Mechanisms of drugs in the treatment of type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM), more commonly known as chronic metabolic disease, is characterized by insufficient insulin secretion or insulin resistance. Due to the rise of T2DM globally, it is of great importance to decrease the number of complications, consequential morbidity, and mortality stemming from hyperglycemia.^[1] The normal steady-state blood glucose level has become an important metric for T2DM prognosis and is recognized as one of the major results of drug therapies for diabetes.^[2] This review outlines nine major types of antidiabetic drugs, relevance to functional mechanisms, which could provide a reference for the research and development of T2DM treatment drugs.

Glucagon-like peptide-1 receptor agonist (GLP-1RA) exerts its hypoglycemic effect mainly by stimulating insulin secretion, reducing endogenous glucose production, delaying gastric emptying, improving insulin sensitivity, and pancreatic beta-cell function, etc^[3] [Figure 1A]. GLP-1RA has many beneficial hypoglycemic effects such as reducing fatty tissues and blood pressure in patients, while some GLP-1RA has also proven to preserve cardiovascular and kidney function. The side effects of GLP-1RA were minimal to most patients, noting primarily gastrointestinal discomfort, increased heart rate, and hypoglycemia.^[4,5] With the development of GLP-1RA, the scope of clinical application is becoming broader. Other notable advantages of GLP-1RA in addition to hypoglycemic demonstrate the potential to delay the onset of prediabetes through impaired fasting glucose or impaired glucose tolerance. Meanwhile, the weight loss and cardiovascular benefits of such drugs are also reported in clinical trials or research.^[6] In conclusion, GLP-1RA has many application prospects that deserve greater investment.

Figure 1.

Schematic representation of different mechanisms of action under T2DM condition. (A) GLP-1RAs and DPP-4 inhibitors, (B) GPR40 agonists and GPR119 agonists, (C) SGLT2 inhibitors, and (D) GKAs. DPP-4: Dipeptidyl peptidase-4; GKAs: Glucokinase agonists; GPR119: G-protein coupled receptor 119; GPR40: G-protein-coupled receptor 40; SGLT2: Sodium-glucose cotransporter 2; T2DM: Type 2 diabetes mellitus.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are known to increase insulin levels, lower blood glucose, and protect the functioning of pancreatic islet cells, which demonstrate a significant role in the treatment of type 2 diabetes.^[7] As a new type of hypoglycemic drug, DPP-4 inhibitors have huge clinical application prospects due to their unique mechanism of action [Figure 1A]. When combined with traditional hypoglycemic drugs (biguanides and sulfonylureas) DPP-4 demonstrates a positive hypoglycemic effect, but the balanced ratios of application dosing should be explored further.^[8]

G-protein-coupled receptor 40 (GPR40) agonists are endogenous long-chain free fatty acids or small molecule agonists, and they not only act on pancreatic beta-cells to directly regulate insulin release but also mediate gastrointestinal enteroendocrine cells to regulate incretin secretion, thereby indirectly promoting glucose-stimulated insulin secretion [Figure 1B].^[9] GPR40 agonists rarely lead to the risk of hypoglycemia and demonstrate fewer side effects. GPR40 agonists are proven to assist in controlling food intake, reducing fatty tissues, and beta-cell apoptosis.^[10,11] GPR40 agonists show great potential even in the early stages of development. However, GPR40 agonists are still in the early stage of development.

G-protein coupled receptor 119 (GPR119) are known to directly promote insulin secretion, and indirectly increase insulin secretion by stimulating the release of glucose-dependent glucose-dependent insulinotropic polypeptide polyp (GIP)/CLP-1 without causing hypoglycemia^[12,13] [Figure 1B]. The remarkable advantages of small molecule GPR119 agonists make it one of the key aspects in the development of T2DM drugs. Despite the clear benefits, no clinical drug candidate has been successfully launched. It is necessary to continue to develop GPR119 agonists by utilizing different structural types and synthesizing many compounds. After rigorous screening, it may find the compound that meets the body's requirements.^[14]

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new type of hypoglycemic drug and can directly promote the excretion of glucose by the kidney. SGLT2 provides a new insulin-independent approach for the treatment of T2DM [Figure 1C]. In addition, SGLT2 inhibitors are known to reduce fatty tissues, lower blood pressure, and increase cardiovascular protection.^[15,16] With the development of clinical studies with renal outcomes as the primary endpoint, the applicable population of SGLT2 inhibitors will be better isolated.

Glucokinase agonists (GKAs) are a brand-new diabetes treatment drug, are known to improve the body's sensitivity to glucose by stimulating the pancreas and liver^[17] [Figure 1D]. Taking HMS5552 can initiate pancreatic islet L-cells in the intestine by stimulating the secretion of glucagon-like peptide-1 (GLP-1), thereby promoting the secretion of insulin, and achieving the effect of glucose control.^[18] The GKAs are still in the clinical research stage.

Many studies have been done on the secretion of glucagon, the interaction of glucagon with its receptor glucagon receptor (GCGR), and the regulation of various cytokine and enzyme functions downstream of GCGR [Supplementary Figure 1]. From these studies, antagonism against glucagon remains a primary innovative therapy for diabetes. GCGR antagonists can significantly relieve hyperglycemia, and the adverse reactions are mainly increased blood pressure and transaminases.^[19] Therefore, there is the possibility of developing a GCGR-related drug with a significant effect and low adverse reactions, which is likely to bring about significant progress in the treatment of type 2 diabetes.^[20,21]

The AMP-activated kinase (AMPK) acts as an energy-sensing enzyme that is activated when cellular energy levels are low and stimulates skeletal muscle uptake of glucose, fat, and other tissue oxidized fatty acids, and reduces hepatic glucose production. When AMPK is activated, it assumes various physiological roles through subunit configuration changes, resulting in the activation of downstream pathways.^[22] Small molecule AMPK activators are expected to become the next antidiabetic drugs to treat T2DM by lowering blood glucose and glycogen synthesis^[23] [Supplementary Figure 2]. Activating AMPK in the brain and heart may have unknown side effects due to AMPK currently existing widely in the human body. Specificity and selectivity will be a primary area of focus in the research and development of AMPK activators.

The protein tyrosine phosphatase-1B (PTP1B) is involved in receptor desensitization through dephosphorylation. PTP1B inhibitors delay receptor desensitization and prolong insulin action, making PTP1B a drug target for the treatment of T2DM^[24] [Supplementary Figure 3], and are receiving great recognition as a therapeutic target. Currently, few PTP1B inhibitors have entered clinical trials, but most PTP1B inhibitors are still in the preliminary research stage. Selectivity and cell membrane permeability are the two major barriers to the development of such drugs.^[25]

T2DM is a metabolic disorder. Diabetic complications have been recognized as a primary risk factor for mortality worldwide. There is a continuing need for potent medications, which are therapeutically specific for T2DM diabetic patients with safe and effective blood glucose control. Intriguingly, some marketed therapeutic drugs have their own characteristics in hypoglycemic control and have been used for a long time in clinical practice. Recently, a growing number of studies are being devoted to exploring diabetic drugs that have not yet reached the market. The hypoglycemic mechanism of action in T2DM drugs provides promising future treatment options for patients with T2DM.

Conflicts of interest

None.