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The role of amylin in the β-cell dysfunction that occurs in patients with diabetes mellitus may be important. Amyloid deposits are found in the pancreata of subjects with Type 2 diabetes and may contribute to β-cell death. It is therefore necessary to study amylin secretion and kinetics to determine whether elevated levels of the peptide are due to elevated secretion, reduced clearance or both. The aim of this study was to measure amylin dynamics during an oral glucose tolerance test (OGTT). We also used a mathematical model of β-cell activity to assess the secretion and kinetics of C-peptide, insulin and amylin in humans during an OGTT. In particular, we were interested in characterizing the physiological meaning of one of the terms in the model, the amylin/C-peptide co-secretion factor (σ). The model has been used in several pathophysiological conditions and results indicate an elevated secretion and clearance of amylin in glucose-intolerant states. Amylin clearance has been found to be similar to that of C-peptide, and much slower than that of insulin. In this study, direct measurements of insulin and amylin secretion in five obese subjects yielded an estimate of the amylin/insulin co-secretion factor of 0.004 with a standard deviation (SD) of 0.002. The point estimate of hepatic clearance was 80 ml min−1, which was much lower than that of insulin (507 ± 94 ml min−1). In addition, the estimated hepatic clearance was not significantly different from zero given its high SD of 213 ml min−1. The absence of hepatic extraction of amylin is therefore a plausible hypothesis, which is also supported by the similarity between amylin and C-peptide clearances. This observation characterizes the physiological meaning of σ and suggests that this parameter is associated mainly with β-cell secretion. © 1997 John Wiley & Sons, Ltd.

The presence of amyloid deposits in the pancreas was first described at the beginning of the 20th century. However, it was not until 1987 that the structure of the amylin molecule was identified. Amylin is a 37-amino-acid peptide hormone that is co-secreted with insulin by the pancreatic beta-cells in response to a nutrient stimulus. It is deficient in patients with Type 1 diabetes and elevated in patients in the early stages of Type 2 diabetes, a condition which is characterized by hyperinsulinaemia. Elevation of plasma amylin levels has also been described in patients with impaired glucose tolerance, obese subjects and in pregnant women with both normal glucose tolerance and gestational diabetes mellitus. However, it appears that deficiencies of amylin secretion appear before those of insulin in patients in the later stages of Type 2 diabetes. Early experimental studies suggested that amylin inhibits basal insulin secretion, and induces insulin resistance in skeletal muscle, leading to the hypothesis that it has a role in the aetiology of Type 2 diabetes. However, a number of more recent experimental studies have indicated that amylin is a third active pancreatic islet hormone that works with insulin and glucagon to maintain glucose homeostasis. Amylin appears to regulate glucose inflow to the circulation by influencing the rate of gastric emptying, and thus the rate at which meal-derived glucose enters the system, and also by inhibiting glucose release and hepatic glucose production in the postprandial period.

A model describing beta-cell secretion during an oral glucose tolerance test (OGTT) is introduced. The aim was to quantify beta-cell activity in different pathologies by analyzing peripheral concentration data of insulin, C-peptide, and islet amyloid polypeptide (IAPP). Insulin appearance in periphery is given by the fraction of C-peptide secretion, CPS(t), which accounts for liver degradation. A novelty of this study is the inclusion of IAPP delivery assumed proportional to CPS(t). Although IAPP fractional clearance is estimated in every subject, the clearances of insulin and C-peptide are assigned from a wide set of previous independent studies. Sensitivity analysis was performed to quantify the "error" in the estimated variables due to these assignments. All parameters relating to beta-cell secretion increased in the glucose-intolerant states [integrated CPS(t)=56 +/- 8 nmol/l in 180 min vs. 32 +/- 3 of controls, P

