We examined the actions of GIP on the two main pancreatic hormones at three distinct glycemic levels and report the novel finding that GIP has inverted glucose-dependent effects on insulin and glucagon secretion. Thus, GIP exhibits glucagonotropic effects during fasting and hypoglycemic conditions when little or no effect on insulin secretion is exerted by the hormone. In contrast, GIP has no effect on glucagon secretion during hyperglycemia, when it robustly potentiates glucose-induced insulin secretion. These findings help to explain most of the controversies, which exist in the literature, regarding the glucagonotropic effect of GIP. First, many of the negative results in healthy subjects could be related to the elevated glucose levels in studies using hyperglycemic clamping (9
). Second, the low sensitivity of earlier glucagon assays could explain the negative glucagon responses seen in the earliest study (5
). Third, in accordance with our results, a reexamination of the original data from the study by Vilsbøll et al. (8
) revealed that short-duration GIP infusions (30 min) at a glycemic level of 5 mmol/L actually gave rise to significant glucagon responses compared with saline, but when the glucose levels were increased stepwise, first to 6 mmol/L and later to 7 mmol/L, the glucagon response was increasingly suppressed, resulting in the nonsignificant differences in total glucagon responses (GIP versus saline) reported in the original publication. Thus, on the basis of the collective human data, a glycemic threshold of ~5.5–6 mmol/L could exist, below which GIP mainly exerts glucagonotropic actions. illustrates that the bifunctional glucose-dependent role of GIP in vivo (in humans) at the physiological PG interval between 3 and 12 mmol/L bears resemblance to the results from perfused rat pancreas reported by Pederson and Brown (4
) more than 30 years ago.
FIG. 4. Glucagon and C-peptide. The in vivo relation of plasma glucagon (dark blue curves, squares) and serum C-peptide (light blue curves, circles) to selected PG values between 3 and 12 mmol/L in the presence of stimulated GIP concentrations (broken lines, (more ...)
Although the combined glucagonotropic and insulinotropic effects of GIP seem to constitute a preserved physiological mechanism in rodents and humans alike, the physiological relevance of the dual hormonal regulating properties of GIP still remains to be elucidated. Several aspects of GIP physiology are interesting in this respect. Of note, GIP release is stimulated dose dependently not only by glucose but also by protein and fat ingestion and is, under physiological (postprandial) circumstances, always present alongside the coincretin, glucagon-like peptide (GLP)-1 (17
). Of interest, despite the glucose-dependent insulinotropic effects of both hormones, GLP-1, in contrast to GIP, has well-established suppressive effects on glucagon (19
) and seemingly also the capability to induce hypoglycemia (21
). Another discerning factor is that GIP signaling robustly has been demonstrated to be involved in fat metabolism in rodents and canine (22
). Yet, although secretion of GIP is elevated in obese subjects (27
) and enhanced by high-fat diets (28
), the relevance of GIP in human fat metabolism remains more elusive (29
). As central nervous tissue rely on stable blood glucose levels, we hypothesize that a role of GIP could be, through its glucagonotropic effect, to provide buffering against reactive hypoglycemia, especially after meals with high protein and fat content. A buffering effect on blood glucose levels is also highly compatible with a role for GIP as an anabolic hormone for adipose tissue and bone (29
With regard to the regulation of pancreatic islet hormone secretion, it is interesting that GIP during euglycemia causes significant glucagon responses with concurrent insulin responses. In addition, during hyperinsulinemic hypoglycemia, glucagon levels were higher during the first 30 min with elevated levels of GIP, despite concomitant higher peripheral and presumably pancreatic intraislet insulin levels. Insulin is a well-known inhibitor of α-cell secretion, but the mechanism by which this inhibition occurs is not well described (2
). A proposed mechanism is changes in paracrine β-cell secretion (i.e., insulin, amylin, γ-aminobutyric acid, zinc ions, etc.) as a director of glucagon secretion commonly referred to as the intraislet hypothesis (31
). Thus, the current results demonstrate a dominant effect of GIP stimulation on glucagon release (presumably from pancreatic α-cells) over the proposed negative impact of insulin (and other products) secreted from neighboring β-cells at euglycemia and hypoglycemia. This is in line with previous results from our group demonstrating that the suppression of glucagon responses during GIP infusions at hyperglycemia does not depend on the concurrent rise in insulin responses, a conclusion drawn from studies in patients with type 1 diabetes who tested negative for C-peptide after an intravenous arginine test (i.e., without paracrine intraislet influence of insulin) (11
). Therefore, the prevailing glycemia, seems to be of greater importance in the regulation of glucagon secretion. The consequences of these parallel insulin and glucagon responses at euglycemic levels were a slight lowering effect on PG. This is a probable consequence of the peripheral (i.e., nonhepatic) influence of insulin during these circumstances but certainly does not exclude some buffering effect of glucagon through hepatic glucose production. The influence of insulin on peripheral tissues was further demonstrated during the excursion toward hypoglycemia, where PG levels were almost completely superimposed on days with GIP and saline. Hence, in the presence of the rather nonphysiological hyperinsulinemia inherent to the clamp in these healthy individuals, the stimulated glucagon levels for the first 30 min were not sufficient to modify the course of the downward-sloping PG curve. During the hyperinsulinemic clamp, the glucagon levels were increased by concomitant GIP infusion only in the physiological range of PG (i.e., in the range of 3.0–5.5 mmol/L), as shown in . The maximal glucagon levels reached (at the lowest PG levels) were similar on days with GIP and saline, probably as a result of maximal stimulation of glucagon secretion induced by hypoglycemia and activity in the autonomic nervous system (observed clinically in most of the subjects by sweating).
The glucagonotropic effects of GIP could have pathophysiological consequences. It is well established that excess secretion of glucagon (weighed against a relative lack of insulin) in the postprandial and fasting state is a major determinant of diabetic hyperglycemia (1
). Furthermore, it is evident that the hyperglucagonemia in type 2 diabetes cannot solely be explained by a lack of insulin (2
). Intriguingly, in patients with type 2 diabetes the insulinotropic effect of GIP is severely deficient (9
). Therefore, in these patients a glucagonotropic effect of GIP could be a factor adding to the mismatched insulin-to-glucagon ratio. The maximal difference in glucagon levels between GIP and saline on the days of euglycemia in the current study amounts to ~4 pmol/L, a difference that could be of clinical relevance in type 2 diabetic patients with insufficient opposing insulin secretion. This is supported by the observation that there is a similar difference (i.e., ~4 pmol/L) in fasting glucagon concentrations between individuals with type 2 diabetes and healthy control subjects (33
). In further support of this notion, recent studies have shown that GIP infused in supraphysiological doses worsens postprandial hyperglycemia (34
) and antagonizes the glucagon-suppressive effects of GLP-1 (35
) in patients with type 2 diabetes. On the other hand, enhanced GIP action in type 2 diabetes could explain the improved glucagon response to hypoglycemia observed during treatment with the dipeptidyl peptidase-4 inhibitor, vildagliptin (37
). The proposed role of GIP as a safeguard against hypoglycemia and its potential pathophysiological implications in type 2 diabetes could benefit from further exploration.
In conclusion, we have demonstrated glucose-dependent glucagonotropic effects of GIP in healthy humans. GIP has no effect on glucagon responses during hyperglycemia when it potentiates insulin secretion. In contrast, GIP increases glucagon levels during fasting and hypoglycemic conditions. Thus, GIP seems to be a physiological pancreatic islet regulator with diverging effects on the two main pancreatic glucoregulatory hormones insulin and glucagon.