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Effects of glucose-dependent insulinotropic polypeptide on glucagon

Christensen, Mikkel; Knop, Filip K.

Cardiovascular Endocrinology & Metabolism: September 2016 - Volume 5 - Issue 3 - p 75–81
doi: 10.1097/XCE.0000000000000093
Review Articles
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The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine cells in the intestinal mucosa in response to nutrient ingestion. It is well known that GIP exerts a strong, glucose-dependent (during elevated blood glucose levels) insulinotropic effect. In recent years, it has become clear that GIP also exerts effects on glucagon secretion. The regulation of glucagon secretion is interesting as the combination of inadequate insulin secretion and excessive glucagon secretion represents an essential contributor towards the hyperglycaemia in patients with type 2 diabetes. Moreover, the absence of a well-timed counterregulatory glucagon response contributes towards an increased risk of hypoglycaemia in patients with type 1 diabetes. Here, we review several studies investigating the effect of GIP on glucagon secretion and discuss the current evidence for a glucose-dependent glucagonotropic effect of GIP in healthy individuals and in patients with diabetes, respectively. We conclude that at fasting glycaemia and lower levels of glycaemia, GIP seems to increase glucagon secretion, with little effect on insulin release, which points towards a bifunctional blood glucose-stabilizing role of GIP in healthy humans. In patients with type 2 diabetes, GIP may contribute to inappropriate glucagon secretion and in patients with type 1 diabetes, GIP augments glucagon responses to hypoglycaemia.

aCenter for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup

bDepartment of Clinical Pharmacology, Bispebjerg Hospital

cInstitute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Correspondence to Mikkel Christensen, MD, PhD, Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Kildegaardsvej 28, DK-2900 Hellerup, Denmark Tel: +45 35 31 38 08; fax: +45 38 67 26 89; e-mail: mch@dadlnet.dk

Received July 4, 2016

Accepted July 4, 2016

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Introduction

The 42 amino acid hormone glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine cells of the small intestine following ingestion of macronutrients – that is, carbohydrate, protein and/or fat 1–3. Traditionally, GIP has been considered a product of specific intestinal K cells located in the proximal small intestine 4. However, fully processed GIP consisting of 42 amino acids – that is, GIP (1–42) – may also be produced in other endocrine cells in the intestinal epithelium 5,6. After a mixed meal, plasma GIP levels remain significantly elevated for 2–3 h 7, but diurnal plasma profiling of GIP shows elevated plasma levels almost throughout the day and basal levels only during the night 8,9. This diurnal plasma profile may be relevant for the understanding of GIP actions at fasting glycaemia. The GIP receptor is expressed widely in bodily tissues, but the functional relevance of the GIP receptor has only convincingly been attributed to the presence in pancreatic islets of β cells and α cells 10,11, bone 12 and adipose tissue 13,14. GIP exerts anabolic effects on bone and adipose tissue in rodent models, but the relevance of these effects in human physiology remains to be determined. Over the past 30 years, there have been controversies with respect to the possibility that deranged GIP secretory responses and a reduced, or even absent, insulinotropic effect of GIP contribute towards type 2 diabetes pathophysiology 15,16. Although the secretion of GIP seems to be relatively unaffected in patients with diabetes 17, evidence supports that the insulinotropic effect of GIP is indeed impaired in patients with diabetes 18,19.

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Defective insulinotropic actions of glucose-dependent insulinotropic polypeptide in diabetes

The presence of a specific defect in the insulinotropic action of GIP in patients with type 2 diabetes was reported in 1993 when Nauck et al.20 described and quantified the efficacy of the two human incretin hormones [GIP and glucagon-like peptide-1 (GLP-1)] during hyperglycaemic clamp experiments (mean plasma glucose: 8.75 mmol/l). Their results showed a reduced insulinotropic effect of GIP, whereas that of GLP-1 was relatively preserved. This led to the conclusion that the reduced incretin effect in patients with type 2 diabetes (described a few years earlier by the same group 21) most likely could be explained by the reduced insulinotropic effectiveness of GIP. Several years later, it was established that a defective insulinotropic effect of GIP (again in comparison with GLP-1) does not exclusively apply to patients with type 2 diabetes. Thus, patients with diabetes of various aetiologies (including diabetes secondary to chronic pancreatitis, monogenic diabetes and latent autoimmune diabetes) all share the common pathophysiological feature of an impaired GIP-induced insulin secretion relative to GLP-1 22,23.

