Let’s Be More Sensitive—How SGLT-2 Inhibitors and GLP-1 Receptor Agonists Affect β-Cell Function in Type 2 Diabetes

In the world of romantic love, we would like our partners to be both sweet and sensitive. But the balance has to be right. Too much sweetness can make us lose interest. And when we lose interest, we often become less sensitive. For β cells, the situation may be similar. In normal physiology, insulin secretion is tightly coupled to ambient glucose levels, rising when glucose levels increase and dipping when glucose levels fall, in a carefully choreographed pas de deux. This ballet is even more complex than it seems. Not only must the β cells sense absolute glucose levels and secrete an appropriate amount of insulin (referred to as β-cell glucose sensitivity), they must also sense the rate of change in glucose levels and other factors and adjust insulin secretion accordingly. They must, by analogy, know where the ballerina will be when she jumps, so that she can be brought safely down to earth. When diabetes develops, this intimate relationship breaks down. As in any failing relationship, it is easy to assign blame. Indeed, multiple metabolic abnormalities are known to contribute to hyperglycemia in type 2 diabetes (1). However, the failure of β cells to adequately compensate for insulin resistance seems to be a primary defect, preceding and predicting the development of diabetes when glucose levels are still normal, and outwardly all appears well (2, 3). As hyperglycemia ensues, the overworked and underappreciated β cells become less able to secrete insulin for a given glucose challenge—their sensitivity has decreased. They become indifferent or “blind” to glucose and no longer respond in a precise and timely fashion, a phenomenon referred to as glucose toxicity. But given a new partner to pique their attention—a nonglucose secretagogue such as arginine, for example—β cells are perfectly able to secrete insulin in a robust fashion. Thus, the β cells are not incapable of secreting insulin, they have just lost interest in their partner, glucose. In metabolism, as in romance, it seems familiarity breeds contempt. What then can be done to save this dysfunctional relationship? In this issue of the Journal, Ali Muhammed Ali and colleagues from the Division of Diabetes at the University of Texas Health Science Center at San Antonio report results of a study in which they compared the effects of 16 weeks of treatment with the sodium-glucose cotransporter-2 (SGLT-2) inhibitor canagliflozin, the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, or the combination of canagliflozin and liraglutide on β-cell function in patients with type 2 diabetes (4). Modeling of frequently sampled oral glucose tolerance tests (OGTTs) allowed the calculation of glucose-stimulated insulin secretion rates, β-cell glucose sensitivity, rate sensitivity, and a potentiation factor that dynamically modulates insulin secretion and reflects both glucose-dependent and glucose-independent processes (for example, incretin hormones and neural modulation). All 3 treatments decreased the glucose area under the curve during the OGTT to a similar extent. Canagliflozin, which causes significant glucosuria, thereby decreasing plasma glucose concentrations, was associated with an almost 2-fold increase in β-cell sensitivity to glucose. Liraglutide, which acts directly on β-cell GLP-1 receptors to enhance insulin secretion in a glucose-dependent manner, increased β-cell glucose sensitivity by 3-fold, significantly more than did canagliflozin. Liraglutide also increased the potentiation factor. Surprisingly, the combination of canagliflozin and liraglutide did not increase β-cell glucose sensitivity or the potentiation factor beyond that achieved with liraglutide alone. In multiple regression analyses, increases in β-cell glucose sensitivity were independently associated with improvements in glycated hemoglobin (HbA1c). What, then, does this study tell us about β-cell dysfunction in diabetes? Treatment with the SGLT-2 inhibitor canagliflozin lowered plasma glucose levels, and this was associated with a secondary improvement in β-cell glucose sensitivity. Thus, glucose toxicity is a demonstrable and reversible component of β-cell dysfunction in uncontrolled type 2 diabetes. Nevertheless, there appears to be a component of β-cell dysfunction that is independent of glucose toxicity. Liraglutide, which decreased the glucose area under the curve during the OGTT to a similar extent as canagliflozin, was associated with a significantly greater improvement in β-cell glucose sensitivity. This is likely due to direct effects of the GLP-1 receptor agonist on β-cells, as has been demonstrated in single-dose studies (5), but may also be due, in part, to some degree of amelioration of glucose toxicity over the 16 weeks of treatment. Notably, the strong and significant correlation between changes in HbA1c (a surrogate of glucose toxicity) and improvements in β-cell glucose sensitivity across all treatments could explain why the combination of canagliflozin and liraglutide did not have additive effects on β-cell glucose sensitivity. Healthy, functional β-cells are critical to long-term glucose control in type 2 diabetes. When they begin to fail, we can support them and restore the failing relationship between glucose and insulin secretion in several ways. First, by decreasing peripheral insulin resistance with a thiazolidinedione, we can off-load β cells, decreasing demand (6). Second, by reducing glucose toxicity with an SGLT-2 inhibitor, we can secondarily improve β-cell glucose sensitivity as was shown in this study. Finally, using a GLP-1 receptor agonist, we can directly enhance β-cell glucose sensitivity as was also shown in this study. Individually, all these approaches have shown benefits. Together, such an ensemble might restore the delicate dance between glucose and insulin secretion, healing the relationship and leading to durable glycemic control. glucagon-like peptide-1 glycated hemoglobin oral glucose tolerance test sodium-glucose cotransporter-2 Disclosure Summary: Dr Pratley reports grants from Hanmi Pharmaceutical Co; grants from Janssen; consulting fees from Merck; grants, speaker fees, and consulting fees from Novo Nordisk; consulting fees from Pfizer; grants from Poxel SA; grants and consulting fees from Sanofi; consulting fees from Scohia Pharma Inc; and consulting fees from Sun Pharmaceutical Industries. Dr Pratley’s services were paid for directly to AdventHealth, a nonprofit organization.