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Background, Aims: In patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects., Patients and Methods: In a two-way crossover design, insulinotropic responses to repeated bolus injection (50 pmol/kg body weight at 30 and 120 min) and continuous infusion of GIP (2 pmol.kg-1.min-1 from 30 to 180 min) under hyperglycaemic clamp conditions (8.5 mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects., Results: Insulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, -13.2 %, p < 0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP., Conclusions: Rapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The glucagon-like peptide-1 (GLP-1) is a multifaceted hormone with broad pharmacological potential. Among the numerous metabolic effects of GLP-1 are the glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, inhibition of food intake, increase of natriuresis and diuresis, and modulation of rodent β-cell proliferation. GLP-1 also has cardio- and neuroprotective effects, decreases inflammation and apoptosis, and has implications for learning and memory, reward behavior, and palatability. Biochemically modified for enhanced potency and sustained action, GLP-1 receptor agonists are successfully in clinical use for the treatment of type-2 diabetes, and several GLP-1-based pharmacotherapies are in clinical evaluation for the treatment of obesity., Scope of Review: In this review, we provide a detailed overview on the multifaceted nature of GLP-1 and its pharmacology and discuss its therapeutic implications on various diseases., Major Conclusions: Since its discovery, GLP-1 has emerged as a pleiotropic hormone with a myriad of metabolic functions that go well beyond its classical identification as an incretin hormone. The numerous beneficial effects of GLP-1 render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders., (Copyright © 2019 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: Obesity has been shown to trigger adaptive increases in pancreas parenchymal and fat volume. Consecutively, pancreatic steatosis may lead to beta-cell dysfunction. However, it is not known whether the pancreatic tissue components decrease with weight loss and pancreatic steatosis is reversible following Roux-en-Y gastric bypass (RYGB). Therefore, the objective of the study was to investigate the effects of RYGB-induced weight loss on pancreatic volume and glucose homeostasis., Methods: Eleven patients were recruited in the Obesity Centre of the University Medical Centre Hamburg-Eppendorf. Before and 6 months after RYGB, total GLP-1 levels were measured during oral glucose tolerance test. To assess changes in visceral adipose tissue and pancreatic volume, MRI was performed. Measures of glucose homeostasis and insulin indices were assessed. Fractional beta-cell area was estimated by correlation with the C-peptide-to-glucose ratio; beta-cell mass was calculated by the product of beta-cell area and pancreas parenchymal weight., Results: Pancreas volume decreased from 83.8 (75.7-92.0) to 70.5 (58.8-82.3) cm 3 (mean [95% CI], P = .001). The decrease in total volume was associated with a significant decrease in fat volume. Fasting insulin and C-peptide were lower post RYGB. HOMA-IR levels decreased, whereas insulin sensitivity increased (P = .03). This was consistent with a reduction in the estimated beta-cell area and mass., Conclusions: Following RYGB, pancreatic volume and steatosis adaptively decreased to "normal" levels with accompanying improvement in glucose homeostasis. Moreover, obesity-driven beta-cell expansion seems to be reversible; however, future studies must define a method to more accurately estimate functional beta-cell mass to increase our understanding of glucose homeostasis after RYGB., (Copyright © 2018 John Wiley & Sons, Ltd.)

Two female patients were admitted due to ketoacidosis. Serum glucose was moderately elevated. The patients exhibited abdominal and neurologic symptoms. Treatment consisted of metformin, insulin glargin and empagliflozin, as well as glimepiride, insulin detemir and empagliflozin, respectively. Treatment with intravenous fluid replacement, insulin, glucose, potassium and buffer solution led to a normalisation of pH and serum glucose levels. Our report describes two cases of atypical ketoacidosis with moderately elevated serum glucose during sodium-glucose co-transporter-2 (SGLT2) inhibitor therapy.

A 64-year-old woman presented with a history of recurrent hypoglycemia. A prolonged fasting test revealed an increased "amended" insulin-glucose ratio. Transabdominal ultrasound (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) did not show abnormal results. An insulinoma was suspected based on a contrast-enhanced endoscopic US examination as well as a (68)gallium-DOTA-exendin-4 positron-emission tomography (PET)/CT. The diagnosis of an insulinoma was confirmed histologically after surgical removal of the tumor. Hypoglycemia did not occur during the postoperative period. The prolonged fasting test is the gold standard for the diagnosis of an insulinoma. Novel imaging procedures, such as contrast-enhanced endoscopic US or (68)gallium-DOTA-exendin-4 PET/CT are valuable additions to the diagnostic workup.

New glucose-lowering drugs have raised the complexity of diabetes treatment in recent years. While metformin is still the first choice in monotherapy for most cases, various options exist for dual combination therapy. In addition, combinations of three different oral glucose-lowering drugs are increasingly used. Insulin therapy is typically initiated using once daily administration of a long-acting insulin. If basal insulin alone is no longer sufficient, treatment can be intensified by adding short-acting insulin at mealtime or by combining basal insulin with oral glucose-lowering drugs or a glucagon-like peptide (GLP)-1 analogue. The choice of the most appropriate glucose-lowering drug should take into account not only the glucose-lowering efficacy, but also the side effect profile of the respective agents; economic factors must be considered as well. Modern treatment of type 2 diabetes should aim for near-normal glucose control.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA1c upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. In contrast, where GLP-1 is administered as a short-term intravenous infusion, a full normalisation of glucose concentrations (approximately 5 mmol/l) has been observed without any risk of gastrointestinal side effects. Subcutaneous infusions or injections of GLP-1 are much less effective. The present analysis relates the proportion of patients who report nausea following treatment with GLP-1 and GLP-1 RAs to the clinical effectiveness of the treatment (represented by the fasting glucose concentration achieved with treatment). The results suggest that GLP-1 RAs injected into the subcutaneous compartment do not exploit the full potential inherent in GLP-1 receptor activation. Reasons for this may include modifications of the peptide molecules in the subcutaneous environment or high local concentrations triggering side effects through GLP-1 receptors on autonomic nerves in subcutaneous adipose tissue. Elucidation of the mechanisms underlying differential responses to GLP-1/GLP-1 RAs administered intravenously vs subcutaneously may help to develop improved agents or modes of administration that are more effective and have fewer side effects.

