Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

Christensen, Mikkel B.; Calanna, Salvatore; Sparre-Ulrich, Alexander Hovard; Kristensen, Peter; Rosenkilde, Mette M.; Faber, Jens; Purrello, Francesco; Hall, Gerrit van; Holst, Jens J.; Vilsbøll, Tina; Knop, Filip K.

doi:10.2337/db14-0440

Cited by 67 publications

(49 citation statements)

References 26 publications

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“…GIP was recently reported to have glucagonotrophic effects [36,37] and to protect against hypoglycaemia in type 1 diabetes [37]. This glucagonotrophic effect of GIP has been suggested to be mediated by GIP receptors present on the pancreatic alpha cells [38].…”

Section: Discussionmentioning

confidence: 99%

The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes

et al. 2014

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Aims/hypothesis The influence of glucagon on glycaemic control in type 1 diabetes is debated. We investigated the relationship between postprandial glucagon levels and HbA 1c during a period up to 60 months after diagnosis of childhood type 1 diabetes. Methods The Danish remission phase cohort comprised 129 children (66 boys) with type 1 diabetes whose mean (SD) age at onset was 10.0 (3.9) years. Liquid mixed-meal tests were performed prospectively at 1, 3, 6 and 12 months and a subset of 40 patients completed follow-up at 60 months. Postprandial (90 min) plasma levels of glucagon, glucose (PG), C-peptide, total glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and HbA 1c were analysed. Multivariate regression (repeated measurements with all five visits included) was applied and results expressed as relative change (95% CI). Results Postprandial glucagon levels increased 160% from 1 to 60 months after diagnosis (p<0.0001). A doubling in postprandial PG corresponded to a 21% increase in postprandial glucagon levels (p=0.0079), whereas a doubling in total GLP-1 levels corresponded to a 33% increase in glucagon levels (p<0.0001). Postprandial glucagon associated negatively with postprandial C-peptide (p=0.017). A doubling in postprandial glucagon corresponded to a 3% relative increase in HbA 1c levels (p=0.0045). Conclusions/interpretation Postprandial glucagon levels were associated with deterioration of glycaemic control and declining beta cell function in the first 5 years after diagnosis of type 1 diabetes. The positive association of glucagon with total GLP-1 and PG suggests that physiological regulation of alpha cell secretion in type 1 diabetes is seriously disturbed.

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Section: Discussionmentioning

confidence: 99%

The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes

et al. 2014

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“…While the mode of its action on the β-cell is similar to that of GLP-1, GIP enhances glucagon secretion from the α-cell (Christensen et al 2015;Christensen et al 2014;Meier et al 2003a). Thus, the net glycaemic effect of GIP is largely dependent on the balance of actions on both pancreatic α-and β-cells.…”

Section: Gipmentioning

confidence: 99%

“…Similarly, the glucagonotropic action of exogenous GIP was observed to be attenuated (but not abolished) during a hyperglycaemic clamp (~12 mmol/L) in type 2 diabetes (Christensen et al 2014). In addition, the infusion of exogenous GIP results in enhanced glucagon secretion and endogenous glucose production in response to insulin-induced hypoglycaemia in both type 1 and 2 diabetes (Christensen et al 2015;Christensen et al 2014), indicating that GIP may be useful for maintaining blood glucose concentrations in the face of hypoglycaemia.…”

Section: Gipmentioning

confidence: 99%

“…The reasons for this clinically important issue are unclear but may be related to modifications of the peptide molecules and/or poor tolerance of high dose associated with subcutaneous administration. Recent observations indicate that the glucagonotropic action of GIP may serve to "rescue" hypoglycaemia in both type 1 and 2 diabetes (Christensen et al 2015;Christensen et al 2014), warranting the evaluation of the clinical effects of GIP receptor agonists on blood glucose homeostasis in diabetes. Paradoxically, however, the "obesogenic" potential of GIP observed in preclinical studies suggests that antagonism of GIP signalling may be useful for treating obesity.…”

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confidence: 99%

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Wu¹,

Rayner²,

Horowitz³

2015

Metabolic Control

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Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the known incretin hormones in humans, released predominantly from the enteroendocrine K and L cells within the gut. Their secretion is regulated by a complex of integrated mechanisms involving direct contact for the activation of different chemo-sensors on the brush boarder of K and L cells and several indirect neuro-immuno-hormonal loops. The biological actions of GIP and GLP-1 are fundamental determinants of islet function and blood glucose homeostasis in health and type 2 diabetes. Moreover, there is increasing recognition that GIP and GLP-1 also exert pleiotropic extra-glycaemic actions, which may represent therapeutic targets for human diseases. In this review, we summarise current knowledge of the biology of incretin hormones in health and metabolic disorders and highlight the therapeutic potential of incretin hormones in metabolic regulation.

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“…However, since two human studies [38,39] have shown that GLP-1 infusion during hypoglycaemia does not potentiate the glucagon response to hypoglycaemia, and since the GLP-1 receptor agonists liraglutide and albiglutide do not affect glucagon counterregulation [39,40], GLP-1 does not appear to be the mediator of t he enhanced counterregulation seen with DPP-4 inhibition. Nevertheless, since there is a quantitative difference in GIR to maintain target glucose during hypoglycaemia between vildagliptin and GIP infusion, and in light of the somewhat contradictory result of one study showing that the GLP-1 receptor agonist exenatide slightly increased glucagon secretion in hypoglycaemia [41], we cannot exclude protective effects besides the GIP-glucagon axis of DPP-4 inhibition using vildagliptin by other DPP-4 substrates, such a GLP-1; this would need to be explored in further studies.…”

Section: Discussionmentioning

confidence: 99%

DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP–glucagon counterregulatory axis in mice

Malmgren

Åhrén

2015

Diabetologia

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Aims/hypothesis Glucose-lowering therapy with dipeptidyl peptidase-4 (DPP-4) inhibitors is associated with a low risk of hypoglycaemia. We hypothesise that DPP-4 inhibition prevents hypoglycaemia via increased glucagon counterregulation through the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). Methods Using a hyperinsulinaemic-hypoglycaemic clamp that targeted 2.5 mmol/l we examined the effects of the DPP-4 inhibitor vildagliptin and GIP infusion on steady state glucose infusion rate (GIR) and glucagon counterregulation in mice. Following up on this, we performed a hyperinsulinaemichypoglycaemic clamp in mice carrying a genetic deletion of the GIP receptor (GIPR −/− mice) or the glucagon receptor (GCGR −/− mice). Results GIR was reduced by 89.0±3.1% (p=7.0×10 ) by vildagliptin and by 38.8±12.6% (p=0.040) by GIP in wildtype (wt) mice, whereas GIR was increased both in GIPR ) compared with wt. By contrast, neither vildagliptin nor GIP had any effect on GIR in GCGR −/− mice.Furthermore, vildagliptin increased intact GIP four-to eightfold during hypoglycaemia and the counterregulatory increase in glucagon levels during hypoglycaemia was augmented by vildagliptin (incremental AUC [iAUC] during clamp was 99.2±22.5 vs 42.0±4.5 pmol/l×min in controls; p=0.039) and GIP (iAUC of fold change during clamp was 372±81 vs 161±40 FC×min with saline; p=0.031). Conclusions/interpretation Based on these results we propose that DPP-4 inhibition protects from hypoglycaemia by augmenting glucagon counterregulation through a GIP-glucagon counterregulatory axis.

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Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes

Cited by 67 publications

References 26 publications

The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes

The influence of glucagon on postprandial hyperglycaemia in children 5 years after onset of type 1 diabetes

Incretins

DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP–glucagon counterregulatory axis in mice

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