The involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon’s secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans’ islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion.
The human pancreas contains 1–2 million islets, each measuring 50–100 μm in diameter and containing ∼2000 cells on average. However, islet cells are only 2% of the overall pancreatic mass. It is notable that up to 65% of the human islet cells are α cells . All islet cells originate from the endoderm. Its differentiation into each islet linage is mediated by the pancreatic and duodenal homeobox 1 (Pdx1) and neurogenin-3 (Ngn3) genes. The further evolution of α cells requires both aristaless-related homeobox (Arx) and forkhead box protein A2 (Fox-A2) action in addition to low expression levels of paired box 4 (Pax4). Other factors important for α cell differentiation include MAF BZIP Transcription Factor B (MafB), NK6 Homeobox (Nkx6.1; Nkx6.2), Pax6 , and RNA Paupar (PAX6 Upstream Antisense RNA). The latter is a novel long noncoding that has been shown to regulate α cell development through alternative splicing of Pax6 .
Glucagon is the primary α cell hormone product. It is derived from the proteolysis of the 160-aminoacid pre-pro-glucagon peptide coded by its gene located in 2q24.216. This gene is strongly expressed in α cells, the brain, and L-cells of the gut. Under normal conditions, α cells synthetize glucagon via proconvertase 2 post translational proteolysis, while L-cells produce glucagon-like peptide-1 (GLP-1) via proconvertase 1/3 pathway.
The classic model of glucagon secretion regulation is explained by glucose-medicated glucagon exocytosis. Anatomically, pancreatic islets are highly vascularized to ensure a rapid glucose and aminoacidic sensing. A glycaemic drop near to threshold stimulates glucagon release . The cellular mechanism behind this glucose-dependent regulation of glucagon secretion is described in Figure 1.
Omar-Hmeadi et al. observed a lack of inhibition in glucagon exocytosis by hyperglycaemia, somatostatin, or insulin in intact islets in α cells from T2DM cadaveric. Instead, hyperglycaemia inhibits α cell exocytosis, but not in the T2DM donor’s α cell or when paracrine inhibition by insulin or somatostatin is blocked. A reduced Surface expression of Somatostatin-receptor-2 in islet from T2DM donors suggests somatostatin resistance, and consequently, elevated glucagon in T2DM may reflect α cell insensitivity to paracrine inhibition during hyperglycaemia .
Extensive emerging evidence has been published among the “bi-hormonal theory” in T2DM pathogenesis in which the coexistence of hyperglucagonemia and relative insulin deficiency increase gluconeogenesis and exacerbates peripheral IR , leading to overt T2DM development. Currently, there is some consensus regarding hyperglucagonemia origin. This is centred on two possible mechanisms: (1) a progressive loss in the regulatory mechanisms in the secretion patterns due to α cells functional alterations , or (2) modification in both the islet microarchitecture and cellularity .
Conclusive evidence has demonstrated a β cell mass reduction and a concomitant decrease in insulin secretion in subjects with long-standing T2DM  and a sensible fall in GABA and serotonin release, which are crucial paracrine regulators of glucagon secretion, as explained previously. However, post-mortem studies have reported an increased α cell mass in subjects with diabetes. Nonetheless, the evidence is not conclusive . This finding can be related to a loss of α cell regulating factors or a compensatory mechanism secondary to β cells mass loss . Nevertheless, multiple studies have reported that an elevation of Interleukin 6 (IL-6) circulating levels in T2DM adult mice is possibly linked with an expansion of α cell mass and hyperglucagonemia , suggesting that α cell proliferation in Type 1 Diabetes Mellitus (T1DM) is probably IL-6-dependent .