Objective: Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy., Research Design and Methods: This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA1c, 7.7 %), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to ≤ 10 or ≤ 20 mg/day, respectively., Results: The primary end point, adjusted mean HbA1c reduction with dapagliflozin (-0.52 %) compared with glipizide (-0.52 %), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (-3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving ≥ 5 % body weight reduction (33.3 %) versus glipizide (2.5 %; p < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5 %) versus glipizide (40.8 %; p < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation., Conclusions: Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Aim: Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion?, Methods: Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8-week treatment period with insulin glargine. Glucose, insulin and C-peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis., Results: Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C-peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non-significant increases in both pulsatile and non-pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass (r(2) = 0.51 and 0.56, respectively), whereas non-pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations (r(2) = 0.0073 and 0.031)., Conclusions: Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous β-cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes., (© 2012 Blackwell Publishing Ltd.)

Aims/hypothesis: Diabetes frequently develops in patients with pancreatic disorders. We aimed to determine the lower threshold of beta cell area for diabetes manifestation as well as the impact of insulin sensitivity on glucose homoeostasis in patients with pancreatic diabetes., Methods: Eighty-two patients undergoing pancreatic surgery underwent pre-operative oral glucose challenge. Fractional pancreatic beta cell area was determined, and indices of insulin sensitivity and beta cell function were calculated., Results: HbA1c and glucose levels were similar in patients with high and intermediate beta cell area, but were significantly higher in those with the lowest beta cell area (p < 0.0001). Insulin secretion was reduced only in patients with the lowest beta cell area (p < 0.001). The relative beta cell deficits at the onset of diabetes and impaired glucose tolerance were 64% and 21%, respectively, based on 2 h glucose levels. Deteriorating insulin sensitivity was associated with a small increase in the incidence of diabetes., Conclusions/interpretation: In conclusion, pancreatic diabetes probably develops after a reduction in beta cell area of ~65%. Post-challenge glucose excursions are much more closely related to pancreatic beta cell area than to fasting glycaemia, thereby underlining the usefulness of the OGTT in patients with pancreatic disorders.

Patients with type 2 diabetes have an increased risk for developing symptoms of heart failure. These can be accompanied by a reduction of left ventricular ejection fraction (HFREF, systolic heart failure) or by a preserved function (HFPEF, diastolic heart failure). The pathophysiology of both entities is distinct and involves impairment of myocardial metabolism and coronary circulation alike. Although diabetes and heart failure often coincide, the management of these patients particularly with respect to the specific benefits or possible hazards of antidiabetic treatment is vague. Therefore, from a pathophysiological as well as clinical viewpoint, 1) diabetic patients with symptoms of heart failure have to be differentiated regarding systolic as well as diastolic left ventricular function by echocardiography and tissue doppler imaging. 2) Heart failure in diabetic patients needs similar attention due to a prognosis and interactions. 3) Optimized blood glucose lowering in combination with improvement of other cardiovascular risk factors is evident for HFREF and is assumed to be beneficial for HFPEF. 4) Antidiabetic medication has to be specifically adapted for both entities. As prospective, controlled studies are scarce, future interventional studies should specifically focus on clinical outcome in diabetic patients with different entities of heart failure., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: The histopathology of lichen sclerosus (LS) suggests abnormalities in extracellular matrix (ECM) composition., Objectives: We aimed to investigate the expression pattern of ECM proteins and related growths factors and Smad signal transducers in LS as compared with healthy skin., Methods: To assess the expression of decorin, biglycan, versican, perlecan, fibronectin, dermatopontin, extracellular matrix protein 1 (ECM-1), matrix metalloproteinase 1, tissue inhibitor of metalloproteinase 1, connective tissue growth factor (CTGF), transforming growth factor β1, and Smad-3 protein, real-time RT-PCR and immunohistochemistry were performed on skin specimens obtained from the genital region of healthy subjects (n = 10) as well as LS patients (n = 26)., Results: Median mRNA as well as mean protein expression of biglycan, versican, fibronectin, and ECM-1 was significantly higher in LS when compared with healthy controls. Both mRNA and protein CTGF expression observed in LS was significantly higher than in controls. CTGF mRNA expression significantly correlated with mRNA expression of biglycan, versican and fibronectin., Conclusions: Expression of ECM proteins (e.g. proteoglycans, ECM-1) and CTGF is altered in LS. TGF-ß/Smad-3 independent up-regulation of CTGF may induce accumulation of ECM proteins and maintain fibrosis in chronic LS., (© 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.)

Although liver damage is a relatively rare adverse effect of oral anticoagulation with phenprocoumon, acute liver failure can be a serious treatment-associated complication. In this contribution, a patient with drug-induced liver failure during oral anticoagulation with phenprocoumon is presented. This case illustrates the need for close laboratory monitoring and suggests that phenrocoumon-induced liver damage should be considered along with other common complications of this treatment.