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Diabetic hyperglucagonaemia: role of glucose-dependent insulinotropic polypeptide

GIP has also been implicated as one of the causal factors in postprandial hyperglucagonaemia in patients with type 2 diabetes. It is quite well established that patients with type 2 diabetes are characterized by fasting and postprandial hyperglucagonaemia, which leads to increased rates of hepatic glucose production and thereby to elevations of fasting and postprandial blood glucose levels 24,25. In fact, studies indicate that postabsorptive hyperglucagonaemia is responsible for as much as 50% of the increment in plasma glucose excursions following oral glucose ingestion in patients with diabetes 26–28. Interestingly, following intravenous administration of glucose – producing identical plasma glucose excursions as the oral intake – the glucagon levels are adequately suppressed 29,30. This implies that gut-derived factors contribute towards the derangement of postprandial glucagon responses, or alternatively, that measurable glucagon is released from the intestine 31,32. Investigations by Lund et al.33 have suggested that GIP could contribute considerably towards this postprandial glucagon response. Similarly, a study in which GIP was administered as a continuous intravenous infusion (4 pmol/kg/min, resulting in supraphysiological plasma concentrations) during a mixed meal test showed that GIP compared with placebo worsened postprandial glycaemic excursions concomitant with elevated glucagon levels in patients with type 2 diabetes 11. Thus, a role of GIP in glucagon secretion, which, in situations with elevated plasma glucose levels, is essentially inappropriate, could be an important element of type 2 diabetic pathophysiology.

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Glucagonotropic effect of glucose-dependent insulinotropic polypeptide

Whether or not GIP as an isolated hormone exerts effects on glucagon secretion has been a question for many years. As early as in 1978, two scientific groups designated glucagon-releasing properties to GIP by showing that GIP augments glucagon secretion in the perfused pancreas of rat and canine at low glucose concentrations 34,35. In the following years, porcine amino acid sequence GIP was administered intravenously in a handful of healthy individuals during fasting or hyperglycaemic conditions 36 or in the perfused porcine pancreas 37 and it did not elicit any detectable glucagon responses. In 1990, however, porcine sequence GIP led to glucagonotropic responses in perfused pancreata from human cadavers 38 and in patients with liver cirrhosis characterized by fasting hyperglucagonaemia 39. In parallel to the clinical investigations, the mechanistic basis for the glucagonotropic effect in rodents was discovered to be partly similar to the one active in β cells, as GIP was shown to stimulate glucagon secretion in rat α cells by cyclic AMP and activation of protein kinase A 40. Subsequent studies in perfused rat pancreata, at low levels of glycaemia, outlined the difference between the incretins in glucagon secretion: GLP-1 inhibited glucagon secretion (likely by somatostatin-dependent paracrine signalling), whereas GIP stimulated glucagon secretion directly 41. Interestingly, a study from 1995 showed that during infusion of GIP or GLP-1 together with physiological amounts of amino acids (i.e. as observed after a protein-rich meal), insulinotropic effects were similar, but the glucose-lowering effect was less with GIP 42. This could be explained by (but not actually noted by the authors) a seemingly greater glucagon response during GIP infusion. Nevertheless, in healthy humans, the glucagonotropic effect of GIP in vivo was reported for the first time in 2003 when administration of GIP as a bolus injection during fasting glycaemia (i.e. fasting plasma glucose of 5.7 mmol/l) resulted in dose-dependent increases in plasma glucagon 43. In the same year, when GIP was administered as a ‘physiological’ infusion for 30 min in healthy humans also clamped at euglycaemia (plasma glucose of 5.1 mmol/l), a slight glucagonotropic effect was also elicited, and when plasma glucose was subsequently elevated to 6 and 7 mmol/l, glucagon levels were increasingly suppressed 44. During hyperglycaemic conditions, several studies have shown that GIP infusion does not exert a glucagonotropic effect in healthy individuals 20,45–48.

Recently, we investigated the effects of GIP on glucagon in four published studies 49–52. The first of these studies was designed to evaluate the glucagonotropic effect of GIP at two different glucose levels independent of the insulinotropic effect of GIP. We therefore recruited patients with type 1 diabetes without endogenous insulin secretion (estimated by an arginine intravenous stimulation test) that could affect glucagon responses. The study used a stepped hyperglycaemic clamp where plasma glucose was clamped at ‘diabetic’ fasting values (mean: 7.4 mmol/l) for the first 90 min and then increased to 1.5 times the fasting values (mean: 11.1 mmol/l) for the final 90 min (Fig. 1). On separate experimental days (conducted in a randomized order), intravenous infusions of saline (placebo) and GIP (at a rate designed to mimic postprandial hormone levels), respectively, were carried out for the initial 50 min in both periods. There was a tendency towards a glucagon response during the lowest glycaemic level, but this was progressively lost during hyperglycaemia. Second, the study suggested that intraislet insulin (which we excluded in these patients) is not necessary for the suppression of glucagon during hyperglycaemia. Importantly, however, α-cell responsiveness to arginine stimulation was preserved (Fig. 2). This confirmed previous studies showing preserved secretory responsiveness of the α cells to certain amino acids in patients with type 1 diabetes 53. We concluded that in patients with type 1 diabetes, GIP does not stimulate the release of glucagon during hyperglycaemia and we speculated that perhaps it was the glucagon-suppressive effect of hyperglycaemia that masked a glucagonotropic effect of GIP.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

