scholarly journals High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jonathan M. Dreyfuss ◽  
Yixing Yuchi ◽  
Xuehong Dong ◽  
Vissarion Efthymiou ◽  
Hui Pan ◽  
...  
Keyword(s):  
High Throughput ◽  
Mediation Analysis ◽  
Growth Hormone Receptor ◽  
Glucose Production ◽  
Linear Modeling ◽  
Empirical Bayesian ◽  
Induce Resistance ◽  
Surgical Diabetes ◽  
Plasma Gh

AbstractTo improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.Trial Registration: Clinicaltrials.gov NCT01073020.

scholarly journals Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

2019 ◽  
Author(s):  
Jonathan M Dreyfuss ◽  
Yixing Yuchi ◽  
Hui Pan ◽  
Xuehong Dong ◽  
Donald C. Simonson ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
High Throughput ◽  
Mediation Analysis ◽  
Growth Hormone Receptor ◽  
Molecular Mechanisms ◽  
Gastric Bypass Surgery ◽  
Plasma Proteome ◽  
Beta Alanine ◽  
Nonsurgical Management

AbstractMolecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Beta-alanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentially-regulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available.

Central KATP channels modulate glucose effectiveness in humans and rodents

2020 ◽  
Author(s):  
Ada Admin ◽  
Michelle Carey ◽  
Eric Lontchi-Yimagou ◽  
William Mitchell ◽  
Sarah Reda ◽  
...  
Keyword(s):  
Katp Channel ◽  
Glucose Production ◽  
Katp Channels ◽  
Endogenous Glucose Production ◽  
Elevated Plasma ◽  
Sprague Dawley ◽  
Glucose Effectiveness ◽  
Sprague Dawley Rats ◽  
The Central Nervous System

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this ‘glucose effectiveness’ is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). ATP-sensitive potassium channels (K<sub>ATP</sub> channels) in the central nervous system (CNS) have been shown to regulate EGP in humans and rodents. We examined the contribution of central K<sub>ATP</sub> channels to glucose effectiveness. Under fixed hormonal conditions (‘pancreatic clamp’ studies), hyperglycemia suppressed EGP by ~50% in both non-diabetic humans and normal Sprague Dawley rats. By contrast, antagonism of K<sub>ATP</sub> channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes in rats were abolished by intracerebroventricular (ICV) administration of the KATP channel agonist diazoxide. These findings indicate that about half of EGP suppression by hyperglycemia is mediated by central K<sub>ATP</sub> channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in T2D.

Impact of lack of suppression of glucagon on glucose tolerance in humans

1999 ◽  
Vol 277 (2) ◽  
pp. E283-E290 ◽  
Author(s):  
Pankaj Shah ◽  
Ananda Basu ◽  
Rita Basu ◽  
Robert Rizza
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Cell Function ◽  
Hormone Secretion ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucagon Suppression

People with type 2 diabetes have defects in both α- and β-cell function. To determine whether lack of suppression of glucagon causes hyperglycemia when insulin secretion is impaired but not when insulin secretion is intact, twenty nondiabetic subjects were studied on two occasions. On both occasions, a “prandial” glucose infusion was given over 5 h while endogenous hormone secretion was inhibited. Insulin was infused so as to mimic either a nondiabetic ( n = 10) or diabetic ( n = 10) postprandial profile. Glucagon was infused at a rate of 1.25 ng ⋅ kg−1 ⋅ min−1, beginning either at time zero to prevent a fall in glucagon (nonsuppressed study day) or at 2 h to create a transient fall in glucagon (suppressed study day). During the “diabetic” insulin profile, lack of glucagon suppression resulted in a marked increase ( P < 0.002) in both the peak glucose concentration (11.9 ± 0.4 vs. 8.9 ± 0.4 mmol/l) and the area above basal of glucose (927 ± 77 vs. 546 ± 112 mmol ⋅ l−1 ⋅ 6 h) because of impaired ( P < 0.001) suppression of glucose production. In contrast, during the “nondiabetic” insulin profile, lack of suppression of glucagon resulted in only a slight increase ( P< 0.02) in the peak glucose concentration (9.1 ± 0.4 vs. 8.4 ± 0.3 mmol/l) and the area above basal of glucose (654 ± 146 vs. 488 ± 118 mmol ⋅ l−1 ⋅ 6 h). Of interest, when glucagon was suppressed, glucose concentrations differed only minimally during the nondiabetic and diabetic insulin profiles. These data indicate that lack of suppression of glucagon can cause substantial hyperglycemia when insulin availability is limited, therefore implying that inhibitors of glucagon secretion and/or glucagon action are likely to be useful therapeutic agents in such individuals.