The incretin hormones gastric inhibitory polypeptide and especially glucagon-like peptide (GLP) have an important physiological function in augmenting postprandial insulin secretion. Since GLP-1 may play a role in the pathophysiology and treatment of type 2 diabetes, assessment of meal-related GLP-1 secretory responses in type 2 diabetic patients vs healthy individuals is of great interest. A common view states that GLP-1 secretion in patients with type 2 diabetes is deficient and that this applies to a lesser degree in individuals with impaired glucose tolerance. Such a deficiency is the rationale for replacing endogenous incretins with GLP-1 receptor agonists or re-normalising active GLP-1 concentrations with dipeptidyl peptidase-4 inhibitors. This review summarises the literature on this topic, including a meta-analysis of published studies on GLP-1 secretion in individuals with and without diabetes after oral glucose and mixed meals. Our analysis does not support the contention of a generalised defect in nutrient-related GLP-1 secretory responses in type 2 diabetes patients. Rather, factors are identified that may determine individual incretin secretory responses and explain some of the variations in published findings of group differences in GLP-1 responses to nutrient intake.

Aims/hypothesis: Diabetes frequently develops in patients with chronic pancreatitis (CP). Partial pancreatectomy has emerged as a treatment option for such patients. We addressed whether the development of diabetes in CP patients is related to pancreatic beta cell area or clinical variables, and which factors predict the diabetes risk after partial pancreatectomy., Methods: Fractional beta cell area was determined in pancreatic tissue samples obtained from 114 CP patients undergoing pancreatic surgery and related to measures of glucose control, as well as clinical and anthropometric data. Seventy-four patients without diabetes at the time of surgery were contacted again 2.5 +/- 1.0 years after partial pancreatectomy in order to obtain information about the post-operative development of diabetes., Results: In the surgical samples in the whole cohort, pancreatic beta cell area was 0.40 +/- 0.06% in patients with and 0.64 +/- 0.06% in those without previously known diabetes (p = 0.039). There was an inverse non-linear relationship between pancreatic beta cell area and fasting glucose concentrations (r = 0.29) as well as HbA(1c) levels (r = 0.36). Nineteen out of 74 previously normoglycaemic patients (26%) developed diabetes over an average period of 2.5 years of follow-up. Pre-operative fasting glucose levels, HbA(1c) and BMI were identified as predictors of diabetes after partial pancreatectomy. However, pancreatic beta cell area did not differ in those who subsequently developed diabetes (0.66 +/- 0.15%) and those who did not (0.62 +/- 0.08%, p = 0.45)., Conclusions/interpretation: Hyperglycaemia in CP patients is associated with reduced beta cell area. However, reduced beta cell area does not predict the development of diabetes, suggesting that other factors are more important determinants of alterations in glucose metabolism in patients with CP.

Introduction: Postprandial hyperglycaemia is often assumed in individuals with high glucose excursions during an oral glucose tolerance test (OGTT), but the relationship between glucose levels during the OGTT and after a mixed meal is yet unclear. We addressed whether (i) glucose concentrations after an oral glucose load are similar to those after a test meal or under daily life conditions and (ii) impaired glucose tolerance (IGT) predicts postprandial hyperglycaemia., Patients and Methods: A total of 60 subjects with normal (NGT), IGT or diabetic (DM) glucose tolerance were examined with an OGTT, a mixed meal challenge (3433 kJ) and a self-determined 10-point home glucose profile., Results: There was a significant correlation between the 120-min OGTT glucose levels and the glycaemic excursions after the test meal and during everyday conditions. However, glucose excursions during the OGTT exceeded those after the test meal and during everyday conditions by approximately 20 and approximately 30% respectively. Likewise, insulin and C-peptide levels rose to higher levels after oral glucose compared with mixed meal ingestion. The mean self-determined diurnal glucose levels were already 10% higher in subjects with IGT compared with NGT subjects (p < 0.0001)., Conclusions: Glucose levels reached after an oral glucose challenge and during real life are correlated to some extent, but the absolute levels of glycaemia greatly differ between both conditions. Therefore, 'postchallenge' glucose levels measured during an OGTT might be used as a predictor of 'postprandial hyperglycaemia', but caution should be taken when both terms are used synonymously. Furthermore, subjects with IGT during an OGTT already exhibit increased postprandial glucose levels under real-life conditions. This suggests that IGT should already be considered an overt disease condition rather than merely a high-risk situation.

Aims/hypothesis: Partial pancreatectomy is frequently performed in patients with pancreatic tumours or chronic pancreatitis, but little is known about the metabolic impact of this intervention. We examined the effects of approximately 50% partial pancreatectomy on glucose homeostasis and insulin secretion., Methods: Fourteen patients with chronic pancreatitis, ten patients with pancreatic carcinoma and 13 patients with benign pancreatic tumours or extra-pancreatic masses (control group) underwent 240 min oral glucose tolerance tests before and after pancreatic tail-resection (n = 12), duodenopancreatectomy (n = 19) or duodenum-preserving pancreatic-head resection (n = 6)., Results: Partial pancreatectomy led to a reduction in post-challenge insulin excursions by 49% in chronic pancreatitis patients, 52% in carcinoma patients and 55% in controls (p < 0.05). Nevertheless, post-challenge glucose concentrations were transiently ameliorated after surgery (p < 0.001). In the control participants, pancreatic-head resection caused a transient reduction of post-challenge glycaemia, whereas pancreatic-tail resection increased both fasting and post-challenge glycaemia (p < 0.05). Insulin sensitivity was highest in chronic pancreatitis patients before surgery (p < 0.01), but remained unchanged by the partial pancreatectomy. High pre-operative body weight and elevated fasting glucose levels were associated with poor glycaemic control after surgery., Conclusions/interpretation: Insulin secretion is diminished after pancreatic-head and -tail resection, but post-challenge glucose concentrations can be ameliorated after pancreatic-head resection. These data highlight the unequal impact of different surgical procedures on glucose control and suggest that obesity and high pre-operative glucose levels should be considered as risk factors for the development of hyperglycaemia after pancreatic surgery.

