Current insights and new perspectives on the roles of hyperglucagonemia in non-insulin-dependent type 2 diabetes

Abstract

Type 2 diabetes is well recognized as a noninsulin-dependent diabetic disease. Clinical evidence indicates that the level of circulating insulin may be normal, subnormal, and even elevated in type 2 diabetic patients. Unlike type 1 diabetes, the key problem for type 2 diabetes is not due to the absolute deficiency of insulin secretion, but because the body is no longer sensitive to insulin. Thus, insulin resistance is increased and the sensitivity to insulin is reset, so increasing levels of insulin are required to maintain body glucose and metabolic homeostasis. How insulin resistance is increased and what factors contribute to its development in type 2 diabetes remain incompletely understood. Overemphasis of insulin deficiency alone may be too simplistic for us to understand how type 2 diabetes is developed and should be treated, since glucose metabolism and homeostasis are tightly controlled by both insulin and glucagon. Insulin acts as a YIN factor to lower blood glucose level by increasing cellular glucose uptake, whereas glucagon acts as a YANG factor to counter the action of insulin by increasing glucose production. Furthermore, other humoral factors other than insulin and glucagon may also directly or indirectly contribute to increased insulin resistance and the development of hyperglycemia. The purpose of this article is to briefly review recently published animal and human studies in this field, and provide new insights and perspectives on recent debates as to whether hyperglucagonemia and/or glucagon receptors should be targeted to treat insulin resistance and target organ injury in type 2 diabetes.

Figure 1

Two classic G protein-coupled glucagon receptor-mediated intracellular signaling pathways in glucagon-targeted cells. To induce an effect, glucagon binds to cell surface GTP-heterotrimeric Gs protein-coupled receptors and activates phospholipase C (PLC)/IP₃/Ca²⁺ and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling. Both signaling pathways are closely involved in mediating glucagon-induced glycogenolysis and gluconeogenesis, leading to hyperglycemia. Pharmacological agents known to block these two signaling pathways also inhibit glucagon-induced hyperglycemic and growth effects in target cells. Abbreviations: AC, adenylyl cyclase; GCGP, the G_s protein-coupled glucagon receptor; H-89, a selective cAMP-dependent PKA inhibitor; PKC, protein kinase C; and U73122, a selective PLC inhibitor. Reprinted with permission from Li and Zhuo [38]. Targeting glucagon receptor signaling in treating metabolic syndrome and renal injury in type 2 diabetes: theory versus promise. Clinical Science 2007; 113, 183–193.

Figure 2

Effects of long-term hyperglucagonaemia induced by infusion of glucagon via osmotic minipump (1 μg/h, i.p., for 4 weeks) and concurrent blockade of GCGR by [des-His¹-Glu⁹] glucagon (5 μg/h via osmotic minipump, i.p.) on fasting blood glucose (A) and glucose tolerance (B) in glucagon-infused mice. **p<0.01 compared with basal (week 0) for fasting blood glucose (in A) or compared with 0 min for the GTT within the same group (in B). ⁺⁺p<0.01, compared with glucagon-infused mice at corresponding periods. Ant, [Des-His¹-Glu⁹]glucagon. Reprinted with permission from Li et al. [14]. Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice. Clin Sci (Lond) 2008; 114(9):591–601.

Figure 3

Effects of cAMP-dependent protein kinase A- or phospholipase C-selective inhibitors on glucagon-induced MAP kinases ERK 1/2 phosphorylation in rat glomerular mesangial cells. Both H-89 and U73122 blocked the effects of glucagon on MAP kinases ERK 1/2 phosphorylation. (A) Western blot of phosphorylated and total ERK 1/2; (B) quantitative changes in phosphorylated ERK 1/2 from control. **p<0.01 vs control; ⁺⁺p<0.01 vs glucagon. Reprinted with permission from Li et al. [35]. Glucagon receptor-mediated ERK 1/2 phosphorylation in rat mesangial cells: role of protein kinase A and phospholipase C. Hypertension 2006; 47, 1–6.

Figure 4

A hypothesis that proposes a potential role of hyperglucagonemia in the development of hyperglycemic and metabolic phenotypes in type 2 diabetes. In human type 2 diabetes, there is an inappropriate increase in the hyperglycemic glucagon over the hypoglycemic insulin. Imbalance of the actions of insulin and glucagon in favoring the latter leads to increases in glycogenolysis and gluconeogenesis in the liver and other tissues, resulting in hyperglycemia, increased insulin resistance (resetting insulin sensitivity to higher levels of insulin) and impaired glucose tolerance. Moreover, glucagon, via direct activation of GCGR-mediated signaling pathways (cAMP-dependent protein kinase A, PI 3-K/PKB/Akt, PLC/[Ca²⁺]_i/PKC, and MAPK/ERK 1/2), stimulates cellular growth and proliferation, leading to target organ injury. GCGR antagonists are expected to block these metabolic and growth effects of hyperglucagonemia in type 2 diabetes, and reset insulin sensitivity to lower insiulin levels. GCGR, G protein-coupled glucagon receptors; MAPK/ERK 1/2, mitogen-activated protein kinase/extracellular regulated kinases 1 and 2; PKA, protein kinase A; PI3-K, PI3-kinase; PKB/Akt, protein kinase B/AKT; and PLC/]Ca²⁺]_i/PKC, phospholipase C/intracellular calcium/protein kinase C. Modified with permission from Li and Zhuo [38]. Targeting glucagon receptor signaling in treating metabolic syndrome and renal injury in type 2 diabetes: theory versus promise. Clinical Science 2007; 113, 183–193.