Continuous Glucagon Infusion Research Articles

In silico validation of a customizable fully-autonomous artificial pancreas with coordinated insulin, glucagon and rescue carbohydrates

Artificial pancreas systems should be designed considering different patient profiles, which is challenging from a control theory perspective. In this paper, a flexible-hybrid dual-hormone control algorithm for an artificial pancreas is proposed. The algorithm handles announced/unannounced meals by means of a non-interacting feedforward scheme that safely incorporates prandial boluses. Also, a coordination strategy is employed to distribute the counter-regulatory actions, which can be delivered as a continuous glucagon infusion via an automated pump, as an oral rescue carbohydrate recommendation, or as a rescue glucagon dose recommendation to be administrated through a glucagon pen. The different configurations of the proposed controller were evaluated in silico using a 14-day virtual scenario with random meal intakes and exercise sessions, achieving above 80% time-in-range and low time spent in hypoglycemia.

Unveiling the Downside of Glucagon Therapy for Neonatal Hypoglycemia: A Case Report

Here we report a case of a late preterm baby, noted to have asymptomatic hypoglycemia and developed transient metabolic acidosis with hyponatremia and hyperkalemia whilst being treated with continuous infusion of glucagon.

FRI667 Profound And Persistent Hypoglycemia With Hepatocellular Carcinoma- A Non-islet Cell Tumor

Abstract Disclosure: A. Muneeb: None. M. Shahid: None. M. Raza: None. H. Zahoor: None. S. Sultan: None. Introduction: Tumor related hypoglycemia is rare and can be caused by islet cell tumors or non-islet cell tumors (NICT). Proposed mechanisms for non-islet cell tumor hypoglycemia (NICTH) include: increased big-IGF production (precursor of IGF2 which acts similar to insulin); increased insulin production; infiltration of liver/adrenals; and autoantibodies to insulin receptors. Clinical Case: A 78-year-old female with pertinent medical history of recently diagnosed locally advanced hepatocellular carcinoma (HCC) was found unresponsive at home. On arrival of EMS, the blood glucose (BG) level was in 30s. Dextrose water was administered that resulted in improvement of her mentation. She was alert and awake when brought to the hospital but was persistently hypoglycemic despite frequent feeding. She was started on dextrose infusion and was admitted for workup of persistent hypoglycemia. She denied history of diabetes, insulin or sulfonylurea use. She reported an admission to another facility for hypoglycemia 4 days ago where adrenal insufficiency was ruled out with normal morning cortisol levels. During this hospitalization, CBC and CMP were unremarkable except low BG. A CT scan of the abdomen/pelvis was consistent with locally advanced HCC. Fasting protocol was started and BG monitoring was performed every 30 minutes. When BG fell below 55 mg/dL; C-peptide, insulin and proinsulin levels were drawn which came back severely suppressed at 0.13 ng/mL, <1 mU/L, and 2.7 pmol/L respectively. IGF2 was low-normal at 339 ng/mL. Given aforementioned workup and exclusion of other causes including medications, insulinoma and adrenal insufficiency, hypoglycemia was attributed to big-IGF mediated NICTH. Dextrose infusion was re-initiated but the patient continued to have BG in 30s, which was verified by both finger-stick and serum chemistry. Dexamethasone was initiated and dextrose infusion was continued. Oncology deemed her a poor surgical candidate. She declined other therapies for HCC. BG stabilized after institution of steroids, dextrose infusion was weaned successfully, and patient was discharged. Conclusion: A high index of suspicion should be held for NICTH in patients with profound hypoglycemia refractory to dextrose infusions in the setting of NICT. The diagnosis of NICTH can be made with suppressed insulin and C-peptide, elevated big-IGF, and normal-reduced IGF2 levels. Management of NICTH related to HCC is tumor resection. However, local anti-tumor therapies can be considered in non-surgical candidates. Since NICTH can be refractory to dextrose infusion, steroids with or without GH are an effective option. In refractory cases, continuous glucagon infusion and parenteral nutrition can be considered. Further research is needed to help develop better treatment options. We hope to contribute to the current literature regarding NICTH and bring awareness to the medical community. Presentation: Friday, June 16, 2023

Nonlinear Mixed Effects Modeling of Glucagon Kinetics in Healthy Subjects.

