European Society of Coloproctology consensus on the surgical management of intestinal failure in adults.

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells.

AIMS: Caffeic acid, naringenin and quercetin are naturally occurring phenolic compounds (PCs) present in many plants as secondary metabolites. The aim of this study was to investigate their effect on glucose-stimulated insulin secretion (GSIS) in INS-1E cells and to explore their effect on expression of genes involved in ß-cell survival and function under normoglycaemic and glucotoxic conditions. METHODS: For acute studies, INS-1E cells were grown in 11 mM glucose (72 h) and then incubated with the PCs (1 h) with 3.3/16.7 mM glucose; whereas, for chronic studies, the cells were grown in 11 mM glucose (72 h) with/without the PCs, and then incubated with 3.3/16.7 mM glucose (1 h); thereafter, GSIS was measured. For GSIS and gene expression studies (GES) under glucotoxic conditions, two sets of cells were grown in 11/25 mM glucose with/without the PCs (72 h): one was used for GES, using real time RT-PCR, and the other was exposed to 3.3/16.7 mM glucose, followed by measurement of GSIS. RESULTS: The study demonstrated that the PCs can enhance GSIS under hyperglycaemic and glucotoxic conditions in INS-1E cells. Moreover, these compounds can differentially, yet distinctly change the expression profile of genes [Glut2 (glucose transporter 2), Gck (glucokinase), Ins1 (insulin 1), Ins2, Beta2 (neurogenic differentiation protein 1), Pdx1 (pancreatic and duodenal homeobox protein 1), Akt1 (RAC-α serine/threonine-protein kinase encoding gene), Akt2 (RAC-ß serine/threonine-protein kinase encoding gene), Irs1 (insulin receptor substrate 1), Acc1 (acetyl CoA carboxylase 1), Bcl2 (ß-cell lymphoma 2 protein), Bax (Bcl-2 associated X protein), Casp3 (Caspase 3), Hsp70 (heat shock protein 70), and Hsp90] involved in ß-cell stress, survival and function. CONCLUSION: The results indicate that the PCs tested enhance GSIS and glucose sensitivity in INS-1E cells. They also modulate gene expression profiles to improve ß-cell survival and function during glucotoxicity.

Impact of glucagon-like peptide-1 (7-36) amide, isosteviol and 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside on leucine-mediated α-cell dysfunction.

AIM: To investigate the acute and chronic effects of l-leucine on pancreatic α-cell function in vitro. Furthermore, we wanted to explore if glucagon-like peptide-1 (GLP-1), isosteviol (ISV) and 5-aminoimidazole-4-carboxamide 1-ß-d-ribofuranoside (AICAR) counteract changes in α-cell function induced by chronic exposure to leucine. METHODS: Isolated mice islets were incubated with 10 mM leucine for 2 or 72 h. We investigated glucagon and insulin secretion at 2 mM and 16.7 mM glucose. In addition, we cultured clonal α-TC1-6 cells with 5 mM leucine, 5 mM leucine plus GLP-1 (10(-6) M), or ISV (10(-6) M) or AICAR (10(-5) M) at high glucose for 72 h. We measured the glucagon secretion, cholesterol (CHO) and triglyceride (TG) content, cell proliferation as well as gene expression. RESULTS: Ten millimolar of leucine for 2 h significantly stimulated glucagon and insulin secretion both at 2 and 16.7 mM glucose in mice islets. After 72 h incubation with 10 mM leucine the glucagon secretion was enhanced at both 2 and 16.7 mM glucose, whereas the glucose-stimulated insulin secretion (16.7 mM glucose) was inhibited. Chronic exposure to 5 mM leucine increased glucagon secretion, CHO and TG content, cell proliferation and Pcsk2 (p < 0.001), MafB (p < 0.05), Gcg (p < 0.001), Prkaa1 (p < 0.01), Hmgcr (p < 0.001), Srebf2 (p < 0.001), Acaca (p < 0.001), Mtor (p < 0.05) mRNA expression in clonal α-TC1-6 cells. While GLP-1 was cable of reducing glucagon hypersecretion and Pcsk2 (p < 0.05) mRNA expression. ISV and AICAR had no effect on leucine-induced glucagon hypersecretion. CONCLUSIONS: Long-term exposure to leucine induces hypersecretion of glucagon secretion, that is, aminoacidotoxicity and influences some key genes of pancreatic α-cells. Interestingly, GLP-1 counteracts the leucine-induced α-cell dysfunction.

Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome.

BACKGROUND AND AIMS: Teduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid and nutrient absorption in patients with short bowel syndrome (SBS). This 24-week placebo-controlled study evaluated the ability of teduglutide to reduce parenteral support in patients with SBS with intestinal failure. METHODS: In 83 patients randomised to receive subcutaneous teduglutide 0.10 mg/kg/day (n = 32), 0.05 mg/kg/day (n = 35) or placebo (n = 16) once daily, parenteral fluids were reduced at 4-week intervals if intestinal fluid absorption (48 h urine volumes) increased ≥ 10%. Responders were subjects who demonstrated reductions of ≥ 20% in parenteral volumes from baseline at weeks 20 and 24. The primary efficacy end point, a graded response score (GRS), took into account higher levels and earlier onset of response, leading to longer duration of response. The intensity of the response was defined as a reduction from baseline in parenteral volume (from 20% to 100%), and the duration of the response was considered the response at weeks 16, 20 and 24. The results were tested according to a step-down procedure starting with the 0.10 mg/kg/day dose. RESULTS: Using the GRS criteria, teduglutide in a dose of 0.10 mg/kg/day did not have a statistically significant effect compared with placebo (8/32 vs 1/16, p=0.16), while teduglutide in a dose of 0.05 mg/kg/day had a significant effect (16/35, p = 0.007). Since parenteral volume reductions were equal (353 ± 475 and 354 ± 334 ml/day), the trend towards higher baseline parenteral volume (1816 ± 1008 vs 1374 ± 639 ml/day, p=0.11) in the 0.10 mg/kg/day group compared with the 0.05 mg/kg/day group may have accounted for this discrepancy. Three teduglutide-treated patients were completely weaned off parenteral support. Serious adverse events were distributed similarly between active treatment groups and placebo. Villus height, plasma citrulline concentration and lean body mass were significantly increased with teduglutide compared with placebo. CONCLUSIONS: Teduglutide was safe, well tolerated, intestinotrophic and suggested pro-absorptive effects facilitating reductions in parenteral support in patients with SBS with intestinal failure. ClinicalTrials.gov number NCT00172185.

Modern treatment of adult short bowel syndrome patients.

By definition, intestinal failure prevails when oral compensation is no longer feasible and parenteral support is necessary to maintain nutritional equilibrium. In the past, conventional treatment has mainly focused on "making the most of what the short bowel syndrome patient still had" by optimizing remnant intestinal function through dietary interventions, antidiarrheals and antisecretory agents. However, modern treatment options are in the near horizon, and the increased understanding of the mediators for intestinal adaptation will lead to the expansion of the limited treatment armamentarium in short bowel syndrome patients with intestinal failure. The clinical meaningfulness and implications of the observed effects of growth hormone, glutamine, glucagon-like peptide 2 (GLP-2) and the dipeptidyl peptidase-4 degradation resistant analog, teduglutide, is presented in this review and balanced against treatment related adverse events and possible unfavourable effects of long-term, possibly lifelong, treatments.

Effects of elevated fatty acid and glucose concentrations on pancreatic islet function in vitro.