scholarly journals Deciphering the Plasma Proteome of Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Mohamed A. Elhadad ◽  
Christian Jonasson ◽  
Cornelia Huth ◽  
Rory Wilson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Hormone Receptor ◽  
Smoking Status ◽  
Underlying Disease ◽  
Sex Hormone Binding Globulin ◽  
Health Study ◽  
Study Cohort ◽  
Incident Type ◽  
Incident Type 2 Diabetes

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1000 plasma proteins in the KORA (Cooperative health research in the Region of Augsburg) F4 cohort (n=993, 110 cases), with subsequent replication in the HUNT3 (Third wave of the Nord-Trøndelag Health Study) cohort (n=940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bi-directional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which eight are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor binding protein-2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations, and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

scholarly journals Deciphering the Plasma Proteome of Type 2 Diabetes

2020 ◽  
Author(s):  
Ada Admin ◽  
Mohamed A. Elhadad ◽  
Christian Jonasson ◽  
Cornelia Huth ◽  
Rory Wilson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Growth Hormone Receptor ◽  
Smoking Status ◽  
Underlying Disease ◽  
Sex Hormone Binding Globulin ◽  
Health Study ◽  
Study Cohort ◽  
Incident Type ◽  
Incident Type 2 Diabetes

With an estimated prevalence of 463 million affected, type 2 diabetes represents a major challenge to health care systems worldwide. Analyzing the plasma proteomes of individuals with type 2 diabetes may illuminate hitherto unknown functional mechanisms underlying disease pathology. We assessed the associations between type 2 diabetes and >1000 plasma proteins in the KORA (Cooperative health research in the Region of Augsburg) F4 cohort (n=993, 110 cases), with subsequent replication in the HUNT3 (Third wave of the Nord-Trøndelag Health Study) cohort (n=940, 149 cases). We computed logistic regression models adjusted for age, sex, BMI, smoking status and hypertension. Additionally, we investigated associations with incident type 2 diabetes and performed two-sample bi-directional Mendelian randomization (MR) analysis to prioritize our results. Association analysis of prevalent type 2 diabetes revealed 24 replicated proteins, of which eight are novel. Proteins showing association with incident type 2 diabetes were aminoacylase-1, growth hormone receptor, and insulin-like growth factor binding protein-2. Aminoacylase-1 was associated with both prevalent and incident type 2 diabetes. MR analysis yielded nominally significant causal effects of type 2 diabetes on cathepsin Z and rennin, both known to have roles in the pathophysiological pathways of cardiovascular disease, and of sex hormone-binding globulin on type 2 diabetes. In conclusion, our high-throughput proteomics study replicated previously reported type 2 diabetes-protein associations, and identified new candidate proteins possibly involved in the pathogenesis of type 2 diabetes.

Effect of IGF-I on FFA and glucose metabolism in control and type 2 diabetic subjects

2002 ◽  
Vol 282 (6) ◽  
pp. E1360-E1368 ◽  
Author(s):  
Thongchai Pratipanawatr ◽  
Wilailak Pratipanawatr ◽  
Clifford Rosen ◽  
Rachele Berria ◽  
Mandeep Bajaj ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Glucose Production ◽  
Endogenous Glucose Production ◽  
Glucose Disposal ◽  
Insulin Resistant ◽  
Control Subjects ◽  
Igf I ◽  
Plasma Ffa ◽  
Type 2 Diabetic

