The Change in Glucagon Following Meal Ingestion Is Associated with Glycemic Control, but Not with Incretin, in People with Diabetes

Background: We aimed to investigate the changes in glucagon levels in people with diabetes after the ingestion of a mixed meal and the correlations of variation in glucagon levels with incretin and clinico-biochemical characteristics. Methods: Glucose, C-peptide, glucagon, intact glucagon-like peptide 1 (iGLP-1), and intact glucose-dependent insulinotropic polypeptide (iGIP) were measured in blood samples collected from 317 people with diabetes before and 30 min after the ingestion of a standard mixed meal. The delta (Δ) is the 30-min value minus the basal value. Results: At 30 min after meal ingestion, the glucagon level showed no difference relative to the basal value, whereas glucose, C-peptide, iGLP-1, and iGIP levels showed a significant increase. In univariate analysis, Δglucagon showed not only a strong correlation with HbA1c but also a significant correlation with fasting glucose, Δglucose, and estimated glomerular filtration rate. However, Δglucagon showed no significant correlations with ΔiGLP-1 and ΔiGIP. In the hierarchical multiple regression analysis, HbA1c was the only variable that continued to show the most significant correlation with Δglucagon. Conclusions: People with diabetes showed no suppression of glucagon secretion after meal ingestion. Patients with poorer glycemic control may show greater increase in postprandial glucagon level, and this does not appear to be mediated by incretin.

Benign-Appearing Glucagonoma Undergoing Malignant Transformation after a Prolonged Period

Glucagonoma are rare neuroendocrine tumors arising in the Langerhans islets of the pancreas. We report a patient with glucagonoma differentiation into a malignant form after 13 years. A 63-year-old asymptomatic man was evaluated for an enhancing lesion at the distal pancreas. Physical examination was normal. Laboratory values were normal except for an elevated serum glucagon level (206 pg/mL, Ref. 50–150). Somatostatin and other tumor markers were normal. A PET scan confirmed abnormal uptake at the distal pancreas, correlating with a CT scan. The patient underwent laparoscopic distal pancreatectomy with resection of a 2.6-cm mass which predominantly expressed glucagon. Serum glucagon levels normalized immediately postoperatively. He remained asymptomatic for 13 years with normal blood glucose, glucagon, and chromogranin levels and normal surveillance MRI scans. Thirteen years following surgery, an elevated serum glucagon level (230 pg/mL) was observed. At this time he also remained asymptomatic. Abdominal MRI and a PET scan revealed hepatic lesions. Biopsy of the hepatic lesion confirmed metastatic glucagonoma. The patient was treated with lanreotide, which normalized the serum glucagon levels, and the tumor size remained stable for 12 months of follow-up. Complete remission without any treatment for more than 13 years confirmed the benign course of the glucagon-secreting tumor. The precipitating factors are unknown. This case highlights the importance of continuous monitoring of neuroendocrine tumors even beyond 10 years.

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.

Relationship Between Fasting Plasma Glucagon Level and Renal Function—A Cross-Sectional Study in Individuals With Type 2 Diabetes

Background and Aim The kidney is the main site for glucagon clearance. However, a recent study showed that hyperglucagonemia in patients with end-stage renal disease might not be caused by full-length intact glucagon. Additionally, the relationship between glucagon and renal function in early-stage chronic kidney disease (CKD) has not yet been characterized. We studied the association of fasting glucagon with renal function across a wide range of glomerular filtration rates (GFRs) in participants with type 2 diabetes. Participants and Methods 326 participants with type 2 diabetes and renal function spanning CKD stage 1 to 5 were included in the present cross-sectional study. Fasting full-length plasma glucagon was quantified using a newly developed ELISA (Mercodia AB, Uppsala, Sweden). Results The fasting plasma glucagon level was elevated linearly from CKD stage 1 to 5 [from a median of 2.5 pM (interquartile range, 1.4 to 4.7) in CKD 1 to a median of 8.3 pM (interquartile range, 5.9 to 12.8) in CKD 5; P for trend < 0.0001], from as early as CKD stage 2 compared with that in stage 1 (Bonferroni-corrected P < 0.0001). The estimated GFR and homeostatic model of assessment–insulin resistance were the main determinants of the fasting glucagon level. These explained 14.3% and 10.3% of the glucagon variance, respectively. Albuminuria was not associated with fasting glucagon after adjustment for estimated GFR. Conclusions Fasting full-length glucagon was elevated linearly with the deterioration in renal function in individuals with type 2 diabetes, even in those with early CKD. In addition to renal function, insulin sensitivity was also a main determinant of glucagon variance.

Glucagon-like peptide-2 and glucagon in patients with acromegaly and Cushing’s disease: secretion features and influence on glucose metabolism

Aim. To analyze secretion of GLP-2 and glucagon in patients with Cushing’s disease (CD) and acromegaly in response to glucose load. Material and methods. The study included 42 patients with Cushing’s disease and acromegaly; the mean patient age was 37.5 years. All patients were newly diagnosed with Cushing’s disease and acromegaly: none of them had a history of previous drug therapy, radiotherapy, or pituitary surgery. All patients underwent the oral glucose tolerance test with measurements of glucose, glucagon, and GLP-2 levels at 0, 30, and 120 min, respectively. Results. A significantly higher glucagon level was observed in CD patients at all cut-off points (р=0.001); in acromegaly patients, the glucagon level did not significantly differ from that in controls (р=0.12). The GLP-2 concentration in CD patients was also significantly higher compared to that in controls (р<0.001). There were no significant differences between acromegaly patients and controls. We also found a strong correlation between GLP-2 and glucagon levels at 0 and 30 min in CD patients. In acromegaly patients, a correlation between GLP-2 and glucagon levels was observed only at 0 min. Different GLP-2 and glucagon secretion patterns in patients with CD and acromegaly suggest a direct influence of glucocorticoids on glucagon secretion and no influence in the case of IGF-1. Conclusion. The found correlation between GLP-2 and glucagon levels might help specify the role of GLP-2 in carbohydrate metabolism regulation. Interactions of cortisol, IGF-1, and GLP-2 look promising for a better understanding of secondary hyperglycemia pathogenesis.