The Functional State of Hormone-Sensitive Adenylyl Cyclase Signaling System in Diabetes Mellitus

Abstract

Diabetes mellitus (DM) induces a large number of diseases of the nervous, cardiovascular, and some other systems of the organism. One of the main causes of the diseases is the changes in the functional activity of hormonal signaling systems which lead to the alterations and abnormalities of the cellular processes and contribute to triggering and developing many DM complications. The key role in the control of physiological and biochemical processes belongs to the adenylyl cyclase (AC) signaling system, sensitive to biogenic amines and polypeptide hormones. The review is devoted to the changes in the GPCR-G protein-AC system in the brain, heart, skeletal muscles, liver, and the adipose tissue in experimental and human DM of the types 1 and 2 and also to the role of the changes in AC signaling in the pathogenesis and etiology of DM and its complications. It is shown that the changes of the functional state of hormone-sensitive AC system are dependent to a large extent on the type and duration of DM and in experimental DM on the model of the disease. The degree of alterations and abnormalities of AC signaling pathways correlates very well with the severity of DM and its complications.

Cross-Talk Between Insulin Signaling and G Protein–Coupled Receptors

“…In hearts from STZ-induced type 1 diabetes mellitus (T1DM) rats, one of the typical features observed is the decreased inotropic and chronotropic responses to βAR stimulation [50–52]. Accordingly, the mRNA and protein levels of β 1 AR in the hearts of STZ-induced diabetic rats and their function in promoting heart rate and contractility are decreased; and these alterations progress along with duration of DM [53, 54]. The reduction in myocardial β 1 AR numbers and mRNA is prevented by insulin therapy [54–56].…”

Beta-adrenergic regulation of adenylyl cyclase signaling system in the myocardium and brain of rats with obesity and type 2 diabetes mellitus as affected by long-term intranasal insulin administration

“…The activation of the β 3 -АR cascade in the myocardium and brain through the cAMP-dependent signaling pathways may represent the mechanism which prevents the excess myocardium stimulation by catecholamines, as the latter were shown to rise in diabetic cardiomyopathy [14]. Thus, there are disturbances in the β-АR agonist-sensitive ACSS at the level of β 1 -АR and β 3 -АR [2,4,11] as well as in coupling the receptors to G s -proteins, or at the level of the downstream cAMP-dependent proteins [15,17]. Practically no changes were revealed at the level of AC which does not change its functional activity in the tested pathologies except for the increased AC activity in the brain of young rats (Fig.…”

“…In the myocardium and coronary vessels of rats with streptozotocin (STZ)-induced DM1 the expression and functional activity of some AC isoforms (chiefly characteristic of the cardiac AC types 5 and 6) are also decreased [10]. In this connection, it is noteworthy that one of the major disorders caused by DM1 is the reduced heart rate reactivity to the inotropic and chronotropic effects during β-agonist stimulation [4,10] due to a reduced density of myocardial β-AR, changes in sensitivity and reactivity of myocardial β-AR to agonists [1,2,4,9,11]. At the same time, the evidence of changes in the adrenergic agonistregulated ACSS in obesity and its combination with type 2 diabetes mellitus (DM2) is insufficient and contradictory, while much more people are suffering these diseases which represent a serious social problem [11].…”

“…At present, there is evidence of considerable changes in the AC sensitivity to different hormonal agents, specifically catecholamines, occurring in obesity and DM2 [2,4,[11][12][13][14][15][16][17]. This may be due to a drop in the functional activity of the ACSS components, disruption of functional coupling between them, pathological activation of other ACSS-related signaling cascades, and fluctuations in levels of the ACSS components caused by changes in their expression, synthesis and degradation [2,4,9,[12][13][14][15][16][17].…”

Progresses of the Past Decade on Factors Contributing to Skeletal Muscle Glycogen Synthase Regulation

“…Upon their secretion, glucagon binds to G-Protein Coupled Receptors (GPCRs) located on the surface of liver cells, whereas, adrenaline will bind to GPCRs on the surface of liver and muscle cells. The binding results in a conformation change of GPCR that leads to the Gs α subunit of the stimulated G protein complex to exchange Guanine Diphosphate (GDP) for Guanine Triphosphate (GTP) and its release from the heterotrimeric complex [21]. The activated Gs α will activate adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cyclic Adenosine Monophosphate (cAMP).…”