Beta cell deficiency underlies both type 1 and type 2 diabetes, and restoration or replacement of beta cell function is therefore the logical long-term solution to therapy. This review sets out to describe the defects in beta cell mass and function in both forms of diabetes, summarises current understanding of the underlying causes of beta cell death, and the methodological limitations of determining beta cell mass in vivo. Finally, the potential effects of current and future treatment regimens on beta cell mass and turnover are considered.

Our aims were (1) by computed tomography (CT) to establish a population database for pancreas volume (parenchyma and fat) from birth to age 100 years, (2) in adults, to establish the impact of gender, obesity, and the presence or absence of type-2 diabetes on pancreatic volume (parenchyma and fat), and (3) to confirm the latter histologically from pancreatic tissue obtained at autopsy with a particular emphasis on whether pancreatic fat is increased in type-2 diabetes. We measured pancreas volume in 135 children and 1,886 adults (1,721 nondiabetic and 165 with type-2 diabetes) with no history of pancreas disease who had undergone abdominal CT scan between 2003 and 2006. Pancreas volume was computed from the contour of the pancreas on each CT image. In addition to total pancreas volume, parenchymal volume, fat volume, and fat/parenchyma ratio (F/P ratio) were determined by CT density. We also quantified pancreatic fat in autopsy tissue of 47 adults (24 nondiabetic and 23 with type-2 diabetes). During childhood and adolescence, the volumes of total pancreas, pancreatic parenchyma, and fat increase linearly with age. From age 20-60 years, pancreas volume reaches a plateau (72.4 +/- 25.8 cm(3) total; 44.5 +/- 16.5 cm(3) parenchyma) and then declines thereafter. In adults, total ( approximately 32%), parenchymal ( approximately 13%), and fat ( approximately 68%) volumes increase with obesity. Pancreatic fat content also increases with aging but is not further increased in type-2 diabetes. We provide lifelong population data for total pancreatic, parenchymal, and fat volumes in humans. Although pancreatic fat increases with aging and obesity, it is not increased in type-2 diabetes., (2007 Wiley-Liss, Inc)

Aims/hypothesis: Type 1 diabetes is characterised by a deficit in beta cell mass thought to be due to immune-mediated increased beta cell apoptosis. Beta cell turnover has not been examined in the context of new-onset type 1 diabetes with diabetic ketoacidosis., Methods: Samples of pancreas were obtained at autopsy from nine patients, aged 12 to 38 years (mean 24.3+/-3.4 years), who had had type 1 diabetes for less than 3 years before death due to diabetic ketoacidosis. Samples of pancreas obtained at autopsy from nine non-diabetic cases aged 11.5 to 38 years (mean 24.2+/-3.4 years) were used as control. Fractional beta cell area (insulin staining), beta cell replication (insulin and Ki67 staining) and beta cell apoptosis (insulin and TUNEL staining) were measured., Results: In pancreas obtained at autopsy from recent-onset type 1 diabetes patients who had died of diabetic ketoacidosis, the beta cell deficit varied from 70 to 99% (mean 90%). The pattern of beta cell loss was lobular, with almost all beta cells absent in most pancreatic lobules; islets in lobules not devoid of beta cells had reduced or a near-normal complement of beta cells. Beta cell apoptosis was increased in recent-onset type 1 diabetes, but to a surprisingly modest degree given the marked hyperglycaemia (30 mmol/l), acidosis and presumably high NEFA. Beta cell replication, scattered pancreatic beta cells and beta cells in exocrine ducts were not increased in recent-onset type 1 diabetes., Conclusions/interpretation: These findings do not support the notion of active beta cell regeneration by replication in new-onset type 1 diabetes under conditions of diabetic ketoacidosis. The gluco-lipotoxicity reported in isolated human islets may be less evident in vivo.

The development of a variety of new substances will considerably expand the therapeutic choices in the treatment of type 2 diabetes. In 2006, the endocannabinoid receptor blocker Rimonabant has been approved for the treatment of type 2 diabetes in Germany. This compound has led to significant reductions of body weight along with improvements of HbA1c levels and lipid profiles, but the lack of health insurance coverage limits its large scale use in germany. In April 2007, the first members of the GLP 1 analogues/incretin mimetics (exenatide, Byetta) and DPP 4 inhbitors (sitagliptin, Januvia) have become available for the treatment of type 2 diabetes in Germany. Both drugs have significantly lowered HbA1c levels in clinical studies. In addition, the incretin mimetics have caused a progressive reduction of body weight, while the DPP 4 inhibitors have been rather weight neutral. Sitagliptin can be administered orally, whereas exenatide has to be injected subcutaneously. Neither the DPP 4 inhibitors, nor the incretin mimetics have led to the development of hypoglycaemia, unless combined with sulfonylureas. Overall, the introduction of these new drug classes will certainly broaden our therapeutic choices in the management of type 2 diabetes. The long-term effects of these drugs on the development of diabetic complications in long-term trials remains to be awaited.

