With changing lifestyles and increasing aging, type 2 diabetes mellitus (T2DM) has become an increasingly heavy burden on human society, with its prevalence exceeding 246 million and still increasing rapidly, and its associated complications becoming the fifth leading cause of death. These sobering figures are a constant wake-up call for us to reflect on a number of fundamental contradictions that have persisted in the field of T2DM therapeutics.
Who will slow down the progression of T2DM?
T2DM is a chronic progressive disease in which islet β-cell failure and the decline of endogenous insulin secretion are the main lines of disease progression. The majority of patients have a progressive glycemic index over the 10-year intervention period and eventually enter the insulin-dependent phase. The ADOPT study showed that patients with newly diagnosed T2DM, whether treated with sulfonylureas, metformin or thiazolidinediones (TZDs), failed to achieve glycemic targets after 3-5 years and required a change in treatment regimen, a rate of progression that is undoubtedly too fast for a disease that can last for decades.
The above results from the UKPDS and ADOPT studies suggest that although elevated blood glucose may be one of the reasons for the increased burden on β-cells and their progressive failure, maintaining the glycemic target status is not sufficient to stop the progression of T2DM, and patients need to change their regimens and increase the intensity of treatment every few years, eventually leading to complete loss of β-cell function and reliance on insulin for glucose-lowering therapy. This means that there is an intrinsic reason for the decline of β-cell function, and we urgently need a class of glucose-lowering drugs that can protect β-cell function while lowering glucose.
Glucose-lowering compliance and hypoglycemic response: a growing paradox Glucose-lowering compliance is a fundamental requirement to reduce the risk of diabetes-related complications and death. A prolonged hyperglycemic state leads to the production of harmful glycosylation end products and generates a state of oxidative stress that greatly increases the risk of macrovascular and microvascular complications. In addition hyperglycemic state also directly constitutes a susceptibility factor for complications such as infections and diabetic foot.
However, as the duration of T2DM and the disease progresses, it becomes more difficult to maintain the glycemic status, and patients gradually need to use more and stronger glucose-lowering drugs to achieve the standard. However, a variety of hypoglycemic drugs have different degrees of hypoglycemic effects, in addition, improper dose and timing of medication, alcohol consumption and changes in lifestyle may trigger hypoglycemic events. In normal people, when blood glucose drops below 5 mmol/ml, physiological reflexes such as elevated glucagon secretion will elevate blood glucose, but the progression of T2DM has impaired the reflex protection mechanism of patients’ response to hypoglycemia. The increasingly intensive hypoglycemic therapy further increases the risk of hypoglycemia in T2DM patients.
The incidence of hypoglycemic events is positively associated with mortality and cardiovascular risk in patients with T2DM. The higher incidence of hypoglycemic events in the intensive glucose-lowering group in the ACCORD study, which achieved lower glycosylated hemoglobin (HbA1c) levels but increased mortality, may have contributed to this outcome. On the other hand, the fear of hypoglycemic events can greatly reduce patients’ compliance with glucose-lowering therapy and make it more difficult to achieve the glucose-lowering target.
For the above reasons, hypoglycemic events constitute an obstacle to the treatment of T2DM. As the patient’s disease progresses, the glycemic index worsens, the intensity of glucose-lowering therapy gradually increases, and glucose-lowering compliance and the risk of hypoglycemia become an increasingly prominent pair of conflicts in the treatment of T2DM.
Can insufficient insulin secretion and insulin resistance be improved simultaneously?
Insufficient insulin secretion and insulin resistance are two basic pathophysiological changes in the pathogenesis of T2DM. In obese T2DM patients, insulin resistance causes relative insulin deficiency and feedback increases insulin secretion from β-cells, thus increasing their load and causing β-cell function decline over time. In contrast, in non-obese T2DM patients, absolute insufficiency of insulin secretion is likely to be the initiating factor for the development of T2DM.