We have developed a noninvasive method to estimate splanchnic glucose uptake (SGU) in humans (oral glucose clamp technique [OG-CLAMP]), which combines a hyperinsulinemic clamp with an oral glucose load (oral glucose tolerance test). We validated this method in 12 nondiabetic subjects using hepatic vein catheterization (HVC) during an oral glucose tolerance test. During HVC, splanchnic blood flow increased from 1,395 +/- 64 to 1,935 +/- 109 ml/min, returning to basal after 180 min and accounted for 45 +/- 7% of SGU in lean and 19 +/- 5% in obese subjects (P < 0.05). SGU estimated during the OG-CLAMP was 22 +/- 2% of the glucose load, and this was significantly correlated (r = 0.90, P < 0.0001) with SGU (35 +/- 4%) and with first pass SGU (24 +/- 3%; r = 0.83, P < 0.001) measured during HVC. SGU was higher in obese than in lean subjects during OG-CLAMP (27 +/- 1% vs 18 +/- 3%, P < 0.01) and HVC (44 +/- 4% vs 26 +/- 5%, P < 0.05). In conclusion, SGU during the OG-CLAMP is well correlated to SGU measured during HVC. An increase in splanchnic blood flow is a major contributor to SGU in lean subjects. SGU is increased in obese subjects as measured by both methods.

Type 2 diabetes mellitus increases the risk of cardiovascular morbidity and mortality and that of microvascular complications such as nephropathy, retinopathy and neuropathy. Its global prevalence is rising and leads to an enormous economic burden. Treatment of hyperglycaemia has been proven to decrease microvascular and macrovascular complications and to improve patients’ quality of life. Prevention and primary treatment of diabetes consists of lifestyle intervention in order to reduce obesity by diet and exercise. As diabetes is a progressive disease, pharmacotherapy needs to be introduced at some point of time to achieve the individualized glycaemic targets. In addition to established medications such as metformin, sulfonylureas and glitazones, recent developments targeting the incretin system or renal glucose absorption offer novel approaches for diabetes treatment. This review attempts to provide an overview about the current and future aspects of the pharmaceutical treatment of type 2 diabetes mellitus.

To elucidate the metabolism of islet amyloid polypeptide (IAPP) with respect to a possible renal elimination we investigated IAPP levels in 20 lean, nondiabetic patients with renal failure maintained on chronic hemodialysis (HD) and in 20 healthy controls. The basal levels of IAPP were significantly higher in uremic patients than in controls (15.1 +/- 3.2 vs. 3.2 +/- 0.2 pM, P < 0.001) suggesting renal excretion of IAPP. To investigate the impact of chronically elevated levels of endogenous IAPP on insulin secretion and insulin sensitivity, a frequently sampled intravenous glucose tolerance test (FSIGT) was performed in a subset of patients on hemodialysis and in age-matched healthy controls (C) and obese patients with normal (NGT) and with impaired glucose tolerance (IGT). Insulin sensitivity index (SI) was 8.7 +/- 1.5 in C (P < 0.05 vs. NGT, P < 0.01 vs. IGT), 5.4 +/- 0.9 in HD (P < 0.05 vs. IGT), 3.1 +/- 1.0 in NGT, and 2.0 +/- 0.5 in IGT. First phase insulin secretion was increased in patients on HD compared with those of several control groups. The results of this study therefore indicate a renal route of metabolism of IAPP. Increased endogenous circulating IAPP levels over a long period of time do not lead to a decrease in insulin release in patients on HD and do not cause the insulin resistance commonly seen in obesity and diabetes. Increased levels of circulating IAPP therefore are not likely to be a pathogenetic factor in the development of non-insulin-dependent diabetes mellitus (NIDDM).

There is considerable and growing interest in neutraceutical products for the treatment of diabetes (1). Recently, it has been shown that caiapo, the extract of white-skinned sweet potato ( Ipomoea batatas ), improves glycemic control in rodents by reducing insulin resistance (2). The aim of our study was to assess the effect of caiapo on glucose metabolism and its tolerability and mode of action in male Caucasian type 2 diabetic patients in a randomized, double-blind prospective study in parallel groups controlled with placebo. A total of 18 male type 2 diabetic patients (age: 58 ± 8 years; weight: 88 ± 3 kg; BMI: 27.7 ± 2.7 kg/m2; means ± SEM) treated by diet alone were randomized to receive placebo or 2 (low dose) or 4 g (high dose) caiapo (four tablets each containing 168 or 336 mg powdered white-skinned sweet potato [ I. batatas ], respectively) before breakfast, lunch, and dinner for 6 weeks. The study protocol was approved by the Ethics Committee of the University of Vienna, and informed consent was obtained from all patients before inclusion into the study. Safety parameters (hematology and blood chemistry, including hepatic enzymes and urinanalysis) were controlled before and at the end of the study, and patients were asked to report any adverse events. Patients were seen weekly during the 6-week trial, and fasting blood glucose was measured. Each subject underwent a frequently sampled intravenous glucose tolerance test (FSIGT) …

