Showing papers by "Geltrude Mingrone published in 2016"

Clinical Outcomes of Metabolic Surgery: Efficacy of Glycemic Control, Weight Loss, and Remission of Diabetes

Abstract: Since the 2007 Diabetes Surgery Summit in Rome, Italy, and the subsequent publishing of the world’s first guidelines for the surgical treatment of type 2 diabetes (T2D), much new evidence regarding the efficacy and safety of metabolic surgery has emerged. Additional observational cohort studies support the superior effects of surgery over medical treatment with respect to glycemic control, weight loss, and even reduction in mortality and microvascular complications associated with T2D. Furthermore, new safety data suggest that the perioperative morbidity and mortality of metabolic surgery (5% and 0.3%, respectively) are now similar to that of common low-risk procedures, such as cholecystectomy and hysterectomy. The largest advance, however, has been the completion of 11 randomized controlled trials from around the globe that compare surgery with medical treatment of T2D. These studies with follow-up duration of 1–5 years involve nearly 800 patients without surgical mortality and with major complication rates of less than 5% and a reoperation rate of 8%. All but 1 of the 11 randomized controlled trials have shown the superiority of surgery over medical management at achieving remission or glycemic improvement. Surgery was also superior to medical treatment with respect to improving cardiovascular risk factors, such as weight loss and dyslipidemia, while reducing medication burden. This new efficacy and safety evidence should help guide physicians across the globe to the appropriate use of surgery as an effective treatment for patients suffering from T2D and obesity.

Endoscopic Duodenal Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim Analysis From the First-in-Human Proof-of-Concept Study

Abstract: OBJECTIVE To assess procedural safety and glycemic indices at 6 months in a first-in-human study of duodenal mucosal resurfacing (DMR), a novel, minimally invasive, upper endoscopic procedure involving hydrothermal ablation of the duodenal mucosa, in patients with type 2 diabetes and HbA1c ≥7.5% (58 mmol/mol) on one or more oral antidiabetic agents. RESEARCH DESIGN AND METHODS Using novel balloon catheters, DMR was conducted on varying lengths of duodenum in anesthetized patients at a single medical center. RESULTS A total of 39 patients with type 2 diabetes (screening HbA1c 9.5% [80 mmol/mol]; BMI 31 kg/m2) were treated and included in the interim efficacy analysis: 28 had a long duodenal segment ablated (LS; ∼9.3 cm treated) and 11 had a short segment ablated (SS; ∼3.4 cm treated). Overall, DMR was well tolerated with minimal gastrointestinal symptoms postprocedure. Three patients experienced duodenal stenosis treated successfully by balloon dilation. HbA1c was reduced by 1.2% at 6 months in the full cohort (P CONCLUSIONS Single-procedure DMR elicits a clinically significant improvement in hyperglycemia in patients with type 2 diabetes in the short-term, with acceptable safety and tolerability. Long-term safety, efficacy, and durability and possible mechanisms of action require further investigation.

Determinants of Diabetes Remission and Glycemic Control After Bariatric Surgery

Abstract: OBJECTIVE Eligibility criteria for bariatric surgery in diabetes include BMI ≥35 kg/m2 and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified. RESEARCH DESIGN AND METHODS Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD). RESULTS Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission ( P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders. CONCLUSIONS Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI.

Insulin resistance, microbiota, and fat distribution changes by a new model of vertical sleeve gastrectomy in obese rats

Abstract: Metabolic surgery improves insulin resistance and type 2 diabetes possibly because of weight loss. We performed a novel sleeve gastrectomy in rats that resects ∼80% of the glandular portion, leaving the forestomach almost intact (glandular gastrectomy [GG]) and compared subsequent metabolic remodeling with a sham operation. GG did not affect body weight, at least after 10 weeks; improved hepatic and peripheral insulin sensitivity likely through increased Akt, glycogen synthase kinase 3, and AMPK phosphorylation; and reduced ectopic fat deposition and hepatic glycogen overaccumulation. Body adipose tissue was redistributed, with reduction of intraabdominal fat. We found a reduction of circulating ghrelin levels, increased GLP-1 plasma concentration, and remodeling of gut microbiome diversity characterized by a lower relative abundance of Ruminococcus and a higher relative abundance of Lactobacillus and Collinsella These data suggest that at least in rat, the glandular stomach plays a central role in the improvement of insulin resistance, even if obesity persists. GG provides a new model of the metabolically healthy obese phenotype.

