Type 2 Diabetes Mellitus (T2DM) and Carbohydrate Metabolism in Relation to T2DM from Endocrinology, Neurophysiology, Molecular Biology, and Biochemistry Perspectives

Abstract

Type 2 diabetes mellitus (T2DM) is a severe disease caused by metabolic disorders, particularly carbohydrate metabolism disorders. The disease is a fatal global trouble characterised by high prevalence rates, causing death, blindness, kidney failure, myocardial infarction, amputation of lower limps, and stroke. Biochemical metabolic pathways like glycolysis, gluconeogenesis, glycogenesis, and glycogenolysis are critical pathways that regulate blood glucose levels with the glucokinase (GK) enzyme playing a central role in glucose homeostasis. Any factor that perturbs the aforementioned biochemical pathways is detrimental. Endocrinological, neurophysiological, and molecular biological pathways that are linked to carbohydrate metabolism should be studied, grasped, and manipulated in order to alleviate T2DM global chaos. The challenge, howbeit, is that, since the body is an integration of systems that complement one another, studying one "isolated" system is not very useful. This paper serves to discuss endocrinology, neurophysiology, and molecular biology pathways that are involved in carbohydrate metabolism in relation to T2DM.

Figure 1

The purinergic receptors' role in governing the secretion of insulin and the survival of β-cells. The GLUT2 facilitates the entrance of glucose. Glycolysis yields ATP. The ATP produced is used to close up the ATP-sensitive channel, K_ATP. The K_ATP channel is made up of 4 (four) Kir6.2 and SUR1 subunits. When the K_ATP closes, the cell membrane potential depolarises and this leads to the opening of the voltage-gated L-type Ca²⁺ channels, generating Ca²⁺ action-potentials. An increase in the cellular Ca²⁺ triggers ATP-insulin-containing secretory vesicles exocytosis. Parasympathetic and sympathetic nerves may also release ATP. Membrane depolarisation and Ca²⁺/Na⁺ influx are facilitated by P2X receptors. P2Y receptors elevate cellular Ca²⁺ and “turn on” protein kinase C (PKC) pathways. Also, other P2Y and adenosine receptors affect the cAMP pathway and possibly Epac signalling. High adenosine concentrations are a “force” that coerces adenosine translocation into the β-cell, thus exerting metabolic effects.

Figure 2

The P2Y12 receptor allows the entrance of a signal from excited CG. Cleavage of the Casp1 from the NLRP3 leads to cellular inflammatory necrosis. The above phenomenon is accompanied by the release of proinflammatory factors like interleukin 1-β (IL-1β). Such proinflammatory factors are known for exaggerating inflammatory response and cell dysfunction. The celiac ganglia take part in carbohydrate metabolism, which in turn is linked to neuroinflammation. The P2Y12 shRNA therapy inhibits the excitation of the celiac ganglia, which is associated with overexpression of P2Y12 receptors and then hepatic glucose homeostasis is restored. GLC is glucose, and G6P is glucose-6-phosphate.

Figure 3

Glucokinase (GK) phosphorylates glucose during glycolysis. High glucose concentrations cause the release of a bound GK in the nucleus by GKRP. Conversely, high fructose-6-phosphate (F-6-P) concentrations cause GK to be bound in the nucleus by the GKRP.