Insulin resistance, hyperinsulinemia, and dyslipidemia are common characteristics of patients with untreated hypertension. However, the link between the vascular and metabolic disturbances is still unclear. To provide further insights into the metabolic picture of subjects with hypertension, we evaluated insulin resistance, pancreatic secretion, and hepatic extraction of the hormone in 16 untreated patients with essential hypertension before and after 12-16 weeks of drug treatment in comparison with 16 age-, sex-, and body weight-matched normotensive control subjects. All subjects underwent an oral and a frequently sampled intravenous glucose tolerance test. Metabolic parameters were calculated by the minimal model technique. The hypertensive patients exhibited a highly reduced tissue insulin sensitivity (2.6 +/- 0.4 versus 9.6 +/- 1.9 10(4) min-1/[microunits/mL]; p < 0.001). The basal secretion rate (70 +/- 11 versus 35 +/- 5 pmol/L per minute) and the total amount of prehepatically secreted insulin (32 +/- 4 versus 16 +/- 2 nmol/L in 4 hours) were significantly increased in the hypertensive patients compared with the control subjects (p < 0.01), whereas the posthepatic insulin delivery rate was not significantly different between the two groups (4.9 +/- 0.6 versus 3.5 +/- 0.3 nmol/L in 4 hours). Hepatic insulin extraction was found to be significantly elevated in the hypertensive patients compared with control subjects (81 +/- 4% versus 69 +/- 3%, p < 0.04). Increased hepatic insulin extraction partially ameliorated B cell hypersecretion in hypertensive patients. After 12-16 weeks of drug treatment, the blood pressure was normalized, but the metabolic profile of the patients remained unchanged. We conclude that elevated insulin extraction in the liver is a specific characteristic of individuals with essential hypertension and partially compensates pancreatic B cell hypersecretion.

Amylin, a 37–amino acid polypeptide, has been identified as the major protein component of pancreatic amyloid deposits in patients with non-insulin-dependent (type II) diabetes mellitus. Amylin is stored and released together with insulin and has been proposed to play a major role in the pathogenesis of type II diabetes. To compare amylin release and its proportion to insulin secretion under different metabolic conditions, oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in healthy, lean control subjects, obese patients with normal and impaired glucose tolerance (NGT and IGT, respectively), and obese type II diabetic patients. Compared with control subjects, basal and stimulated amylin secretion during OGTT was significantly higher in obese patients with NGT and IGT but not in type II diabetic patients. The integrated amylin response was significantly higher in obese patients with NGT than lean control subjects and type II diabetic patients matched for degree of obesity. The amylin-insulin ratio decreased slightly in obese subjects with NGT and IGT and significantly in type II diabetic patients. Amylin secretion was significantly stimulated during IVGTT in control subjects and obese patients with NGT and IGT but not in type II diabetic patients. These findings suggest that amylin is physiologically released by pancreatic β-cells in a constant ratio to insulin in nondiabetic subjects. Glucose-stimulated amylin secretion is increased in obese subjects with NGT and IGT. In type II diabetes mellitus, amylin secretion relative to that of insulin is decreased, and amylin is not stimulated by IVGTT.