To date, the lack of a model of glucagon kinetics precluded the possibility of estimating and studying glucagon secretion in vivo, e.g., using deconvolution, as done for other hormones like insulin and C-peptide. Here, we used a nonlinear mixed effects technique to develop a robust population model of glucagon kinetics, able to describe both the typical population kinetics (TPK) and the between-subject variability (BSV), and relate this last to easily measurable subject characteristics. Thirty-four models of increasing complexity (variably including covariates and correlations among random effects) were identified on glucagon profiles obtained from 53 healthy subjects, who received a constant infusion of somatostatin to suppress endogenous glucagon production, followed by a continuous infusion of glucagon (65 ng/kg/min). Model selection was performed based on its ability to fit the data, provide precise parameter estimates, and parsimony criteria. A two-compartment model was the most parsimonious. The model was able to accurately describe both the TPK and the BSV of model parameters as function of body mass and body surface area. Parameters were precisely estimated, with central volume of distribution V1 = 5.46 L and peripheral volume of distribution V2 = 5.51 L. The introduction of covariates resulted in a significant shrinkage of the unexplained BSV and considerably improved the model fit. We developed a robust population model of glucagon kinetics. This model provides a deeper understanding of glucagon kinetics and is usable to estimate glucagon secretion in vivo by deconvolution of plasma glucagon concentration data.

Management of Non-Islet-Cell Tumor Hypoglycemia: A Clinical Review

Non-islet cell tumor hypoglycemia (NICTH) is a rare but serious paraneoplastic syndrome in which a tumor secretes high molecular weight IGF-II, causing hypoglycemia. Complete tumor resection is curative but is often delayed or unfeasible. There is no clear "standard of care" for managing these patients. PubMed searches were conducted for: "non-islet-cell tumor hypoglycemia," "NICTH," "Doege-Potter," "Doege-Potter syndrome," "high molecular weight IGF-II," and "big IGF-II." Relevant articles were reviewed in detail. We limited our review to English-language articles, focusing on 1988-2013 (corresponding with the elucidation of the pathophysiology of NICTH). The available literature exists as case reports or small case series, with a void of higher-order treatment studies. Thus, an evidence-based approach to data synthesis was difficult. Nevertheless, the available literature is presented objectively with an attempt to describe clinically useful trends and findings in the management of NICTH. Appropriate identification of NICTH and prompt and complete tumor resection represents ideal management. However, when prompt resection is not feasible, iv glucose or dextrose often does not suffice to prevent hypoglycemia. In such cases, we suggest consideration of local antitumor therapies for disease control and trial of glucocorticoids alone or in combination with GH. Continuous glucagon infusion can be successful if the patient has a positive response to a glucagon stimulation test, and parenteral nutrition may allow higher glucose delivery, but both are limited by the need for continuous iv infusion. Diazoxide and octreotide have no role in NICTH.

Diazoxide treatment for persistent hypoglycemia in a small for gestational age preterm infant with adequate low insulin levels

Abstract Small for gestational age (SGA) newborn infants can have prolonged hypoglycemia due to diminished glycogen stores, diminished alternative energy substrates, or hyperinsulinism. Recurrent episodes of hypoglycemia are strongly correlated with persistent neuro-developmental and physical growth deficits. Treatment includes glucose supplements or medications affecting insulin secretion, gluconeogenesis, or glycogenolysis. Diazoxide suppresses insulin secretion by acting as an ATP-sensitive potassium channel agonist to prevent membrane depolarization, calcium influx, and insulin secretion. Therefore, it is used in persistent hypoglycemia of neonates associated with hyperinsulinism. We report a case of a female SGA preterm infant who had persistent hypoglycemia (>2 weeks of age) with low adequate serum insulin levels and no other clear biochemical evidence of hyperinsulinism or other abnormalities. As a result of an inability to control her glucose levels without high intravenous levels of glucose and continuous glucagon infusion, she was treated successfully with diazoxide, which was discontinued when the infant reached 5 kg. No side effects were noted. In rare cases of persistent hypoglycemia, and a need for high glucose infusion rate but with adequate low insulin levels even without biochemical evidence supportive of hyperinsulinism, diazoxide treatment can be offered with close monitoring of glucose levels and possible side effects. The exact mechanism is not clear and deserves further evaluation.

