alpha cell

**Location and histology** - Alpha cells make up ~15-20% of islet cells and sit mainly at the islet periphery (the mantle). Beta cells (~60-70%) are in the core, delta cells (~5-10%) are scattered, and PP cells are mostly in the head of the pancreas. - They arise from the endodermal pancreatic bud. Development depends on the transcription factor Arx. Beta cells depend on Pdx1/Pax4.

**Product: glucagon** - A 29-amino-acid peptide derived from preproglucagon. Alpha cells process it using prohormone convertase 2 (PC2). Intestinal L cells use PC1/3 and produce GLP-1 and GLP-2 from the same precursor.

**Regulation** - Stimulated by: hypoglycemia, amino acids (especially alanine and arginine, so protein meals), epinephrine/sympathetic stimulation, cortisol, and fasting. - Inhibited by: hyperglycemia, insulin, somatostatin (from delta cells), GLP-1, and free fatty acids/ketones. - Insulin has a paracrine inhibitory effect on alpha cells. This is why glucagon is inappropriately elevated in type 1 diabetes and contributes to hyperglycemia/DKA.

**Mechanism of action** - Glucagon binds a G protein-coupled receptor (Gs) → ↑adenylyl cyclase → ↑cAMP → ↑PKA. - Liver (main target): ↑glycogenolysis (phosphorylase activation), ↑gluconeogenesis, ↑ketogenesis, ↓glycolysis, and ↓glycogen synthesis (inhibits glycogen synthase). It does not break down muscle glycogen, because muscle lacks glucagon receptors. - Adipose tissue: ↑lipolysis. - Heart: positive inotrope and chronotrope. This is why it is used for β-blocker overdose. - Smooth muscle: relaxes the GI tract. It is used as a radiologic aid and for food bolus impaction.

**Clinical correlations** 1. **Glucagonoma**: an alpha cell neuroendocrine tumor. Usually presents in adults ~50-60 years old. - Necrolytic migratory erythema (an erythematous rash with blistering and crusting that migrates, often on the groin, perineum, and extremities). - Mild diabetes/glucose intolerance. - DVT/hypercoagulability. - Depression, plus weight loss, anemia, and stomatitis/glossitis. - Diagnosis: markedly elevated fasting glucagon, then CT/MRI. Treatment is surgical resection. Octreotide can be used for symptoms. It may be associated with MEN1 (3 P's: Pituitary, Parathyroid, Pancreas). 2. **Hypoglycemia**: a glucagon injection or intranasal glucagon is first-line when IV access is not available. It requires hepatic glycogen stores, so it is less effective in starvation, alcohol-related hypoglycemia, and advanced liver disease. 3. **Type 1 DM**: absent insulin → loss of alpha cell suppression → hyperglucagonemia. Alpha cell response to hypoglycemia is also impaired over time (hypoglycemia unawareness). 4. **Type 2 DM**: hyperglucagonemia contributes to fasting hyperglycemia. GLP-1 agonists and DPP-4 inhibitors lower glucagon secretion in a glucose-dependent way. Pramlintide (amylin analog) also suppresses glucagon. 5. **Pancreatectomy/pancreatitis**: loss of alpha cells makes hypoglycemia worse and harder to recover from.

**High-yield comparisons** - Alpha: glucagon (↑glucose). Beta: insulin and C-peptide, amylin. Delta: somatostatin (inhibits insulin, glucagon, and GH). PP cells: pancreatic polypeptide. - Glucagon is a counterregulatory hormone, along with epinephrine, cortisol, and GH. - Alpha cells in tissue stain with immunohistochemistry for glucagon.