A pathophysiological approach in the treatment of patients with diabetes mellitus
Like any drug development process, developing novel anti-diabetic drugs is a difficult endeavour. This holds especially true in the midst of the wave of novel drugs and drug classes that we have seen entering the market over the last years. To be successful in this area, it is crucial to think beyond blood glucose levels when developing novel compounds.
Insulin resistance, alpha-, and beta cell dysfunction characterize the pathophysiological triade in the development of type 2 diabetes mellitus. Investigation of drug effects and/or drug interactions with these components in the development and progression of diabetes mellitus can provide more rationality for the selection of drugs or drug combinations in the treatment of the disease. To address the importance of islets of langerhans in diabetes and their complicated balance, this text deals with the islets of Langerhans and the alpha- and beta cell function in diabetes. It then shifts focus to the pharmacological intervention and methods to study the cells' function to enable developers choose the right tools for their clinical trials in this field.
Blood glucose and the role of the Islet of Langerhans
In individuals without diabetes, blood glucose is kept within a narrow range by a complex interaction of several regulatory pathways. In patients with diabetes mellitus, these well balanced signalling pathways become unsettled with a loss of blood glucose control. The islet of Langerhans play a crucial role in the pathogenesis of type 1 and type 2 diabetes mellitus. The human island of Langerhans cover alpha-, beta-, delta-, and pancreatic polypeptide (pp) secreting cells. The cytoarchitecture of the human islet, where the beta cells show close associations with the other endocrine islet cells, suggest comprehensive paracrine interactions. Islets are densely vascularised and the islet cells are exposed to changes in the arterial milieu, like insulin fluctuations. Insulin derived from the beta cell, as well as glucagon derived from the alpha cell, are drained in to the portal circulation where they reach the liver tissue. In the liver tissue, the insulin/glucagon ratio controls for hepatic gluconeogenesis, glycogenesis, and glycogenolysis. In the fasting state, basal levels of glucagon account for up to 70% of circulating glucose levels (1). As illustrated in figure 1, rising blood glucose levels increase the release of insulin from the beta cell and supress glucagon secretion from the alpha cell, and vice versa.
By changing the ratio of glucagon to insulin within the portal circulation, alpha- and beta cell activity accounts for hepatic glucose release during low blood glucose concentrations and hepatic glucose uptake in case of high blood glucose concentrations.
Alpha cells express a high number of insulin receptors on their surface, and paracrine increments in insulin concentrations within the pancreatic islets suppress the release of glucagon from the alpha cell. In this context, it is remarkable that alpha cells are exposed to 100 times more insulin than peripheral tissues. Interestingly, recent data suggest that insulin may also regulate glucagon secretion through actions in the ventromedial hypothalamus and the activation of autonomic pathways (2,3). In the opposite way, declining blood glucose concentrations cause a decrease in the local intra-islet insulin concentration, and thereby an unrestrained release of glucagon from the alpha cells (4,5). Elimination of the insulin receptor from pancreatic alpha cells was shown to abolish the glucagon response to low glucose concentrations (6), and a couple of recent investigations found that a decline in intra-islet insulin concentration is important to trigger an appropriate glucagon response to hypoglycaemia. Several factors are known to modulate the secretory response of alpha and beta cells, such as gastrointestinal hormones (7,8), catecholamines (9,10), local Zn2+ concentration (11,12), and the autonomic nervous system (13,14).
Alpha- and beta cell function in diabetes mellitus type 1
In type 1 diabetes mellitus, autoimmune destruction of the beta cells leads to the development of an absolute insulin deficiency. In this case, alpha cells comprise approximately 75% of the total islet cell mass (15). In parallel, the glucagon levels increase in patients with type 1 diabetes most probably due to a loss of paracrine suppression from intra-islet insulin. Elevated glucagon levels in patients with type 1 diabetes are supposed to count for insulin resistance and the difficulties to achieve adequate blood glucose control. An elevated glucagon/insulin ratio has been shown to accelerate gluconeogenesis and fatty acid oxidation leading to the formation of ketone bodies (16), most probably contributing to an increased risk of ketonemia in patients with type 1 diabetes mellitus. While glucagon levels in patients with type 1 diabetes are elevated, no appropriate increase in glucagon appears in response to low blood glucose levels (17). The missing counter regulatory response in type 1 diabetes mellitus is explained by the lack of an intra-islet drop in insulin concentration, keeping off an appropriate signalling for the alpha cell to increase glucagon secretion (17-19). The missing “intra-islet switch off signal” is a major driver of the increased risk for severe hypoglycaemia in patients with type 1 diabetes. Subcutaneous application of insulin in patients with diabetes mellitus causes a misallocation in the insulin distribution, with high insulin levels in peripheral tissues and an inappropriate glucagon / insulin ratio in the portal circulation.
Alpha- and beta cell function in diabetes mellitus type 2
Type 2 Diabetes mellitus (T2DM) is a complex disease, characterized by insulin resistance, followed by declining beta cell function and a disrupted glucagon-insulin balance. Disturbed pro-insulin processing with declining insulin levels and an elevation in fasting and postprandial glucagon levels characterize the development and progression of T2DM (20-22). An increase in the precursor molecule of insulin, intact proinsulin, was identified as a potent marker for the prediction of beta cell failure and often precedes the development of type 2 diabetes mellitus (23,24). Numerous studies suggested an association between increased intact proinsulin levels and the development of cardiovascular complications in subjects with or without diabetes (25-30). Even though the exact mechanism how proinsulin might be involved in the pathogenesis of atherogenesis is not fully understood, there is increasing evidence that proinsulin raises plasminogen activator inhibitor-1 (PAI-1) levels (31-33), thereby accelerating the high pro-thrombotic potency observed in patients with T2DM. In addition, proinsulin was found to bind with high affinity to the insulin-receptor-A-isoform leading to a pronounced activation of the ERK/p70S6K downstream signalling cascade (34), thereby, accelerating the mitogenic and atherogenic signalling of the insulin receptor.