Aims/hypothesis: The incretin effect describes the augmentation of postprandial insulin secretion by gut hormones. It is not known whether glucagon secretion is also influenced by an incretin effect. A glucagon suppression deficiency has been reported in some patients with type 2 diabetes, but it is unclear whether this abnormality is present prior to diabetes onset. We therefore addressed the questions: (1) Is glucagon secretion different after oral and during intravenous glucose administration? (2) If so, is this related to the secretion of incretin hormones? (3) Is glucagon secretion abnormal in first-degree relatives of patients with type 2 diabetes?, Materials and Methods: We examined 16 first-degree relatives of patients with type 2 diabetes and ten matched control subjects with an oral glucose load (75 g) and with an 'isoglycaemic' intravenous glucose infusion., Results: Glucagon levels were significantly suppressed by both oral and intravenous glucose (p < 0.0001), but glucagon suppression was more pronounced during intravenous glucose administration (76 +/- 2%) than after oral glucose administration (48 +/- 4%; p < 0.001). The differences in the glucagon responses to oral and i.v. glucose were correlated with the increments in gastric inhibitory polypeptide (GIP) (r = 0.60, p = 0.001) and glucagon-like peptide (GLP)-1 (r = 0.46, p < 0.05). There were no differences in glucagon levels between first-degree relatives and control subjects., Conclusions/interpretation: Despite the glucagonostatic actions of GLP-1, the suppression of glucagon secretion by glucose is diminished after oral glucose ingestion, possibly due to the glucagonotropic actions of GIP and GLP-2. Furthermore, in this group of first-degree relatives, abnormalities in glucagon secretion did not precede the development of other defects, such as impaired insulin secretion.

Aims/hypothesis: Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases?, Methods: Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy., Results: Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour., Conclusions/interpretation: One or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumour-distant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.

Aims/hypothesis: We investigated whether there was evidence of attempted beta cell regeneration in the pancreas obtained from a patient with recent-onset type 1 diabetes, and if so by what mechanism this occurred., Subjects, Materials and Methods: We examined pancreas tissue from a lean 89-year-old patient (BMI 18.0 kg/m(2)) with recent-onset type 1 diabetes who had had a distal pancreatectomy to remove a low-grade pancreatic intraepithelial neoplasia., Results: In the tumour-free tissue, the fractional beta cell area was 0.54+/-0.2% of pancreas area (about one-third of that in non-diabetic humans). CD3-positive T lymphocytes and macrophages had infiltrated the majority of the islets. Subclassification of the T cell population revealed a predominance of CD8-positive cells over CD4-positive cells. Beta cell apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling [TUNEL] staining) was greatly increased, consistent with ongoing immune-mediated beta cell destruction. There was also a marked increase (more than approximately 100-fold) in the frequency of beta cell replication (0.69+/-0.15% Ki67-positive beta cells) in all blocks examined., Conclusions/interpretation: The present report provides direct evidence of attempted beta cell regeneration through the mechanism of beta cell replication in a case of newly diagnosed type 1 diabetes, and affirms that beta cell apoptosis is an important mechanism for beta cell loss in type 1 diabetes.

Aims/hypothesis: Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed., Methods: 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1)) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a (13)C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA., Results: GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, -0.023+/-0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31+/-5% after meal ingestion (p<0.01)., Conclusions/interpretation: GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.

Aims/hypothesis: Beta cell destruction in type 1 diabetes is apparently mediated by the release of cytokines. We questioned whether cytokine-induced apoptosis preferentially kills replicating beta cells., Materials and Methods: In the first experiment, rat insulinoma (RIN) cells were studied for 36 h by time-lapse video microscopy. Cells were exposed to three doses of a cytokine mixture (maximal concentration: IL-1beta 50 U/ml; TNF-alpha 1,000 U/ml; IFN-gamma 1,000 U/ml) or vehicle and analysed for the total cell number (2-h intervals) and timing of each cell death and division. In the second experiment, isolated human islets were incubated with the same cytokine mixture for 24 h and examined for replication and paired (postmitotic) apoptosis., Results: In the first experiment, after application of cytokines, apoptosis occurred most frequently immediately after the next or subsequent cell mitosis (p<0.05). In the second experiment, cytokines caused increased apoptosis in human islets, with an increase in the proportion of postmitotic apoptotic pairs (p<0.001)., Conclusions/interpretation: Cytokine-induced beta cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. Efforts to expand beta cell mass in type 1 diabetes by fostering beta cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed.

Aims/hypothesis: Type 1 diabetes is widely held to result from an irreversible loss of insulin-secreting beta cells. However, insulin secretion is detectable in some people with long-standing type 1 diabetes, indicating either a small population of surviving beta cells or continued renewal of beta cells subject to ongoing autoimmune destruction. The aim of the present study was to evaluate these possibilities., Materials and Methods: Pancreatic sections from 42 individuals with type 1 diabetes and 14 non-diabetic individuals were evaluated for the presence of beta cells, beta cell apoptosis and replication, T lymphocytes and macrophages. The presence and extent of periductal fibrosis was also quantified., Results: Beta cells were identified in 88% of individuals with type 1 diabetes. The number of beta cells was unrelated to duration of disease (range 4-67 years) or age at death (range 14-77 years), but was higher (p<0.05) in individuals with lower mean blood glucose. Beta cell apoptosis was twice as frequent in type 1 diabetes as in control subjects (p<0.001), but beta cell replication was rare in both groups. The increased beta cell apoptosis in type 1 diabetes was accompanied by both increased macrophages and T lymphocytes and a marked increase in periductal fibrosis (p<0.001), implying chronic inflammation over many years, consistent with an ongoing supply of beta cells., Conclusions/interpretation: Most people with long-standing type 1 diabetes have beta cells that continue to be destroyed. The mechanisms underlying increased beta cell death may involve both ongoing autoimmunity and glucose toxicity. The presence of beta cells despite ongoing apoptosis implies, by definition, that concomitant new beta cell formation must be occurring, even after long-standing type 1 diabetes. We conclude that type 1 diabetes may be reversed by targeted inhibition of beta cell destruction.

