abnormality of glucagon secretion

Abnormal Glucagon Secretion: An Overview

Abnormal glucagon secretion refers to an excessive or inappropriate release of the hormone glucagon by the alpha cells in the pancreas. This can lead to various metabolic consequences, including:

• Hyperglycemia: Elevated blood glucose levels due to increased glucagon secretion, which stimulates glycogenolysis and gluconeogenesis.
• Fasting hyperglycemia: High blood glucose levels during fasting periods, often seen in individuals with diabetes mellitus.
• Postprandial hyperglycemia: Increased blood glucose levels after meals, also common in diabetic patients.

Causes of Abnormal Glucagon Secretion

The causes of abnormal glucagon secretion are not fully understood but may involve:

• Defects in the intrinsic A cell glucoreceptor: Alterations in the glucoreceptor, which senses glucose levels and regulates glucagon secretion.
• Insulin lack: Insufficient insulin production or action, leading to increased glucagon secretion as a compensatory mechanism.
• Glucotoxicity: High glucose levels damaging pancreatic islet cells, including alpha cells, leading to abnormal glucagon secretion.

Consequences of Abnormal Glucagon Secretion

The consequences of abnormal glucagon secretion can be severe and include:

• Diabetic ketoacidosis: A life-threatening complication of diabetes characterized by high blood glucose and ketone levels.
• Hyperglucagonemia: Elevated plasma glucagon concentrations contributing to hyperglycemia.

Regulation of Glucagon Secretion

Glucagon secretion is regulated by various mechanisms, including:

• Blood glucose concentration: Glucagon release increases when blood glucose falls below 50-60 mg/dL and decreases at higher glucose levels.
• K ATP channels: These channels play a role in regulating glucagon secretion, particularly under low-glucose conditions.

References

• [1] Abnormal glucagon response to arginine and its normalization in [3]
• [2] Glucagon secretion increases when blood glucose concentration falls below 50-60 mg/dL [4]
• [5] Elevated plasma concentrations of glucagon and hyperglucagonemia contribute to the hyperglycemia of diabetes [5]
• [6] Abnormal Pancreatic Glucagon Secretion and Postprandial Hyperglycemia In Diabetes Mellitus [8]
• [7] Alpha cell insulin resistance may underlie the abnormal up-regulation of glucagon secretion Type 2 diabetes [9]
• [10] Loss of proper β- and α-cell physical interaction in islets likely contributes to the dysregulated glucagon secretion in diabetic patients [11]

Note: The numbers in square brackets refer to the corresponding references in the provided context.

Abnormal Glucagon Secretion: Signs and Symptoms

Abnormalities in glucagon secretion can manifest in various ways, depending on the underlying condition. Here are some possible signs and symptoms:

• Weight loss: Despite increased appetite, patients with glucagon-secreting tumors or other conditions may experience weight loss due to hyperglycemia and impaired glucose utilization ([6], [9]).
• Diabetes mellitus: Elevated plasma concentrations of glucagon can contribute to hyperglycemia, leading to diabetes mellitus ([4], [14]).
• Hypoglycemia: Abnormal glucagon levels can also cause low blood sugar (hypoglycemia), with symptoms including shaking or trembling, sweating and chills, dizziness or lightheadedness ([10], [12]).
• Necrolytic migratory erythema: A characteristic skin rash associated with glucagonoma syndrome, characterized by necrotic lesions that migrate across the body ([8], [9]).
• Fatigue: Persistent tiredness might indicate glucose not being adequately mobilized from glycogen stores ([7]).
• Hyperglycemia: High blood sugar levels can lead to a range of symptoms, including polydipsia (increased thirst), polyphagia (increased hunger), polyuria (frequent urination), and blurred vision ([14]).

It's essential to note that these symptoms can be non-specific and may appear in various conditions. A proper diagnosis by a healthcare professional is necessary to determine the underlying cause of abnormal glucagon secretion.

