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.
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.
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).
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.
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.
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.
There are no conflicts of interest.
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