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Objective: Extracellular microRNAs (miRNAs) represent functional biomarkers for obesity and related disorders; this study investigated plasma miRNAs in insulin resistance phenotypes in obesity., Methods: One hundred seventy-five miRNAs were analyzed in females with obesity (insulin sensitivity, n = 11; insulin resistance, n = 19; type 2 diabetes, n = 15) and without obesity (n = 12). Correlations between miRNA level and clinical parameters and levels of 15 miRNAs in a murine obesity model were investigated., Results: One hundred six miRNAs were significantly (adjusted P ≤ 0.05) different between controls and at least one obesity phenotype, including miRNAs with the following attributes: previously reported roles in obesity and altered circulating levels (e.g., miR-122, miR-192); known roles in obesity but no reported changes in circulating levels (e.g., miR-378a); and no current reported role in, or association with, obesity (e.g., miR-28-5p, miR-374b, miR-32). The miRNAs in the latter group were found to be associated with extracellular vesicles. Forty-eight miRNAs showed significant correlations with clinical parameters; stepwise regression retained let-7b, miR-144-5p, miR-34a, and miR-532-5p in a model predictive of insulin resistance (R 2  = 0.57, P = 7.5 × 10 -8 ). Both miR-378a and miR-122 were perturbed in metabolically relevant tissues in a murine model of obesity., Conclusions: This study expands on the role of extracellular miRNAs in insulin-resistant phenotypes of obesity and identifies candidate miRNAs not previously associated with obesity., (© 2017 The Obesity Society.)

Type 2 diabetes mellitus (T2DM) results from a combination of progressive insulin resistance and loss of pancreatic beta cell function and/or mass. Insulin signalling occurs through the insulin receptor, (INSR) which is alternatively spliced into two isoforms: INSRA (-exon 11) and INSRB (+exon 11). Because the INSR isoforms have different functional characteristics, their relative expression ratio has been implicated in the pathogenesis of insulin resistance and T2DM. We studied levels of INSR isoform mRNA in liver samples taken from 46 individuals with or without T2DM at Roux-en-Y (RYGB) surgery, and on average 17 (± 5.6) months later in 16 of the same individuals (8 diabetic and non-diabetic patients). INSRA or INSRB was also overexpressed in HepG2 cells to ascertain their effect on AKT phosphorylation and PCK1 expression as markers of insulin-mediated metabolic signalling. We found the INSRB:A isoform ratio was reduced in individuals with T2DM in comparison to those with normal glucose tolerance and normalised with remission of diabetes. The INSRB:A ratio increased due to a reduction in the alternatively spliced INSRA isoform following remission of diabetes. Overexpressing INSRA isoform in HepG2 hepatoma cells reduced inhibition of PCK1 transcription and did not increase AKT phosphorylation in response to insulin load compared to the effect of overexpressing the B isoform. Data presented here revitalizes the role of the INSR isoforms in the pathogenesis of T2DM, and suggests that an abrogated INSRB:A ratio that favours the INSRA isoform may negatively impact insulin-mediated metabolic signalling.

Background: Type 2 diabetes mellitus (T2DM) is a progressive disease resulting from increasing insulin resistance and reduced pancreatic β-cell insulin secretion. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) inhibits insulin signalling and may contribute to the pathogenesis of T2DM. Others have found elevated ENPP1 levels in muscle, fat, and skin tissues from insulin resistant individuals, but similar data on liver ENPP1 is lacking. The purpose of this study was to compare expression and protein concentrations of ENPP1 in liver between patients with and without T2DM., Methods: Roux-en-Y gastric bypass surgery (RYGB) results in remission of insulin resistance and T2DM thus presenting an opportunity to examine some critical aspects of these conditions. We measured liver ENPP1 gene and protein expression in individuals with or without T2DM at RYGB and on average 17 (±5.6) months later., Results: We found liver ENPP1 protein abundance was lower in individuals with T2DM than in those with normal glucose tolerance, and increased after RYGB surgery in those individuals who had remission of T2DM. ENPP1 positively correlated with insulin sensitivity at the liver (as measured by HOMA-IR), which is contrary to what others have reported in other insulin target tissues., Conclusions: Liver ENPP1 expression in T2DM is the reverse of that expected based on expression in other tissues and is likely due to the unique role the liver has in insulin clearance. The work presented here adds another dimension to the role of ENPP1, and supports the hypothesis that ENPP1 may act as a natural modulator of insulin signalling in the liver.