Aims/hypothesis: The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion., Materials and Methods: On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg(-1) min(-1); 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA., Results: Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration., Conclusions/interpretation: These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

Glucose-dependent insulinotropic polypeptide (GIP) is released from K-cells in the gut after meal ingestion, and acts in concert with glucagon-like peptide 1 (GLP-1) to augment glucose-stimulated insulin secretion. While derivatives of GLP-1 are under active investigation for the treatment of type 2 diabetes, the case is different for GIP. Indeed, the insulinotropic effect of GIP is almost absent in patients with type 2 diabetes. In addition, the unfavourable pharmacokinetic profile of native GIP obviates its clinical application. Different analogues of GIP exhibiting prolonged stability and enhanced biological potency have been generated in order improve the anti-diabetic properties of GIP. However, glucose-normalisation, as is typically observed during the intravenous administration of GLP-1 in patients with type 2 diabetes, has not yet been achieved with GIP or its derivatives. Since GIP appears to play a role in lipid physiology and elevated levels of GIP have been associated with obesity, antagonising GIP action has been proposed as a therapeutic strategy for obesity. This concept has recently been reinforced by the observation that GIP receptor knock-out mice are protected from high-fat diet-induced obesity. However, eliminating the effect of endogenous GIP may at the same time impair postprandial insulin secretion, thereby severely disturbing glucose homeostasis. Therefore, therapeutic strategies based on either augmenting or antagonising GIP action are far from being established alternatives for the future therapy of type 2 diabetes or obesity.

Background/aims: In vitro studies suggest that glucagon-like peptide 2 (GLP-2), secreted from enteroendocrine cells in the gastrointestinal tract after food intake, is able to ameliorate mucosal injury in settings of human disease characterized by injury and dysfunction of the intestinal mucosal epithelium. We evaluated this potential of GLP-2 after epithelial trauma by using two in vitro models measuring intestinal epithelial cell proliferation and cell migration., Materials and Methods: Injuries were induced in confluent monolayers of the small intestinal cells lines IEC-6 and IEC-18, as well as in the colonic cell lines Caco-2 and Colo 320. GLP-2 (50-500 nM) or other peptides were added to the media. Wound healing was investigated after 24 h by quantification of the number of cells migrating across the wound edge. Proliferation of cells was assessed by using photometric mitochondrial incorporation measurement of MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide). Monoclonal TGF-beta antibodies were added to wounded monolayers to examine whether the GLP-2-induced wound healing was TGF-beta-mediated., Results: Migration assessments revealed a significant stimulation of GLP-2-induced migration in IEC-6 and IEC-18 monolayers compared to the placebo group. No effect was observed in the colon cancer cell lines Caco-2 and Colo 320. Results of the proliferation assays show a significant inhibition of proliferation by GLP-2 in small intestinal cell lines whereas a dose-dependent stimulation of proliferation in colonic epithelial cells was observed. Addition of neutralizing TGF-beta1 antibodies to wounded IEC-6 and IEC-18 monolayers incubated with GLP-2 significantly reduced the number of migrating cells to the level of the placebo group., Conclusions: In our in vitro model, it was shown that the GLP-2-induced improvement of intestinal wound healing is TGF-beta-mediated. These effects were predominant in the epithelium of the small intestine compared to colonic epithelium. Our findings provide further insight into mechanisms leading to GLP-2-induced mucosal wound healing. These results suggest that GLP-2 or analogues of this peptide may potentially be useful for the treatment of intestinal disorders characterized by injury and ineffective repair of the intestinal mucosa., (Copyright 2004 Elsevier B.V.)

In the UGDP study, published in the 1970s, a high incidence of cardiovascular mortality was found in patients treated with the sulfonylurea agent tolbutamide. Impaired ischaemic preconditioning is presumed to be the most important mechanism for the excess cardiovascular mortality observed. However, as tolbutamide has only a low affinity for cardiac sulfonylurea receptors, interference with ischaemic preconditioning seems unlikely to account for this excess mortality. Several smaller studies also failed to establish a definite link between sulfonylurea treatment before acute myocardial infarction and in-hospital mortality. However, when the myocardium becomes exposed to repeated or prolonged periods of ischaemia, ischaemic preconditioning may become clinically important. Myocardial ischaemia can also develop during emergency or elective angioplasty and during coronary bypass surgery. Therefore discontinuation of sulfonylurea treatment should be considered in these circumstances.

A follow-up study of first-degree relatives of type 2 diabetic patients presented the opportunity to study the association of components of the metabolic syndrome with oral glucose tolerance in these subjects. In 1992, 25 years after the first analysis of the cohort, we performed 75-g oral glucose tolerance tests and measured anthropometric data (body mass index, waist-hip ratio), insulin and C-peptide concentrations, and parameters of lipoprotein metabolism (free fatty acids, triglycerides, cholesterol, HDL cholesterol). Of 135 participants, 71 had normal glucose tolerance (GT), 22 had impaired GT, and 42 had diabetic GT (WHO 1985 criteria). Impaired glucose tolerance and diabetes were significantly (Kruskal-Wallis test) associated with advanced age (p=0.001), higher body mass index (p=0.005) and waist-hip ratio (p=0.027), systolic hypertension (p=0.031), elevated basal insulin concentrations (p<0.001), higher free fatty acids (p<0.001) and triglycerides (p=0.017), and lower HDL cholesterol (p=0.003); no associations were found with total and LDL cholesterol levels (Friedewald's formula, p=0.25). Abnormalities (obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, pathological oral glucose tolerance) were associated with significant deterioriations in all other components of the metabolic syndrome, if their number exceeded three. Disturbances of oral glucose tolerance are present in a high percentage of first-degree relatives after 25 years of follow-up (51% of those tested). Impaired or diabetic glucose tolerance in such a cohort was associated with overweight, hypertension and disturbances of lipoprotein metabolism characteristic of the metabolic syndrome. Hypercholesterolemia (LDL-cholesterol) is not a component of the metabolic syndrome in a German population with a high hereditary burden regarding type 2 diabetes. A metabolic syndrome should certainly be diagnosed if three components are present, although even in the presence of only two components, an elevated risk is evident.