References:

[4] SK Venugopal, Elevated plasma concentrations of glucagon and hyperglucagonemia contribute to the hyperglycemia of diabetes. [6] Dec 16, 2022, The tumor's presence is characterized by glucagon overproduction, weight loss, hyperglycemia, diabetes mellitus, hypoaminoacidemia, normochromic anemia... [7] Early Signs of Glucagon Secretion Defects · Fatigue: Persistent tiredness might indicate glucose not being adequately mobilized from glycogen stores. [8] Patients with glucagon-secreting tumors may present with classic glucagonoma syndrome, consisting of necrolytic migratory erythema, diabetes, and diarrhea... [9] Aug 12, 2022, Glucagonoma (rare tumor of the pancreas) with symptoms of a skin rash called necrotizing migratory erythema, weight loss, mild diabetes, anemia... [10] What are the symptoms of glucagon-related conditions? Depending on the situation and condition, you can experience low and/or high blood sugar from abnormal glucagon levels. [12] As hypoglycemia worsens, signs and symptoms can include: Confusion, unusual behavior or both, such as the inability to complete routine tasks; Loss of coordination... [14] Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia.

Glucagon Secretion Abnormality Diagnostic Tests

Glucagon secretion abnormality can be diagnosed through various tests that measure the levels of glucagon in the blood or assess its stimulatory effect on growth hormone (GH) production. Here are some diagnostic tests used to detect abnormalities in glucagon secretion:

• Glucagon Blood Test: This test measures the amount of glucagon in the blood, which can indicate abnormal glucagon secretion. Abnormal results may suggest conditions such as hypoglycemia or hyperglycemia [1][2].
• Glucagon Stimulation Test (GST): This test assesses the body's response to glucagon by measuring GH levels after administering a glucagon injection. The GST is used to diagnose adult growth hormone deficiency (GHD) and has been shown to have high sensitivity and specificity in identifying GHD [3][4].
• Insulin Tolerance Test (ITT): Although not directly related to glucagon secretion, the ITT is another GH stimulation test that can be used to diagnose GHD. However, its safety concerns limit its wider use [5].

Key Points

• Abnormal glucagon secretion can lead to conditions such as hypoglycemia or hyperglycemia.
• The glucagon blood test measures glucagon levels in the blood and may indicate abnormal secretion.
• The glucagon stimulation test (GST) assesses GH production after a glucagon injection and is used to diagnose adult GHD.
• The insulin tolerance test (ITT) can also be used to diagnose GHD, but its safety concerns limit its use.

References

[1] Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures. 6th ed. St Louis, MO: Elsevier Saunders; 2013:580-581. [2] Mojica [3] Gomez et al. [] evaluated 119 adult subjects (73 GHD diagnosed by ITT and 46 healthy controls), and demonstrated that GST had 100% sensitivity and 100% specificity using a peak of 3 µg/L. [4] The authors underlined a negative correlation between GST results and body weight, suggesting that higher doses of glucagon may be required for individuals with higher body weights [6]. [5] Results: Testing for confirmation of adult GHD should only be considered if there is a high pretest probability, and the intent to treat if the diagnosis is confirmed. The insulin tolerance test (ITT) and glucagon stimulation test (GST) are the two main tests used in the United States. While the ITT has been accepted as the gold-standard test, its safety concerns hamper wider use [7]. [6] Gomez et al. [] evaluated 119 adult subjects (73 GHD diagnosed by ITT and 46 healthy controls), and demonstrated that GST had 100% sensitivity and 100% specificity using a peak of 3 µg/L. [7] Results: Testing for confirmation of adult GHD should only be considered if there is a high pretest probability, and the intent to treat if the diagnosis is confirmed. The insulin tolerance test (ITT) and glucagon stimulation test (GST) are the two main tests used in the United States. While the ITT has been accepted as the gold-standard test, its safety concerns hamper wider use [8].

Glucagon-like peptide-1 (GLP-1) agonists are a class of medications used to treat type 2 diabetes mellitus (T2DM) and obesity, which directly inhibit the secretion of glucagon from α-cells in the pancreas [1]. These medications can also indirectly influence α-cells by inhibiting the secretion of other hormones.

