Mikael Ekelund

Islet amyloid polypeptide in the gut and pancreas: Localization, ontogeny and gut motility effects.

The occurrence of islet amyloid polypeptide (IAPP) in the gut and pancreas of several species and during ontogeny of the rat, was studied using immunocytochemistry. Effects of IAPP on rat ileal smooth muscle were assessed in vitro. Islets of most, but not all, species examined, displayed IAPP in insulin cells and, in some species, also in somatostatin- and peptide YY (PYY)-containing cells. In the gut, expression of IAPP varied among species; when present, IAPP was most abundant in the proximal part and co-localized with somatostatin, PYY, gastrin/cholecystokinin, enteroglucagon or serotonin. IAPP was first demonstrated at embryonic day 12 and 16 in islet and gastrointestinal endocrine cells, respectively. IAPP relaxed gut muscle and reduced electrical field stimulation-evoked contractions, presumably by inhibiting acetylcholine release. Thus, IAPP expression in islets is consistent with an important role for IAPP in fuel metabolism; the gastrointestinal expression and motor effects of IAPP suggest that IAPP may modulate gastrointestinal function.

Management of suspected anastomotic leak after bariatric laparoscopic Roux-en-y gastric bypass

Anastomotic leak is one of the most serious complications following bariatric laparoscopic Roux‐en‐Y gastric bypass (LRYGB), and associated with high morbidity rates and prolonged hospital stay. Timely management is of utmost importance for the clinical outcome. This study evaluated the approach to suspected leakage in a high‐volume bariatric surgery unit.

Gastric bypass improves ss-cell function and increases β-cell mass in a porcine model.

The most frequently used and effective treatment for morbid obesity is Roux-en-Y gastric bypass surgery (RYGB), which results in rapid remission of type 2 diabetes in most cases. To what extent this is accounted for by weight loss or other factors remains elusive. To gain insight into these mechanisms, we investigated the effects of RYGB on β-cell function and β-cell mass in the pig, a species highly reminiscent of the human. RYGB was performed using linear staplers during open surgery. Sham-operated pigs were used as controls. Both groups were fed a low-calorie diet for 3 weeks after surgery. Intravenous glucose tolerance tests were performed 2 weeks after surgery. Body weight in RYGB pigs and sham-operated, pair-fed control pigs developed similarly. RYGB pigs displayed improved glycemic control, which was attributed to increases in β-cell mass, islet number, and number of extraislet β-cells. Pancreatic expression of insulin and glucagon was elevated, and cells expressing the glucagon-like peptide 1 receptor were more abundant in RYGB pigs. Our data from a pig model of RYGB emphasize the key role of improved β-cell function and β-cell mass to explain the improved glucose tolerance after RYGB as food intake and body weight remained identical.

Effects of ingestion routes on hormonal and metabolic profiles in gastric-bypassed humans

CONTEXT Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult. OBJECTIVE To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient. DESIGN Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites. RESULTS The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4-2-fold, P < .05) and suppressed fatty acid levels (∼50%, P < .05). CONCLUSIONS These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance.

SIK2 regulates CRTCs, HDAC4 and glucose uptake in adipocytes

ABSTRACT Salt-inducible kinase 2 (SIK2) is an AMP-activated protein kinase (AMPK) related kinase abundantly expressed in adipose tissue. Our aim was to identify molecular targets and functions of SIK2 in adipocytes, and to address the role of PKA-mediated phosphorylation of SIK2 on Ser358. Modulation of SIK2 in adipocytes resulted in altered phosphorylation of CREB-regulated transcription co-activator 2 (CRTC2), CRTC3 and class IIa histone deacetylase 4 (HDAC4). Furthermore, CRTC2, CRTC3, HDAC4 and protein phosphatase 2A (PP2A) interacted with SIK2, and the binding of CRTCs and PP2A to wild-type but not Ser358Ala SIK2, was reduced by cAMP elevation. Silencing of SIK2 resulted in reduced GLUT4 (also known as SLC2A4) protein levels, whereas cells treated with CRTC2 or HDAC4 siRNA displayed increased levels of GLUT4. Overexpression or pharmacological inhibition of SIK2 resulted in increased and decreased glucose uptake, respectively. We also describe a SIK2–CRTC2–HDAC4 pathway and its regulation in human adipocytes, strengthening the physiological relevance of our findings. Collectively, we demonstrate that SIK2 acts directly on CRTC2, CRTC3 and HDAC4, and that the cAMP–PKA pathway reduces the interaction of SIK2 with CRTCs and PP2A. Downstream, SIK2 increases GLUT4 levels and glucose uptake in adipocytes.

