Improving glycaemic control in type 2 diabetes: Stimulate insulin secretion or provide beta‐cell rest?

Abstract

Type 2 diabetes (T2D) is characterized by a gradual decline in pancreatic beta cell function that determines the progressive course of the disease. While beta-cell failure is an important contributor to hyperglycaemia, chronic hyperglycaemia itself is also detrimental for beta-cell function, probably by inducing prolonged secretory stress on the beta cell as well as through direct glucotoxic mechanisms that have not been fully defined. For years, research has been carried out in search of therapies targeting hyperglycaemia that preserve long-term beta-cell function in T2D, a quest that is still ongoing. Current strategies aim to improve glycaemic control, either by promoting endogenous insulin secretion, such as sulfonylureas, or by mechanisms that may impact the beta cell indirectly, for example, providing beta-cell rest through insulin treatment. Although overall long-term success is limited with currently available interventions, in this review we argue that strategies that induce beta-cell rest have considerable potential to preserve long-term beta-cell function. This is based on laboratory-based studies involving human islets as well as clinical studies employing intensive insulin therapy, thiazolidinediones, bariatric surgery, short-acting glucagon-like peptide (GLP)-1 receptor agonists and a promising new class of diabetes drugs, sodium-glucose-linked transporter (SGLT)-2 inhibitors. Nevertheless, a lack of long-term clinical studies that focus on beta-cell function for the newer glucose-lowering agents, as well as commonly used combination therapies, preclude a straightforward conclusion; this gap in our knowledge should be a focus of future studies.

Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal‐related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes

“…Thus, because the lixisenatide‐induced deceleration of gastric emptying has led to a marked reduction in the typical postprandial insulin release after breakfast, it is conceivable that the beta‐cell insulin secretory capacity was partly restored, thereby providing greater insulin responses after the subsequent meal. A similar phenomenon has previously been observed after transient inhibition of insulin secretion using, eg, somatostatin or potassium channel openers as well as during exogenous insulin therapy . Considering the fact that the amount of insulin secreted after breakfast typically represents the largest increment in insulin throughout the day, such mechanisms would also argue in favour of administering lixisenatide prior to breakfast rather than other meals later during the day.…”

“…One potential explanation could be a (partially) persisting effect on gastric emptying at subsequent meals. Alternatively, it seems possible that lixisenatide exerts an insulin‐sparing effect after breakfast, which may enhance beta‐cell function at the subsequent meals through the mechanism of beta‐cell rest …”

Comprehensive analysis of body composition and insulin traits associated with intra‐pancreatic fat deposition in healthy individuals and people with new‐onset prediabetes/diabetes after acute pancreatitis

“…The finding of higher IFD in participants with NODAP and an inverse association between IFD and insulin sensitivity suggest that IFD might be involved in the pathogenesis of NODAP (Appendix S1 and Figure S2) and associated metabolic abnormalities. Future studies are warranted to investigate whether the inter‐relationship between IFD and insulin sensitivity is an epiphenomenon or a driving force for altered insulin traits in relation to subsequent NODAP …”

Effect of once weekly dulaglutide by baseline beta‐cell function in people with type 2 diabetes in the AWARD programme

“…Furthermore, treatment that could exert less stress on the beta‐cell may contribute to some degree of preservation of insulin secretion over time. Moreover, therapies that reduce beta‐cell workload or induce beta‐cell rest may be most beneficial in individuals with T2D and prominent beta‐cell impairment . In this respect, there has been growing interest in glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) as a treatment option for patients with lower beta‐cell function.…”