GLP-1 defects in diabetes

Glucagon-like peptide-1 (GLP-1) is secreted from the intestinal L-cells upon nutrient stimulation and regulates glucose levels by stimulating secretion of insulin (insulinotropic effects) in a glucose-dependent manner (the incretin effect). The incretin effect is severely impaired in subjects with type 2 diabetes (T2D) but the underlying mechanisms are still incompletely understood. In subjects with impaired glucose tolerance (IGT) and T2D, reduced levels of circulating GLP-1 have been observed in cross-sectional studies. Regardless of other changes, a reduced GLP-1 secretion must result in a reduced insulinotropic stimulus to the β-cells and may therefore contribute to the decreased incretin effect in T2D. Also, the role of the reduced incretin effect for development of T2D is unclear, although several studies have indicated that the loss is an early event in the development from minimal glucose disturbances to frank diabetes. Therefore, further studies are required. Ideally, longitudinal studies of predisposed subjects (i.e. obesity, first-degree relatives, post gestational diabetes) followed until diagnosis of T2D would be necessary for elucidating if, indeed, impaired GLP-1 secretion predisposes and contributes to the development of T2D. If so, this may have important clinical consequences suggesting that early intervention with incretin-based therapies might prolong the time to overt T2D development. In the following section we will focus on the GLP-1 defects in T2D.

The incretin effect is impaired in subjects with T2D

The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), stimulate insulin secretion in a glucose-dependent manner and are responsible for up to 70% of postprandial insulin responses in healthy individuals [1]. This effect is markedly impaired in subjects with T2D [2]. The mechanism underlying the loss of the incretin effect is not completely understood, but it is generally accepted that the insulinotropic effects of GLP-1 and GIP are seriously impaired in T2D subjects. However, whereas the effect of GIP is almost completely lost, regardless of dose, GLP-1 seems mainly to have lost potency, so that supraphysiological doses are still effective. This retained effect of GLP-1 in T2D subjects has made GLP-1 receptor agonism an attractive drug target in T2D. It is generally assumed that the loss of the incretin effect contributes importantly to the inadequate insulin secretion in T2D, and therefore probably to its pathophysiology, but does it also play a role in the etiology of the disease? A reduction of the incretin effect is an important and early characteristic in developing T2D [3], but it has been argued that the impairment is due to β-cell failure and that the loss is therefore an epiphenomenon. To better understand this controversy we start by reviewing potential causes for GLP-1 defects in T2D.

GLP-1 defects in subjects with T2D

Regarding GLP-1, there are two ways in which GLP-1 can be involved in defective incretin effect in T2D subjects: Either the secretion or the action of GLP-1 is impaired. In principle, its elimination rate could also be altered, but this does not seem to be the case [4]. As discussed above, infusions of supraphysiological doses of GLP-1 in healthy and T2D subjects markedly stimulate insulin secretion and may near-normalize insulin secretion, illustrating the preservation of the insulinotropic effects in these patients.

Regarding secretion, Toft-Nielsen et al assessed GLP-1 levels in plasma from 54 T2D subjects and found a marked reduction in postprandial GLP-1 levels, particular in the late postprandial phase (from 60 minutes and onwards), indicating that a lower secretion of GLP-1 may contribute to the impaired incretin effect in T2D. Several subsequent studies, including more participants (50+), reported similar negative effects of T2D on GLP-1 levels [4][5]. However, in other studies there were no significant reductions [6]. A meta-analysis of 22 trials could not confirm that a reduced GLP-1 secretion is a general characteristic of T2D subjects, but interestingly found that deteriorating glycaemic control may be associated with impairment of GLP-1 secretion [7]. How do we reconcile these findings? Nauck et al tried to examine the discrepancy by building a multiple linear regression model on the data. Interestingly, they identified several factors (body mass index, inter-individual differences in GLP-1 secretion, and treatment with metformin) that might affect GLP-1 concentrations as was also concluded by Toft Nielsen [8] and Holst et al [3]; inadequate matching, therefore could easily explain the discrepant findings.