Mucosal glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide cell numbers in the super-obese human foregut after gastric bypass

BACKGROUND Super-obesity, a body mass index>50 kg/m(2), is difficult to treat. Many studies have focused on the anatomic changes of the intestines; the physiologic background is not clearly identified. It is established that Roux-en-Y gastric bypass (RYGB) augments secretion of glucagon-like peptide-1 (GLP-1), peptide tyrosine tyrosine (PYY), and insulin, but other aspects of gut hormone cell function in the alimentary limb are unknown. OBJECTIVE To study the effects of laparoscopic RYGB on enteroendocrine cells. SETTING University-affiliated, high-volume bariatric surgery center. METHODS Eighteen nondiabetic patients were drawn from the present study (NCT 01514799), randomizing between biliopancreatic (BP) limbs of either 60 cm (BP60) or 200 cm (BP200). Demographic characteristics did not differ at baseline or 12 months. Pouch and jejunal biopsies were obtained intraoperatively and using endoscopy at 12 months. Mucosal height and density of hormone-producing cell populations were assessed and mRNA expression measured with real-time polymerase chain reaction. RESULTS In perianastomotic jejunum, a 4.9-fold increase in GLP-1 cell density was evident 12 months after RYGB, most pronounced in the BP200-group. The densities of glucose-dependent insulinotropic polypeptide (GIP) cells and PYY immunoreactive cells were doubled after 12 months. GIP mRNA was unaffected, but GLP-1 and PYY mRNA were lower 12 months after RYGB. RYGB had no impact on villi length or density of ghrelin-, cholecystokinin-, neurotensin-, secretin-, or serotonin-producing cells after 12 months. Pouch mucosal height and cell densities of ghrelin-, histamine-, serotonin-, and somatostatin-producing cells remained unaffected by RYGB in both groups. CONCLUSIONS RYGB selectively increased the density of incretin-producing cell populations in the jejunum. This may provide anatomic explanation for the observed increased plasma levels of incretins.

Non-operative management of blunt liver trauma: feasible and safe also in centres with a low trauma incidence.

BACKGROUND AND AIMS Non-operative management (NOM) of blunt liver trauma is currently, if possible, the preferred treatment of choice. The present study evaluates the experience of blunt liver injury in adults in a Swedish university hospital. MATERIAL AND METHODS Forty-six patients with blunt liver trauma were treated from January 1994 through to December 2004. Patient charts were reviewed retrospectively to examine injury severity score (ISS), liver injury grade, diagnostics, treatment and outcome. RESULTS Thirty-five patients (76%) were initially treated non-operatively and 11 (24%) patients had immediate surgery. In four (11%) patients, NOM failed and the patients required surgery 8-72 h after admission. Patients failing non-operative care had a significantly lower systolic blood pressure on admission as compared with patients with successful NOM (P = 0.001). Patients immediately operated upon had higher ISS (P < 0.001) and were haemodynamically unstable to a greater extent (P < 0.001) as compared with patients initially considered for NOM. Operated patients had increased transfusion requirements (P < 0.001), longer total hospital stay (P = 0.011) and stay in the intensive care unit (ICU) unit (P < 0.001) as compared with NOM. One immediately operated and one failed NOM died (total mortality 4%). Seventeen patients in the NOM group were successfully treated without surgery despite the presence of at least one described risk factor. CONCLUSIONS Most patients with blunt liver trauma can be treated without surgery, and non-operative management may be performed even in the presence of established risk factors.