Among the current hypoglycemic drugs, metformin and thiazolidinediones (TZD) can improve insulin resistance but have no significant effect on insulin secretion, while insulinotropic agents (such as sulfonylureas and glinides) and exogenous insulin can supplement the deficiency of endogenous insulin secretion, but have no significant improvement on insulin resistance. For most T2DM, insulin resistance and deficiency often coexist, and due to the lack of drugs that can improve both pathological conditions, T2DM patients often need combination therapy to achieve glucose reduction, which greatly increases the complexity and difficulty of treatment.
Enterostatin and DPP-4 inhibitors: the new dawn of T2DM treatment The search for glucose-lowering drugs that protect β-cells and are largely free of hypoglycemia and can improve both insulin insufficiency and insulin resistance has been a goal pursued by the endocrinology community for many years. In the 1980s, physiological studies found that oral administration of glucose could cause more insulin release than intravenous infusion, suggesting the existence of some endogenous substances that could regulate insulin release, and such substances only promote insulin secretion after glucose consumption. Subsequent studies have revealed that this glucose-dependent substance that promotes insulin release is a type of peptide hormone produced by endocrine cells in the small intestine, which has been named enteroglucagon by the endocrinology community. The main physiological effects of enteroglucagon in humans include glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which account for more than 60% of total insulin secretion after meals. These two enteroglucagon can bind to specific receptors on the surface of pancreatic β-cells and many other cells to exert physiological effects that are beneficial for lowering glucose.
The major difference between enteroglucagon and other insulin-producing substances is that it increases insulin secretion only at high glucose levels. Under low glucose conditions, enteroglucagon binds to specific receptors on the surface of β-cells, triggering only a small amount of inward flow of calcium ions and a trace release of insulin. In contrast, at high glucose levels, the intracellular ATP level in β cells increased, which opened the ATP-dependent potassium channels, delayed cell repolarization, prolonged the time course of calcium ion inward flow after enteroglucagon binding to the receptor, and significantly increased the release of insulin.
Further studies showed that enteroglucagon has the potential to improve islet β-cell function and reduce insulin resistance. After receiving enteroglucagon infusion for 6 weeks, T2DM patients receiving glucose load could have a significant increase in C-peptide levels and a significant 77% increase in insulin sensitivity, indicating a significant improvement in both insulin secretory function and insulin resistance status. In animal tests and in vitro studies, enteroglucagon also activated β-cell regeneration, maintained the morphology of human β-cells, and inhibited β-cell apoptosis.
In addition, enteroglucagon has a wide range of extrapancreatic effects; GLP-1 delays gastric emptying, and after long-term infusion, it also acts on the feeding center of the hypothalamus to increase satiety, thus causing patients to eat less. These effects also have a positive effect on the control of body weight and caloric intake in patients with T2DM.
These physiological effects make enterostatin an attractive therapeutic substance. It is conceivable that a drug that can effectively increase enteroglucagon levels in the body is likely to have the following properties: promote insulin secretion only during hyperglycemia without essentially causing hypoglycemia, reduce insulin resistance while improving insulin secretion, and delay the progression of T2DM by protecting beta cells. These effects are likely to help resolve several long-standing paradoxes in the field of T2DM therapeutics.
However, natural enteroglucagon can only be administered by injection and is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), which is widely present in tissues, and has a half-life of no more than a few minutes in the body, necessitating continuous infusion for glycemic control.
The pharmaceutical industry has found a way out by developing drugs that inhibit DPP-4 and increase its level by delaying the breakdown of endogenous enteroglucagon. Stagliptin (trade name Januvia) is the first oral DPP-4 inhibitor approved for the treatment of T2DM worldwide. In several clinical studies, selegiline has shown definite hypoglycemic efficacy with little risk of hypoglycemia and a significant improvement in islet beta-cell function, confirming previous assumptions about the properties of DPP-4 inhibitors. A large number of clinical studies are continuing to validate the glucose-lowering efficacy, safety and endpoint event benefits of selegiline. It is foreseeable that DPP-4 inhibitors, represented by selegiline, are likely to play a significant role in the future treatment of T2DM and fill the gaps in the existing therapeutic tools.