The effects of insulin-like growth factor I (IGF-I) and insulin on free fatty acid (FFA) and glucose metabolism were compared in eight control and eight type 2 diabetic subjects, who received a two-step euglycemic hyperinsulinemic (0.25 and 0.5 mU · kg−1 · min−1) clamp and a two-step euglycemic IGF-I (26 and 52 pmol · kg−1 · min−1) clamp with [3-3H]glucose, [1-14C]palmitate, and indirect calorimetry. The insulin and IGF-I infusion rates were chosen to augment glucose disposal (Rd) to a similar extent in control subjects. In type 2 diabetic subjects, stimulation of Rd (second clamp step) in response to both insulin and IGF-I was reduced by ∼40–50% compared with control subjects. In control subjects, insulin was more effective than IGF-I in suppressing endogenous glucose production (EGP) during both clamp steps. In type 2 diabetic subjects, insulin-mediated suppression of EGP was impaired, whereas EGP suppression by IGF-I was similar to that of controls. In both control and diabetic subjects, IGF-I-mediated suppression of plasma FFA concentration and inhibition of FFA turnover were markedly impaired compared with insulin ( P < 0.01–0.001). During the second IGF-I clamp step, suppression of plasma FFA concentration and FFA turnover was impaired in diabetic vs. control subjects ( P < 0.05–0.01). Conclusions: 1) IGF-I is less effective than insulin in suppressing EGP and FFA turnover; 2) insulin-resistant type 2 diabetic subjects also exhibit IGF-I resistance in skeletal muscle. However, suppression of EGP by IGF-I is not impaired in diabetic individuals, indicating normal hepatic sensitivity to IGF-I.

Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes

2006 ◽  
Vol 34 (5) ◽  
pp. 798-801 ◽  
Author(s):  
X. Fang ◽  
G. Sweeney
Keyword(s):  
Glucose Production ◽  
Metabolic Effects ◽  
Globular Domain ◽  
Insulin Mimetic ◽  
Receptor Isoforms ◽  
Molecular Events ◽  
Obesity And Diabetes ◽  
Insulin Dependent ◽  
Increased Sensitivity

Nutritional control of molecular events has become of great interest given the increased incidence of diet-induced obesity, and consequently Type 2 (non-insulin-dependent) diabetes, in recent years. The altered adipose tissue content in obese individuals results in an altered profile of circulating adipokines, and here we focus on adiponectin, whose circulating levels decrease in obese individuals. Adiponectin is a 30 kDa protein but circulates primarily as hexameric, oligomeric and, to a lesser extent, trimeric forms. Full-length adiponectin can also be cleaved to produce a fragment containing the globular domain that exerts potent metabolic effects. Adiponectin has insulin-mimetic and -sensitizing actions including stimulation of glucose uptake in skeletal muscle and suppression of glucose production in liver. Hence, adiponectin has attracted great interest as an antidiabetic agent. Adiponectin acts via two receptor isoforms, AdipoR1 (adiponectin receptor 1) and AdipoR2, which have distinct tissue distributions and affinities for recognition of the various adiponectin forms. Expression of AdipoR isoforms can be regulated by hyperinsulinaemia and hyperglycaemia with the consequence of increased sensitivity or resistance to specific forms of adiponectin. In summary, regulation of adiponectin or AdipoR expression may be of great importance in the development of metabolic perturbations characteristic of Type 2 diabetes in obese individuals.

scholarly journals High-Throughput Approaches onto Uncover (Epi)Genomic Architecture of Type 2 Diabetes

Genes ◽  
2018 ◽  
Vol 9 (8) ◽  
pp. 374 ◽  
Author(s):  
Anna Dziewulska ◽  
Aneta Dobosz ◽  
Agnieszka Dobrzyn
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islets ◽  
High Throughput ◽  
Target Genes ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Genomic Landscape ◽  
A Genome ◽  
Next Generation Sequencing Ngs

Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., TCF7L2, PPARG, KCNJ1, HNF1A, PTPN1, and CDKAL1) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (KCNQ1 and ADRA2A) and population risk of T2D (SLC16A11, TPCN2, PAM, and CCND2). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to α-cells (GCG, IRX2, and IGFBP2) and β-cells (INS, ADCYAP1, INS-IGF2, and MAFA). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in TCF7L2, THADA, KCNQ1, TXNIP, SOCS3, SREBF1, and KLF14 loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.

Sign in / Sign up

Export Citation Format

Share Document