AIMS/HYPOTHESIS: The aims of this study were to elucidate long-term effects of increased fatty acids and glucose concentrations on islet hormone secretion, triglyceride (TG) accumulation and fuel metabolism, and to determine the role of insulin on glucagon secretion. METHODS: Isolated normal mouse islets were exposed to palmitate (0.6 mM) in the presence of high glucose (16.7 mM). After 48 h culture, glucagon secretion and content, insulin secretion and content, TG content and glucose oxidation were measured. The impact of etomoxir, an inhibitor of carnitine palmitoyl transferase-1, as well as of insulin, and alterations in gene expression were also investigated. RESULTS: In the presence of palmitate, (i) high glucose caused no statistically significant suppression of glucagon while this was seen in the absence of palmitate; (ii) the insulin response to high glucose was impaired and (iii) an accumulation of TG and a decline in glucose oxidation were detected, whereas the glucagon content remained unchanged. However, etomoxir was capable of reducing glucagon secretion. Addition of exogenous insulin (10(-10)-10(-6) M) failed to restore alpha cell response to normal. Furthermore, 0.6 mM palmitate reduced the mRNA levels of acetyl-CoA carboxylase-1 and sterol regulatory element-binding protein-1c. CONCLUSIONS/INTERPRETATION: In summary, high concentrations of palmitate and glucose cause a relative increase in glucagon secretion, a decline in insulin secretion, a loss of alpha cell sensitivity to glucose and an accumulation of TG. The inability of insulin to suppress glucagon may be because of insulin resistance of alpha cells.

Isosteviol increases insulin sensitivity and changes gene expression of key insulin regulatory genes and transcription factors in islets of the diabetic KKAy mouse.

AIMS: Isosteviol (ISV), a diterpene molecule, is an isomer of the backbone structure of a group of substances with recently proven antidiabetic capabilities in both man and rodents. The aim of this study was to investigate if ISV possesses beneficial effects on the metabolism in the diabetic KKAy mouse and to establish the long-term in vivo effects of ISV on the gene expression profile of key insulin regulatory genes in islets. METHODS: Twenty KKAy mice, aged 5 weeks, were divided into two groups and treated for 9 weeks with either (i) standard chow diet (control) or (ii) chow + 20 mg/kg body weight of ISV. Blood samples were collected before and after intervention and were subsequently analysed. As a non-diabetic control group, 10 normal C57BL mice were fed with standard chow diet. Gene expression was determined in islets by quantitative real-time RT-PCR and Affymetrix microarray. RESULTS: We demonstrated that long-term treatment with ISV improves glucose homeostasis, increases insulin sensitivity, lowers plasma triglycerides and lowers weight in the diabetic KKAy mice. Furthermore, ISV markedly changes the gene expression profile of key insulin regulatory genes GLUT2, Ins1, Ins2, Pdx1/Ipf1, Beta2/Neurod1, Pax6 and 11-beta-HSD-1 and beta-cell transcription factors Nkx2-2, Nkx6-1, C/EBPalpha and FoxA2 in isolated islets of the KKAy mice. CONCLUSIONS: The results indicate that ISV improves glucose and insulin sensitivity as well as improving the lipid profile and upregulates the gene expression of key beta-cell genes, including insulin regulatory transcription factors.

Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels.

Recently, we showed that rebaudioside A potently stimulates the insulin secretion from isolated mouse islets in a dose-, glucose- and Ca(2+)-dependent manner. Little is known about the mechanisms underlying the insulinotropic action of rebaudioside A. The aim of this study was to define the signalling system by which, rebaudioside A acts. Isolated mouse islets were used in the cAMP[(125)I] scintillation proximity assay to measure total cAMP level, and in a luminometric method to measure intracellular ATP and ADP concentrations. Conventional and permeabilized whole-cell configuration of the patch-clamp technique was used to verify the effect of rebaudioside A on ATP-sensitive K(+)-channels from dispersed single beta cells from isolated mouse islets. Insulin was measured by radioimmunoassay from insulinoma MIN6 cells. In the presence of 16.7 mM glucose, the addition of the maximally effective concentration of rebaudioside A (10(-9) M) increased the ATP/ADP ratio significantly, while it did not change the intracellular cAMP level. Rebaudioside A (10(-9) M) and stevioside (10(-6) M) reduced the ATP-sensitive potassium channel (K(ATP)) conductance in a glucose-dependent manner. Moreover, rebaudioside A stimulated the insulin secretion from MIN6 cells in a dose- and glucose-dependent manner. In conclusion, the insulinotropic effect of rebaudioside A is mediated via inhibition of ATP-sensitive K(+)-channels and requires the presence of high glucose. The inhibition of ATP-sensitive K(+)-channels is probably induced by changes in the ATP/ADP ratio. The results indicate that rebaudioside A may offer a distinct therapeutic advantage over sulphonylureas because of less risk of causing hypoglycaemia.

