Response to Comment on: Knop et al. (2007) Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? <i>Diabetes</i> 56:1951–1959

Knop, Filip K.; Vilsbøll, Tina; Madsbad, Sten; Krarup, Thure; Holst, Jens J.

doi:10.2337/db07-1522

Cited by 104 publications

(159 citation statements)

References 18 publications

Supporting

Mentioning

143

Contrasting

Unclassified

Order By: Relevance

“…As the increase in insulin resistance in the two groups was identical, our results suggest that insulin resistance and glucose intolerance contribute as separate factors to the reduced incretin effect in patients with type 2 diabetes. Even though our study design per se does not allow us to conclude that the reduced incretin effect observed is a consequence and not a cause of the declining glucose tolerance, previous studies [11,35] from our group have addressed this question, and together the evidence supports the former. The mechanistic explanation for the impaired incretin effect in our study does not involve a reduced secretion of the two incretin hormones GLP-1 and GIP (measured as total hormones to capture all changes in secretion, independent of possible variations in dipeptidyl peptidase-4 (DPP-4) activity [36]) as neither GLP-1 nor GIP secretion decreased during OGTT after dexamethasone.…”

Section: Discussionmentioning

confidence: 77%

“…The loss of the incretin effect is associated with a reduced insulinotropic effect of GLP-1 [9,10] and an almost complete loss of latephase insulin secretion in response to GIP [10]. The incretin effect is also reduced in diabetes secondary to chronic pancreatitis [11], suggesting that the impairment is secondary to the development of diabetes [11] and raising the question of when the defect becomes apparent. Prediabetes is characterised by insulin resistance [12], and if secretion of insulin is insufficient to compensate for this, the result is IGT or frank diabetes [12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis The aim of this study was to evaluate the separate impact of insulin resistance and impaired glucose tolerance (IGT) on the incretin effect. Methods Twenty-one healthy glucose-tolerant first-degree relatives of patients with type 2 diabetes underwent a 75 g OGTT, an isoglycaemic i.v. glucose test and a mixed meal to evaluate the incretin effect before and after treatment with dexamethasone to increase insulin resistance. Beta cell glucose sensitivity, beta cell index and fasting proinsulin were measured as indices of beta cell function.Results After dexamethasone, ten individuals had increased insulin resistance but normal glucose tolerance (NGT), while 11 individuals with an equal increase in insulin resistance developed IGT. In the NGT and IGT groups, the incretin effects were 71±3.2% and 67±4.6% (p00.4) before treatment, but decreased significantly in both groups to 58±5.2% and 32±8.8% (p<0.05 between groups) after treatment. Dexamethasone increased total glucagon-like peptide-1 and glucose-dependent insulinotropic peptide responses to the OGTT. The impaired incretin effect in NGT was observed in the absence of reductions in beta cell glucose sensitivity and beta cell index during i.v. glucose, corrected for insulin resistance, but in parallel with increased proinsulin/C-peptide ratio. Conclusion/interpretation Insulin resistance and IGT, representing two stages in the path towards diabetes, are associated with differential reductions in the incretin effect seen before the development of IGT and overt type 2 diabetes. The reduction is unrelated to secretion of incretin hormones, but is related to insulin resistance and subtle beta cell defects, and is further aggravated on development of IGT.Trial registration: ClinicalTrials.gov NCT00784745.

show abstract

Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The incretin effect explains approximately 50-70% of insulin secretion after an oral glucose load in healthy individuals but secretion is markedly reduced (approximately 10-30%) in patients with type 2 diabetes [14][15][16]. To date, two incretin hormones have been identified: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [12,13].…”

