Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity

Knop, Filip K.; Aaboe, Kasper; Vilsbøll, Tina; Vølund, Anders; Holst, Jens J.; Krarup, Thure; Madsbad, Sten

doi:10.1111/j.1463-1326.2011.01549.x

Cited by 171 publications

(177 citation statements)

References 47 publications

Supporting

Mentioning

148

Contrasting

Unclassified

Order By: Relevance

“…This finding suggest that fasting hyperglucagonaemia is a very early feature in the pathophysiology of type 2 diabetes, which is in accordance with earlier findings in insulin-resistant obese people with normal glucose tolerance [29].…”

Section: Discussionsupporting

confidence: 82%

“…Importantly, the arginine response was unaffected by dexamethasone, indicating that the diminished incretin action of the two hormones is not related to a global dysfunction of the beta cells [12]. Rather, our results indicate that the impaired insulinotropic effects of GLP-1 and GIP represent a very early, specific beta cell defect, which can explain the impaired incretin effect in, for instance, obese individuals with insulin resistance [29]. A reduced effect of GIP in first-degree relatives of patient with type 2 diabetes and in women with a history of gestational diabetes has been found in previous studies [30,31].…”

Section: Discussionmentioning

confidence: 57%

See 1 more Smart Citation

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

et al. 2015

View full text Add to dashboard Cite

Aims/hypothesis We evaluated the insulinotropic properties of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in healthy individuals at risk of developing type 2 diabetes before and after glucocorticoidinduced insulin resistance. Methods Nineteen healthy, glucose tolerant, first-degree relatives of type 2 diabetic patients underwent OGTT and 7 mmol/l and 15 mmol/l glucose clamps with concomitant infusions of GLP-1, GIP or NaCl and a final infusion of arginine for determination of maximum beta cell capacity before and after treatment with dexamethasone. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. Results After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose concentrations, while beta cell function indices generally increased according to the increased resistance. First-phase insulin responses induced by GLP-1 and GIP at 7 mmol/l and maximal beta cell secretory capacity did not differ before and after dexamethasone, while second-phase responses to 7 mmol/l and first-phase responses to 15 mmol/l glucose were reduced equally for both hormones.Conclusions/interpretation Glucocorticoid-induced insulin resistance in individuals at risk of type 2 diabetes leads to a reduced insulinotropic effect of the incretin hormones. This reduction was not associated with a decrease in the maximal beta cell secretory capacity, indicating that the reduced incretin effect in the developing dysglycaemia of the present experimental model is due to a specific early reduction of the insulinotropic effects of the incretin hormones. Trial registration: Clinicaltrials.gov NCT02235584

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 57%

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

et al. 2015

View full text Add to dashboard Cite

show abstract

“…We found that the patients exhibited emerging signs of insulin resistance (with beta cell hypersecretion) and postprandial hyperglucagonemia, both of which are known precursors involved in the development of overt metabolic disturbances and weight gain. 23,24 Our findings of altered lipid levels (elevated fasting cholesterol, LDL cholesterol, and triglycerides and lower fasting HDL cholesterol) are in agreement with observations of dyslipidemia, even in the absence of weight gain. 25,26 Preclinical data have indicated that, by modulating the gene expression, antipsychotics affect the synthesis of cellular fatty acid and cholesterol.…”

Section: Discussionsupporting

confidence: 79%

Glucometabolic Hormones and Cardiovascular Risk Markers in Antipsychotic-Treated Patients

