What Role Does Insulin Play In Diabetes – Various theories for the hormonal basis of diabetes have been proposed and discussed in the past few decades. Previously, insulin deficiency was the only hormone deficiency that directly led to metabolic disorders associated with diabetes. Although glucagon and its receptors are neglected in this framework, a growing number of studies have shown that they play a central role in the development and progression of diabetes. However, the molecular mechanisms underlying the effects of glucagon are still unclear. This review summarizes recent research on the mechanisms by which glucagon and its receptor are involved in the pathogenesis of diabetes, as well as the association between GCGR mutation rates in populations and the incidence of diabetes. In addition, we summarize how recent research clearly establishes glucagon as a potential therapeutic target for diabetes.

Diabetes is a metabolic disorder characterized by hyperglycemia due to absolute deficiency of insulin secretion (type 1 diabetes, T1D), or a combination of insulin resistance and insufficient compensatory insulin secretion (type 2 diabetes, T2D) (1). However, every type of diabetes in animals and humans is associated with hyperglucagonemia (2-4), so increased glucagon is more critical than insulin deficiency for the development of diabetes (4, 5). Increasing evidence shows that glucagon and glucagon receptor (GCGR) blockade can reduce hyperglycemia in animals and humans, clearly establishing the important role of glucagon and GCGR in the pathogenesis of diabetes (6, 7).

What Role Does Insulin Play In Diabetes

Glucagon is a linear peptide containing 29 amino acids. It is secreted by islet α-cells and mainly targets liver cells (8). GCGR is a G protein-coupled receptor (GPCR) mainly detected in islet β-cells and hepatocytes ( 9 ). After glucagon specifically binds to GCGR, it promotes liver glycogen breakdown and raises blood glucose levels to stimulate insulin secretion (10, 11). Glucagon-like peptide-1 (GLP-1), expressed predominantly in intestinal L cells, activates the glucagon-like peptide-1 receptor (GLP-1R) to regulate metabolism ( 12 , 13 ). Glucagon and GLP-1 are derived from the same biosynthetic precursor of proglucagon and are involved in the regulation of lipid and cholic acid metabolism, thus playing pivotal roles in glucose metabolism and the pathogenesis of diabetes (7, 12, 13).

Roller Coaster Effect (fluctuating Sugar Levels) In Diabetes

In this review, we review the controversial relationship between glucagon and diabetes-related metabolic disorders based on recent research, emphasizing recent evidence supporting an important role for glucagon. We also elucidate the association between GCGR mutations in populations and the incidence of diabetes. In addition, we summarize pharmacological strategies to provide a new basis for the treatment of diabetes.

The debate over the relative roles of hormones in the regulation of metabolic disorders associated with diabetes has spanned decades. In 1921, the discovery of insulin was considered one of the greatest advances in medical history. This led to the development of the insulin-centric view, which proposes that all metabolic disorders associated with diabetes are directly caused by a lack of insulin secretion (14). Glucagon was not yet characterized and therefore was not associated with these metabolic disorders. The insulin-centric theory was accepted for more than half a century until Unger et al. presented the bihormone theory at a conference in 1975 (15, 16).

According to the theory of two-hormone regulation, diabetes is caused by the abnormal secretion of insulin and glucagon (15, 16). Some of the metabolic disorders associated with diabetes are directly caused by insulin deficiency, such as increased lipolysis, increased proteolysis, and decreased glucose utilization. Others, such as decreased glycogen synthesis, increased ketogenesis, increased hepatic glycogenolysis, and gluconeogenesis, are direct effects of excess glucagon (15–18) (Figure 1). Glucagon has glucogenic, ketogenic and gluconeogenic functions, and in conditions of insulin deficiency, it mediates severe endogenous hyperglycemia and hyperketonemia. Therefore, the direct cause is the significant increase in glucose and ketone levels in severe manifestations of diabetes (19). In diabetic patients with relatively stable insulin levels, increased glucagon causes hyperglycemia and glycosuria (17). Glucagon suppression may be an effective adjunct to routine antihyperglycemic therapy in patients with diabetes (20-22).

Figure 1 Hormonal regulation of glucose homeostasis in islet cells. This diagram shows the metabolic effects of glucagon and insulin. Blood glucose levels affect insulin and glucagon secretion. Insulin deficiency leads to increased lipolysis, increased proteolysis, and decreased glucose utilization, while excess glucagon leads to decreased glycogen synthesis, increased ketogenesis, increased glycogenolysis, and gluconeogenesis. The red arrow indicates a stimulatory effect, while the blue arrow indicates an inhibitory effect.

Do Premixed Insulins Have A Place In 21st Century Diabetes Care?

