Bengt Isaksson

Optimising islet engraftment is critical for successful clinical islet transplantation

Clinical islet transplantation is currently being explored as a treatment for persons with type 1 diabetes and hypoglycaemia unawareness. Although ‘proof-of-principle’ has been established in recent clinical studies, the procedure suffers from low efficacy. At the time of transplantation, the isolated islets are allowed to embolise the liver after injection in the portal vein, a procedure that is unique in the area of transplantation. A novel view on the engraftment of intraportally transplanted islets is presented that could explain the low efficacy of the procedure.

Visuospatial skills and computer game experience influence the performance of virtual endoscopy

Advanced medical simulators have been introduced to facilitate surgical and endoscopic training and thereby improve patient safety. Residents trained in the Procedicus Minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR) laparoscopic simulator perform laparoscopic cholecystectomy safer and faster than a control group. Little has been reported regarding whether factors like gender, computer experience, and visuospatial tests can predict the performance with a medical simulator. Our aim was to investigate whether such factors influence the performance of simulated gastroscopy. Seventeen medical students were asked about computer gaming experiences. Before virtual endoscopy, they performed the visuospatial test PicCOr, which discriminates the ability of the tested person to create a three-dimensional image from a two-dimensional presentation. Each student performed one gastroscopy (level 1, case 1) in the GI Mentor II, Simbionix, and several variables related to performance were registered. Percentage of time spent with a clear view in the endoscope correlated well with the performance on the PicSOr test (r = 0.56, P < 0.001). Efficiency of screening also correlated with PicSOr (r = 0.23, P < 0.05). In students with computer gaming experience, the efficiency of screening increased (33.6% +- 3.1% versus 22.6% +- 2.8%, P < 0.05) and the duration of the examination decreased by 1.5 minutes (P < 0.05). A similar trend was seen in men compared with women. The visuospatial test PicSOr predicts the results with the endoscopic simulator GI Mentor II. Two-dimensional image experience, as in computer games, also seems to affect the outcome.

Intramuscular Autotransplantation of Pancreatic Islets in a 7‐Year‐Old Child: A 2‐Year Follow‐Up

A 7‐year‐old girl with severe hereditary pancreatitis underwent total pancreatectomy. A total of 160 000 islet equivalents (6400 islet/kg) were transplanted to the brachioradialis muscle of the right forearm. Her plasma C‐peptide level was undetectable after pancreatectomy but increased to 1.37 ng/mL after 17 days; at this time point, her insulin requirement was 0.75 units of insulin/kg/day. At 5‐ and 27‐months, her hemoglobin A1c (HbA1c) and insulin requirements were 4.5 and 5.3% and 0.3 and 0.18 units/kg/day, respectively. Basal and stimulated C‐peptide levels were 0.67 ± 0.07 and 3.36 ± 1.37 ng/mL, respectively. Stimulated insulin levels were 30% higher in the islet‐bearing arm compared to the contralateral arm after glucagon stimulation. After surgery and islet transplantation, the quality of life improved dramatically and she gained 8 kg of weight. In summary, a normal HbA1c, a low insulin requirement and the absence of recurrent hypoglycemia and the gradient of insulin between the arms indicate that the intramuscularly transplanted islets contribute to a long‐term clinically significant metabolic control.

Lipolysis—Not inflammation, cell death, or lipogenesis—Is involved in adipose tissue loss in cancer cachexia†

Cancer cachexia is an important, negative prognostic marker that has been linked to systemic inflammation and cell death through unclear mechanisms. A key feature of cancer cachexia is loss of white adipose tissue (WAT) because of increased adipocyte lipolysis and possibly reduced lipid synthesis (lipogenesis). In this study, the authors investigated whether alterations in fat cell numbers, lipogenesis, or cytokine and/or leukocyte infiltration could account for some of the functional changes observed in WAT in cancer cachexia.