Adult presentation of a congenital duodenal diaphragm

1. Neoptolemos JP, London NJM, Carr-Locke DL. Assessment of the main pancreatic duct integrity by endoscopic retrograde pancreatography in patients with acute pancreatitis. Br J Surg 1993;80:94-9. 2. Kozarek RA, Ball TJ, Patterson DJ, et al. Endoscopic transpapillary therapy for disrupted pancreatic duct and peripancreatic fluid collections. Gastroenterology 1991;100:1362-70. 3. Thomas H, Madanur M, Bartlett A, et al. Pancreatic traumad12-year experience from a tertiary center. Pancreas 2009;38:113-6. 4. Varadarajulu S, Noone TC, Tutuian R, et al. Predictors of outcome in pancreatic duct disruption managed by endoscopic transpapillary stent placement. Gastrointest Endosc 2005;61:568-75. 5. Huckfeldt R, Agee C, Nichols WK, et al. Nonoperative treatment of traumatic pancreatic duct disruption using an endoscopically placed stent. J Trauma 1996;41:143-4. 6. Pederzoli P, Bassi C, Falconi M, et al. Conservative treatment of external pancreatic fistulas with parenteral nutrition alone or in combination with continuous intravenous infusion of somatostatin, glucagon or calcitonin. Surg Gynecol Obstet 1986;163:428-32.

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40-45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.

Non-Islet-Cell Tumor Hypoglycemia and Lactic Acidosis in a Child with Congenital HIV and Burkitt's Lymphoma

Non-islet-cell tumor hypoglycemia (NICTH) is a rare cause of hypoglycemia associated with tumors of mesenchymal, epithelial, or hematopoietic origin. Lactic acidosis is likewise an uncommon complication of hematological malignancy associated mainly with leukemia and lymphoma. Most cases of NICTH and lactic acidosis have been described in the adult population. We report a child with congenital HIV and AIDS who developed Burkitt's lymphoma, lactic acidosis and NICTH. An 11 year-old boy with AIDS, cerebral palsy and seizure disorder presented with intractable hypoglycemia 12 days after diagnosis of Burkitt's lymphoma. He had persistent hypoglycemia (serum glucose 20-40 mg/dl; 1.1-2.2 mmo/l) despite glucose infusion rate of 6 mg/kg/minute and trial of diazoxide treatment. Critical sample obtained at time of hypoglycemia showed insulin at 1.78 microU/ml (normal <5 microU/ml), pro-insulin 5.6 pmol/l (<18.8 pmol/l), IGF-I <25 ng/ml (80-723 ng/ml), IGF-II 422 ng/ml (610-1,217 ng/ml), lactate 15.6 mmol/l (normal: 0.5-2.2 mmol/l), cortisol 21 microg/dl (580 nmol/l; normal >10 microg/dl; 276 nmol/l), and negative insulin antibodies. He remained alert and seizure free despite profound hypoglycemia. A 1 mg glucagon stimulation test showed a rise in serum glucose of 29 mg/dl (>1.6 mmol/l). Continuous glucagon infusion at 0.15-0.3 mg/h maintained euglycemia until the time of his demise (1 month after admission) due to complications of his underlying illness. We present a case of lactic acidosis and NICTH in an 11 year-old boy with AIDS and Burkitts's lymphoma. We review the mechanism of hyperlacticacidemia in supporting cerebral function during profound hypoglycemia. NICTH and lactic acidosis in association with malignancy carries a poor prognosis. In this patient, continuous glucagon infusion was a successful alternative to corticosteroid treatment in maintaining euglycemia.

The Use of Glucagon and other Antidotes in a Case of Beta‐Blocker and Calcium Channel Blocker Overdose

We report a case of metoprolol and nifedipine overdose complicated by hypotension which responded to intravenous boluses of calcium chloride and glucagon. The blood pressure was subsequently stabilised by continuous glucagon infusion with the aid of an insulin‐dextrose drip. The discussion is focused on the role of antidotes and catecholamine inotropes in the management of beta‐blocker and calcium channel blocker poisoning.