Bariatric surgery versus non-surgical treatment for obesity

Abstract: STUDY QUESTION What are the summary effects of bariatric surgery compared with non-surgical treatment for obesity on body weight loss, comorbidities, adverse events, and quality of life? SUMMARY ANSWER Bariatric surgery is more effective in inducing body weight loss and remission of type 2 diabetes and metabolic syndrome after a maximal follow-up of 2 years, no cardiovascular events or deaths were reported after bariatric surgery, and the most common adverse events after bariatric surgery were iron deficiency anaemia and reoperations.

Short-Term Effects of Laparoscopic Adjustable Gastric Banding Versus Roux-en-Y Gastric Bypass

Abstract: OBJECTIVE Bariatric surgery has been shown to have important long-term metabolic effects resulting in enhanced insulin sensitivity and improved glucose tolerance in patients with type 2 diabetes. The contribution of reduced caloric intake to these beneficial effects of surgery remains unclear. The aim of this study was to compare the short-term effects (1 week) of bariatric surgical procedures with a very low caloric intake (VLCI) on insulin sensitivity (IS) and insulin secretion (ISR) in nondiabetic obese subjects. RESEARCH DESIGN AND METHODS Twenty obese patients without diabetes (BMI 44.2 ± 0.7 kg/m2) were admitted to the clinic for 1 week. At baseline and 1 week after VLCI (600 kcal/day), subjects received a hyperinsulinemic-euglycemic clamp with tracer infusion to quantify endogenous glucose production (EGP), lipolysis (rate of appearance of glycerol [RaGlycerol]), peripheral insulin sensitivity (insulin-stimulated glucose disposal [M value] divided by the steady-state plasma insulin concentration [M/I]), hepatic insulin sensitivity (Hep-IS [= 1/(EGP × insulin)]), and adipose insulin sensitivity (Adipo-IS [= 1/(RaGlycerol × insulin)]). An intravenous glucose bolus was administered at the end of the insulin clamp to measure ISR and β-cell function (disposition index [DI]). Approximately 3 months later, patients were admitted for laparoscopic adjustable gastric banding (LAGB) (n = 10) or Roux-en-Y gastric bypass (RYGB) (n = 10), and restudied 1 week after surgery under the same caloric regimen (600 kcal/day). RESULTS After 1 week of VLCI, patients lost 2.1 kg without significant changes in Hep-IS, Adipo-IS, M/I, or DI. RYGB and LAGB led to greater weight loss (5.5 and 5.2 kg, respectively), and to significant improvement in Hep-IS, EGP, and lipolysis. Only RYGB improved Adipo-IS and M/I. No change in ISR or DI was observed in either surgical group. CONCLUSIONS Bariatric surgery improves IS within 1 week. These metabolic effects were independent of caloric intake and more pronounced after RYGB compared with LAGB.

Changes in insulin sensitivity and secretion after sleeve gastrectomy.

Abstract: Background Sleeve gastrectomy is indicated for the treatment of obesity and related co-morbidity including diabetes. The dynamic changes in insulin secretion and sensitivity after sleeve gastrectomy are unknown. Methods Whole-body insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique, and insulin secretion by C-peptide deconvolution after an oral glucose tolerance test (OGTT), before and 3, 6 and 12 months after sleeve gastrectomy in morbidly obese subjects. The time course of glucagon-like peptide (GLP) 1, as a marker of insulin secretion following OGTT, was also assessed. Results Ten patients were included in the study. Median (range) baseline insulin sensitivity (M-value) increased from 84·0 (20·2–131·4) mmol per kg per min at baseline to 122·8 (99·0–179·3) mmol per kg per min at 12 months after surgery (P = 0·015). Fasting insulin sensitivity, measured by homeostatic model assessment of insulin resistance, which represents a surrogate index of hepatic insulin resistance, decreased from 3·3 (1·9–5·5) to 0·7 (0·5–1·1) mg/dl·µunits/ml (P < 0·001). Total insulin secretion, measured as incremental area under the curve (AUC), after OGTT decreased from 360·4 (347·9–548·0) to 190·1 (10·1–252·0) mmol/l·180 min at 12 months (P = 0·011). The AUC for GLP-1 increased from 258·5 (97·5–552·6) to 5531·8 (4143·0–7540·9) pmol/l·180 min at 12 months after sleeve gastrectomy (P < 0·001). In multiple regression analysis, 51 per cent of the M-value variability was explained by GLP-1 secretion. Conclusion Sleeve gastrectomy improved insulin sensitivity and reduced insulin secretion within 6 months after surgery. Although there was a correlation between insulin sensitivity and bodyweight, the major driver of the improvement in insulin sensitivity was GLP-1 secretion.