Background: Severely obese type 2 diabetics who undergo Roux-en Y gastric bypass surgery have significant improvements in glycaemic control. Little work has been undertaken to establish the independent predictors of such resolution or to develop a predictive model. The aim of this study was to develop a mathematical model and establish independent predictors for the resolution of diabetes., Methods: A consecutive sample of 130 severely obese type 2 diabetics who underwent gastric bypass surgery for weight loss from November 1997 to May 2007 with prospective pre-operative documentation of biochemical and clinical measurements was followed up over 12 months. Logistic discrimination analysis was undertaken to identify those variables with independent predictive value and to develop a predictive model for resolution of type 2 diabetes. Consecutive samples of 130 patients with body mass index (BMI) ≥ 35 with type 2 diabetes were selected. One hundred and twenty-seven patients completed the study with a sufficient data set. Patients were deemed unresolved if (1) diabetic medication was still required after surgery; (2) if fasting plasma glucose (FPG) remained >7 mmol/L; or (3) HbA1c remained >7%., Results: Resolution of diabetes was seen in 84%, while diabetes remained but was improved in 16% of patients. Resolution was rapid and sustained with 74% of those on medication before surgery being able to discontinue this by the time of discharge 6 days following surgery. Five pre-operative variables were found to have independent predictive value for resolution of diabetes, including BMI, HbA1c, FPG, hypertension and requirement for insulin. Two models have been proposed for prediction of diabetes resolution, each with 86% correct classification in this cohort of patients., Conclusions: Type 2 diabetes resolves in a very high percentage of patients undergoing gastric bypass surgery for severe obesity. The key predictive variables include pre-operative BMI, HbA1c, FPG, the presence of hypertension and diabetic status.

Background: In 2008, Troy et al. hypothesised that under fasting conditions, intestinal gluconeogenesis generates glucose levels in the portal vein which trigger the portal sensor to change insulin resistance and that this mechanism contributes to the effects of Roux-en-Y gastric bypass (RYGB) surgery on type 2 diabetes mellitus (T2DM). In a recent paper, Kashyap et al. (Int J Obes 34(3):426-471, 2010) cited this hypothesis as a potential explanation for the early changes in insulin sensitivity and beta cell function seen after RYGB. We proposed a study to examine this possibility., Methods: We simultaneously sampled fasting portal venous blood and central venous blood in 28 patients (eight diabetics and 20 non-diabetics) before and again six days after RYGB surgery in morbidly obese patients, for measurement of glucose levels., Results: We found no significant difference in the glucose levels from the two sites either before or after RYGB in diabetic patients and a small, but significant difference in the post-operative glucose levels from non-diabetic patients (4.2 vs 4.0 mM, p < 0.0001)., Conclusions: Direct simultaneous measurement of fasting glucose in portal and central venous blood before and 6 days after RYGB provides no evidence to support the hypothesis that intestinal gluconeogenesis contributes to the resolution of T2DM seen after RYGB.

Background: Gastric bypass has repeatedly been shown to improve and even cure type 2 diabetes by substantially improving insulin resistance. The mechanism by which it achieves this is not currently known, but some have hypothesized that there may be important humoral effects brought about by the bypass of the stomach, duodenum or proximal jejunum. A better understanding of the time course of the changes in insulin resistance after surgery might assist our understanding of potential mechanisms., Methods: Intravenous glucose tolerance tests (IVGTT) were performed in 26 severely obese patients on the morning of gastric bypass surgery and again 6 days later. In addition insulin resistance was assessed in 71 patients undergoing gastric bypass surgery by the homeostasis model assessment (HOMA) method before surgery, and again at 6 days, 3, 6, 9, and 12 months. Patients were divided into 3 groups for analysis: diabetics, impaired glucose tolerance and normal glucose tolerance., Results: All 3 groups of patients were noted to have insulin resistance prior to surgery. This was greatest in the diabetic patients, as indicated by HOMA. There was marked loss of/improvement in insulin resistance within 6 days of gastric bypass by both IVGTT and HOMA methods in all groups, which was maintained over the 12-month period. The study included 31 diabetic patients, of whom only 3 required medication following hospital discharge., Conclusion: The changes in insulin resistance seen after gastric bypass, which are responsible for the resolution or improvement of type 2 diabetes occur within 6 days of the surgery, before any appreciable weight loss has occurred. This finding has implications for our understanding of the mechanism of insulin resistance in severely obese patients and is consistent with a humoral mechanism emanating from the GI tract.