Reproduction of Features of the Glucagonoma Syndrome with Continuous Intravenous Glucagon Infusion as Therapy for Tumor-Induced Hypoglycemia

To describe the adverse effects of continuous intravenous infusion of glucagon as therapy for tumor-induced hypoglycemia and to correlate these treatment-related effects with symptoms of endogenous hyper-glucagonemia. We reviewed three cases in which patients received continuous glucagon therapy for tumor-induced hypoglycemia and experienced adverse side effects to the treatment. We noted that these adverse events were consistent with changes that are described in the literature as symptoms of the glucagonoma syndrome. Continuous intravenous glucagon infusion has evolved as a reliable and efficacious modality for the treatment of tumor-induced hypoglycemia. We report the adverse events of venous thromboembolism, necrolytic migratory erythema, and angular cheilitis in conjunction with continuous intravenous glucagon treatment. These complications resemble symptoms that characterize the human model of hyperglucagonemia--the glucagonoma syndrome--which is associated with hyperglucagonemia and alpha-islet cell neoplasms of the pancreas. Symptoms that characterize the islet cell neoplasm-related glucagonoma syndrome may develop in patients receiving an infusion of exogenous glucagon. This observation lends support to the suggestion that glucagon may have a direct, causative role.

Endoscopic pancreatic stent insertion for treatment of pseudocyst after distal pancreatectomy

Pancreatic fistula and pseudocyst are common complications of pancreatic resection. 1 Ridgeway MG Stabile B. Surgical management and treatment of pancreatic fistulas. Surg Clin North Am. 1996; 76: 1159-1173 Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar , 2 Bassi C Falconi M Pederzoli P Pancreatic fistula. in: 3rd ed. Surgical diseases of the pancreas. : Williams & Wilkins, Baltimore1998: 827-834 Google Scholar Such complications prolong hospitalization and may lead to abscess formation, sepsis, and hemorrhage. 1 Ridgeway MG Stabile B. Surgical management and treatment of pancreatic fistulas. Surg Clin North Am. 1996; 76: 1159-1173 Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar , 2 Bassi C Falconi M Pederzoli P Pancreatic fistula. in: 3rd ed. Surgical diseases of the pancreas. : Williams & Wilkins, Baltimore1998: 827-834 Google Scholar Most fistulas and pseudocysts resolve spontaneously, albeit over lengthy periods, with conservative treatment including pancreatic rest (no oral intake with total parenteral nutrition or octreotide administration) and adequate drainage (drains placed during the initial operation or postoperatively via the percutaneous approach). 1 Ridgeway MG Stabile B. Surgical management and treatment of pancreatic fistulas. Surg Clin North Am. 1996; 76: 1159-1173 Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar , 2 Bassi C Falconi M Pederzoli P Pancreatic fistula. in: 3rd ed. Surgical diseases of the pancreas. : Williams & Wilkins, Baltimore1998: 827-834 Google Scholar , 3 Pederzoli P Bassi C Falconi M Albrigo R Vantini I Micciolo R. Conservative treatment of external pancreatic fistulas with parenteral nutrition alone or in combination with continuous intravenous infusion of somatostatin, glucagon or calcitonin. Surg Gynecol Obstet. 1986; 163: 428-432 PubMed Google Scholar , 4 Prinz RA Pickleman J Hoffman JP. Treatment of pancreatic cutaneous fistulas with a somatostatin analog. Am J Surg. 1988; 155: 36-42 Abstract Full Text PDF PubMed Scopus (139) Google Scholar For pancreatic fistulas and pseudocysts refractory to conservative treatment, surgical intervention is indicated but is often technically difficult and associated with a high morbidity rate (13%). 5 Lipsett PA Cameron JL. Internal pancreatic fistula. Am J Surg. 1992; 163: 216-220 Abstract Full Text PDF PubMed Scopus (121) Google Scholar Only a few reports have described endoscopic pancreatic stent placement for treatment of pancreatic duct leakage after pancreatic resection. 6 Saeed ZA Ramirez FC Hepps KS. Endoscopic stent placement for internal and external pancreatic fistulas. Gastroenterology. 1993; 105: 1213-1217 PubMed Google Scholar , 7 Sarzen CD. Endoscopic management of pancreatic duct leak complicated by retrogastric abscess. Am J Gastroenterol. 1995; 90: 2039-2041 PubMed Google Scholar Herein is described a case in which endoscopic transpapillary placement of a pancreatic stent was effective treatment for a pancreatic pseudocyst that developed after distal pancreatectomy.

