ReviewIncretin dysfunction in type 2 diabetes: Clinical impact and future perspectivesL’effet incrétine dans le diabète de type 2
Section snippets
The incretin effect
In the 1930s, Dr Jean La Barre from Belgium introduced the term “incretin” to describe a substance in the gut mucosa that produces hypoglycaemia when injected into normal animals, but not in those who had undergone pancreatectomy [1]. Dr Hans Heller from Austria made a similar suggestion a few years later, although he suggested the term “duodenin” for this tentative substance [2]. Both La Barre and Heller suggested that the tentative substance(s) could be used in the treatment of diabetes,
Incretin effect in type 2 diabetes
In 1986 it was demonstrated that the incretin effect is reduced in type 2 diabetes patients; in 14 such patients, it contributed only approximately 20% to the insulin response to oral glucose (50 g) [7]. Later studies confirmed the reduced incretin effect in type 2 diabetes and concluded that the incretin effect contributed to approximately 35% of the insulin response to oral glucose (75 g) in type 2 diabetes, as it was demonstrated in eight patients [10] and 21 patients [11]. Furthermore, by
Basis of the incretin effect
The incretin effect depends largely on the two main incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, both of which are released after oral glucose ingestion and potentiate glucose-stimulated insulin secretion [15]. There are two major components in the incretin effect: release of incretin hormones from the gut; and the effects of incretin hormones on beta-cells, leading to insulin secretion. This suggests that the impaired incretin effect in type 2 diabetes could
Incretin hormone secretion in type 2 diabetes
The incretin hormones GIP and GLP-1 are released when nutrients from meal ingestion (or simple macronutrient ingestion) reach the cells in the gut that produce these incretin hormones [15]. Incretin hormone secretion is mediated through direct stimulation of the enteroendocrine cells by nutrients and is therefore not only dependent on the type of macronutrient or macronutrient load, but also on the rate of gastric-emptying and intestinal transit time. Incretin hormone secretion is also
Incretin hormone-induced insulin secretion
When GIP and GLP-1 are infused intravenously, they both potently potentiate and augment glucose-stimulated insulin secretion. However, this insulinotropic action of GIP has convincingly and repeatedly been demonstrated to be reduced in type 2 diabetes [15], [18], [19], [36], [37]. The effect appears to be associated with the diabetic condition, as it was not found in the relatives of patients with type 2 diabetes [19], [38] or in women with previous gestational diabetes mellitus [39], whereas
Clinical consequences
The impaired incretin effect in type 2 diabetes is a therapeutic target as there are now tools that can both stimulate GLP-1 receptors (using GLP-1 receptor agonists) and increase circulating levels of active incretin hormones (using DPP-4 inhibitors) [4], [51], [52]. Incretin-based therapy may be regarded as a therapy to restore an early defect in type 2 diabetes that, in turn, targets the main islet dysfunction of the disease. Islet dysfunction in type 2 diabetes involves both alpha- and
Future research
Although a considerable body of knowledge has been amassed since the initial discovery of incretins some 80 years ago and the success of incretin therapy in patients with type 2 diabetes has become evident over the past several years, there is much that remains to be studied. It is important that future studies include more detailed evaluations of the variability of incretin hormone secretion and effects in well-defined subpopulations of type 2 diabetes patients, and look at whether the results
Disclosure of interest
The author has received honoraria for lectures and been a member of advisory boards for AstraZeneca, Bristol-Myers Squibb, GSK, Eli Lilly, Novartis, Novo Nordisk, Merck and Sanofi-Aventis, which are all companies producing GLP-1 receptor agonists or DPP-4 inhibitors.
References (56)
GLP-1 for type 2 diabetes
Exp Cell Res
(2011)- et al.
New interpretation of oral glucose tolerance
Lancet
(1964) - et al.
Secretion of incretin hormones (GIP and GLP-1) and incretin effect after oral glucose in first-degree relatives of patients with type 2 diabetes
Regul Pept
(2004) - et al.
Incretin hormone secretion over the day
Vitam Horm
(2010) - et al.
Synergism by individual macronutrients explains the marked early GLP-1 and islet hormone responses to mixed meal challenge in mice
Regul Pept
(2012) - et al.
Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance
Metabolism
(2004) - et al.
Effect of porcine gastric inhibitory polypeptide on β-cell function in type I and type II diabetes mellitus
Metabolism
(1987) - et al.
Similar insulin secretory response to a gastric inhibitory polypeptide bolus injections at euglycaemia in first-degree relatives of patients with type 2 diabetes and control subjects
Metabolism
(2003) - et al.
The insulinotropic effect of GIP is impaired in patients with chronic pancreatitis and secondary diabetes mellitus as compared to patients with chronic pancreatitis and normal glucose tolerance
Regul Pept
(2007) - et al.
Potentiated beta-cell response to non-glucose stimuli in insulin-resistance C57BL/6J mice
Eur J Pharmacol
(1998)
Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomized, controlled trial
Lancet
Sur les possibilités d’un traitement du diabète par l’incrétine
Bull Acad R Med Belg
Über das insulinotrope Hormon der Darmschleimhaut (Duodenin)
Arch Exp Pharmakol
Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus
N Engl J Med
Plasma insulin responses to oral and intravenous glucose administration
J Clin Endocrinol Metab
Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses
J Clin Endocrinol Metab
The augmenting effect on insulin secretion by oral versus intravenous glucose is exaggerated by high-fat diet in mice
J Endocrinol
Impaired regulation of the incretin effect in patients with type 2 diabetes
J Clin Endocrinol Metab
Reduced incretin effect in type 2 diabetes. Cause or consequence of the diabetic state?
Diabetes
Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as isoglycemic intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes
J Clin Endocrinol Metab
The dynamic incretin adaptation and type 2 diabetes
J Clin Endocrinol Metab
Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance
Am J Physiol Endocrinol Metab
Physiology of incretins in health and disease
Rev Diabet Stud
Differential islet and incretin hormone responses in morning versus afternoon after standardized meal in healthy men
J Clin Endocrinol Metab
Loss of incretin effect is a specific, important, and early characteristic of type 2 diabetes
Diabetes Care
Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired β-cell function
Diabetes
Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients
Diabetes
Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients
J Clin Endocrinol Metab
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2021, Pharmacological ResearchCitation Excerpt :GLP-1 secretion can be triggered by the direct stimulation of enteroendocrine cells through nutrient exposures upon food intake. This phenomenon is affected not only by the type and load of macronutrients (i.e. carbohydrates, proteins, and lipids) but also by the rate of gastric emptying and intestinal transit time [12,39]. Glucose is a potent stimulant of GLP-1 secretion, but other nutrients from meal components are also effective, such as fructose, long-chain fatty acids, some proteins, and certain amino acids [39,41].
What Is GLP-1 Really Doing in Obesity?
2020, Trends in Endocrinology and MetabolismCitation Excerpt :Because dietary fibers strongly impact the composition of the gut microbiota, it is likely that experimental results obtained by simple comparison between a typical laboratory chow (15% fiber) and commercial refined HFD (5% fiber) are related to differences in the content of fiber than that of fat. Increased GLP-1 secretion during obesity development suggests the induction of GLP-1 resistance [21,48]. The loss of the incretin effect has been observed in T2DM subjects, obese subjects [10,49], diabetic rats [50], and HFD-fed rodents [51,52].
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2018, Encyclopedia of Endocrine Diseases