Amylin is a 37-amino acid pancreatic polypeptide, probably involved in the pathophysiology of Type 2 (non-insulin-dependent) diabetes mellitus. We have determined amylin in human plasma by extraction-based radioimmunoassay (Sep-Pak C18). Of 23 healthy control subjects plasma amylin was determined as 11.9 +/- 3.5 ng/l. Of 27 patients with Type 2 diabetes receiving insulin the amylin levels were lower, and in 16 patients with Type 2 diabetes on oral medication they were higher than in the control subjects; 8.2 +/- 4.4 ng/l (p less than 0.01) vs 18.8 +/- 9.9 ng/l (p less than 0.05). In 14 Type 1 (insulin-dependent) diabetic patients we found extremely low mean amounts of amylin: 2.9 +/- 1.9 ng/l (p less than 0.002). Thus, basal amylin appears to be associated with the capacity to release insulin. An oral glucose load stimulated the release of amylin, this was more pronounced in patients with Type 2 diabetes than in healthy subjects. An excellent correlation of mean amylin with mean insulin concentrations was obtained (r = 0.949). In patients with Type 2 diabetes amylin was reduced congruent to decreases in C-peptide during a hyperinsulinaemic, euglycaemic glucose clamp experiment (r = 0.971 for linear correlation between C-peptide levels and amylin). We conclude, that amylin and insulin are co-secreted in humans, and that the amylin release is under feedback-control by insulin.

2 men) preand 1 year post-bariatric surgery (vertical banded gastroplasty 8, gastric bypass 5, duodenal switch 3). Patients on anti-hypertensive or cholesterol lowering drugs were excluded. We measured leptin, lactate, pyruvate, 2,3-diphosphoglycerate (2,3-DPG), pH, and the OTR by dynamic oximetry. OTR methodology initiated in our laboratory and consists of the evaluation of the rate of hemoglobin desaturation in vitro as the blood O2 saturation goes from 100% to 60%. The endpoint of anaerobic glycolysis is lactate, of aerobic it is pyruvate. The lactate-pyruvate ratio decreases with increasing aerobic glycolysis. 2,3-DPG, an intermediate in glycolysis, modulates the hemoglobin/oxygen dissociation curve; when 2,3-DPG decreases, the curve shifts to the left, reducing the OTR. Statistical analysis by t-test. Results: The 1 year average %EBWL was 55.6% (37.7 kg). All calculated indicators decreased: leptin -34.8% (p .04), lactate/ pyruvate ratio -16% (p .12), 2,3-DPG -38.8% (p .001), and pH -.7% (p .05). The OTR decreased -18.3% (p .03 at 5 minutes. Conclusion: Bariatric surgery is associated with changes in metabolic parameter indicative of a shift from anaerobic to more energy efficient aerobic metabolism.

Background: Patients with type 1 diabetes mellitus (DM1) have to be active participants in their treatment because they are inevitably responsible for their own day-to-day-care. Availability of mobile Internet access is advancing rapidly and mobile phones are now widely available at low cost. Thus, mobile phones have the potential to assist in daily diabetes management and to enable a telemedical interaction between patients and health care professionals. Objective: The aim of the study was to evaluate the feasibility and user acceptance of a mobile phone–based data service to assist DM1 patients on intensive insulin treatment. Methods: A software application called Diab-Memory (based on Java 2 Mobile Edition) has been developed to support patients when entering diabetes-related data with synchronization to the remote database at the monitoring center. The data were then processed to generate statistics and trends, which were provided for the patient and his/her health care professional via a Web portal. The system has been evaluated in the course of a clinical before-after pilot trial. Outcome measures focused on patients’ adherence to the therapy, availability of the monitoring system, and the effects on metabolic status. General user acceptance of the system was evaluated using a questionnaire. Results: Ten patients (four female) with DM1 participated in the trial. Mean age was 36.6 years (± 11.0 years) and prestudy glycated hemoglobin (HbA1c) was 7.9% (± 1.1%). A total of 3850 log-ins were registered during the 3 months of the study. The total number of received datasets was 13003, which equates to an average of 14 transmitted parameters per patient per day. The service was well accepted by the patients (no dropouts), and data transmission via mobile phone was successful on the first attempt in 96.5% of cases. Upon completion of the study, a statistically significant improvement in metabolic control was observed (HbA1c: prestudy 7.9% ± 1.1% versus poststudy 7.5% ± 0.9%;P= .02). While there was a slight decrease in average blood glucose level (prestudy 141.8 mg/dL ± 22.5 mg/dL vs poststudy 141.2 mg/dL ± 23.1 mg/dL;P= .69), the difference was not statistically significant. Conclusion: The results of the clinical pilot trial indicate that this proposed diabetes management system was well accepted by the patients and practical for daily usage. Thus, using the mobile phone as patient terminal seems to provide a ubiquitous, easy-to-use, and cost efficient solution for patient-centered data acquisition in the management of DM1. To confirm the promising results of the pilot trial further research has to be done to study long-term effects on glycemic control and cost-effectiveness. [J Med Internet Res 2007;9(5):e36]