The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia

Tumor hypoglycemia can be recurrent and severe enough to interfere with definitive antineoplastic treatment. Therefore, rapid commencement of effective therapy is essential. This is best accomplished by identifying which of the hypoglycemic processes is involved, as treatments differ. Some patients present with hypoglycemia and liver metastases; among them, only a few develop hypoglycemia as a result of a failure of hepatic glucose production. Most develop hypoglycemia as a result of an insulin-mediated process--either the secretion of insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II by an extrapancreatic tumor. Administration of glucagon can rapidly make the two groups distinguishable, thus allowing institution of therapy and prompt symptomatic control of hypoglycemia. The charts of seven patients with tumor hypoglycemia and liver metastases who had a glucagon stimulation test (serial glucose measurements after a 1 mg infusion of glucagon) as part of the workup for hypoglycemia were retrospectively reviewed. Those patients whose test revealed a rise in serum glucose of >30 mg/ dL were subsequently treated as outpatients, with a continuous glucagon infusion delivered by a portable pump. Three patients had an insulinoma and four had non-islet cell tumor hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal sarcoma, and hemangiopericytoma, respectively. All of the patients had liver metastases. Evaluation of these patients included a glucagon stimulation test (1 mg intravenous push), which quickly provided information about the mechanism of tumor hypoglycemia and the direction towards therapy. All patients with insulinoma responded to glucagon with a rise in blood serum glucose levels, indicating adequate glycogen stores. The four patients with NICTH had mixed responses: in two patients, the response suggested that hypoglycemia was due to an insulin-like tumor product; glucose levels did not rise in the other two cases, indicating that hypoglycemia was due to poor hepatic glycogen reserve/liver failure. In all cases, a glycemic response to glucagon predicted good response to long term treatment with glucagon (0.06-0.3 mg/hour, via intravenous infusion pump). The glucagon stimulation test is a simple and fast approach that serves to clarify the etiology of hypoglycemia (diagnostic use) and guide effective long term strategies for its control (therapeutic use) in patients with neoplastic diseases and liver metastases.

The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia

BACKGROUND. Tumor hypoglycemia can be recurrent and severe enough to interfere with definitive antineoplastic treatment. Therefore, rapid commencement of effective therapy is essential. This is best accomplished by identifying which of the hypoglycemic processes is involved, as treatments differ. Some patients present with hypoglycemia and liver metastases; among them, only a few develop hypoglycemia as a result of a failure of hepatic glucose production. Most develop hypoglycemia as a result of an insulin-mediated process-either the secretion of insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II by an extra-pancreatic tumor. Administration of glucagon can rapidly make the two groups distinguishable, thus allowing institution of therapy and prompt symptomatic control of hypoglycemia. METHODS. The charts of seven patients with tumor hypoglycemia and liver metastases who had a glucagon stimulation test (serial glucose measurements after a I mg infusion of glucagon) as part of the workup for hypoglycemia were retrospectively reviewed. Those patients whose test revealed a rise in serum glucose of >30 mg/ dL were subsequently treated as outpatients, with a continuous glucagon infusion delivered by a portable pump. RESULTS. Three patients had an insulinoma and four had non-islet cell tumor hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal sarcoma, and hemangiopericytoma, respectively. All of the patients had liver metastases. Evaluation of these patients included a glucagon stimulation test (1 mg intravenous push), which quickly provided information about the mechanism of tumor hypoglycemia and the direction towards therapy. All patients with insulinoma responded to glucagon with a rise in blood serum glucose levels, indicating adequate glycogen stores. The four patients with NICTH had mixed responses: in two patients, the response suggested that hypoglycemia was due to an insulin-like tumor product; glucose levels did not rise in the other two cases, indicating that hypoglycemia was due to poor hepatic glycogen reserve/liver failure. In all cases, a glycemic response to glucagon predicted good response to long term treatment with glucagon (0.06-0.3 mg/hour, via intravenous infusion pump). CONCLUSIONS. The glucagon stimulation test is a simple and fast approach that serves to clarify the etiology of hypoglycemia (diagnostic use) and guide effective long term strategies for its control (therapeutic use) in patients with neoplastic diseases and liver metastases.