Lifestyle factors and pancreatic cancer risk: A cohort study from the Swedish Twin Registry

Dear Sir, Even though pancreatic cancer is the 5th-leading cause of cancer deaths in the Western world,1 little is known about the etiology of the disease. Lifestyle and other risk factors for pancreatic cancer have been examined in many epidemiologic studies, most of which were case-control studies. The conclusions of many of these are dubious because of small sample size, low participation and use of proxy respondents. Only cigarette smoking stands out as a likely causal agent in epidemiologic studies. However, cigarette smoking can explain only about 25% of the incidence.2 Studies have also suggested that coffee, ethanol, obesity, high energy intake and high consumption of fat, carbohydrates and animal protein may be risk factors.3–5 Some studies have shown decreased risks associated with frequent consumption of fruits and vegetables, but this has not been observed consistently.3 It is possible that factors other than those that have been investigated may affect the development of pancreatic cancer. Our study examined the effects of diet, coffee, ethanol, tobacco use, BMI, physical activity and change in body weight on pancreatic cancer incidence in a cohort study of twins established in 1958 and followed by the Swedish Twin Registry. The cohort, which provided prospective information concerning exposure, included male and female same-sexed twin pairs who were born from 1886–1925 and were both living in Sweden in 1961. At the 1961 baseline, self-administered questionnaires regarding lifestyle factors were mailed to 25,778 registrees. However, 1,288 of these were found to have already died. Additional questionnaires were administered in 1963 and 1967. Our current study included 12,204 females and 9,680 males who responded to these questionnaires with information on at least some of the potential risk factors. The overall response rate to the questionnaires was 85%. Subjects with pancreatic cancer were included in the analysis only if the diagnosis was made from 1969–97. Ninety percent of the tumors were histologically confirmed. The median age at enrollment in the cohort was 56 years. Subjects were followed from exposure assessment to 1 of 3 study endpoints: diagnosis of pancreatic cancer, death or the end of the study on December 31, 1997. Cancer incidence was ascertained by record linkage to the Swedish Cancer Registry (documented to be 98% complete).6 Death was ascertained by linkage to the Swedish Cause of Death Registry. During the follow-up period (median 16 years), there were 176 incident cases of pancreatic cancer diagnosed at a median age of 73 years. The total number of pancreatic cancer cases included in the risk analysis of each lifestyle factor is less than 176 incident cases because some subjects did not answer all the questions on the questionnaires. The internal dropout rate varied considerably between the different questions. In the questionnaires, smoking status was assessed as nonsmoker, former smoker or current smoker. Current smokers reported the number of cigarettes smoked per day and were coded as light (1–10 cigarettes/day) and regular (11 /day) based on the combination of responses to the questionnaires in 1961 and 1967. Ethanol consumption was self-reported in 1967 as amount and frequency of beer, wine and spirits intake. Ethanol consumption was coded as grams pure ethanol per month (Table I). Coffee consumption was assessed as number of cups per day (Table I). The 1967 questionnaires also included questions about the frequency of consumption of 10 food groups: fruit/vegetables, eggs, pork, beef, sausages, fish, potatoes, flour/grain products, pastry and sweets. The response alternatives were no part, a small part, a moderate part and a large part of the diet (for pastry and sweets: less than daily, daily and several times a day) . The alternatives no part and a small part were combined as low or no part for analysis. Physical activity during leisure hours was assessed as low (responses were hardly any physical exercise or light physical exercise, e.g., regular walks, light gardening) and high (responses were regular exercise or hard physical training). Physical activity at work was assessed as sedentary or physical (responses were physical or hard physical). Weight was selfreported in kilograms and height in centimeters. BMI (in kg/ m) was used as a measure of relative body weight. BMI scores were divided into 4 groups according to WHO criteria for thinness and overweight.7 BMI 18.5–24.99 was selected as the reference category. Weight was self-reported for the actual age when the subject answered the questionnaire and for ages 25 and 40. Adult weight gain was assessed by subtracting weight at age 25 years from weight at enrollment. The relative risk of pancreatic cancer was estimated through Cox proportional hazards modeling using the SAS program

The common -675 4G/5G polymorphism in the plasminogen activator inhibitor -1 gene is strongly associated with obesity.