Insulin Signaling in Insulin Resistance States and Cancer: A Modeling Analysis.

Abstract: Insulin resistance is the common denominator of several diseases including type 2 diabetes and cancer, and investigating the mechanisms responsible for insulin signaling impairment is of primary importance. A mathematical model of the insulin signaling network (ISN) is proposed and used to investigate the dose-response curves of components of this network. Experimental data of C2C12 myoblasts with phosphatase and tensin homologue (PTEN) suppressed and data of L6 myotubes with induced insulin resistance have been analyzed by the model. We focused particularly on single and double Akt phosphorylation and pointed out insulin signaling changes related to insulin resistance. Moreover, a new characterization of the upstream signaling of the mammalian target of rapamycin complex 2 (mTORC2) is presented. As it is widely recognized that ISN proteins have a crucial role also in cell proliferation and death, the ISN model was linked to a cell population model and applied to data of a cell line of acute myeloid leukemia treated with a mammalian target of rapamycin inhibitor with antitumor activity. The analysis revealed simple relationships among the concentrations of ISN proteins and the parameters of the cell population model that characterize cell cycle progression and cell death.

Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

Abstract: Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

How to Choose the Best Metabolic Procedure

Abstract: Bariatric/metabolic surgery has proven to be effective in inducing and maintaining diabetes remission—although with a percentage of patients undergoing hyperglycemia relapse—weight loss, and improvement of the cardiovascular risk. It is, however, associated with mortality, although low, and early and late complications. In particular, metabolic complications are related to vitamin deficiency due to the erratic absorption of the supplemented vitamins and to the unpredictable compliance of patients to vitamin and trace element supplementation. In addition, often, the general practitioners and even the specialists are unaware of the clinical effects of metabolic dysfunction following malabsorptive surgery. The choice of the surgical procedure should be the balance between benefits and risks. Our review addresses this important question trying to give some suggestions.

Original article Early effect of Roux-en-Y gastric bypass on insulin sensitivity and signaling

Abstract: Background: A large body of literature indicates the rapidity with which Roux-en-Y gastric bypass (RYGB) improves glycemic control. However, the underlying physiologic mechanisms are still a matter of debate. Setting: Catholic University, School of Medicine, Rome, Italy. Methods: Ten morbidly obese patients, before and 4 weeks after RYGB, and 10 healthy controls were studied. We measured insulin sensitivity as the homeostasis model assessment–estimated insulin resistance (HOMA-IR) and by the euglycemic hyperinsulinemic clamp, and phosphorylation of protein kinase B (Akt) on Ser473 and Thr308 and of GSK3 α-β on Ser 9 and Ser21 in skeletal muscle biopsy specimens by Western blot analysis. Results: Obese patients before RYGB displayed reduced insulin sensitivity (M value) and clearance and increased fasting Akt phosphorylation on Ser473 compared with controls. M significantly increased after surgery (from 2.6 0.6 to 2.8 0.7 mg/kg fat free mass/min, P ¼ .026) but remained far below the values in controls (10.0 3.8 mg/kg fat free mass/min, P o .001). Insulin clearance increased from 453.5 117.5 to 555.2 61.6 (P ¼ .00076), becoming similar to that of controls 582.2 59.0 mU/m 2 /min. HOMA-IR decreased from 4.1 0.07 to 2.3 0.5 (P ¼ .004), becoming comparable with controls (2.2 0.9). The hyperphosphorylation of Akt on Ser473 observed at fasting before RYGB was significantly reduced thereafter, becoming similar to that of healthy controls; the other phosphorylation states remained unchanged. Conclusions: Following RYGB, we found a prompt improvement of hepatic insulin resistance with normalization of hepatic insulin clearance and a small amelioration of whole-body insulin sensitivity. The supranormal levels of Akt Ser473 observed at fast in the skeletal muscle tissue at baseline were normalized after RYGB, and their changes correlated with those of both hepatic and peripheral insulin resistance. Although other mechanisms of action, such as the effect of weight loss and reduced food intake, cannot be excluded, the reduction of muscle Akt hyperphosphorylation on the serine residue can play a role in the early improvement of insulin