Adrian T. Billeter

Nitrosative stress but not glycemic parameters correlate with improved neuropathy in nonseverely obese diabetic patients after Roux-Y gastric bypass

BACKGROUND Diabetic neuropathy is common in type 2 diabetic patients (T2DM) but tight glycemic control does not improve the symptoms. In contrast, Roux-Y gastric bypass (RYGB) has a positive effect on active neuropathic symptoms, independent from glycemic control. The purpose of the present study was to identify potential mechanisms of improved diabetic neuropathic symptoms after RYGB. METHODS A prospective cohort of 20 patients with insulin-dependent T2DM and BMI < 35 kg/m(2) were treated with RYGB. Nineteen patients had complete follow-up. Fasting glucose, HbA1c (glycated hemoglobin), markers for nitrosative, carbonyl, and oxidative stress (nitrotyrosine, carboxylated-lysine (CML), methylglyoxal, oxidized low-density-lipoprotein (oxLDL)) as well as Neuropeptid Y and Neurokinin A were investigated over 12 months. Neuropathy was assessed using the Neuropathy Deficit Score (NDS). RESULTS The preoperative NDS improved within twelve months (5.1 ± 0.6 to 2.6 ± 0.4, P = .010). Fasting glucose and HbA1c also improved compared to preoperative values (201.1 ± 16.6 mg/dL to 128 ± 8.7 mg/dL, P = .004 and 8.5 ± 0.3% (53 ± 3.3 mmol/mol) to 7 ± 0.3% (67 ± 3.3 mmol/mol), P = .001, respectively). Nitrotyrosine, CML, and methylglyoxal all 3 decreased postoperatively (1067.3 ± 266.9 nM to 355.8 ± 36.4 nM, P = .003; 257.1 ± 10.2 ng/ml to 215.3 ± 18.3 ng/ml, P = .039; 402.3 ± 3.9 nM to 163.4 ± 10.3 nM, P = .002). OxLDL remained unchanged. Fasting glucose and HbA1c did not correlate with improved neuropathy. The decrease in nitrotyrosine correlated with improvement in the NDS after 6 and twelve months (r = .9, P < .001 and r = .68, P = .03). The decrease in methylglyoxal after 6 months correlated with decrease in NDS after twelve months (r = 0.897, P = .003). CONCLUSION RYGB seems to improve oxidative, nitrosative and carbonyl stress, known to have a causal role in diabetic neuropathy.

Malabsorption as a Therapeutic Approach in Bariatric Surgery

Background: The increasing prevalence of obese patients will lead to a more frequent use of bariatric procedures in the future. Compared to conservative medical therapy, bariatric procedures achieve greater weight loss and superior control of comorbidities, resulting in improved overall mortality. Methods: A search for current literature regarding mechanisms, indications, and outcomes of bariatric surgery was performed. Results: In order to care for patients after bariatric surgery properly, it is important to understand its mechanisms of action and effects on gastrointestinal physiology. Recent investigations indicate that the beneficial effects of bariatric procedures are much more complex than simply limiting food intake or an associated malabsorption. Changes in gastrointestinal hormone secretion, energy expenditure, intestinal bacterial colonization, bile acid metabolism, and epigenetic modifications resulting in altered gene expression are likely responsible for the majority of the beneficial effects of bariatric surgery. Malabsorptive bariatric procedures divert the flow of bile and pancreatic enzymes from food and therefore limit the digestion and absorption of nutrients, resulting in reduced calorie intake and subsequent weight loss. Essential micronutrients such as vitamins and trace elements are also absorbed to a lesser extent, potentially leading to severe side effects. Conclusion: To prevent malnutrition, dietary supplementation and regular control of micronutrient levels are mandatory for patients undergoing malabsorptive bariatric procedures, in whom the fat-soluble vitamins A and D are commonly deficient.

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis

Transient inflammation in adipose tissue triggers Jak-TGFβ signaling to promote beige adipocyte differentiation. Committing progenitors to adipogenesis Promoting the “browning” of white fat has been proposed as a strategy to combat obesity. Beige adipocytes, which are intermediate between fat-storing white adipocytes and thermogenic brown adipocytes, can emerge from the differentiation of adipocyte progenitors in adipose tissue in response to β3-adrenergic stimulation. Using primary human and mouse cells and ex vivo mouse models, Babaei et al. (see also the Focus by Sun et al.) found that the Jak family of kinases promoted the commitment of adipocyte progenitors to beige adipogenesis. Through the downstream transcription factor Stat3, Jak inhibited TGFβ signaling and prevented adipocyte progenitors from differentiating into smooth muscle cells. β3-Adrenergic stimulation of lipolysis, which transiently triggers inflammation, induced the production of the cytokines IL-6 and IL-11, which activated the Jak/Stat3 pathway. These results delineate a pathway that is activated by transient inflammation in adipose tissue that steers adipocyte progenitors toward differentiation into a thermogenically active form of fat. The transient activation of inflammatory networks is required for adipose tissue remodeling including the “browning” of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

Meta‐analysis of metabolic surgery versus medical treatment for microvascular complications in patients with type 2 diabetes mellitus

This study aimed to examine the effect of metabolic surgery on pre‐existing and future microvascular complications in patients with type 2 diabetes mellitus (T2DM) in comparison with medical treatment. Although metabolic surgery is the most effective treatment for obese patients with T2DM regarding glycaemic control, it is unclear whether the incidence or severity of microvascular complications is reduced.

Meta‐analysis of immunonutrition in major abdominal surgery

The objective of this study was to evaluate the potential benefits of immunonutrition in major abdominal surgery with special regard to subgroups and influence of bias.