Randomised clinical trial: 2% taurolidine versus 0.9% saline locking in patients on home parenteral nutrition.

BACKGROUND: The catheter lock solutions 2% taurolidine and 0.9% saline are both used to prevent catheter-related bloodstream infections (CRBSIs) in home parenteral nutrition patients. AIMS: To compare the effectiveness and safety of taurolidine and saline. METHODS: This multicentre double-blinded trial randomly assigned home parenteral nutrition patients to use either 2% taurolidine or 0.9% saline for 1 year. Patients were stratified in a new catheter group and a pre-existing catheter group. Primary outcome was the rate of CRBSIs/1000 catheter days in the new catheter group and pre-existing catheter group, separately. RESULTS: We randomised 105 patients, of which 102 were analysed as modified intention-to-treat population. In the new catheter group, rates of CRBSIs/1000 catheter days were 0.29 and 1.49 in the taurolidine and saline arm respectively (relative risk, 0.20; 95% CI, 0.04-0.71; P = 0.009). In the pre-existing catheter group, rates of CRBSIs/1000 catheter days were 0.39 and 1.32 in the taurolidine and saline arm respectively (relative risk, 0.30; 95% CI, 0.03-1.82; P = 0.25). Excluding one outlier patient in the taurolidine arm, mean costs per patient were $1865 for taurolidine and $4454 for saline (P = 0.03). Drug-related adverse events were rare and generally mild. CONCLUSIONS: In the new catheter group, taurolidine showed a clear decrease in CRBSI rate. In the pre-existing catheter group, no superiority of taurolidine could be demonstrated, most likely due to underpowering. Overall, taurolidine reduced the risk for CRBSIs by more than four times. Given its favourable safety and cost profile, taurolidine locking should be considered as an additional strategy to prevent CRBSIs. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01826526.

Crosstalk between cardiomyocyte-rich perivascular tissue and coronary arteries is reduced in the Zucker Diabetic Fatty rat model of type 2 diabetes mellitus.

AIM: We tested the hypothesis that crosstalk between cardiomyocyte-rich perivascular tissue (PVT) and coronary arteries is altered in diabetes. METHODS: We studied the vasoactive effects of PVT in arteries from the Zucker Diabetic Fatty (ZDF) rat model of type 2 diabetes, streptozotocin (STZ)-treated Wistar rats with type 1 diabetes, and corresponding - heterozygous Zucker Lean (ZL) or vehicle-treated Wistar - control rats. Vasocontractile and vasorelaxant functions of coronary septal arteries with and without PVT were investigated using wire myography. RESULTS: After careful removal of PVT, vasoconstriction in response to serotonin and thromboxane analogue U46619 was similar in arteries from ZDF and ZL rats, whereas depolarization-induced vasoconstriction - caused by elevating extracellular [K+ ] - was reduced in arteries from ZDF compared to ZL rats. PVT inhibited serotonin-, U46619- and depolarization-induced vasoconstriction in arteries from ZL rats, but this anticontractile influence of PVT was attenuated in arteries from ZDF rats. Methacholine-induced vasorelaxation was smaller in arteries from ZDF than ZL rats both with and without PVT, and the antirelaxant influence of PVT was comparable between arteries from ZDF and ZL rats. We observed no differences in vasoconstriction, vasorelaxation or PVT-dependent vasoactive effects between arteries from STZ- and vehicle-treated Wistar rats. CONCLUSION: Anticontractile influences of PVT are attenuated in coronary arteries from ZDF rats but unaffected in arteries from STZ-treated rats. Signs of endothelial dysfunction are evident in coronary septal arteries - with and without PVT - from ZDF rats but not STZ-treated rats. We propose that altered signalling between cardiomyocyte-rich PVT and coronary arteries can contribute to cardiovascular complications in type 2 diabetes mellitus.

