose-dependent insulinotropic peptide, dipeptidyl peptidase inhibitors, sodium-glucose cotransporter 2 inhibitors. The search was carried out from 2000 to 2022, but the review presents the results studies published mainly in the last 3 years, due to the requirements of the journal for the maximum amount of work and the number of sources.

Hepatoprotective and hypoglycemic effect of lactic acid fermented Indian Gooseberry-Amla beverage on chronic alcohol-induced liver damage and diabetes in rats

BackgroundPlant-based fermented foods rich in lactic acid bacterial metabolites, antioxidants, and phytochemicals, can promote recovery from ethanol-induced liver damage by restoring liver antioxidant levels and suppressing liver inflammation, and improving certain metabolic disorders such as diabetes mellitus. MethodsIn the present study, the protective effects of nutraceutical-enriched lactic acid-fermented Amla beverage on chronic alcohol-induced biochemical modulations and diabetes in Wistar rats were investigated. ResultsThe hepatoprotective studies showed that the fermented beverage was able to reverse the damage caused to the liver with ethanol administration in terms of liver index, liver enzymes (AST, ALT), serum enzymes (g-GT), and serum TG, TCH, hepatic TG, LPO levels, antioxidants (GSH, TSOD, CAT, GSH-Px). Along similar lines, in the hypoglycemic studies, the fermented beverage evidently improved body weight, and fasting blood glucose levels, reducing fasting HbAlc levels, improving C-peptide and GLP-1 levels, and alleviating renal dysfunction and lipid metabolism compared with diabetic rats. All these outcomes were supported by histological observations within the liver and pancreas. ConclusionThe present study suggests that the consumption of fermented Amla beverage may have a protective effect against chronic alcohol-induced toxicity and diabetes. The effects of fermented Amla beverage may be attributed to antioxidant activity, flavonoids, bioactive compounds produced by LAB and their metabolites, which help to counteract free radicals induced by ethanol and in reducing glucagon levels, enhancing glucose utilization, leading to a decrease in blood glucose. The results show that fermented Amla beverage has positive effects in reducing the detrimental effect of alcohol and diabetes.

Hookworm infection induces glycometabolic modulation in South Indian individuals with type 2 diabetes

ObjectivesA number of epidemiological studies have demonstrated that there is an inverse relationship between helminth infections and diabetes mellitus, suggesting that helminth infection may have a positive effect on type 2 diabetes mellitus (T2DM). However, the association between hookworm infection and T2DM has barely been studied. Hence, we aimed to investigate and analyze the interaction and association between hookworm infection and T2DM. MethodsWe examined the effect of hookworm infection on biochemical parameters, including plasma random blood glucose, glycated hemoglobin, and the plasma levels of pancreatic hormones, incretins, and adipokines in individuals with T2DM with (INF, n = 35) or without (UN, n = 35) hookworm infection. Moreover, we re-evaluated these analyte concentrations in a subset of INF individuals 6 months following anthelmintic therapy. ResultsCompared to UN individuals, INF individuals had significantly lowered levels of random blood glucose and glycated hemoglobin. INF individuals also exhibited significantly diminished levels of adiponectin, adipsin, C-peptide, insulin, and glucagon compared to UN individuals. In contrast, INF individuals displayed substantially elevated levels of visfatin and incretins compared to UN individuals. Interestingly, this effect was not seen following anthelmintic treatment. ConclusionOur study findings indicate that concomitant hookworm infection exerts a beneficial effect on glycometabolic parameters in T2DM.

Glucagon and Its Receptors in the Mammalian Heart.

Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system axis. The cardiac effects of glucagon vary according to species, region, age, and concomitant disease. Depending on the species and region studied, the contractile effects of glucagon can be robust, modest, or even absent. Glucagon is detected in the mammalian heart and might act with an autocrine or paracrine effect on the cardiac glucagon receptors. The glucagon levels in the blood and glucagon receptor levels in the heart can change with disease or simultaneous drug application. Glucagon might signal via the glucagon receptors but, albeit less potently, glucagon might also signal via glucagon-like-peptide-1-receptors (GLP1-receptors). Glucagon receptors signal in a species- and region-dependent fashion. Small molecules or antibodies act as antagonists to glucagon receptors, which may become an additional treatment option for diabetes mellitus. Hence, a novel review of the role of glucagon and the glucagon receptors in the mammalian heart, with an eye on the mouse and human heart, appears relevant. Mouse hearts are addressed here because they can be easily genetically modified to generate mice that may serve as models for better studying the human glucagon receptor.

Alpha cell receptor for advanced glycation end products associate with glucagon expression in type 1 diabetes

Hypoglycemia in type 1 diabetes associates with changes in the pancreatic islet α cells, where the receptor for advanced glycation end products (RAGE) is highly expressed. This study compared islet RAGE expression in donors without diabetes, those at risk of, and those with type 1 diabetes. Laser-dissected islets were subject to RNA bioinformatics and adjacent pancreatic tissue were assessed by confocal microscopy. We found that islets from type 1 diabetes donors had differential expression of the RAGE gene (AGER) and its correlated genes, based on glucagon expression. Random forest machine learning revealed that AGER was the most important predictor for islet glucagon levels. Conversely, a generalized linear model identified that glucagon expression could be predicted by expression of RAGE signaling molecules, its ligands and enzymes that create or clear RAGE ligands. Confocal imaging co-localized RAGE, its ligands and signaling molecules to the α cells. Half of the type 1 diabetes cohort comprised of adolescents and a patient with history of hypoglycemia—all showed an inverse relationship between glucagon and RAGE. These data confirm an association between glucagon and islet RAGE, its ligands and signaling pathways in type 1 diabetes, which warrants functional investigation into a role for RAGE in hypoglycemia.

Pro-resolving role of glucagon in lipopolysaccharide-induced mice lung neutrophilia.

Prior research demonstrated that glucagon has protective roles against inflammation, but its effect on the resolution of inflammation remains elusive. Using in vitro and in vivo approaches, this study aimed to investigate the pro-resolving potential of glucagon on pulmonary neutrophilic inflammation caused by lipopolysaccharide. Lipopolysaccharide induced an increase in the proportions of neutrophils positives to glucagon receptor (GcgR) in vitro. In addition, lipopolysaccharide induced an increase in the neutrophil accumulation and expression of GcgR by the inflammatory cells in the lungs, however, without altering glucagon levels. Intranasal treatment with glucagon, at the peak of neutrophilic inflammation, reduced the neutrophil number in the bronchoalveolar lavage (BAL), and lung tissue within 24 h. The reduction of neutrophilic inflammation provoked by glucagon was accompanied by neutrophilia in the blood, an increase in the apoptosis rate of neutrophils in the BAL, enhance in the pro-apoptotic Bax protein expression, and decrease in the anti-apoptotic Bcl-2 protein levels in the lung. Glucagon also induced a rise in the cleavage of caspase-3 in the lungs; however, it was not significant. Glucagon inhibited the levels of IL-1β and TNF-α while increasing the content of pro-resolving mediators transforming growth factor (TGF-β1) and PGE2 in the BAL and lung. Finally, glucagon inhibited lipopolysaccharide-induced airway hyper-reactivity, as evidenced by the reduction in lung elastance values in response to methacholine. In conclusion, glucagon-induced resolution of neutrophilic inflammation by promoting cessation of neutrophil migration and a rise of neutrophil apoptosis and the levels of pro-resolving mediators TGF-β1 and PGE2.