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Glucagon responses to glucose-dependent insulinotropic polypeptide during hyperglycaemia

In two subsequent studies, we investigated the glucose dependence of the glucagonotropic actions of GIP in healthy individuals and in patients with type 2 diabetes during fasting glycaemia, hyperglycaemia and insulin-induced hypoglycaemia 50,51. The glucagon results obtained during hyperglycaemia (plasma glucose of 12 mmol/l) in these two populations could explain some of the controversy that had surrounded glucagonotropic responses to GIP. As mentioned above, GIP has been implicated in the inappropriate postprandial glucagon response in patients with type 2 diabetes 11,33. As was the case in the initial study in patients with type 1 diabetes (described above) 49, we found that in healthy individuals, hyperglycaemic clamping (i.e. intravenous glucose administration) effectively suppresses glucagon levels, whereas the situation is quite different in patients with type 2 diabetes, where glucose-induced suppression of glucagon is delayed and inefficient (Fig. 3) 50,51. Thus, in patients with type 2 diabetes, GIP seemed to affect the unfavourably already delayed glucagon suppression by hyperglycaemia, and this was not the case in healthy individuals 50,51. This unfavourable glucagon suppression is obvious when presented as percentage suppression from baseline values (Fig. 3). It is important for the interpretation of these fractional differences that the baseline glucagon values were significantly higher in the patients with type 2 diabetes than in the healthy individuals (12.5±1.5 vs. 7.1±0.7 pmol/l, P<0.005). Nevertheless, some degree of glucagon suppression in response to hyperglycaemia was evident in all research participants, and glucagon tended to be lower during GIP infusions in healthy individuals 50.

Fig. 3

Fig. 3

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Glucagon responses to glucose-dependent insulinotropic polypeptide during fasting or lower glycaemia

If hyperglycaemia per se could impede a possible glucagon-stimulating effect of GIP, then it is likely that hypoglycaemia may unmask such an effect. The study in healthy individuals showed that, overall, GIP augmented the glucagon responses when plasma glucose was in the ‘physiological range’ – that is, between 3.5 and 5.5 mmol/l 50. Combined with the fact that no glucagonotropic effect of GIP was observed at higher glucose levels and an inverse effect was noted in the insulin secretion estimated by C-peptide level, in these human experiments, we reproduced the relation between plasma glucose and glucagon and C-peptide levels (Fig. 4) first described in rat pancreas by Pederson and Brown 34.

Fig. 4

Fig. 4

Using a design similar to the one in healthy individuals, patients with type 2 diabetes, investigated at fasting (diabetic) and insulin-induced hypoglycaemia, also presented with glucagon-secretory responses in a pattern similar to the results found in healthy volunteers 51. Thus, at lower levels of glycaemia, initial (i.e. after 30 min), but not peak glucagon responses (at study end), were higher during GIP infusions.

We also carried out a study in patients with type 1 diabetes, with a slightly different design, but also using insulin to induce hypoglycaemia and at the same time administering an intravenous infusion of GIP 52. The results from this study are presented in Fig. 5; we found that a significant glucagon response to GIP occurred during the ‘hypoglycaemia recovery phase’ (i.e. plasma glucose <5 mmol/l after insulin infusion was stopped) 52. Seemingly, the decreasing insulin levels during the recovery phase unmasked the glucagonotropic effects of GIP 52.

Fig. 5

Fig. 5

Hence, on the basis of these studies and the collective evidence from the literature summarized above, it seems reasonable to conclude that GIP in humans stimulates glucagon secretion when plasma glucose levels are in the fasting range or lower (i.e. <5.5 mmol/l).