Section: Introductionmentioning

confidence: 99%

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis The aim of this work was to compare the glucose-lowering efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitors between Asian and non-Asian patients with type 2 diabetes. Methods We searched MEDLINE, EMBASE, LILACS, CENTRAL, ClinicalTrials.gov and conference proceedings. Studies were eligible if they were randomised controlled trials with a treatment duration of at least 12 weeks, compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy, had information on ethnicity and HbA 1c values and were published or described in English. A systematic review and meta-analysis with a meta-regression analysis was conducted. Results Among 809 potentially relevant studies, 55 trials were included. A meta-analysis revealed that DPP-4 inhibitors lowered HbA 1c to a greater extent in studies with ≥50% Asian participants (weighted mean difference [WMD] −0.92%; 95% CI −1.03, −0.82) than in studies with <50% Asian participants (WMD −0.65%; 95% CI −0.69, −0.60). The between-group difference was −0.26% (95% CI −0.36, −0.17, p<0.001). The baseline BMI significantly correlated with the HbA 1c -lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA 1c <7.0% (53.0 mmol/mol) was higher in studies with ≥50% Asian participants (3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0]). The fasting plasma glucose-lowering efficacy was higher with monotherapy in the Asiandominant studies, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. Conclusions/interpretation DPP-4 inhibitors exhibit a better glucose-lowering efficacy in Asians than in other ethnic groups; this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.

show abstract

“…However, more recently it's been suggested that the secretion of GIP and GLP-1 is normal in type 2 diabetic patients [51]. This strongly suggests a role for incretin hormones or their actions in the treatment of type 2 diabetes [39,[52][53][54][55].…”

Section: Incretin Hormonesmentioning

confidence: 99%

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Thompson¹

2013

Clin Exp Pharmacol

View full text Add to dashboard Cite

It has been estimated that approximately 8.4% of the world population currently live with diabetes mellitus and type 2 diabetes is the most common form. Type 2 diabetes increases the risk of complications such as heart attacks, blindness, amputations and kidney failure. Glucagon like Peptide-1 (GLP-1) is an effective insulinotropic agent and therefore its effects on insulin secretion have been greatly examined for more than two decades. It is a polypeptide hormone secreted by the intestinal L-cells into the blood in response to food uptake. GLP-1 has a very short half-life in vivo due to the rapid proteolytic degradation by Dipeptidyl Peptidase IV (DPP-IV). Therefore DPP-IV resistant GLP-1 analogues, Exenatide and Liraglutide, have been developed and are currently being used in the treatment of type 2 diabetes. GLP-1 agonist functions by binding to its receptor, GLP1R, on the cell surface.The GLP-1R belongs to the class B peptide receptor family based on its structure and function. The binding of GLP-1 to its receptor results in activation of Gαs coupled adenylyl cyclase and the production of cyclic Adenosine Monophosphate (cAMP), which enhances glucose-induced insulin secretion. Continuous GLP-1R activation also causes insulin secretion and pancreatic islet β-cell proliferation and neogenesis. The GLP-1R is internalised following its activation, which regulates the biological responsiveness of the receptor. Structurally the GLP-1R contains a large N-terminal extracellular domain (TM1-TM7) joined by three intracellular loops (ICL1, ICL2, ICL3) and three extracellular loops (ECL1, ECL2, ECL3), and an intracellular C-terminal domain. These domains play critical roles in GLP-1R trafficking to the cell surface, and also in agonist dependent activation and internalisation of the receptor. This review is focused on type 2 diabetes, its treatment with GLP-1, GLP-1R structure and function, and the physiological affects resulting from GLP-1R activation.

show abstract

Response to Comment on: Knop et al. (2007) Reduced Incretin Effect in Type 2 Diabetes: Cause or Consequence of the Diabetic State? Diabetes 56:1951–1959

Cited by 104 publications

References 18 publications

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

Steroid-induced insulin resistance and impaired glucose tolerance are both associated with a progressive decline of incretin effect in first-degree relatives of patients with type 2 diabetes

Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis

Type 2 Diabetes Mellitus and Glucagon Like Peptide-1 Receptor Signalling

Contact Info

Product

Resources

About