In addition to GLP-1 agonists, there are other pharmacological agents that enhance endogenous glucagon secretion, such as GPR119 agonists and isoform-selective somatostatin receptor antagonists [3].

Some glucose-lowering drug classes, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, decrease glucagon secretion [4]. These medications can help reduce elevated glucagon levels that contribute to the pathophysiology of hyperglycemia in subjects with type 2 diabetes.

Octreotide and lanreotide injections can also be used to manage glucagon excess by reversing its effects and preventing further complications [6].

The use of novel somatostatin receptor 2 antagonists (SSTR2a) may resolve some of the dysfunction in glucagon counterregulation in diabetes, which could potentially lead to improved treatment outcomes [7].

It's worth noting that the primary mechanism of action of sulfonylureas is to increase insulin secretion through effects on beta cells, and a direct effect on pancreatic glucagon secretion would not be expected [12]. However, understanding how these drugs interact with glucagon secretion may help optimize treatment.

References:

[1] Glucagon-like peptide-1 (GLP-1) agonists are a class of medications utilized to treat type 2 diabetes mellitus (T2DM) and obesity. [3] Pharmacological agents that enhance endogenous glucagon secretion, such as GPR119 agonists and isoform-selective somatostatin receptor antagonists [4] Some glucose-lowering drug classes, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, decrease glucagon secretion [6] Octreotide and lanreotide injections can help reverse the effects of glucagon excess [7] The use of novel somatostatin receptor 2 antagonists (SSTR2a) may resolve some of the dysfunction in glucagon counterregulation in diabetes

Differential Diagnosis of Abnormal Glucagon Secretion

Abnormal glucagon secretion can be a symptom of various underlying conditions, making differential diagnosis crucial for proper treatment. Here are some possible causes:

• Diabetes Mellitus: Both type 1 and type 2 diabetes are associated with abnormal glucagon secretion. In both cases, fasting plasma glucagon levels are often elevated [6].
• Glucagonoma: A rare functioning neuroendocrine tumor that secretes excess glucagon, leading to a syndrome characterized by widespread dermatitis, weight loss, glossitis, and abnormal glucose tolerance [10][11].
• Alpha Cell Insulin Resistance: This condition may underlie the abnormal up-regulation of glucagon secretion in type 2 diabetes [8].
• Local Inflammation and Immunological Insults: These factors can contribute to α-cell abnormalities in diabetes, making it difficult for β-cells to influence paracrine regulation [9].
• Hypoglycemia: Abnormal glucagon response can lead to hypoglycemic episodes, particularly in individuals with diabetes [7][15].

Key Considerations

When differentiating between these conditions, consider the following:

• Clinical Presentation: Symptoms such as widespread dermatitis, weight loss, and abnormal glucose tolerance may suggest glucagonoma or alpha cell insulin resistance.
• Laboratory Results: Elevated fasting plasma glucagon levels are often seen in diabetes mellitus, while glucagonomas typically present with high concentrations of glucose [10].
• Differential Diagnosis: In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results obtained at the same time or at different time points [13].

References

[6] Diabetes mellitus is the most common condition associated with abnormal glucagon secretion. [8] Alpha cell insulin resistance may underlie the abnormal up-regulation of glucagon secretion Type 2 diabetes (72). [9] The causes of α-cell abnormalities in diabetes also remain unclear. Local inflammation, immunological insults, diminished paracrine β-cell influence ... [10] Glucagonomas are neuroendocrine tumors of the pancreatic islets that secrete glucagon. [11] Glucagonomas are rare functioning neuroendocrine tumors that secrete glucagon. [13] In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results obtained at the same time (e.g., A1C and FPG) or at two different time points. ... [15] Hypoglycemia is often defined by a plasma glucose concentration below 70 mg/dL; however, signs and symptoms may not occur until plasma glucose concentrations drop below 55 mg/dL.