Effects of endogenous GIP in patients with type 2 diabetes

2021 ◽  
Author(s):  
Signe Stensen ◽  
Lærke S Gasbjerg ◽  
Liva L. Krogh ◽  
Kirsa Skov-Jeppesen ◽  
Alexander H. Sparre-Ulrich ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Receptor Antagonist ◽  
Bone Homeostasis ◽  
Collagen Crosslinks ◽  
Ad Libitum ◽  
Postprandial Insulin ◽  
Gip Receptor

Objective: The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. Design: A randomized, double-blinded, placebo-controlled, crossover study. Methods: Ten patients with overweight/obesity and type 2 diabetes (mean±SD; HbA1c 52±11 mmol/mol; BMI 32.5±4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1,200 pmol × kg-1 × min-1), or placebo (saline) during two separate, 230-minute, standardized, liquid mixed meal tests followed by an ad libitum meal. Subcutaneous adipose tissue biopsies were analyzed. Results: Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide%±SEM; -14±6%, p=0.021) and peak glucagon (Δ%±SEM; -11±6%, p=0.046), but had no effect on plasma glucose (p=0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX;±SEM; -4.9±2 ng/ml × min, p=0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, ad libitum meal consumption or adipose tissue triglyceride content. Conclusions: Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.

scholarly journals The Mineralocorticoid Receptor Antagonist Eplerenone Suppress Interstitial Fibrosis in Subcutaneous Adipose Tissue in Type 2 Diabetes Patients

2020 ◽  
Author(s):  
Ada Admin ◽  
Marie Louise Johansen ◽  
Jaime Ibarrola ◽  
Amaya Fernández-Celis ◽  
Morten Schou ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Receptor Antagonist ◽  
Subcutaneous Adipose Tissue ◽  
Mineralocorticoid Receptor ◽  
Prostaglandin D2 ◽  
Type I ◽  
Mineralocorticoid Receptor Antagonist ◽  
Subcutaneous Adipose

Activation of the mineralocorticoid receptor (MR) may promote dysfunctional adipose tissue in patients with type 2 diabetes, where increased pericellular fibrosis has emerged as a major contributor. The knowledge of the association between the MR, fibrosis and the effects of an MR antagonist (MRA) in human adipocytes remains very limited. The present sub-study including 30 participants was prespecified as part of the Mineralocorticoid Receptor Antagonist in type 2 Diabetes (MIRAD) trial, randomizing patients to either high dose eplerenone or placebo for 26 weeks. In adipose tissue biopsies, changes in fibrosis were evaluated by immunohistological examinations and by the expression of mRNA and protein markers of fibrosis. Treatment with an MRA reduced pericellular fibrosis, synthesis of the major subunits of collagen type I and VI, and the profibrotic factor α-smooth muscle actin, as compared to placebo in subcutaneous adipose tissue. Furthermore, we found decreased expression of the MR and downstream molecules neutrophil gelatinase–associated lipocalin, galectin-3, and lipocalin-like prostaglandin D2 synthase with an MRA. In conclusions, we present original data demonstrating reduced fibrosis in adipose tissue with inhibition of the MR, which could be a potential therapeutic approach to prevent the extracellular matrix remodeling of adipose tissue in type 2 diabetes.

Characterisation and glucoregulatory actions of a novel acylated form of the (Pro3)GIP receptor antagonist in type 2 diabetes

2007 ◽  
Vol 388 (2) ◽  
Author(s):  
Victor A. Gault ◽  
Kerry Hunter ◽  
Nigel Irwin ◽  
Brett Greer ◽  
Brian D. Green ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Receptor Antagonist ◽  
Gip Receptor

scholarly journals Decrement of postprandial insulin secretion determines the progressive nature of type-2 diabetes

2006 ◽  
Vol 155 (4) ◽  
pp. 615-622 ◽  
Author(s):  
Wan Sub Shim ◽  
Soo Kyung Kim ◽  
Hae Jin Kim ◽  
Eun Seok Kang ◽  
Chul Woo Ahn ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Diabetic Patients ◽  
Β Cell ◽  
Type 2 Diabetic Patients ◽  
C Peptide ◽  
Duration Of Diabetes ◽  
Type 2 Diabetic ◽  
Postprandial Insulin