In vivo and in vitro degradation of glucagon-like peptide-2 in humans.

Glucagon-like peptide-2 (GLP-2), an intestinal product of glucagon gene expression which induces intestinal growth in mice, has been proposed as a treatment for intestinal insufficiency. GLP-2 is metabolized extensively by dipeptidyl peptidase IV (DPP-IV) in rats, but less is known about its fate in humans. Therefore, GLP-2 metabolism was investigated in healthy volunteers after 1) a 500-Cal mixed meal (n = 6), 2) iv infusion of synthetic human GLP-2 (0.8 pmol/kg x min; n = 8), 3) a sc bolus injection (400 microg; n = 9), and 4) in vitro incubation in plasma and blood (1,000 pmol/L; n = 4). GLP-2 concentrations were determined by N-terminal RIA measuring only intact GLP-2, side-viewing RIA measuring intact and degraded forms [e.g. GLP-2-(3-33) arising from DPP-IV degradation], and high performance liquid chromatography (HPLC). Meal ingestion elevated plasma GLP-2 (intact, 16 +/- 3 to 73 +/- 10 pmol/L at 90 min), and HPLC revealed two immunoreactive components: intact GLP-2 (57 +/- 2%) and GLP-2-(3-33). GLP-2 infusion increased plasma levels [intact, 9 +/- 4 to 131 +/- 11 pmol/L; total, 23 +/- 7 to 350 +/- 18 pmol/L; the differences represent GLP-2-(3-33)]. The elimination t(1/2) values were 7.2 +/- 2 min (intact GLP-2) and 27.4 +/- 5.4 min [GLP-2-(3-33)], and MCRs were 6.8 +/- 0.6 and 1.9 +/- 0.3 mL/kg x min, respectively. Subcutaneous injection increased intact GLP-2 to maximally 1,493 +/- 250 pmol/L at 45 min, whereas total GLP-2 increased to 2,793 +/- 477 pmol/L at 90 min. At 60 min, plasma contained 69 +/- 1% intact GLP-2. In vitro the t(1/2) values were 8.0 +/- 1.5 h (plasma) and 3.3 +/- 0.3 h (blood). GLP-2-(3-33) was the only degradation product identified by HPLC, and a DPP-IV inhibitor abolished the degradation of GLP-2 in vitro. We conclude that GLP-2 is extensively degraded to GLP-2-(3-33) in humans, presumably by DPP-IV. Nevertheless, 69% remains intact 1 h after GLP-2 injection, supporting the possibility of sc use in patients with intestinal insufficiency.

Differences in essential fatty acid requirements by enteral and parenteral routes of administration in patients with fat malabsorption.

BACKGROUND: Essential fatty acid (EFA) requirements of patients receiving home parenteral nutrition (HPN) are uncertain. OBJECTIVE: The objective was to evaluate the influence of the route of administration (enteral compared with parenteral) on plasma phospholipid EFA concentrations. DESIGN: Intestinal absorption, parenteral supplement of EFAs, and plasma phospholipid EFA concentrations were investigated in balance studies in 4 groups (A, B, C, and D) of 10 patients with short-bowel syndrome and a fecal loss of >2000 kJ/d. Groups A (fat malabsorption <50%) and B (fat malabsorption >50%) did not receive HPN, whereas group C received HPN containing lipids (7.5 and 1.2 g/d linoleic and linolenic acids, respectively) and group D received fat-free HPN. RESULTS: Intestinal absorption of linoleic and linolenic acids was 8.9 and 1.3 g/d and 2. 6 and 0.4 g/d in groups A and B, respectively, whereas EFA absorption was negligible in groups C and D. Thus, intestinal absorption of EFAs in group A corresponded to parenteral EFA supplements in group C, whereas group D was almost totally deprived of EFAs. The median plasma phospholipid concentration of linoleic acid decreased by 21.9%, >16.3%, >13.8%, 11.0%, and >7.7% and linolenic acid by 0.3%, 0.2%, 0.2%, >0.2%, and 0.1%, respectively, in 10 healthy control subjects and groups A, B, C, and D (P < 0.001). CONCLUSIONS: Intestinally absorbed EFAs maintained plasma EFA status better than did an equal quantity of parenterally supplied EFAs. Intravenous requirements of EFAs in patients with negligible absorption of EFAs are probably higher than the amounts recommended to patients with preserved intestinal absorption of EFAs.