A large body of evidence implicates hyperglucagonemia in the maintenance of increased rates of hepatic glucose output in T2DM (35,36). Under fasting conditions hyperglucagonemia sustains glucose overproduction, and impaired glucagon suppression after a meal contributes to the postprandial hyperglycemia in T2DM (21,37). Elevated fasting and postprandial glucagon levels substantially contribute to insulin resistance and decrease the efficacy of antidiabetic drugs, including treatment with exogeneous insulin (38-40). Beside the mismatch in islet cell functionality, increased beta cell apoptosis and a proliferation of alpha cells characterize islet cell remodelling in patients with type 2 diabetes mellitus (41).
Pharmacological effects on alpha- and beta cell function
Various new pharmacological approaches have been introduced in the treatment of diabetes mellitus. Other new mechanistic pathways to treat patients with T2DM are the topic of ongoing preclinical and clinical research. Some of these therapeutic strategies directly address glucagon specific pathways (20,42). Therefore, the armamentarium for pharmacological interventions in patients with diabetes mellitus is growing consistently. This implies an increasing need to understand the effects of different pharmacological interventions on the pathophysiology of the disease beyond their obvious effects on blood glucose levels.
While metformin and glitazones affect insulin sensitivity, sulfonylureas and GLP-1 based treatments interact with alpha and/or beta cell activity. It seems noteworthy that sulfonylureas and GLP-1 based treatments regulate blood glucose values by totally different effects on alpha and beta cell function. In the post-absorptive state, sulfonylureas predominantly augment the release of insulin from the beta cell, leading to an expeditious exhaustion of the beta cell as indicated by an immediate increase in the release of proinsulin and an increase in the rate of apoptosis (43,44). In case of low blood glucose values, sulfonylureas still evolve their stimulatory effects on the beta cell and inhibit the release of glucagon from the alpha cell, driving protracted hypoglycemic episodes in patients with T2DM (45). Interestingly, sulfonylureas augment the glucagon secretion from the alpha cell in patients with T1DM, most probably due to the absence of beta cells within the pancreatic islet (46,47). In contrast to sulfonylureas, treatment with DPP-IV inhibitors were shown to reduce the postprandial release of glucagon from the alpha cell, thereby taking of the postprandial workload from the beta cell with a subsequent fall of proinsulin concentrations in the blood (48). Therefore, sulfonylureas control postprandial glucose values by stimulating the release of insulin from the beta cell, while DPP-IV inhibitors reduce postprandial release of glucagon from the alpha cell with a subsequent relief of strain from the beta cell. DPP-IV inhibitors enhance alpha cell responsiveness to both the suppressive effect of hyperglycemia and the stimulatory effect of hypoglycemia (49).
SGLT-2 inhibitors, a new class of antidiabetic agents reduce blood glucose by increasing glucose excretion through the kidneys. Interestingly, recent investigations revealed an increase in endogenous glucose production following treatment with SGLT-2 inhibitors, most probably caused by an increase in plasma glucagon levels (50,51). The underlying molecular pathways causing the counter-regulators increase in alpha cell activity are topic of numerous scientific discussions. There is increasing evidence that the combination of SGLT-2 inhibition and DPP-IV inhibition evolves additive effects on blood glucose control with a restoration of overall islet cell physiology (41).
Assessing insulin resistance, alpha-, and beta cell function in diabetes mellitus
There are numerous options to investigate the different components in the pathophysiology of T2DM (20,36). As shown in the table below, standardised clamp procedures might be helpful to evaluate insulin resistance, alpha and beta cell function in patients with T2DM. A standardised meal test or a hyperglycemic clamp can provide information on the capacity of the beta cell to respond to increasing blood glucose concentrations. The additional measurement of proinsulin during increasing blood glucose levels will provide further information about the functional capacity of the beta cell. Additional measurement of glucagon provides information about the alpha- and beta cell interaction and a sufficient suppression of the alpha cells under hyperglycemic conditions. Measurement of the glucose infusion rate (M-value) and glucagon levels within a euglycemic-hyperinsulinemic clamp allows the characterization of insulin resistance and alpha cell responsiveness. In contrast, a stepwise hypoglycemic clamp can be used for the evaluation of alpha- and beta cell function during low blood glucose levels providing important information about the counter-regulatory capacity during treatment with different antidiabetic treatments. The different clamp investigations can be complemented by a pharmacological stimulation of the alpha- and beta cells with arginine to obtain information about the overall functional capacity of the alpha- and beta cells.
Conclusion
In conclusion, insulin resistance, alpha-, and beta cell dysfunction characterize the pathophysiological Triade in the development of type 2 diabetes mellitus. Investigation of drug effects and/or drug interactions with these components in the development and progression of diabetes mellitus can provide more rationality for the selection of drugs or drug combinations in the treatment of the disease.
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