Brain Signaling Systems in the Type 2 Diabetes and Metabolic Syndrome: Promising Target to Treat and Prevent These Diseases

Figures & data

Figure 1.  Insulin and leptin signaling.

AKT: Protein kinase B; GLUT4: Insulin-regulated glucose transporter of the type 4; GSK3: Glycogen synthase kinase 3; IRS1/2: Insulin receptor substrates 1 and 2; JAK2: Janus kinase-2; mTOR: Mammalian target of rapamycin; p85-PI3K and p110-PI3K: Regulatory (p85) and catalytic (p110) subunits of heterodimeric p85/p110 phosphatidylinositol 3-kinase; PDE3B: Phosphodiesterase of the subtype 3B; PDK: Phosphoinositide-dependent kinase; PI-3,4,5-P(3): Phosphatidylinositol 3,4,5-triphosphate; PKC: Protein kinase C; STAT3: Signal transducer and activator of transcription of the type 3.

Figure 2.  The hormone-sensitive adenylyl cyclase signaling system.

α_sβγ and α_iβγ: Heterotrimeric G_s- and G_i-proteins; 5-HT_1,4,6,7R: 5-hydroxytryptamine receptors of the types 1, 4, 6 and 7; cAMP: 3′,5′-cyclic adenosine monophosphate; CREB: cAMP response element-binding; D_1,2DAR: Dopamine receptors of the types 1 and 2; EPAC: cAMP-responsive Rap1 guanine nucleotide exchange factor; GLP-1: Glucagon-like peptide-1; MC₄R: Melanocortin receptor of the type 4; PKA: Protein kinase A; Rap1: Ras-related protein 1.

Table 1.  The approach to the improvement of brain signaling systems regulated by hormones and neuromediators in Type 2 diabetes mellitus and metabolic syndrome.

Approach/strategy	Current state	Future prospects
The increase of brain levels of hormones and neuromediators due to their intranasal administration, the use of the reuptake inhibitors and the BBB-penetrating analogs of hormonal agents	The use of intranasal insulin to correct the neurodegenerative disorders and in experimental T2DM [117,119,120,122,124]; the use of BBB-penetrating analogs of leptin in experimental obesity and T2DM [185,206,207]; the use of SSRI and intranasal 5-HT to treat diabetic patients and in experimental conditions [34,258–262]	The development of effective approaches to intranasal and inhalation routes of administration of leptin, melanocortins and other regulators of the brain signaling; the development of nanoparticles for nasal delivery of hormonal agents; the development of the BBB-penetrating conjugates of hormonal agents with chitosan, PEG and other macromolecular carriers
The use of highly selective agonists/antagonists of hormonal receptors, which selectively regulate specific signaling pathways and influence a certain type of neuronal cells	The use of DA2R-agonist bromocriptine to improve glucose tolerance and cardiovascular functions in diabetic patients [210,212,215–223]; the use of leptin-derived peptide ([D-Leu-4]-OB-3) in experimental models of T2DM [198–200]; the use of the 5-HT2CR-agonists to improve glucose tolerance in experimental model of T2DM [40]; the use of the MC4R agonists (Nle^4,D-Phe^7-α-MSH, BIM-22493, AZD2820, etc.) to improve feeding behavior, insulin sensitivity and cognitive functions in experimental models of metabolic disorders [298,300,304,310,312–317]	The development of new classes of highly selective agonists of the leptin, melanocortin and GLP-1 receptors, including the low-molecular-weight compounds, and the development of biased (functionally selective) agonists of 5-HTR and DAR
The application of hormones/neuromediators analogs resistant to the degradation	The use of proteolysis-resistant GLP-1 analogs (exendin-4, liraglutide, etc.) to improve feeding behavior, glycemic control and insulin sensitivity, and to prevent neurodegenerative changes in patients with T2DM and in experimental models of metabolic disorders [333–335,342,343,345,346]	The use of proteolysis-resistant GLP-1 analogs to treat patients with T2DM and MS; the development of the proteolysis-resistant leptin and melanocortin analogs by the chemical modification, the amino acid substitutions and the synthesis of truncated analogs
The use of agents that enhance synthesis and secretion of hormones and neuromediators and prevent their degradation in the CNS	The use of dipeptidyl peptidase-4 inhibitors to restore the insulin sensitivity and the metabolic processes in patients with MS and T2DM [333–338]; the use of IDE inhibitors to improve glucose tolerance in experimental metabolic disorders [128,129]	The development of therapeutic approaches to effective clinical use of dipeptidyl peptidase-4 inhibitors alone and in the combination with other CNS regulators and antidiabetic drugs; the search of IDE inhibitors suitable for clinic application; the search of pharmacological regulators of the enzymes responsible for brain synthesis of DA, 5-HT and other neuromediators
The application of regulators that act at the postreceptor stages of neuronal signal transduction	The use of PTP1B inhibitors (Trodusquemine, Claramine) to improve insulin and leptin sensitivity in experimental metabolic disorders [142–144,204]	The search of new highly selective regulators of phosphatases, protein kinases, cAMP-phosphodiesterases, and other proteins controlling the postreceptor stages of insulin, IGF-1 and leptin signaling, and their use in clinical endocrinology
The coordinated regulation of two or more brain signaling systems	Administration of leptin with insulin, amylin, cholecystokinin and GLP-1 analog to enhance their effects on the animals with experimental metabolic disorders and in clinical trials [186–193]; administration of bromocryptine with insulin, metformin, glipizide and pioglitazone to synergize their effects in patients with T2DM and in experimental diabetes [219,222,225,228]; co-administration of MC4R agonists and GLP-1 analogs to improve insulin sensitivity and energy expenditure in experimental animals much more effectively than monotherapy [319]	The search of the most effective approaches to co-administration of hormonal regulators of the brain signaling systems in diabetic pathology; the optimization of the schemes for clinical application of synergistically acting hormones, including the decrease of their effective doses and the duration of treatment

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