Essential fatty acid deficiency in patients receiving home parenteral nutrition.

Home parenteral nutrition (HPN), initiated in patients with severe malabsorption or decreased oral intake, may exhaust stores of essential fatty acids and cause clinical manifestations, mainly dermatitis. Plasma fatty acid profiles were measured by gas-liquid chromatography in 37 healthy control subjects and 56 patients receiving HPN. The concentration (% by wt of total fatty acids) of 18:2n-6 was 22.8% and 11.4% (P < 0.001), whereas 18:3n-3 was 0.2% and 0.1% (P < 0.01) in control subjects and patients, respectively. Reduced small bowel length was associated with aggravated biochemical signs of essential fatty acid deficiency (EFAD). The effect of parenteral lipid on plasma phospholipids was evaluated in subgroups of patients. In patients with > 200 cm of remaining small intestine, those receiving parenteral lipids had only minor changes in the fatty acids of plasma phospholipids compared with patients not receiving parenteral lipids. In patients with < 100 cm of remaining small intestine, those receiving parenteral lipids had increased concentrations of total n-6 fatty acids; however, these did not reach the concentrations in control subjects. No differences were seen in n-3 fatty acids. Twenty-five of the 56 patients receiving HPN reported skin problems. No differences were found in plasma phospholipid fatty acids, Holman index, or the supply of parenteral lipids between patients with and without skin problems. Patients receiving HPN had biochemical signs of EFAD. Parenteral lipids did not increase the concentration of essential fatty acids to values comparable with those of control subjects, but 500 mL 20% Intralipid once a week was sufficient to prevent an increase in the Holman index above 0.2.

Essential fatty acid deficiency in patients with severe fat malabsorption.

Essential fatty acid deficiency is commonly described in patients receiving parenteral nutrition, but the occurrence in patients with severe fat malabsorption not receiving parenteral nutrition is uncertain. One hundred twelve patients were grouped according to their degree of fat malabsorption: group 1, < 10% (n = 52); group 2, 10-25% (n = 21); group 3, 25-50% (n = 24); and group 4, > 50% (n = 15). Fecal fat was measured by the method of Van de Kamer the last 2 of 5 d of a 75-g fat diet. Serum fatty acids in the phospholipid fraction were measured by gas-liquid chromatography after separation by thin-layer chromatography and expressed as a percentage of total fatty acids. The concentration of linoleic acid in groups 1, 2, 3, and 4 was 21.7%, 19.4%, 16.4%, and 13.4% respectively (P < 0.001). The concentration of linolenic acid in groups 1, 2, 3, and 4 was 0.4%, 0.4%, 0.3% and 0.3%, respectively (P = 0.017). Evidence of essential fatty acid deficiency, defined as a serum concentration of linoleic acid less than the lower limit if the 95% CI in patients without fat malabsorption (group 1), was 5% (1/21), 38% (9/24), and 67% (10/15) in groups 2, 3, and 4, respectively. A considerable proportion of patients with gastrointestinal diseases resulting in malabsorption of > 25-50% of dietary fat intake and not treated with parenteral nutrition have biochemical signs of essential fatty acid deficiency. The clinical effect of these changes are yet to be elucidated.

