Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery

Gastric bypass surgery (GBP) leads not only to considerable and consistent weight loss but to a number of beneficial metabolic effects, often including a swift remission of type 2 diabetes (T2DM). Increases in the gut hormone GLP-1 are considered central to this effect, although several other mechanism are likely involved. One complication to GBP is post-bariatric hypoglycaemia (PBH), where the individual suffers from episodes of low blood sugar after meals. The mechanism behind this is incompletely understood.  Previous research has reported an attenuation of the counterregulatory response to hypoglycaemia in patients after GBP. Many hypoglycaemic episodes also appear to be asymptomatic. Together, this has led to the hypothesis that GBP and PBH may involve an adaptation to lower blood glucose levels, a lowered glycaemic set point. As much of hypoglycaemia counterregulation involves the central nervous system (CNS), such an adaptation would presumably involve neuroendocrine mechanism. Experimental treatment with GLP-1 receptor agonists (GLP-1RA) has been reported as successful against PBH, which is paradoxical as GLP-1RA stimulate insulin release.  The aim of this thesis is to further explore the metabolic changes after GBP that may influence glycaemic control. In Paper I, euglycaemic-hypoglycaemic clamps were used to assess whether infusion with GLP-1RA affects the counterregulatory response to hypoglycaemia after GBP. In Paper II, normoglycaemic-hypoglycaemic clamps were performed before and after GBP during simultaneous brain imaging with fMRI and FDG-PET techniques, cognitive testing and assessment of counterregulatory hormones. Paper III details the time course of metabolic changes after GBP in patients with previous T2DM with focus on adipose tissue, including gene expression, and possible anti-inflammatory effects. Paper IV approaches the same question as Paper I, this time in the setting of a standardized meal test. All papers include assessment of heart rate variability (HRV) as a potential reflection of autonomic nervous system (ANS) activity.  In Paper I, we do not find indications that GLP-1RA affects counterregulatory hormones, but that it may affect ANS activation during hypoglycaemia. In contrast, Paper IV reports higher cortisol levels with GLP1-RA after a meal, and indications of ANS effects, but no effect on post-prandial glucose levels. Results from Paper II support the hypothesis that GBP attenuates hormonal counterregulatory responses and affects how the CNS responds to hypoglycaemia. In Paper III we report sustained improvements in glucose uptake in adipocytes, potentially indications of decreased low-grade inflammation and signs of transient increases in parasympathetic activity.

Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery

Gastric bypass surgery (GBP) leads not only to considerable and consistent weight loss but to a number of beneficial metabolic effects, often including a swift remission of type 2 diabetes (T2DM). Increases in the gut hormone GLP-1 are considered central to this effect, although several other mechanism are likely involved. One complication to GBP is post-bariatric hypoglycaemia (PBH), where the individual suffers from episodes of low blood sugar after meals. The mechanism behind this is incompletely understood.  Previous research has reported an attenuation of the counterregulatory response to hypoglycaemia in patients after GBP. Many hypoglycaemic episodes also appear to be asymptomatic. Together, this has led to the hypothesis that GBP and PBH may involve an adaptation to lower blood glucose levels, a lowered glycaemic set point. As much of hypoglycaemia counterregulation involves the central nervous system (CNS), such an adaptation would presumably involve neuroendocrine mechanism. Experimental treatment with GLP-1 receptor agonists (GLP-1RA) has been reported as successful against PBH, which is paradoxical as GLP-1RA stimulate insulin release.  The aim of this thesis is to further explore the metabolic changes after GBP that may influence glycaemic control. In Paper I, euglycaemic-hypoglycaemic clamps were used to assess whether infusion with GLP-1RA affects the counterregulatory response to hypoglycaemia after GBP. In Paper II, normoglycaemic-hypoglycaemic clamps were performed before and after GBP during simultaneous brain imaging with fMRI and FDG-PET techniques, cognitive testing and assessment of counterregulatory hormones. Paper III details the time course of metabolic changes after GBP in patients with previous T2DM with focus on adipose tissue, including gene expression, and possible anti-inflammatory effects. Paper IV approaches the same question as Paper I, this time in the setting of a standardized meal test. All papers include assessment of heart rate variability (HRV) as a potential reflection of autonomic nervous system (ANS) activity.  In Paper I, we do not find indications that GLP-1RA affects counterregulatory hormones, but that it may affect ANS activation during hypoglycaemia. In contrast, Paper IV reports higher cortisol levels with GLP1-RA after a meal, and indications of ANS effects, but no effect on post-prandial glucose levels. Results from Paper II support the hypothesis that GBP attenuates hormonal counterregulatory responses and affects how the CNS responds to hypoglycaemia. In Paper III we report sustained improvements in glucose uptake in adipocytes, potentially indications of decreased low-grade inflammation and signs of transient increases in parasympathetic activity.

Anastomotic Strictures After Roux-en-Y Gastric Bypass : a Cohort Study from the Scandinavian Obesity Surgery Registry

BackgroundRoux-en-Y gastric bypass (RYGB) is the most common bariatric procedure worldwide. Anastomotic stricture is a known complication of RYGB. The aim was to explore the incidence and outcomes of strictures within the Scandinavian Obesity Surgery Registry (SOReg).MethodSOReg included prospective data from 36,362 patients undergoing bariatric surgery in the years 2007–2013. Outcomes were recorded at 30-day and at 1-year follow-up according to the standard SOReg routine. The medical charts of patients suffering from stricture after RYGB were requested and assessed.SettingNational bariatric surgery registryResultsAnastomotic stricture within 1 year of surgery was confirmed in 101 patients representing an incidence of 0.3%. Risk factors for stricture were patient age above 60 years (odds ratio (OR), 6.2 95% confidence interval (CI) 2.7–14.3), circular stapled gastrojejunostomy (OR 2.7, 95% CI 1.4–5.5), postoperative anastomotic leak (OR 8.9 95%, CI 4.7–17.0), and marginal ulcer (OR 30.0, 95% CI 19.2–47.0). Seventy-five percent of the strictures were diagnosed within 70 days of surgery. Two dilatations or less was sufficient to successfully treat 50% of patients. Ten pecent of patients developed perforation during dilatation, and the risk of perforating at each dilatation was 3.8%. Perforation required surgery in six cases but there was no mortality. Strictures in SOReg may be underreported, which could explain the low incidence in the study.ConclusionMost strictures present within 2 months and are successfully treated with two dilatations or less. Dilating a strictured gastrojejunostomy entails a risk of perforation (3.8%).</p