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Involvement of glucose-dependent insulinotropic polypeptide in the physiological defence against hypoglycaemia

The physiological defence against decreasing plasma glucose concentrations in humans is normally described as the combination of (i) a decrease in β-cell insulin secretion, (ii) an increase in α-cell glucagon secretion and (iii) increased sympathoadrenal responses 54. In patients with type 1 diabetes, the first two mechanisms are severely compromised 53,55–57. In the absence of a sufficient glucagon response, the final defence against hypoglycaemia relies on the autonomic adrenergic response, but this response also attenuates over time 58,59. Interestingly, the a cells remain responsive to other stimuli such as arginine (Fig. 2) or alanine 60 and to some degree exercise-induced hypoglycaemia 61. Nevertheless, defective β cells are likely to play a pivotal role in the loss of a-cell secretory response 62,63, and defective glucagon counter-regulation can be detected early in the course of type 1 diabetes and progress with β-cell loss 54,56. Thus, when investigating a-cell stimuli, the amount of residual β cells function is important. The possible role of partially preserved β-cell function was shown in a study investigating theophylline on glucagon secretion in patients with type 1 diabetes (mean diabetes duration ∼4 years and slightly preserved glucagon response also on the control day) 64. Theophylline administration resulted in faster plasma glucose recovery and a higher rate of glucose appearance 64, and the relatively preserved glucagon responses in these patients may have been important for that result. In contrast, the antimuscarinergic agent atropine administered to patients with longstanding type 1 diabetes (mean diabetes duration of 19 years and severely compromised glucagon response) did not alter the (already absent) glucagon response to hypoglycaemia 65.

As mentioned, we performed investigations during hypoglycaemia in patients with type 1 diabetes and found a clear glucagon response to GIP (Fig. 5) 52. These patients had a median diabetes duration of 12 years, were C-peptide negative and had almost no glucagon responses on the placebo days (white square symbols in Fig. 5) 52. This makes the finding of a stimulatory effect of GIP on glucagon responses during hypoglycaemia quite remarkable. We also compared the glucagon response to GIP with that of GLP-1 during hypoglycaemia in patients with type 1 diabetes. Initially, GLP-1 suppressed glucagon levels, although in comparison with placebo days, where glucagon was also close to the lower detection limit, the impact was without clinical relevance. Thus, the glucagonotropic effect of GIP strongly contrasts with that of GLP-1.

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Consequences of glucose-dependent insulinotropic polypeptide-induced glucagon responses

In all the studies, we measured the amounts of glucose needed to maintain the glucose clamps at each glycaemic level. These glucose amounts integrate the impact of all measured (and unmeasured) hormonal changes during the experiments. During hyperglycaemia, these responses were dominated by insulin and resulted in 75% (healthy) and 25% (type 2 diabetes) more glucose needed to maintain the clamps during GIP compared with saline infusion 50,51. It is likely that the dysregulated glucagon secretion (evident in Fig. 3), together with the elevated glucose levels, impaired insulinotropic effect and impaired insulin actions in type 2 diabetes all contribute towards this unfavourable decreased glucose disposal in patients with type 2 diabetes compared with healthy individuals. However, the clinical significance of the dysregulated glucagon response to GIP observed in our studies may not be that important in the postprandial situation in humans, where the opposing effects of GIP and GLP-1 on glucagon might outweigh each other, similar to what was observed during isoglycaemic clamping by Lund et al.33. Rather unexpectedly, there was no need for glucose infusions during the fasting glycaemia in healthy individuals and patients with type 2 diabetes. Thus, the glucose-disposing impact of GIP during fasting glycaemia was strikingly nonexistent and similar in healthy individuals and patients with type 2 diabetes, which probably reflects the similar (and on the GIP days opposing) insulin and glucagon responses. During hypoglycaemia in patients with type 1 and type 2 diabetes, we had to infuse less glucose on the GIP days compared with the saline days 52. These differences may be explained by the GIP-induced stimulation of glucagon secretion during lower levels of glycaemia and may represent a novel way to improve pharmacologically glucagon counterregulation and prevent insulin-induced hypoglycaemia in patients with diabetes.

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Conclusion

Evidence supports the notion that GIP acts as a bifunctional regulator of both insulin and glucagon secretion. Thus, the effects of GIP on glucagon seem to be glucose dependent and active during fasting and hypoglycaemia. In patients with type 1 diabetes, the glucagon-stimulating effects of GIP could translate into an improved counterregulatory glucagon response to experimental insulin-induced hypoglycaemia, which could potentially be used therapeutically by combining insulin treatment with GIP-based treatment modalities. We speculate that the primary physiological role of GIP is to stabilize blood glucose, while coordinating nutrient disposal in peripheral tissues (through insulin) and having permissive anabolic actions in adipose tissue and bone. The acronym GIP has been constant, whereas the hormone name has evolved alongside our understanding of the physiology. Possibly an even more appropriate term for GIP could evolve in the future and one proposal could be Glucose-stabilizing Intestinal Peptide.

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Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

gastric inhibitory peptide; glucagon; glucose-dependent insulinotropic peptide; glucose-stabilizing intestinal peptide; incretin; incretin effect

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