Experimental approaches: dietary and hormone therapy.

Patients who suffer from intestinal failure depend on parenteral support to maintain nutritional equilibrium. In this chapter, recommendations for evaluation the absorptive capacity of patients with intestinal failure are defined, and the evidence and magnitude of the effect of dietary and hormone therapy is given. Regarding dietary advice, the effects of employment of diets with various carbohydrate:fat ratios in short-bowel syndrome (SBS) patients with and without a preserved colon is presented. Focus has been placed on the use of growth hormone but also on the use of a novel intestinotrophic hormone, glucagon-like peptide 2, in the promotion of intestinal adaptation in SBS patients. Overall, the ultimate aim in the treatment of SBS patients is to optimize remnant intestinal function, thereby eliminating the need for parenteral support and improving quality of life in these patients.

Stevioside acts directly on pancreatic beta cells to secrete insulin: actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K+-channel activity.

The natural sweetener stevioside, which is found in the plant Stevia rebaudiana Bertoni, has been used for many years in the treatment of diabetes among Indians in Paraguay and Brazil. However, the mechanism for the blood glucose-lowering effect remains unknown. To elucidate the impact of stevioside and its aglucon steviol on insulin release from normal mouse islets and the beta-cell line INS-1 were used. Both stevioside and steviol (1 nmol/L to 1 mmol/L) dose-dependently enhanced insulin secretion from incubated mouse islets in the presence of 16.7 mmol/L glucose (P < .05). The insulinotropic effects of stevioside and steviol were critically dependent on the prevailing glucose concentration, ie, stevioside (1 mmol/L) and steviol (1 micromol/L) only potentiated insulin secretion at or above 8.3 mmol/L glucose (P < .05). Interestingly, the insulinotropic effects of both stevioside and steviol were preserved in the absence of extracellular Ca2+. During perifusion of islets, stevioside (1 mmol/L) and steviol (1 micromol/L) had a long-lasting and apparently reversible insulinotropic effect in the presence of 16.7 mmol/L glucose (P < .05). To determine if stevioside and steviol act directly on beta cells, the effects on INS-1 cells were also investigated. Stevioside and steviol both potentiated insulin secretion from INS-1 cells (P < .05). Neither stevioside (1 to 100 micromol/L) nor steviol (10 nmol/L to 10 micromol/L) influenced the plasma membrane K+ adenosine triphosphate ((K+)ATP)-sensitive channel activity, nor did they alter cyclic adenosine monophosphate (cAMP) levels in islets. In conclusion, stevioside and steviol stimulate insulin secretion via a direct action on beta cells. The results indicate that the compounds may have a potential role as antihyperglycemic agents in the treatment of type 2 diabetes mellitus.

Antihyperglycemic and blood pressure-reducing effects of stevioside in the diabetic Goto-Kakizaki rat.

Stevioside, a glycoside present in the leaves of the plant, Stevia rebaudiana Bertoni (SrB), has acute insulinotropic effects in vitro. Its potential antihyperglycemic and blood pressure-lowering effects were examined in a long-term study in the type 2 diabetic Goto-Kakizaki (GK) rat. Rats were fed 0.025 g x kg(-1) x d(-1) of stevioside (purity > 99.6%) for 6 weeks. An intra-arterial catheter was inserted into the rats after 5 weeks, and conscious rats were subjected to arterial glucose tolerance test (2.0 g x kg(-1)) during week 6. Stevioside had an antihyperglycemic effect (incremental area under the glucose response curve [IAUC]): 985 +/- 20 (stevioside) versus 1,575 +/- 21 (control) mmol/L x 180 minutes, (P <.05), it enhanced the first-phase insulin response (IAUC: 343 +/- 33 [stevioside] v 136 +/- 24 [control] microU/mL insulin x 30 minutes, P <.05) and concomitantly suppressed the glucagon levels (total AUC: 2,026 +/- 234 [stevioside] v 3,535 +/- 282 [control] pg/mL x 180 minutes, P <.05). In addition, stevioside caused a pronounced suppression of both the systolic (135 +/- 2 v 153 +/- 5 mm Hg; P <.001) and the diastolic blood pressure (74 +/- 1 v 83 +/- 1 mm Hg; P <.001). Bolus injections of stevioside (0.025 g x kg(-1)) did not induce hypoglycemia. Stevioside augmented the insulin content in the beta-cell line, INS-1. Stevioside may increase the insulin secretion, in part, by induction of genes involved in glycolysis. It may also improve the nutrient-sensing mechanisms, increase cytosolic long-chain fatty acyl-coenzyme A (CoA), and downregulate phosphodiesterase 1 (PDE1) estimated by the microarray gene chip technology. In conclusion, stevioside enjoys a dual positive effect by acting as an antihyperglycemic and a blood pressure-lowering substance; effects that may have therapeutic potential in the treatment of type 2 diabetes and the metabolic syndrome.