Ghrelin a novel peptide consisting of 28 amino acids was first identified in the stomach in 1999. It is mainly produced in endocrine cells of the human gastric mucosa, but it was also found in several other tissues e. g. in the pituitary, the hypothalamus and the pancreas. The functional receptor belongs to the family of the 7-transmembrane G-protein receptors and is predominantly detected in the pituitary and at lower levels in hypothalamic nuclei, the stomach, heart, lungs, kidneys, gut, the adipose and many other tissues. According to the widespread distribution of the peptide and its receptor, ghrelin has multiple biological effects: it stimulates the release of growth hormone in the pituitary and induces a rise in the serum concentration of ACTH, cortisol, catecholamines and prolactin. Ghrelin causes an increase of food intake and body weight by stimulating the production of neuropeptide Y (NPY) and agouti-related protein (AGP) in the nucleus arcuatus. It further leads to elevated concentrations of plasma glucose. A physiological antagonism between ghrelin and GLP-1 in the hypothalamic regulation of appetite is being discussed. The basic serum level of ghrelin depends on the state of nutrition and is negatively correlated with the body-mass-index. It shows a certain pattern of variation before and after food intake with a preprandial increase and a postprandial decrease. Ghrelin modulates gastric acid secretion and the gastrointestinal motility via vagal cholinergic pathways. The discovery of ghrelin definitely contributes to the understanding of the growth-hormone secretion and of the regulation of appetite and food intake.

Introduction: Patients with type 2 diabetes show a significantly higher mortality after acute myocardial infarction than non-diabetic patients. The influence of sulfonylureas on the survival after acute myocardial infarction is still under debate., Patients and Methods: Survival of 562 patients, consecutively admitted to an intensive care unit with the diagnosis acute myocardial infarction, was prospectively assessed for > 3 years. At the time of hospital admission, patients were grouped as (a) non-diabetic patients; (b) patients with newly diagnosed type 2 diabetes; (c) patients with known type 2 diabetes not treated with sulfonylureas and (d) patients with known type 2 diabetes treated with sulfonylureas. Survival-analysis was performed according to Kaplan-Meier., Results: 324 patients were non-diabetics, in 86 cases type 2 diabetes was newly diagnosed at the time of hospital admission, 77 patients with known diabetes had taken sulfonylureas (glibenclamide in all cases) prior to the acute myocardial infarction, 75 patients were on any other antidiabetic treatment. Long-term-survival was significantly shorter in patients with type 2 diabetes compared to the non-diabetic patients (p < 0.0001). However, no significant differences were observed between the patients with type 2 diabetes treated with sulfonylurea-drugs and those receiving any other antidiabetic treatment (p = 0.53), Conclusions: An antidiabetic treatment with sulfonylurea-drugs prior to acute myocardial infarction does not have negative effects on the long-term survival. Larger prospective studies will be necessary to finally clarify this question.

Aims/hypothesis: In the isolated perfused pancreas, gastric inhibitory polypeptide (GIP) has been shown to enhance glucagon secretion at basal glucose concentrations, but in healthy humans no glucagonotropic effect of GIP has yet been reported. Therefore, we studied the effect of GIP on glucagon secretion under normoglycaemic conditions., Methods: Ten healthy subjects (9 men, 1 woman; age 33+/-11; BMI 26.8+/-2.2 kg/m(2)) received three different doses of intravenous GIP (7, 20, and 60 pmol/kg body weight) and placebo. Venous blood samples were drawn over 30 min for glucagon and GIP concentrations (specific radioimmunoassays). In addition, 31 healthy subjects (16 men, 15 women; 42+/-11 years; BMI 24.4+/-2.7 kg/m(2)) were studied with 20 pmol GIP/kg. Statistics were done with RM-ANOVA and Duncan's post hoc tests., Results: Gastric inhibitory polypeptide dose-dependently stimulated glucagon secretion ( p=0.019) with a maximal increment after 10 min. Incremental glucagon concentrations (Delta(10-0 min)) were 0.1+/-0.7, 1.4+/-0.5, 2.4+/-0.5, and 3.4+/-0.8 pmol/l (for placebo and for 7, 20, and 60 pmol GIP/kg, respectively; p=0.017). After the injection of 20 pmol GIP/kg b.w. in 31 healthy subjects, glucagon concentrations increased over the baseline from 7.5+/-0.5 to 9.3+/-0.7 pmol/l ( p=0.0082)., Conclusions/interpretation: Glucagon secretion is dose-dependently stimulated by GIP at basal glucose concentrations. The absence of a glucagonotropic GIP effect in previous studies could be due to the hyperglycaemic conditions used in these experiments. Our results underline differences between GIP and the glucagonostatic incretin GLP-1.

Background/aims: Pancreas transplantation is an established method of treating Type 1 diabetes. It was our aim to test the consequences of pancreas transplantation in a Type 2 diabetic patient by determining insulin secretion and sensitivity before and after surgery., Patients and Methods: A female patient with Type 2 diabetes and end-stage nephropathy was treated with combined pancreas and kidney transplantation. Before surgery and at 4 weeks, 6 months and 2 years afterwards, insulin sensitivity was measured using hyperinsulinemic euglycemic clamps and insulin secretion was quantified after oral glucose or intravenous glucagon challenges., Results: The patient was insulin resistant before surgery (glucose infusion 4.6 mg. kg (-1). min (-1), normal range 6.4 +/- 0.5 mg.kg( -1). min (-1). Insulin sensitivity declined further after transplantation (1.4 and 3.0 mg. kg -1. min -1 after 4 weeks and 6 months, respectively), but improved to 5.4 mg. kg (-1). min (-1) after 2 years. Insulin secretion was greatly impaired before surgery. Insulin and C-peptide responses after oral glucose and intravenous glucagon increased into the normal range from 6 months after surgery onwards and oral glucose tolerance remained non-diabetic (IGT)., Conclusions: Insulin resistance is first aggravated after pancreas transplantation, probably due to immunosuppressive treatment including glucocorticoids, but improves on the long term. The initially impaired insulin secretion from the transplant may also be explained by the action of glucocorticoids or by transient and reversible organ damage.

