Introduction

After Paul Langerhans’s discovery of the pancreatic islets in 1869 (1), Diamare found in 1899 that they contain two types of cells (2), which Lane in 1907 designated as α- and β-cells (3) (later also A and B cells). In 1915 Homans predicted that the B cells are the origin of ‘an internal secretion vital to the utilization of dextrose’ (4), and the glucose-lowering hormone, insulin, was discovered by Banting and Best in 1921 (5). In 1923 Murlin et al. observed that pancreatic insulin extracts sometimes were contaminated with a hyperglycaemic factor (6) that was named glucagon (7), whose production was eventually linked to the α-cells by Sutherland and De Duve in 1948 (8). Claes Hellerström, who is honoured in the current issue of this journal, made significant contributions in the glucagon field in his early scientific career. Together with his mentor Bo Hellman, Hellerström invented a silver impregnation technique that revealed A cell heterogeneity (9). The silver-positive and -negative A cells were named A1 and A2, respectively. They also provided indirect evidence that glucagon originates from the A2 cells by showing that they undergo pronounced nuclear atrophy after glucagon injections (10). Hellerström later pioneered studies of glucagon biosynthesis in guinea pig islets (11) as well as studies of metabolism (oxygen consumption) in A cell-enriched islets from streptozotocin-diabetic guinea pigs (12). Hellman and Lernmark showed that the α1 or A1 cells, which later proved to be identical to the D cells defined by Bloom in 1931 (13), secrete a factor that inhibits insulin secretion (14). This D cell (δ-cell) factor was later identified as somatostatin (15). There is still some confusion with regard to the use of the Greek or Latin designations, but the glucagon-producing cells are nowadays mostly referred to as α-cells and those secreting insulin and somatostatin as β- and δ-cells, respectively, which is the nomenclature subsequently used in this review.

With the discovery of insulin, life-saving treatment of diabetic patients rapidly became possible (16). It is consequently not surprising that most research has been focused on insulin and its actions in the search for improved strategies for optimizing blood glucose control and preventing secondary diabetes complications. Although it has become increasingly clear that hypersecretion of glucagon contributes to hyperglycaemia in diabetes (see (17) for review), it may have surprised many when the Unger group provided evidence that lack of insulin does not lead to diabetes in mice if the blood glucose-elevating effect of glucagon is prevented (18,19). However, disruption of glucagon action/secretion did not improve glucose tolerance in diabetic mice in another study (20).

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Whereas diabetic hyperglycaemia may persist undetected for long periods of time, severe hypoglycaemia is acutely life-threatening due to the brain’s strong dependence on glucose as energy source. Glucagon is the major glucose counter-regulatory hormone, and its physiologically most important role is to prevent hypoglycaemia. Glucagon secretion is consequently stimulated when the blood sugar concentration falls below the resting level. Unfortunately, also this mechanism is compromised in diabetes (21), implying deteriorated recovery from dangerous hypoglycaemia that may occur accidentally in patients subjected to aggressive glucose-lowering treatment to reduce diabetes complications. Being essential for survival and well-being, the release of insulin and glucagon is controlled by multiple direct and indirect mechanisms. The blood glucose concentration is e.g. monitored by glucose-sensing cells in the portal vein area and in different regions of the brain, resulting in parasympathetic stimulation of insulin release in hyperglycaemia and glucagon release in hypoglycaemia, as well as sympathetic inhibition of insulin and stimulation of glucagon secretion in hypoglycaemia (22,23). However, the contribution of neural influence may differ between species since human islets are less innervated than rodent islets (24). Moreover, it is clear that glucose control of insulin and glucagon secretion persists in the perfused pancreas and isolated pancreatic islets. The subsequent focus will be on the glucose regulation of glucagon release that occurs within the pancreatic islets.

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Already 30 years ago there was a unifying theory how the β-cells recognize glucose and the subsequent signalling that triggers release of insulin (25). The major aspects of the so-called consensus hypothesis are still valid and imply that glucose is rapidly taken up by the β-cells and metabolized to generate ATP. The resulting increase of the ATP/ADP ratio closes ATP-sensitive K+ (KATP) channels to depolarize the β-cell and open voltage-dependent L-type Ca2+ channels. Subsequent influx of Ca2+ raises the cytoplasmic Ca2+ concentration ([Ca2+]i), which is the most important trigger of insulin release. This model consequently implies that the β-cells have an intrinsic capacity to sense glucose and release insulin as required, but [Ca2+]i-triggered secretion can also be enhanced or reduced by increase or decrease of cAMP, as well as by modulation of protein kinase C and the protein phosphatase calcineurin, mediated by paracrine effects of α-cell glucagon, δ-cell somatostatin and neurotransmitters like acetylcholine and noradrenaline (26,27).

The understanding of how glucose regulates glucagon secretion from the α-cells has progressed much more slowly, and it is remarkable that fundamentally different mechanisms continue to be proposed. Although Ca2+ and cAMP are generally believed to have similar secretion-triggering and -amplifying functions for glucagon as for insulin secretion (28-33), recent data indicate that glucagon release may sometimes be controlled independently of [Ca2+]i (34-36). Lack of paracrine inhibition of the α-cells is often considered to underlie glucagon hypersecretion in diabetic hyperglycaemia, and paracrine factors have also been implicated in glucose control of glucagon secretion in hypoglycaemia. However, the spectrum of putative paracrine factors released from adjacent islet cells clearly differs under hypo- and hyperglycaemia due to specific glucose sensitivities of the different islet cell types (Figure 1). This review will therefore consider how glucose controls glucagon secretion by α-cell interactions with other islet cells as well as by α-cell-intrinsic mechanisms that contribute differently depending on the prevailing glucose concentration (Figure 2). The present contribution extends and updates a previous review with similar focus on glucose (37) but is more limited than another review (38) with regard to other modulators of glucagon release.

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