Objective: Type-2 diabetes is a progressive disease. However, little is known about whether decreased fasting or postprandial pancreatic β-cell responsiveness is more prominent with increased duration of diabetes. The aim of this study was to evaluate the relationship between insulin secretion both during fasting and 2 h postprandial, and the duration of diabetes in type-2 diabetic patients. Design: Cross-sectional clinical investigation. Methods: We conducted a meal tolerance test in 1466 type-2 diabetic patients and calculated fasting (M0) and postprandial (M1) β-cell responsiveness. Results: The fasting C-peptide, postprandial C-peptide, M0, and M1 values were lower, but HbA1c values were higher, in patients with diabetes duration > 10 years than those in other groups. There was no difference in the HbA1c levels according to the tertiles of their fasting C-peptide level. However, in a group of patients with highest postprandial C-peptide tertile, the HbA1c values were significantly lower than those in other groups. After adjustment of age, sex, and body mass index (BMI), the duration of diabetes was found to be negatively correlated with fasting C-peptide (γ = −0.102), postprandial C-peptide (γ = −0.356), M0 (γ = −0.263), and M1 (γ = −0.315; P < 0.01 respectively). After adjustment of age, sex, and BMI, HbA1c was found to be negatively correlated with postprandial C-peptide (γ = −0.264), M0 (γ = −0.379), and M1 (γ = −0.522), however, positively correlated with fasting C-peptide (γ = 0.105; P < 0.01 respectively). In stepwise multiple regression analysis, M0, M1, and homeostasis model assessment for insulin resistance (HOMA-IR) emerged as predictors of HbAlc after adjustment for age, sex, and BMI (R2 = 0.272, 0.080, and 0.056 respectively). Conclusions: With increasing duration of diabetes, the decrease of postprandial insulin secretion is becoming more prominent, and postprandial β-cell responsiveness may be a more important determinant for glycemic control than fasting β-cell responsiveness.

Protein Co-Ingestion Strongly Increases Postprandial Insulin Secretion in Type 2 Diabetes Patients

2014 ◽  
Vol 17 (7) ◽  
pp. 758-763 ◽  
Author(s):  
Ralph J.F. Manders ◽  
Dominique Hansen ◽  
Antoine H.G. Zorenc ◽  
Paul Dendale ◽  
Joris Kloek ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Postprandial Insulin ◽  
Diabetes Patients

Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with Type 2 diabetes

2016 ◽  
Vol 130 (19) ◽  
pp. 1753-1762 ◽  
Author(s):  
Ilaria Barchetta ◽  
Francesco Angelico ◽  
Maria Del Ben ◽  
Michele Di Martino ◽  
Flavia Agata Cimini ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Fat Deposition ◽  
Metabolic Phenotype ◽  
Ectopic Fat ◽  
Model Assessment ◽  
Fat Accumulation

Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-β%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin-resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65–0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients.

scholarly journals Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial

2019 ◽  
Vol 110 (5) ◽  
pp. 1098-1107 ◽  
Author(s):  
Yanislava Karusheva ◽  
Theresa Koessler ◽  
Klaus Strassburger ◽  
Daniel Markgraf ◽  
Lucia Mastrototaro ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Crossover Trial ◽  
Branched Chain Amino Acids ◽  
Short Term ◽  
Microbiome Composition ◽  
Branched Chain

ABSTRACT Background Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits. Objective We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity. Methods This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling. Results After the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes. Conclusions Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients. This trial was registered at clinicaltrials.gov as NCT03261362.

scholarly journals The Antiinflammatory Cytokine Interleukin-1 Receptor Antagonist Protects from High-Fat Diet-Induced Hyperglycemia

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2208-2218 ◽  
Author(s):  
Nadine S. Sauter ◽  
Fabienne T. Schulthess ◽  
Ryan Galasso ◽  
Lawrence W. Castellani ◽  
Kathrin Maedler
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Receptor Antagonist ◽  
High Fat Diet ◽  
Cell Function ◽  
Interleukin 1 ◽  
High Fat ◽  
Β Cell

Subclinical inflammation is a recently discovered phenomenon in type 2 diabetes. Elevated cytokines impair β-cell function and survival. A recent clinical trial shows that blocking IL-1β signaling by IL-1 receptor antagonist (IL-1Ra) improves β-cell secretory function in patients with type 2 diabetes. In the present study, we provide further mechanisms of the protective role of IL-1Ra on the β-cell. IL-1Ra prevented diabetes in vivo in C57BL/6J mice fed a high-fat/high-sucrose diet (HFD) for 12 wk; it improved glucose tolerance and insulin secretion. High-fat diet treatment increased serum levels of free fatty acids and of the adipokines resistin and leptin, which were reduced by IL-1Ra treatment. In addition, IL-1Ra counteracted adiponectin levels, which were decreased by high-fat feeding. Studies on isolated islets revealed that IL-1Ra specifically acted on the β-cell. IL-1Ra protected islets from HFD treated animals from β-cell apoptosis, induced β-cell proliferation, and improved glucose-stimulated insulin secretion. Insulin mRNA was reduced in islets from mice fed a HFD but normalized in the IL-1Ra group. Our results show that IL-1Ra improves β-cell survival and function, and support the potential role for IL-1Ra in the treatment of diabetes.

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