Background: Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal anti-inflammatory drug (NSAID), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the mechanism of its anticancer function remains unclear. The aim of this study was to determine the effects of acetylsalicylic acid on proliferation, apoptosis, and invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines., Materials and Methods: After treatment with various concentrations of ASA, cell proliferation was measured in the human colon cancer cell line SW480. Apoptotic cells were identified by transmission electron microscopy, acridine orange staining, and flow cytometry. The invasive potential of SW480 cells was detected using an in vitro invasion assay. The production of carcinoembryonic antigen was measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6, and nm23 were evaluated by immunocytochemistry., Results: ASA significantly inhibited the proliferation of SW480 cells and stimulated apoptosis. Production of carcinoembryonic antigen and the invasive potential of SW480 cells were also inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6 expression and up-regulation of nm23 expression were observed in SW480 cells. No obvious effect of ASA was found on Bax expression., Conclusion: Our findings reveal that ASA inhibits the proliferation and promotes apoptosis in the human colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon cancer cell line. Our results also suggest that ASA decreases the invasive potential of these colon cancer cells. Decreased CEA content and CD44v6 expression and elevated nm23 expression may contribute to the effect of ASA on invasive potential of SW480 colon cancer cells.

Background and Objective: An impaired glucose tolerance as well as type 2 diabetes are associated with an increased cardiovascular mortality. This study was undertaken to determine whether this is also true for impaired glucose tolerance in immediate temporal relation with an acute myocardial infarction (AMI)., Patients and Methods: The survival of 562 patients (232 females, 330 males; age 68 +/- 13 years) consecutively admitted to the intensive care unit of a medical department with the diagnosis of AMI, were prospectively evaluated over a span of more than 3 years. Type 2 diabetes had been previously known in 152, while it was newly diagnosed in 83 patients. Oral glucose tolerance tests (OGTT) were performed in 129, but the test was not performed in 222 patients. Survival was analysed with the Kaplan-Meier test., Results: Among the 129 patients who had had an OGTT, it was normal in 60 (47%), 45 (35%) had impaired glucose tolerance and 24 (19%) were found to have previously undiagnosed diabetes (WHO criteria). Survival of all patients with type 2-diabetes was significantly worse than in the remainder of patients (p < 0.0001). In patients with impaired glucose tolerance the survival time was significantly shorter than in those with normal glucose tolerance (p = 0.029). Even after excluding those patients who had died in the acute post-infarction phase, the difference between patients with normal and with impaired glucose tolerance remained significant (p = 0.034)., Conclusion: Patients with impaired glucose tolerance have a significantly shorter survival after AMI than those with a normal glucose tolerance. Blood glucose concentration 2 hours after oral glucose intake thus seems to be an important predictor of death after AMI.

History: A 33-year-old female nurse (married; two children; BMI 30.9 kg/m2) had recurrent episodes of symptomatic hypoglycaemia over some months., Investigations: Two fasting tests were terminated after 26 hours because the patient became unconscious. Improved insulin/glucose ratio was infinity and 6.1 [mU/l]/[mg/dl] (normal value < 0.5). An hyperinsulinaemic-hypoglycaemic angle "clamp test" produced a C-peptide suppression to minimally 0.26 - 0.38 nmol/l (normal value 0.06 +/- 0.01 nmol). There was no spontaneous or paradoxical burst in insulin or C-peptide concentration after either the fasting or the "clamp test". Serum analysis of sulphonylurea on several occasions documented an increase of glibenclamide above therapeutic range., Treatment and Course: The patient denied any intake of oral antidiabetic preparations, but there were no further hypoglycaemia attacks in subsequent months., Diagnosis: The demonstration of sulphonylurea in serum confirmed the diagnosis of factitious hypoglycaemia., Conclusion: With regard to insulin or C-peptide suppression, the results of the fasting and clamp tests are the same in factitious hypoglycaemia and insulinoma. However, under the influence of sulphonylurea drugs there are no insulin or C-peptide bursts so typical of insulinoma. In case of doubt, detection of sulphonylurea preparations in serum or urine is the only reliable way of diagnosing factitious hypoglaema due to the ingestion of sulphonylurea.

In patients with type 2 diabetes, gastric inhibitory polypeptide (GIP) has lost much of its insulinotropic activity. Whether this is similar in first-degree relatives of patients with type 2 diabetes is unknown. A total of 21 first-degree relatives, 10 patients with type 2 diabetes, and 10 control subjects (normal oral glucose tolerance) were examined. During a hyperglycemic "clamp" (140 mg/dl for 120 min), synthetic human GIP (2 pmol. kg(-1). min(-1)) was infused intravenously (30-90 min). With exogenous GIP, patients with type 2 diabetes responded with a lower increment (Delta) in insulin (P = 0.0003) and C-peptide concentrations (P < 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects (Delta insulin: P = 0.04; Delta C-peptide: P = 0.016) but significantly higher than in patients with type 2 diabetes (P < or = 0.05). The responses over the time course were below the 95% CI derived from control subjects in 7 (insulin) and 11 (C-peptide) of 21 first-degree relatives of patients with type 2 diabetes. In conclusion, a reduced insulinotropic activity of GIP is typical for a substantial subgroup of normoglycemic first-degree relatives of patients with type 2 diabetes, pointing to an early, possibly genetic defect.