Incretin enhancement without hyperinsulinemia: α-glucosidase inhibitors

Abstract

The α-glucosidase inhibitors are a time-tested, but under-utilized, class of oral hypoglycemic effects. Recent understanding of the importance of the incretin pathway, coupled with evidence about the incretin enhancing effects of these molecules, is covered in this editorial. The authors call for greater recognition of the beneficial effects of this class of drugs in the management of Type 2 diabetes.

Keywords::

• acarbose
• cardiovascular safety
• diabetes
• postprandial glycemia
• voglibose

Current diabetes pharmacotherapeutics is marked by equipoise. Multiple, and at times, conflicting evidence combine to make appropriate choice of anti-diabetic drugs a challenge [1,2]. The multiple effects of available medicines, and the need to balance expected efficacy with potential side effects, also contribute to this challenge. A composite end point, that is, lowering of HbA1c (glycated hemoglobin), lack of hypoglycemia and lack of weight gain, has now replaced the glucocentric targets of the past [3].

Many of the unwanted adverse effects of conventional anti-diabetic therapy are mediated by hyperinsulinemia. Sulfonylureas stimulate the β-cells to recreate more insulin in a glucose-independent manner [4]. This mechanism of action leads to hypoglycemia, which in turn encourages defensive snacking and promotes weight gain. Pioglitazone, by its agonist action on peroxisome-proliferation activator receptor-γ receptors, can cause weight gain, increasing both adipose tissue mass and fluid retention [5]. Metformin is one conventional oral hypoglycemic drug which is relatively devoid of the risk of hypoglycemia and weight gain. This is because it has an insulin-sensitizing effect which reduces insulin concentration [6].

The relatively newer class of dipeptidyl peptidase-4 inhibitors work by a different mechanism. Through a glucose-dependent stimulation of the β-cells, achieved by increasing the endogenous levels of glucagon-like peptide 1 (GLP 1), these drugs aim for euglycemia. The concurrent reduction in glucagon levels reduces the work load of the β-cells [7]. Dipeptidyl peptidase-4 use leads to a situation where high levels of incretin hormones and insulin coexist with each other. Hyperinsulinemia has been implicated in the pathogenesis of many complications related to diabetes. It is an essential part of the metabolic syndrome, and its presence creates a vicious cycle sorts, by worsening insulin resistance and obesity [8]. It stands to reason, therefore, that a drug which achieves glycemic control while reducing insulin levels will have beneficial effects upon the β cell, and upon overall physiology. At the same time, the physiological benefits of incretin hormones are well known [7]. A drug which can combine incretin enhancement with insulin suppression, therefore, could emerge as the treatment of choice in Type 2 diabetes.

The α-glucosidase inhibitors (AGIs) have been available for over three decades now. They act by inhibiting the digestion of enterally absorbed carbohydrates, thus reducing the glycemic burden on the body. While this mechanism justifies their predominant action upon postprandial glycemia, it does not explain the definite effect of AGIs that has been observed on fasting glucose levels [8,9].

Recent research has uncovered an incretin-based mechanism of AGIs. These drugs, by inhibiting α-glucosidase in the proximal small intestine, allow large amounts of undigested carbohydrates to reach the distal small intestine. The ileum, which is rich in entero-endocrine L-cells, produces GLP-1 upon exposure to nutrients, especially carbohydrates [10]. The oral ingestion of acarbose dependently decreases the absorption of carbohydrates, increases their ileal (small intestine) delivery, prolongs the absorption time and increases intestinal flow rates. Augmentation of GLP-1 release by acarbose may be due to the absorption of carbohydrates along a longer length of intestine, prolongation of the absorptive process, accelerated intestinal transit time or increased delivery of carbohydrate residues to distal intestine stimulating the L-cells [11]. Thus, AGIs stimulate a long-lasting, sustained rise in endogenous GLP-1, by a mechanism distinct from that of other incretin-based therapies such as DPP-4I or GLP-1 receptor agonists. This mechanism of action is supported by results of single-dose studies, short-term (up to 2 weeks long) studies and long-term (24 week long) trials with acarbose, in normal individuals as well as in persons with diabetes [8,11–13].

While DPP-4 I use does increase GLP-1 concentrations, it also stimulates the release of insulin from the β-cells. As their action is glucose dependent, they stimulate the β cell for shorter periods of time than sulfonylureas. AGIs, on the other hand, reduce plasma insulin and C-peptide concentrations, thus creating a potentially beneficial situation in persons at risk of, or with preexisting, metabolic syndrome. Intake of acarbose results in competitive inhibition of α-glucosidases in the upper small intestine. This process delays the formation of monosaccharides, which are formed by cleavage from oligosaccharides and disaccharides from starch. Only monosaccharides can pass through the gut wall, and the speed of increase in their concentration determines the absolute blood glucose concentration and the stimulation of insulin secretion. An increase in glucose from the intestine, insulin secretion and the effects of insulin on the peripheral organs are the major factors in glucose kinetics after a meal. By delaying the uptake of monosaccharides from the gut, acarbose modifies the generation of the prandial and postprandial glucose concentrations already at this stage. This results in a lower degree of stimulation of insulin and proinsulin secretion [14]. The decrease in insulin secretion is secondary to reduced postprandial glucose and is most dramatic in individuals with high insulin secretory rates. No change or an increase in insulin secretion may occur in patients with inherently low insulin secretion. No effects of acarbose on first- or second-phase insulin release during a hyperglycemic clamp are evident [15].

AGIs have also been studied in combination with DPP-4 I [16,17]. In clinical studies, combination therapy with AGIs and DPP-4 I in patients with T2DM has clearly been shown to reduce daily glucose fluctuations, improve secretory patterns of immunoreactive insulin and increase the plasma levels of incretin hormones (active GLP-1, gastric inhibitory polypeptide), with a paradoxical rise in immunoreactive glucagon [16].

Acarbose is the only oral anti-diabetic molecule, in fact, apart from metformin, to have undisputed proof of cardiovascular safety [18]. It is possible that this facet of acarbose is driven by a combination of insulin lowering and GLP-1 enhancement. The ability of acarbose to increase the levels of serum nitric oxide and nitric oxide synthase [10] may contribute to its cardioprotective effects. Voglibose, too, have been demonstrated to have cardioprotective effects through its interaction with GLP1 receptors [19]. While most of these data have been in public domain for two decades, it is only in recent years that we have begun to appropriate the importance of incretin biology in the pathogenesis of diabetes. With this in mind, the relevance of the AGIs, a long neglected class of oral glucose-lowering drugs, gains momentum.

The AGIs are given place of pride in guidelines for management of diabetes from countries as diverse as South Korea, Lebanon, Libya, Mexico and Tunisia [20]. This is backed by evidence of their efficacy, safety and tolerability. In certain recommendations, however, AGIs are not mentioned prominently [1]. This may be due to a misplaced perception of the severity of gastrointestinal side effects, which may not be tolerated by some persons. A ‘start low, go slow’ dosage strategy, however, minimizes such effects and enhances the tolerability of these drugs. Acarbose, in fact, has been found to be efficacious as a once-daily or twice-daily dose in selected individuals [21]. Taking acarbose with the first mouthful of food also increase the efficacy and reduces C peptide levels [22].

Perhaps, a renewed focus upon the AGIs’ dual properties of incretin enhancement and insulin sparing effects is in order. In-depth understanding of these aspects may facilitate optimal use of these time-tested molecules, which promise the best of both worlds to the person with diabetes.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.