Perforated peptic duodenal ulcer in a paraesophageal hernia--a case report of a rare surgical emergency.

BackgroundParaesophageal hernias are quite common and sometimes feared due to the risk of incarceration and strangulation of any herniated organ. The hereby reported combination of an incarcerated paraesophageal hernia containing a perforated peptic ulcer is extremely rare.Case presentationAn elderly man with multiple medical conditions was admitted due to severe upper abdominal pain. The patient was found to have a paraesophageal hernia and underwent a laparotomy. In the hernia, a perforated benign peptic duodenal ulcer was found. The duodenal defect was over-sewn, the hernial defect was closed and the former hernial cavity was drained by a right-sided chest tube. The patient was discharged one month after surgery and was found to do well at follow-up one month after discharge.ConclusionThis is the first report of a patient surviving the extremely rare and life-threatening combination of a perforated peptic duodenal ulcer in a paraesophageal hernia.

Superantigen activates the gp130 receptor on adipocytes resulting in altered adipocyte metabolism

OBJECTIVE The bacteria Staphylococcus aureus is part of the normal bacterial flora and produces a repertoire of enterotoxins which can cause food poisoning and toxic shock and might contribute to the pathogenesis of inflammatory diseases. These enterotoxins directly cross-link the T cell receptor with MHC class II, activating large amounts of T cells and are therefore called superantigens. It was recently discovered that the superantigen SEA binds to the cytokine receptor gp130. As obesity and type 2 diabetes are highly associated with inflammation of the adipose tissue and gp130 has been shown to play an important role in adipocytes, we wanted to investigate the effect of SEA on adipocyte signaling and function. MATERIALS/METHODS Binding of SEA to gp130 was examined using surface plasmon resonance in a cell free system. Effects of SEA on adipocyte signaling, insulin sensitivity and function were studied using western blotting and biological assays for lipolysis, lipogenesis and glucose uptake. RESULTS We demonstrate that SEA binds to gp130 with a medium affinity. Furthermore, SEA induces phosphorylation of a key downstream target, STAT3, in adipocytes. SEA also inhibits insulin-induced activation of PKB and PKB downstream signaling which was associated with reduced basal and insulin induced glucose uptake, reduced lipogenesis as well as reduced ability of insulin to inhibit lipolysis. CONCLUSIONS SEA inhibits insulin signaling as well as insulin biological responses in adipocytes supporting that bacterial infection might contribute to the development of insulin resistance and type 2 diabetes.

Alterations in cyclic nucleotide phosphodiesterase activities in omental and subcutaneous adipose tissues in human obesity

Objective:To elucidate the activity and expression of cyclic nucleotide phosphodiesterase (PDE) families in omental (OM) and subcutaneous (SC) adipose tissue and adipocytes, and to study alterations in their activity in human obesity.Design:Cross-sectional, translational research study.Patients:In total, 25 obese and 9 non-obese subjects undergoing gastrointestinal surgery participated in the study.Results:Inverse correlations between PDE activities and body mass index (BMI) were seen in both SC and OM adipose tissue. Inverse correlations between total PDE and PDE3 activity and BMI were seen in OM adipocytes but not in SC adipocytes. In both SC and OM adipose tissue of obese patients, total PDE and PDE3 activities were decreased compared with the controls. In SC adipose tissue of Type 2 diabetes (T2D) patients, the PDE activity not inhibitable by PDE3 or PDE4 inhibitors (PDEn) was increased compared with obese non-diabetic patients. In addition to PDE3 and 4 isoforms, PDE7B, PDE9A and PDE10A proteins were also detected in adipose tissue or adipocytes.Conclusions:Multiple PDE families are present in human adipose tissue and their activities are differentially affected by obesity and T2D.