Aims/hypothesis. Plasminogen activator inhibitor 1 (PAI-1) increases in several insulin-resistant conditions such as obesity. We tested the hypothesis that the PAI-1 gene might be a candidate for obesity and Type II (non-insulin-dependent) diabetes mellitus. Methods. We investigated the frequency of a common and functional –675 4G/5G promoter polymorphism in the PAI-1 gene in 188 lean, 70 overweight (BMI 25–30 kg/m2) and 247 obese otherwise healthy Scandinavian subjects. Results. The genotypic (p = 0.002), or allelic (p = 0.0004) distribution differed markedly between the three groups. Homozygocity for 4G was more common among obese people, whereas homozygocity for 5G was more common among lean subjects. Heterozygocity was evenly distributed. The lean and overweight groups did not differ in frequency distribution. The relative risk for being obese in comparison to being lean for 4G/4G was threefold higher (p = 0.0003). Also, carriers of the 4G allele in the heterozygous or homozygous form were distributed differently between the three groups (p = 0.006). The 4G carriers were more common among the obese than the lean group. The latter group did not differ from the overweight group. The relative risk of being obese in comparison with lean was twofold increased in 4G carriers (p = 0.0015). Similar results were obtained in men and women. Conclusion/interpretation. Thus, the common –675 4G/5G polymorphism in the PAI-1 gene is strongly linked to obesity and a markedly increased risk for obesity is associated with the 4G allele in its homozygous form. [Diabetologia (2002) 45: ▪–▪]

Evidence for an Important Role of CIDEA in Human Cancer Cachexia

Loss of fat mass in cancer cachexia is linked to increased adipocyte lipolysis; however, the fate of the excess fatty acids (FA) generated by lipolysis is not known. We investigated if the adipocyte-specific gene cell death-inducing DNA fragmentation factor-alpha-like effector A (CIDEA) could be involved. CIDEA mRNA expression was assessed in s.c. white adipose tissue from 23 cancer cachexia patients, 17 weight-stable cancer patients, and 8 noncancer patients. CIDEA was also overexpressed in adipocytes in vitro. CIDEA expression was increased in cancer cachexia (P < 0.05) and correlated with elevated levels of FAs and reported weight loss (P < 0.001). CIDEA overexpression in vitro increased FA oxidation 2- to 4-fold (P < 0.01), decreased glucose oxidation by 40% (P < 0.01), increased the expression of pyruvate dehydrogenase kinase (PDK) 1 and PDK4 (P < 0.01), and enhanced the phosphorylation (inactivation) of the pyruvate dehydrogenase complex (PDC). Inactivation of PDC facilitates FA oxidation by favoring the metabolism of FAs over glucose to acetyl-CoA. In accordance with the in vitro data, PDK1 and PDK4 expression correlated strongly with CIDEA expression in white adipose tissue (P < 0.001). We conclude that CIDEA is involved in adipose tissue loss in cancer cachexia and this may, at least in part, be due to its ability to inactivate PDC, thereby switching substrate oxidation in human fat cells from glucose to FAs.

Impaired insulin action on phosphatidylinositol 3-kinase activity and Glucose transport in skeletal muscle of pancreatic cancer patients

Introduction Glucose intolerance or overt diabetes occurs in 80% of patients with pancreatic cancer (PC). This associated metabolic disorder includes peripheral insulin resistance, which may be caused by factors produced by the PC. The mechanism underlying PC-associated insulin resistance has not been clearly defined. Aim To characterize basal and insulin-stimulated glucose transport, phosphatidylinositol (PI) 3-kinase activity, and glucose transporter 4 (GLUT4) in skeletal muscles of PC patients. Methodology Skeletal muscle samples were obtained from the abdominal wall of 17 PC patients during surgery. Control muscles were sampled in the same way from 11 donors undergoing abdominal surgery for benign diseases. PI 3-kinase activity, glucose transport, and GLUT4 were assessed in vitro in these muscles. Results In the presence of physiologic concentrations of insulin, glucose transport and PI 3-kinase activity were significantly decreased in the PC group compared with controls. At supraphysiologic insulin concentrations, glucose transport was significantly decreased but PI 3-kinase activity was normalized. In the absence of insulin, these parameters were not significantly different between PC and control groups. Muscle GLUT4 contents were similar between PC and control groups. Conclusion Defects in insulin-mediated PI 3-kinase activity and glucose transport contribute to the insulin resistance in patients with PC.