The role of glucagon administration in the diagnosis and treatment of patients with tumor hypoglycemia

BACKGROUND Tumor hypoglycemia can be recurrent and severe enough to interfere with definitive antineoplastic treatment. Therefore, rapid commencement of effective therapy is essential. This is best accomplished by identifying which of the hypoglycemic processes is involved, as treatments differ. Some patients present with hypoglycemia and liver metastases; among them, only a few develop hypoglycemia as a result of a failure of hepatic glucose production. Most develop hypoglycemia as a result of an insulin-mediated process-either the secretion of insulin by an islet-cell tumor or the secretion of insulin-like growth factor-II by an extrapancreatic tumor. Administration of glucagon can rapidly make the two groups distinguishable, thus allowing institution of therapy and prompt symptomatic control of hypoglycemia. METHODS The charts of seven patients with tumor hypoglycemia and liver metastases who had a glucagon stimulation test (serial glucose measurements after a 1 mg infusion of glucagon) as part of the workup for hypoglycemia were retrospectively reviewed. Those patients whose test revealed a rise in serum glucose of >30 mg/dL were subsequently treated as outpatients, with a continuous glucagon infusion delivered by a portable pump. RESULTS Three patients had an insulinoma and four had non-islet cell tumor hypoglycemia (NICTH) due to hepatocellular carcinoma, colon carcinoma, meningeal sarcoma, and hemangiopericytoma, respectively. All of the patients had liver metastateses. Evaluation of these patients included a glucagon stimulation test (1 mg intravenous push), which quickly provided information about the mechanism of tumor hypoglycemia and the direction towards therapy. All patients with insulinoma responded to glucagon with a rise in blood serum glucose levels, indicating adequate glycogen stores. The four patients with NICTH had mixed responses: in two patients, the response suggested that hypoglycemia was due to an insulin-like tumor product; glucose levels did not rise in the other two cases, indicating that hypoglycemia was due to poor hepatic glycogen reserve/liver failure. In all cases, a glycemic response to glucagon predicted good response to long term treatment with glucagon (0.06-0.3 mg/hour, via intravenous infusion pump). CONCLUSIONS The glucagon stimulation test is a simple and fast approach that serves to clarify the etiology of hypoglycemia (diagnostic use) and guide effective long term strategies for its control (therapeutic use) in patients with neoplastic diseases and liver metastases. Cancer 1998; 82:1585-92. © 1998 American Cancer Society.

Failure of pulsatile infusion to increase glucagon's satiating potency

Intraportal infusions of glucagon elicit a dose-related reduction in the size of rats' spontaneous meals. The glucagon doses required to reduce meal size, however, appear large in comparison to plasma glucagon concentrations during meals. Because prandial glucagon secretion may be pulsatile, however, pulsatile glucagon infusions may reduce meal size more potently than continuous infusions. To test that hypothesis, I compared the effects of a single 2-min infusion of 6.8 μg/min glucagon and two 1-min pulses of the same glucagon concentration separated by 1 min. Glucagon was infused via the hepatic portal vein during male rats' first spontaneous meal of the last quarter of the dark phase, and meal patterns were recorded by a computer. The results did not support the hypothesis. Meal size was reduced comparably in each infusion condition (from ∼3.1 g in the control conditions to ∼2.3 g after continuous glucagon infusion and ∼2.2 g after pulsatile infusion). This result is discussed in relation to tests of glucagon antibody administration that indicate endogenous glucagon is a physiological control of meal size in rats. Additionally, in contrast to previous reports, glucagon infusion during late dark spontaneous meals decreased the length of the subsequent intermeal intervals, suggesting that glucagon's satiating effect was transient.