Secondly, is the loss of incretin effect merely an epiphenomenon of a diminished β-cell secretory capacity? As clearly demonstrated in a recent study investigating the effects of exogenous GIP and GLP-1 in individuals predisposed for T2D during glucose clamping at different glucose levels, decreased insulinotropic activity at physiological levels of GIP and GLP-1 could be demonstrated, but a final infusion of arginine documented that there was ample secretory capacity available[9]. This suggests that the loss of incretin effect is independent of a diminished β-cell secretory capacity and therefore may represent causal factor rather than an epiphenomenon. At the molecular level, β-cell experiments have indicated diminished expression of both incretin receptors on the β-cell during chronic hyperglycemia, while lowering glucose levels could restore receptor expression. Whether a similar decreased expression is seen in humans is difficult to investigate, but studies with bolus injections of large doses of GLP-1 and GIP have shown preservation of small early insulin responses to both hormones, indicating that their relative densities are preserved in spite of dramatic differences with respect to late phase secretion [10].

In summary, there is agreement that the insulinotropic effect of physiological amounts of GLP-1 is severely reduced, and impaired GLP-1 secretion may not be a universal characteristic in all subjects with T2D. However, when present, reduced GLP-1 secretory responses probably contribute to the loss of the incretin effect and must therefore be considered a substantial contributor to the pathophysiology of T2D.

Why is GLP-1 secretion impaired in subjects with T2D?

The mechanism underlying impaired secretion of GLP-1 in T2D subjects is under debate and to our knowledge conclusive studies do not exist, but the impairment may be caused by either a diminished sensitivity to nutrients or by some kind (endocrine/paracrine?) of inhibition. Genetics studies (e.g. ADDITION-PRO) have not yet identified gene variations as significant regulators for GLP-1 responses (although the diabetes associated TCF7L2 variant was thought to influence GLP-1 secretion, the later research established the variants to influence β-cell responses to the incretin hormones[11]); in addition, it has been shown that first-degree relatives of diabetic subjects have normal secretory GLP-1 responses [12]. A high body mass index, increased insulin resistance (e.g. induced in healthy subjects using prednisolone) and deteriorating glucose tolerance each have been associated with reduced GLP-1 secretion [5][13]suggesting that obesity may cause an early impairment of GLP-1 secretory responses and that progression of T2D over time may lead to further impairment of the response [14]. In contrast to GLP-1, glucagon, the glucose-regulating hormone from the pancreatic α-cells, is increased in subjects with T2D [15]. It has been reported that GLP-1 inhibits glucagon – probably through a somatostatin-dependent paracrine mechanism – raising the question whether glucagon may also inhibit GLP-1 secretion in a classic feedback regulation mechanism. However, this would require expression of glucagon receptors on the L-cell, which have been searched for (in mice) but not found yet. A single study identified glucagon as a tonic suppressor of GLP-1 secretion [16] whereas other studies did not [17]. Neuropathy, one of the many complications in subjects with T2D, may (in contribution to hyperglycemia) delay gastric emptying, which is why impairment of GLP-1 secretion have been proposed to be due to a reduced antro-duodenal transit of nutrients. However, in a large study, neuropathy was not associated with a decreasing GLP-1 response.

Does an impairment of the incretin effect (GLP-1 secretion) predispose to diabetes?

If impairment of the incretin effect predisposes to T2D, then subjects with increased risk of developing diabetes (i.e. subjects with impaired glucose tolerance and impaired fasting glucose) might be expected to have reduced GLP-1 secretion. In previous studies subjects with impaired glucose tolerance (IGT) have been found both to have [8] and not to have significant lower GLP-1 secretory responses compared to controls [13]. However, very recently a large, new study (ADDITION-PRO [5]) clearly demonstrated reduced secretory GLP-1 responses in subjects with impaired glucose homeostasis as well as in obese subjects. However, in these studies gender (female were significant, males were not) appeared to be an effect modifier.

In conclusion, causality of GLP-1 secretion defects as a predisposing factor for T2D still remains to be demonstrated. Longitudinal studies of prediabetic subjects followed until diagnosis of T2D and further through progression of the disease, may be the only reliable method for determining if a progressive loss of GLP-1 secretion ultimately leads to T2D as well as disease progression.


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