Summary Low density lipoprotein (LDL-C) levels determine the cardiovascular risk. Previous studies indicated an LDL-C target attainment of around 50 %, but no Austrian wide analysis on results for the federal states was available. We therefore sought to detect potential differences. Design: Open-label, non-interventional, longitudinal study, registered: www.clinicaltrials.gov NCT 01381679. In all, 746 statin treated patients not at LDL-C goal received intensified therapy for 12 months. The sample was split into nine subgroups, representing the federal states of Austria. We detected an east-west gradient for baseline LDL-C. Individual target values were achieved by 37.2 % (range: 26.1–57.7 %). After 12 months, LDL-C

Zusammenfassung Adipositas und Typ 2 Diabetes werden heute gerne unter dem Namen „Diabesity“ zusammengefasst. Das trägt dem Umstand Rechnung, dass die Adipositas dem Diabetes häufig vorangeht und wohl der wichtigste Faktor in der Zunahme des Typ 2 Diabetes mellitus ist. Der Body-Mass-Index (BMI) ist nur ein sehr grobes Maß der Körperverfettung. Sogar Normalgewichtige können bei Muskelmangel zu viel Körperfett aufweisen (Sarkopenie), weswegen Messungen des Bauchumfanges und des Körperfettes empfohlen werden (z. B. BIA). Lebensstilmanagement mit Ernährung und Bewegung ist eine der wichtigsten Maßnahmen in der Diabetesprävention. In der Therapie des Typ 2 Diabetes hat das Gewicht als sekundärer Zielparameter zunehmend Bedeutung erlangt. Auch die Wahl der antidiabetischen Therapie, aber auch der Begleittherapien, nimmt immer mehr darauf Rücksicht. Welchen Stellenwert Antiadiposita selbst in der antidiabetischen Therapie erlangen werden, wird durch zukünftige Studien zu klären sein. Die bariatrische Chirurgie ist derzeit bei einem Typ 2 Diabetes mit BMI > 35 kg/m2 indiziert und kann zumindest teilweise zur Diabetes-Remission beitragen, sie muss aber in ein entsprechendes lebenslanges Betreuungskonzept eingebunden sein.

Background Bariatric patients often suffer from vitamin D deficiency (VDD), and both, morbid obesity and VDD, are related to non-alcoholic fatty liver disease. However, limited data are available regarding best strategies for treating VDD, particularly, in bariatric patients undergoing omega-loop gastric bypass (OLGB). Therefore, we examined the efficacy and safety of a forced vitamin D dosing regimen and intervention effects in liver fibrotic patients.

Insulin resistance in visceral obesity is substantially driven by adipose tissue inflammation, particularly by macrophages accumulating in obese adipose tissue. In contrast, adipose tissue macrophages express the hemoglobin scavenger receptor (CD163) and heme oxygenase-1 (gene: HMOX1) that together protect from oxidative stress. Our aim was to evaluate the expression of CD163 and HMOX1 in intra-abdominal visceral (omental) and subcutaneous adipose tissue as well as circulating soluble CD163 concentrations in human obesity and its association with adipose tissue inflammation, body fat distribution and insulin resistance.CD163, HMOX1 and CD68 mRNA expression in visceral and subcutaneous adipose tissue, serum concentration of soluble CD163 in morbidly obese patients (body mass index (BMI)40 kg m(-2)), who underwent laparoscopic surgery for gastric banding (n=20), matched for age and sex to controls (BMI30 kg m(-2); n=20) was analyzed.CD163 expression was highly upregulated in human adipose tissue and soluble CD163 serum concentration was elevated in obese vs lean subjects. HMOX1 was upregulated in adipose tissue by obesity as well and expressed predominantly in macrophages. Although CD163 expression strictly correlated with macrophage abundance, HMOX1 was additionally upregulated within macrophages. This upregulation was significantly lower in visceral compared with subcutaneous adipose tissue. Strikingly, relative visceral adipose tissue expression of HMOX1 negatively correlated with waist-to-hip ratio and the homeostasis model assessment of insulin resistance (both P=0.024).Visceral obesity is associated with defective upregulation of heme oxygenase-1 in visceral adipose tissue. A lack of this antioxidative and anti-inflammatory enzyme in visceral adipose tissue could contribute to the development of insulin resistance.