Metabolic Effects of Combination Therapy with Insulin and Continuous Subcutaneous Infusion of Glucagon at Night in a Diabetic Patient after Total Pancreatectomy

Metabolic Effects of Combination Therapy with Insulin and Continuous Subcutaneous Infusion of Glucagon at Night in a Diabetic Patient after Total Pancreatectomy

Impaired TSH Secretion during Sustained Hyperglucagonemia in Anesthetized Dogs

We previously demonstrated that hyperglucagonemia may be responsible for thyroid hormone alterations noted in some nonthyroidal illnesses. Since TSH secretion is also known to be altered in many subjects with several nonthyroidal illnesses, we assessed the influence of sustained hyperglucagonemia on TSH secretory pattern in 5 anesthetized dogs. Serum TSH concentrations were determined after a 16-h fast and again at intervals of 15 min during sustained hyperglucagonemia (515-645 pg/mL) induced by iv bolus administration of glucagon 0.1 mg followed by a continuous glucagon infusion 3 ng/kg/min for 3 h. TRH (200 micrograms) was administered iv at 60 min to assess the influence of sustained hyperglucagonemia on the hypothalamic pituitary thyrotroph axis during the study. A control study was also conducted using normal saline instead of glucagon, and both studies were performed in a randomized sequence. Basal TSH levels were not significantly different during both studies. However, serum TSH declined significantly during sustained hyperglucagonemia prior to TRH administration (delta TSH, pre-TRH, -0.86 +/- 0.24 vs 0.02 +/- 0.07 ng/mL for normal saline, p < 0.01). Furthermore, TSH response to iv TRH administration was significantly blunted during glucagon infusion alone as expressed by both the absolute rise (delta TSH, post-TRH, 1.1 +/- 0.5 vs 5.9 +/- 1.7 ng/ml for normal saline, p < 0.01) as well as an integrated response over a 2-h period (sigma TSH, post-TRH, 4.0 +/- 1.1 vs 11.7 +/- 3.5 ng/min/mL, p < 0.001). Therefore, this study demonstrates that sustained hyperglucagonemia inhibits basal TSH secretion as well as TSH response to iv TRH administration, a TSH secretory pattern similar to that noted at the peak of many nonthyroidal illnesses.

A nucleoside mixture and its sparing effect on de novo purine nucleotide synthesis.

Total parenteral nutrition (TPN) is a well-accepted method of managing patients to protect body composition and stimulate recover from lean body mass. While amino acids, carbohydrates and fats are essential to nutrition, nucleic acid precursors such as bases, nucleosides and nucleotides are considered less important because they are endogenously synthesized to meet the bodily requirements. However, these precursors may be necessary when the de novo synthesis of nucleotides is inadequate. This inadequate situation may occur during periods of severe surgical stress, infection, or long-term TPN treatment.1 The use of nucleic acid components in TPN was investigated in rats by Ogoshi et al., using OG-VI comprising inosine, 5’-sodium guanylate, cytidine, uridine and thymidine.2, 3 Several effects of OG-VI, including a protein sparing effect in hepatectomized rats4, have been reported as a result of the provision of nucleotide precursors.4–7 Yet, it is not fully clear whether the OG-VI ends up sufficiently being utilized to spare the de novo synthesis of nucleotides in response to bodily need. The aim of this study was to investigate whether parenteral administration of OG-VI spares the de novo purine nucleotide synthesis which is closely associated with protein metabolism. Two experimental rat models were used which were stimulated for the de novo synthesis by continuous infusion of glucagon (glucagon model)8 or by 70% hepatectomy (hepatectomized model).9 KeywordsTotal Parenteral NutritionPurine NucleotidePurine SynthesisNucleic Acid ComponentTotal Parenteral Nutrition SolutionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Fatal Intoxication with Amlodipine

Although poisoning with calcium channel blocking agents is frequent, to our knowledge no cases involving amlodipine have been published. We describe here a case of amlodipine intoxication, in which protracted hypotension did not respond to vasopressor therapy alone. After the addition of continuous calcium chloride and glucagon infusion, blood pressure was restored and vasopressor therapy could be tapered off substantially. When calcium and glucagon were interrupted because of severe hypercalcemia and hyperglycemia, the patient developed irreversible hypotension and died. Either glucagon or calcium or both, and to some extent vasopressors, seem to have constituted effective treatment of hypotension in this case.