The glucagonocentric hypothesis was proposed by Unger et al. Based on the following evidence: (a) Hyperglucagonemia is present in all forms of diabetes. (b) Marked hyperglucagonemia is caused by injection of anti-insulin serum into the normal pancreas. (c) During complete insulin deficiency, all metabolic manifestations of diabetes can be suppressed by glucagon suppressors, such as somatostatin, and in the global knockout of Gcgr (Gcgr).

) mice, showing that destruction of β cells does not cause diabetes (4). Therefore, compared to insulin deficiency, excess glucagon plays a more fundamental role in the development of diabetes.

Gcgr -/- mice were designed to further understand the role of GCGR in the development of diabetes. These mice do not respond to glucagon at any concentration and their fasting blood glucose levels are lower than wild type mice. These knockout mice show increased glucose tolerance and insulin sensitivity during the insulin tolerance test (23). When the β-cells of Gcgr−/− mice were killed by streptozotocin (STZ) and insulin secretion was inhibited, the animals did not develop hyperglycemia, indicating that Gcgr−/− mice do not develop T1D even under conditions of insulin deficiency ( 24 ). . After transient restoration of defective Gcgr with an adenovirus vector, blood glucose levels in mice increased after β-cell destruction ( 25 ). When Gcgr was inactivated again, blood glucose levels returned to normal, indicating that in the absence of glucagon, insulin deficiency does not lead to abnormal blood glucose levels, and that the abnormal blood glucose concentration caused by insulin deficiency can be restored by removing the effect. . Glucagon (25). Hence, blocking Gcgr can restore hyperglycemia in rodent models of insufficient insulin secretion. However, this effect requires a certain number of β cells (26). Active GLP-1 was detected in pancreatic perfusion from Gcgr −/− but not wild-type mice ( 27 ), and FGF21 additively with GLP-1 to prevent insulinopenic diabetes in glucagon-deficient mice ( 28 ), which Most of the risk is reduced, it works. from Gcgr -/- diabetic mice. In contrast, deletion of Gcgr means that glucagon cannot function normally, which can cause a series of metabolic problems, such as hyperglucagonemia and compensatory α-cell hyperplasia (23, 29, 30). Therefore, the above phenomena should be monitored in the development of GCGR antagonists. The therapeutic potential of GCGR is not fully understood and should be the basis for further studies. However, established animal models provide an effective tool for developing strategies to reduce the incidence of diabetes.

In healthy individuals, high blood glucose stimulates beta-cell insulin secretion and suppresses glucagon secretion. Low blood sugar inhibits beta cell insulin secretion and glucagon secretion is stimulated (Figure 1). However, hyperglucagonemia was present in patients with diabetes, including T1D (31) and T2D (32). No significant difference in plasma glucagon level was observed between T1D and T2D (31, 32). Absolute deficiency or relative deficiency of insulin secretion weakened insulin inhibition on glucagon (4).

Insulin Supply Chain: Complexity Of Drug Deliveries

The role of glucagon is essential in paracrine regulation within islets. Svendsen et al ( 27 ) used isolated perfused pancreases from wild-type, Glp-1r knockout, diphtheria toxin-induced proglucagon deletion, β-cell-specific Gcgr knockout, and Gcgr −/− mice to examine glucagon-induced insulin secretion. They found that paracrine glucagon actions are required to maintain normal insulin secretion and that intra-islet glucagon signaling involves activation of GCGR and GLP-1R. Loss of GCGR or GLP-1R does not alter the insulin response, whereas combined blockade of both receptors significantly reduces insulin secretion ( 27 ). Furthermore, Gcgr −/− mice display normal blood glucose levels and increased glucagon levels in glucose-stimulated insulin secretion (GSIS) assays after treatment with 10 mM ( 33 ) or 12 mM ( 27 ) glucose. This is similar to the levels observed in control rats, suggesting that the insulin-enhancing effect of glucagon is mainly mediated through the GLP-1R. However, as a downstream receptor of glucagon, the physiological significance of the β-GCGR cell remains subtle. Zhang et al. (34) reported that glucagon potentiates insulin secretion via the β-cell GCGR at physiological but not high glucose concentrations, and that β-cell GCGR activation increases GSIS more than GLP-1R in a high-fat diet. These findings suggest that GCGR contributes to the maintenance of glucose homeostasis during nutrient overload. These studies emphasized the essential role of GCGR on β-cells in mediating glucose homeostasis and catabolic state and indicated that GCGR is closely related to the pathogenesis of diabetes. Accordingly, studies of the mechanisms by which GCGR regulates insulin secretion are of great importance.

In pancreatic β-cells, GLUT2, a glucose transporter protein, is required for GSIS (35). Glucose binding to GLUT2 is a key pathway leading to increased ATP levels, deionization, increased intracellular calcium concentration, and increased insulin exocytosis. GLUT1 expression was decreased in Gcgr−/− mice but increased in wild-type mice after glucose stimulation ( 36 ). As a paracrine hormone, glucagon binds to GCGR with high affinity, while also exerting a “spillover” effect upon binding.

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