Evaluation of the LigaSure ™ Vessel Sealing System for bowel transection and intestinal anastomosis—an experimental study in a porcine model

BackgroundThe purpose of the present study is to assess the value of the LigaSure™ Vessel Sealing System (LVSS) as a means for bowel transection and intestinal anastomosis.MethodsWe compared the LVSS for (1) transecting bowel and (2) creation of an intestinal anastomosis with standard methods such as stapler (S) and hand-sewn (HS) in a porcine model. For each study arm, i.e., bowel transection and anastomosis creation, both the small bowel and colon were examined. In total, ten transections and ten anastomoses were performed for each. Burst and anastomotic leak pressures were compared.ResultsIn the study arm 1, LVSS achieved lowest burst pressures in both small bowel (LVSS 39.8 ± 3.6 mmHg, S 81.9 ± 3.9, HS 111.9 ± 14.7 mmHg, p < 0.0001) and colon transections (LVSS 21.5 ± 2.6 mmHg, S 79.5 ± 4.9, HS 91.0 ± 5.2 mmHg, p < 0.0001). There was no difference in burst pressures between S and HS in both small bowel and colon transections. In the study arm 2, LVSS showed the lowest anastomotic leak pressures for small bowel (LVSS 26.4 ± 2.6 mmHg, S 52.1 ± 6.2, HS 87.4 ± 7.0 mmHg, p < 0.0001) and colonic anastomoses (LVSS 16.9 ± 1.3 mmHg, S 55.9 ± 4.3, HS 74.4 ± 4.4 mmHg, p < 0.0001). Furthermore, small bowel and colonic anastomoses using S demonstrated significantly lower leak pressures than HS anastomosis p < 0.001 and p = 0.004, respectively.ConclusionsThe LVSS achieves significantly lower burst pressures and anastomotic leak pressures for bowel transection and intestinal anastomosis than S and HS techniques. However, due to the achieved pressure levels of 39.8 ± 3.6 mmHg, LVSS appears to be a sufficient stand-alone method for bowel transection. Whether it can be used to perform intestinal anastomosis warrants further research in a survival model.

Klinische Evidenz der metabolischen Chirurgie

The metabolic effect of bariatric surgery is well-established and is considered to be self-evident in morbidly obese patients with a body mass index (BMI) > 40 kg/m(2). Metabolic surgery performed on patients with obesity grades II (BMI 35-40 kg/m(2)) and I (BMI 30-35 kg/m(2)) according to the World Health Organization (WHO) has increased in recent years; however, the indications for metabolic surgery in obesity grades I and II are currently under debate due to insufficient evidence. In the last 5 years several highly qualified randomized clinical trials have been published which evaluated the effect of metabolic surgery in patients with obesity grades I and II in comparison to conservative therapy. Based on these data the efficacy of metabolic surgery in short-term follow-up (12-36 months) is unquestionable when compared to conservative therapy according to the current guidelines. Besides improved glycemic control and remission of diabetes, metabolic surgery has the potential to have a positive influence on diabetic complications, such as diabetic retinopathy, nephropathy and polyneuropathy, as well as on comorbidities, such as arterial hypertension and dyslipidemia. Future clinical trials should address the long-term (> 36 months) effects of metabolic surgery, patient selection criteria and choice of procedure.

Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context‐specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone‐dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta‐adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.

Clinical evidence for metabolic surgery

The metabolic effect of bariatric surgery is well-established and is considered to be self-evident in morbidly obese patients with a body mass index (BMI) > 40 kg/m(2). Metabolic surgery performed on patients with obesity grades II (BMI 35-40 kg/m(2)) and I (BMI 30-35 kg/m(2)) according to the World Health Organization (WHO) has increased in recent years; however, the indications for metabolic surgery in obesity grades I and II are currently under debate due to insufficient evidence. In the last 5 years several highly qualified randomized clinical trials have been published which evaluated the effect of metabolic surgery in patients with obesity grades I and II in comparison to conservative therapy. Based on these data the efficacy of metabolic surgery in short-term follow-up (12-36 months) is unquestionable when compared to conservative therapy according to the current guidelines. Besides improved glycemic control and remission of diabetes, metabolic surgery has the potential to have a positive influence on diabetic complications, such as diabetic retinopathy, nephropathy and polyneuropathy, as well as on comorbidities, such as arterial hypertension and dyslipidemia. Future clinical trials should address the long-term (> 36 months) effects of metabolic surgery, patient selection criteria and choice of procedure.

Klinische Evidenz der metabolischen Chirurgie@@@Clinical evidence for metabolic surgery

The metabolic effect of bariatric surgery is well-established and is considered to be self-evident in morbidly obese patients with a body mass index (BMI) > 40 kg/m(2). Metabolic surgery performed on patients with obesity grades II (BMI 35-40 kg/m(2)) and I (BMI 30-35 kg/m(2)) according to the World Health Organization (WHO) has increased in recent years; however, the indications for metabolic surgery in obesity grades I and II are currently under debate due to insufficient evidence. In the last 5 years several highly qualified randomized clinical trials have been published which evaluated the effect of metabolic surgery in patients with obesity grades I and II in comparison to conservative therapy. Based on these data the efficacy of metabolic surgery in short-term follow-up (12-36 months) is unquestionable when compared to conservative therapy according to the current guidelines. Besides improved glycemic control and remission of diabetes, metabolic surgery has the potential to have a positive influence on diabetic complications, such as diabetic retinopathy, nephropathy and polyneuropathy, as well as on comorbidities, such as arterial hypertension and dyslipidemia. Future clinical trials should address the long-term (> 36 months) effects of metabolic surgery, patient selection criteria and choice of procedure.