Ebdrup¹,

Knop²,

Madsen³

et al. 2014

J. Clin. Psychiatry

View full text Add to dashboard Cite

Objective: Treatment with antipsychotic drugs is widely associated with metabolic side effects such as weight gain and disturbed glucose metabolism, but the pathophysiologic mechanisms are unclear.Method: Fifty nondiabetic (fasting plasma glucose ≤ 7.0 mmol/L), antipsychotic-treated male patients (ICD-10 diagnosis code F20, F21, F22, F25, F28, or F60; mean ± SD age = 33.0 ± 6.7 years; body mass index [BMI; kg/ m 2 ] = 26.0 ± 4.7; waist circumference = 95.9 ± 13.3 cm; glycated hemoglobin A 1c [HbA 1c ] = 5.7% ± 0.3%) and 93 age-and waist circumference-matched healthy male controls (age = 33 ± 7.3 years; BMI = 26.1 ± 3.9; waist circumference = 94.6 ± 11.9 cm; HbA 1c = 5.7% ± 0.3%) participated in this cross-sectional study. Blood was sampled in the fasting state and 90 minutes after ingestion of a standardized liquid meal (2,268 kJ). The primary outcomes were glucometabolic hormones and cardiovascular risk markers. Data were collected between March 2008 and February 2010.Results: Compared to healthy controls, patients were characterized by elevated fasting levels of proinsulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) (P < .05) and higher postprandial levels of insulin, proinsulin, C-peptide, and GIP (P ≤ .02). Also, patients exhibited elevated plasma levels of C-reactive protein and signs of dyslipidemia. Fasting plasma levels of insulin, glucagon, glucagon-like peptide-1 (GLP-1), ghrelin, leptin, adiponectin, tumor necrosis factor-α, plasminogen activator inhibitor-1, and interleukin-6 and postprandial levels of glucagon, GLP-1, ghrelin, leptin, and adiponectin did not differ between groups. Conclusions:Presenting with an insulin resistant-like pattern, including beta cell hypersecretion and elevated GIP levels, nondiabetic antipsychotic-treated patients display emerging signs of dysmetabolism and a compromised cardiovascular risk profile. The appetite-regulating hormones GLP-1 and ghrelin appear not to be influenced by antipsychotic treatment. Our findings provide new clinical insight into the pathophysiology associated with metabolic side effects of antipsychotic treatment and put emphasis on the importance of implementing metabolic screening into psychiatric practice.Trial Registration: ClinicalTrials.gov identifier NCT00627757 Clin Psychiatry 2014;75(9):e899-e905 J

show abstract

“…In rats submitted to sleeve gastrectomy or gastric bypass, a significant increase in plasma glucagon followed a rise in plasma insulin, but with a descending GIR that recovered at 60 min. Although an increased fasting plasma glucagon and delayed glucose-stimulated suppression has been described in humans with type 2 diabetes (Knop et al 2012), meal-induced or glucose-stimulated glucagon secretion increased after gastric bypass, albeit with improved glucose tolerance (Laferrère et al 2008, Salehi et al 2011. A similar postprandial rise in glucagon has been observed in humans with type 1 diabetes, not submitted to surgery, whereas glucagon in b-cell-competent individuals remained stable (Cooperberg & Cryer 2009).…”

Section: Discussionmentioning

confidence: 60%

Glucagon secretion after metabolic surgery in diabetic rodents

Eickhoff¹,

Louro²,

Matafome³

et al. 2014

Journal of Endocrinology

View full text Add to dashboard Cite

Excessive or inadequate glucagon secretion promoting hepatic gluconeogenesis and glycogenolysis is believed to contribute to hyperglycemia in patients with type 2 diabetes. Currently, metabolic surgery is an accepted treatment for obese patients with type 2 diabetes and has been shown to improve glycemic control in Goto-Kakizaki (GK) rats, a lean animal model for type 2 diabetes. However, the effects of surgery on glucagon secretion are not yet well established. In this study, we randomly assigned forty 12-to 14-week-old GK rats to four groups: control group (GKC), sham surgery (GKSS), sleeve gastrectomy (GKSG), and gastric bypass (GKGB). Ten age-matched Wistar rats served as a non-diabetic control group (WIC). Glycemic control was assessed before and 4 weeks after surgery. Fasting-and mixed-meal-induced plasma levels of insulin and glucagon were measured. Overall glycemic control improved in GKSG and GKGB rats. Fasting insulin levels in WIC rats were similar to those for GKC or GKSS rats. Fasting glucagon levels were highest in GKGB rats. Whereas WIC, GKC, and GKSS rats showed similar glucagon levels, without any significant meal-induced variation, a significant rise occurred in GKSG and GKGB rats, 30 min after a mixed meal, which was maintained at 60 min. Both GKSG and GKGB rats showed an elevated glucagon:insulin ratio at 60 min in comparison with all other groups. Surprisingly, the augmented post-procedural glucagon secretion was accompanied by an improved overall glucose metabolism in GKSG and GKGB rats. Understanding the role of glucagon in the pathophysiology of type 2 diabetes requires further research.

show abstract

Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity

Abstract: Our findings suggest that reduced incretin effect and fasting hyperglucagonaemia constitute very early steps in the pathophysiology of T2DM detectable even in obese people who despite their insulin-resistant state have NGT.

Cited by 171 publications

References 47 publications

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

Glucometabolic Hormones and Cardiovascular Risk Markers in Antipsychotic-Treated Patients

Glucagon secretion after metabolic surgery in diabetic rodents

Contact Info

Product

Resources

About