The fasting proinsulin-to-insulin ratio is a currently used marker of β-cell dysfunction. This ratio is calculated at the basal condition, but its behavior in dynamic conditions, i.e., during glucose stimulation, could be more informative. Given the different kinetics of the peptides, a mathematical model was necessary to analyze the oral glucose tolerance test (OGTT) data of insulin, C-peptide, and proinsulin in 55 healthy (NGT), 30 impaired glucose-tolerant (IGT), and 31 type 2 diabetic (T2DM) subjects. The model provided for secretion and disappearance of the peptides and an index of β-cell function under dynamic conditions. Total proinsulin secretion during the OGTT was not different ( P > 0.053) among NGT (0.17 ± 0.01 mmol/l in 3 h), IGT (0.22 ± 0.02), and T2DM (0.21 ± 0.02) subjects. The proinsulin-to-insulin molar ratio measured from basal samples was higher ( P < 0.0001) in T2DM (0.39 ± 0.05) than in NGT (0.14 ± 0.01) and IGT (0.13 ± 0.02) subjects, and similar results ( P < 0.003) were found by the dynamic index (0.27 ± 0.04, 0.14 ± 0.01, 0.15 ± 0.01 in T2DM, NGT, IGT subjects, respectively). The basal ratio significantly correlated with the dynamic index, and the regression line slope was lower than 1 (0.43 ± 0.08, 0.61 ± 0.10, and 0.56 ± 0.03 in NGT, IGT, and T2DM subjects, respectively, P < 0.0001). Impaired β-cell function in T2DM could then be indicated by proinsulin-to-insulin indexes at both basal and dynamic phases.

OBJECTIVE To evaluate β-cell secretion and glucose metabolism in lean subjects with gestational diabetes mellitus (GDM) compared with that in subjects with normal pregnancy and obesity. RESEARCH DESIGN AND METHODS Insulin secretion, insulin sensitivity (S1), and hepatic insulin extraction were assessed in pregnant women with GDM before and after delivery and in those with normal glucose tolerance (NGT) in comparison to healthy nonpregnant lean and obese women. Kinetic analysis of glucose, insulin, and C-peptide plasma concentrations during oral and intravenous glucose tolerance tests was performed by mathematical modeling. RESULTS S1 was blunted in pregnant women with GDM by 84% and in those with NGT by 66% compared with lean nonpregnant women (P < 0.005 vs. healthy nonpregnant lean control subjects; P < 0.05, GDM vs. pregnant women with NGT), whereas glucose effectiveness was decreased by 33% in both pregnant groups (P < 0.05 vs. healthy nonpregnant lean control subjects). Insulin secretion was 30% higher (P < 0.05) in subjects with GDM than in pregnant women with NGT or in nonpregnant lean women, but decreased (P < 0.005) when compared with obese women with a comparable degree of insulin resistance. Fractional hepatic insulin extraction was similar in both pregnant groups, being lower (P < 0.0001) by 30% versus nonpregnant females. β-cell sensitivity to glucose for insulin release was decreased in subjects with GDM versus pregnant women with NGT as well as nonpregnant women by 40-50% (P < 0.01). Twelve weeks after delivery, GDM returned to normal glucose tolerance, but S1 remained 50% lower than that in lean nonpregnant women, while β-cell sensitivity to glucose did not change (P < 0.01 vs. healthy nonpregnant lean control subjects). CONCLUSIONS Pregnancy is characterized by insulin resistance, diminished hepatic insulin extraction, and glucose effectiveness. Lean subjects with GDM are additionally characterized by having more pronounced insulin resistance and inadequate insulin secretion, which persist after delivery. Compared with other insulin-resistant prediabetic states like impaired glucose tolerance (IGT), defective insulin secretion seems to be a predominant defect in lean GDM subjects, indicating that it might represent a specific prediabetic condition.