Skeletal muscle insulin resistance after trauma: insulin signaling and glucose transport

Surgical trauma induces peripheral insulin resistance; however, the cellular mechanism has not been fully elucidated. We examined the effects of surgical trauma on insulin receptor signaling and glucose transport in skeletal muscle, a tissue that plays a predominant role in maintaining glucose homeostasis. Surgical trauma was induced by intestinal resection in the rat. Receptor phosphorylation was not altered with surgical trauma. Phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase association was increased by 60 and 82% compared with fasted and fed controls, respectively (P < 0. 05). Similar results were observed for insulin receptor substrate-1-associated PI 3-kinase activity. Insulin-stimulated protein kinase B (Akt kinase) phosphorylation was increased by 2.2-fold after surgical trauma (P < 0.05). The hyperphosphorylation of Akt is likely to reflect amplification of PI 3-kinase after insulin stimulation. Submaximal rates of insulin-stimulated 3-O-methylglucose transport were reduced in trauma vs. fasted rats by 51 and 38% for 100 and 200 microU/ml of insulin, respectively (P < 0.05). In conclusion, insulin resistance in skeletal muscle after surgical trauma is associated with reduced glucose transport but not with impaired insulin signaling to PI 3-kinase or its downstream target, Akt. The surgical trauma model presented in this report provides a useful tool to further elucidate the molecular mechanism(s) underlying the development of insulin resistance after surgical trauma.Surgical trauma induces peripheral insulin resistance; however, the cellular mechanism has not been fully elucidated. We examined the effects of surgical trauma on insulin receptor signaling and glucose transport in skeletal muscle, a tissue that plays a predominant role in maintaining glucose homeostasis. Surgical trauma was induced by intestinal resection in the rat. Receptor phosphorylation was not altered with surgical trauma. Phosphotyrosine-associated phosphatidylinositol (PI) 3-kinase association was increased by 60 and 82% compared with fasted and fed controls, respectively ( P < 0.05). Similar results were observed for insulin receptor substrate-1-associated PI 3-kinase activity. Insulin-stimulated protein kinase B (Akt kinase) phosphorylation was increased by 2.2-fold after surgical trauma ( P < 0.05). The hyperphosphorylation of Akt is likely to reflect amplification of PI 3-kinase after insulin stimulation. Submaximal rates of insulin-stimulated 3- O-methylglucose transport were reduced in trauma vs. fasted rats by 51 and 38% for 100 and 200 μU/ml of insulin, respectively ( P< 0.05). In conclusion, insulin resistance in skeletal muscle after surgical trauma is associated with reduced glucose transport but not with impaired insulin signaling to PI 3-kinase or its downstream target, Akt. The surgical trauma model presented in this report provides a useful tool to further elucidate the molecular mechanism(s) underlying the development of insulin resistance after surgical trauma.

Chronically Administered Islet Amyloid Polypeptide in Rats Serves as an Adiposity Inhibitor and Regulates Energy Homeostasis

Aims/Hypothesis: Islet amyloid polypeptide (IAPP) reduces food intake and body weight in laboratory animals. In addition, IAPP appears to regulate nutrient metabolism. In the present studies, we investigated the effect of chronic IAPP treatment on different aspects of energy homeostasis. Methods: IAPP was infused (25 pmol/kg/min) from subcutaneous osmotic pumps for 2–7 days. Rats in 2 saline-infused control groups were fed ad libitum (AF) or pair-fed (PF) against the IAPP-treated rats. Results: As expected, the IAPP infusion reduced food intake and body weight gain. In addition, the IAPP treatment decreased the epididymal fat pad (vs. PF rats, p < 0.05) and lowered circulating levels of triglycerides (vs. PF rats, p < 0.05), free fatty acids (vs. PF rats, p < 0.05), leptin (vs. both AF and PF rats, p < 0.05) and insulin (vs. AF rats, p < 0.05). In contrast, glucose and protein metabolism in the IAPP-treated rats was largely unchanged, as shown in results regarding serum glucose, glucose transport in skeletal muscle, blood urea nitrogen, and glycogen and protein content in the liver and in skeletal muscle. Conclusion/Interpretation: In summary, chronic IAPP exposure led to a changed lipid metabolism, which was characterized by decreased adiposity, hypolipidemia and hypoleptinemia, and to unchanged glucose and protein homeostasis. These results were similar to those seen in rodents during chronic exposure to another satiety/adiposity regulator, leptin. In conclusion, chronically administered IAPP plays a role as a satiety and adiposity signal in rats, and helps regulate energy homeostasis.