Potential targets for glucagon-like peptide 2 (GLP-2) in the rat: distribution and binding of i.v. injected (125)I-GLP-2.

Glucagon-like peptide 2 (GLP-2) is a 33-amino acid (1-33) intestinotrophic peptide. In this study, the distribution and binding of i.v. injected radiolabeled GLP-2 (1-33) were investigated in rats using autoradiography in order to target possible binding sites. The major part of (125)I-GLP-2 (1-33) was distributed to kidneys, liver, and the gastrointestinal tract. In the small intestine, a high density of grains was localized in the epithelium with a predominance in the luminal part of the villus. The saturability of (125)I-GLP-2 (1-33) was investigated by administration of excess amounts of non-radioactive GLP-2 (1-33) or the primary metabolite of GLP-2 degradation, GLP-2 (3-33). In the small intestine, (125)I-GLP-2 was displaced both by non-radioactive GLP-2 (1-33) and (3-33), suggesting that the uptake of GLP-2 (1-33) in the small intestine is receptor-specific and that the metabolite GLP-2 (3-33) may interact with the GLP-2 receptor.

Vitamin B12 absorption after ileorectal anastomosis for Crohn's disease: effect of ileal resection and time span after surgery.

OBJECTIVE: To examine the impact of ileorectal anastomosis on vitamin B12 absorption, as measured by the Schilling test, in patients with Crohn's disease. PATIENTS: Eighty-two patients with Crohn's disease who had undergone ileorectal anastomosis. METHODS: Of the 82 patients with Crohn's disease and ileorectal anastomosis, 75 had their absorption of vitamin B12 tested using the Schilling test at least once while their first ileorectal anastomosis was functioning, corresponding to 605 years of observation. RESULTS: An ileal resection of more than 60 cm invariably resulted in decreased vitamin B12 absorption. In patients who had less than 60 cm of their ileum resected 53% had test results, indicating that vitamin B12 was malabsorbed. The extent of malabsorption did not correlate with the length of ileal loss in this subgroup of patients (r = -0.26; P = 0.053). Even resections of 10 cm or less were associated with malabsorption in 38% of patients. This suggests that factors other than the remaining ileal length are important for vitamin B12 absorption in Crohn's disease patients with ileorectal anastomosis. An improvement in vitamin B12 absorption over the years was not observed in the 35 patients in whom the test was repeated, and intraindividual Schilling test results fluctuated between pathological and normal values in several patients. CONCLUSIONS: Most Crohn's disease patients with ileorectal anastomosis have vitamin B12 malabsorption. Individuals with more than 60 cm of ileal loss are particularly affected and testing for malabsorption appears superfluous in this group. Approximately 50% of the patients with resections of 60 cm or less malabsorbed vitamin B12, but it was not possible to predict which patients should receive vitamin B12 substitutes based on the length of the remaining ileum alone. However, it may also be difficult to make a rational therapeutic decision based on the results of the Schilling test, because the test shifted between normal and pathological values over time in many of the patients studied.