Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

Alssema, Marjan; Rijkelijkhuizen, J.M.; Holst, Jens J.; Teerlink, Tom; Scheffer, P; Eekhoff, Elisabeth M. W.; Gastaldelli, Amalia; Mari, Andrea; Hart, Leen M ’t; Nijpels, Giel; Dekker, Joost

doi:10.1530/eje-13-0487

Cited by 51 publications

(67 citation statements)

References 47 publications

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“…Similar observations were reported in patients with type 2 diabetes with exaggerated GIP secretion and dissociated insulin response (24,25). GIP peptide stability could be increased due to the reduction of circulating DPP4 in Hnf1a mutant mice.…”

Section: Discussionsupporting

confidence: 85%

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

et al. 2015

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Hepatocyte nuclear factor-1α (HNF1α) is a transcription factor expressed in tissues of endoderm origin. Mutations in HNF1A are associated with maturity-onset diabetes of the young 3 (MODY3). Mice deficient for Hnf1α are hyperglycemic, with their pancreatic β-cells being defective in glucose-sensing insulin secretion. The specific mechanisms involved in this defect are unclear. Gut hormones control glucose homeostasis. Our objective was to explore whether changes in these hormones play a role in glucose homeostasis in the absence of Hnf1α. An increase in ghrelin gene transcript and a decrease in glucose-dependent insulinotropic polypeptide (GIP) gene transcripts were observed in the gut of Hnf1α-null mice. These changes correlated with an increase of ghrelin and a decrease of GIP-labeled cells. Ghrelin serological levels were significantly induced in Hnf1α-null mice. Paradoxically, GIP levels were also induced in these mice. Treatment of Hnf1α-null mice with a ghrelin antagonist led to a recovery of the diabetic symptoms. We conclude that upregulation of ghrelin in the absence of Hnf1α impairs insulin secretion and can be reversed by pharmacological inhibition of ghrelin/GHS-R interaction. These observations open up on future strategies to counteract ghrelin action in a program that could become beneficial in controlling non–insulin-dependent diabetes.

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Section: Discussionsupporting

confidence: 85%

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

et al. 2015

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“…By contrast, postprandial GIP responses were higher compared with OGTT and were further augmented with the increasing fat content of the meals, confirming the important physiological role of fat in GIP release as demonstrated previously in obese (33) as well as lean subjects (34). Both reduced, normal and increased GLP1 and GIP responses have previously been observed in patients with T2DM, but studies are difficult to compare (6) and only few studies directly assess incretin responses following both OGTT and meals in T2DM vs matched controls (16,35). Possibly, our findings of similar incretin responses reflect the disease duration, as deteriorating glycaemic control might impair L cell secretion only in long-standing disease, but our results may also reflect the careful matching of patients and controls in terms of factors that modulate incretin release (6).…”

Section: European Journal Of Endocrinologysupporting

confidence: 80%

Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1

Sonne

Rehfeld

Holst

et al. 2014

European Journal of Endocrinology

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Objective: Recent preclinical work has suggested that postprandial flow of bile acids into the small intestine potentiates nutrient-induced glucagon-like peptide 1 (GLP1) secretion via bile acid-induced activation of the G protein-coupled receptor TGR5 in intestinal L cells. The notion of bile-induced GLP1 secretion combined with the findings of reduced postprandial gallbladder emptying in patients with type 2 diabetes (T2DM) led us to speculate whether reduced postprandial GLP1 responses in some patients with T2DM arise as a consequence of diabetic gallbladder dysmotility. Design and methods: In a randomised design, 15 patients with long-standing T2DM and 15 healthy age-, gender-and BMI-matched control subjects were studied during 75-g oral glucose tolerance test (OGTT) and three isocaloric (500 kcal) and isovolaemic (350 ml) liquid meals: i) 2.5 g fat, 107 g carbohydrate and 13 g protein; ii) 10 g fat, 93 g carbohydrate and 11 g protein; and iii) 40 g fat, 32 g carbohydrate and 3 g protein. Basal and postprandial plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP1, glucose-dependent insulinotropic polypeptide (GIP), cholecystokinin and gastrin were measured. Furthermore, gallbladder emptying and gastric emptying were examined. Results: Gallbladder emptying increased with increasing meal fat content, but no intergroup differences were demonstrated. GIP and GLP1 responses were comparable among the groups with GIP levels being higher following high-fat meals, whereas GLP1 secretion was similar after both OGTT and meals. Conclusions: In conclusion, patients with T2DM exhibited normal gallbladder emptying to meals with a wide range of fat content. Incretin responses were similar to that in controls, and an association with postprandial gallbladder contraction could not be demonstrated.

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“…It has been controversial whether the impaired incretin effect observed in type 2 diabetes and obesity may result from a reduction in the release of incretin hormones and, if so, whether this reduction occurs prior to the development of type 2 diabetes and obesity (4)(5)(6)(7)(8)28,29). A general belief has been that impaired GLP-1 release in overt type 2 diabetes and obesity is a phenomenon secondary to other metabolic abnormalities (4,30).…”

Section: Discussionmentioning

confidence: 99%

“…Due to the large number of study participants, samples were only collected at three time points during the OGTT. However, since the response of GLP-1 to oral glucose has been shown to peak around 30 min independent of the degree of dysglycemia (8,12,32) the estimated AUCs are likely to include the peak GLP-1 response.…”

Section: Study Strengths and Limitationsmentioning

confidence: 99%

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

et al. 2015

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The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear.We assessed GLP-1 response to oral glucose in a large study population of lean and obese men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and b-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.

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Preserved GLP-1 and exaggerated GIP secretion in type 2 diabetes and relationships with triglycerides and ALT

Cited by 51 publications

References 47 publications

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

Ghrelin Inhibition Restores Glucose Homeostasis in Hepatocyte Nuclear Factor-1α (MODY3)–Deficient Mice

Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1

GLP-1 Response to Oral Glucose Is Reduced in Prediabetes, Screen-Detected Type 2 Diabetes, and Obesity and Influenced by Sex: The ADDITION-PRO Study

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