J. Larsson

Effect of dietary supplement on nutritional status and clinical outcome in 501 geriatric patients—a randomised study

The present study was designed to evaluate to the effect of dietary supplements on clinical outcome and nutritional status in a large group of geriatric patients (n = 501). The patients were randomised into an experimental group which received nutritional supplementation (400 kcal) as well as a standard hospital diet, and a control group on hospital diet alone. The nutritional state was measured on admission and after 8 and 26 weeks by anthropometry, serum protein analysis and a delayed hypersensitivity skin test. Protein energy malnutrition was defined as the presence of three or more abnormal parameters. 28.5% of patients showed evidence of malnutrition on admission. Hospitalisation itself resulted in a gradual deterioration in nutritional status. Nutritional supplementation generally improved nutritional state. Among those patients who were well nourished on admission, and subsequently receiving dietary supplementation, 8.3% fulfilled malnutrition criteria after 26 weeks, while 21.1% were considered malnourished in the control group (p < 0.05). The improvement observed in transport proteins was probably related to nutritional support and not just to the reversal of inflammation. In the initially well nourished group of more than 300 patients, the mortality rate was 8.6% in those given nutritional support compared to 18.6% in the control group (p < 0.02).

Islet Amyloid Polypeptide in Patients with Pancreatic Cancer and Diabetes

BACKGROUND The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. METHODS We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. RESULTS Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P < 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P < 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. CONCLUSIONS Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.

The relationship between diabetes and pancreatic cancer.

About 80% of pancreatic cancer patients have glucose intolerance or frank diabetes. This observation has led to the following two hypotheses: i. pancreatic cancer causes the associated diabetes and ii. the conditions associated with diabetes promote the development of pancreatic cancer. Evidence supporting both hypotheses has been accumulated in previous studies. This article reviews these studies, especially those that have been conducted recently.

Is profound peripheral insulin resistance in patients with pancreatic cancer caused by a tumor-associated factor?

Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is characterized by high plasma levels of insulin. In type II diabetes that is not associated with pancreatic cancer, peripheral insulin resistance and impaired muscle glycogen synthesis are major pathogenic factors. We investigated peripheral insulin sensitivity in patients with pancreatic cancer before and after tumor removal. The effects of pancreatic tumor extracts on glycogen synthesis in skeletal muscle in vitro and the tumor content of pancreatic islet hormones were also investigated. Marked peripheral insulin resistance was found in the patients with pancreatic cancer and was more pronounced in the diabetic patients than in the nondiabetic patients. Insulin sensitivity was not correlated with weight loss, tumor size, or bilirubin levels but improved after surgery. Tumor extracts from diabetic patients with pancreatic cancer caused a marked reduction of glycogen synthesis in skeletal muscle in vitro. All tumors contained islet hormones but not in concentrations sufficient to explain the effect on glycogen synthesis. These findings indicate that a diabetogenic factor associated with pancreatic adenocarcinomas could be involved in the development of the profound peripheral insulin resistance and thereby could contribute to the high incidence of diabetes observed in patients with pancreatic cancer.

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 correlation between anergy, malnutrition and clinical outcome in an elderly hospital population

The nutritional state of 482 out of 501 newly admitted elderly patients was assessed by anthropometry, serum protein analyses and the delayed hypersensitivity skin test (DH) on admission and after 8 and 26 weeks. The mean age of the women was 81.3 +/- 7.7 and of the men 77.9 +/- 9.3. Protein-energy malnutrition (PEM) was initially defined as three or more subnormal criteria, one in each of the three categories of measurement. The data was then reanalysed excluding anergy and using the two other criteria only. The prevalence of PEM on the first assessment was 28.5% and was 10% higher when anergy was excluded as a criterion. PEM was more common in women and increased with age. The anergic patients had lower mean values in serum protein and anthropometry than those with normal reactivity. Anergic patients had a higher mortality rate and more pressure sores than the reactive group. Nutritional supplementation was associated with an increase in skin reactivity.

Islet hormone secretion in pancreatic cancer patients with diabetes.

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon. and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.

Sufficiency of postprandial plasma levels of islet amyloid polypeptide for suppression of feeding in rats

Our objective was to study whether islet amyloid polypeptide (IAPP) produces satiety by an endocrine mechanism. We used a rat model to determine whether postprandial plasma levels of IAPP are comparable to those required to inhibit feeding when IAPP is administered by continuous intravenous infusion. Food intake in rats with aortic catheters increased plasma IAPP levels from a fasting level of 10.8 ± 0.5 pM to a peak level of 19.0 ± 1.0 pM at 2.2 ± 0.5 h. In rats with jugular vein and aortic catheters, the threshold intravenous dose for IAPP suppression of feeding was between 1 and 3 pmol ⋅ kg-1 ⋅ min-1. The 3 pmol ⋅ kg-1 ⋅ min-1dose decreased 4-h intake by ∼25% by decreasing meal frequency rather than meal size. This dose increased plasma IAPP by ∼24 pM. These results suggest that postprandial plasma levels of IAPP are not quite sufficient to independently produce satiety.

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.