Barriers to insulin initiation and intensification and how to overcome them.

AIMS: To review published evidence and clinical experience of the perceived barriers to insulin initiation and intensification and to develop solutions for patient management. METHOD: Literature review and workshop discussions. RESULTS: Many patients with diabetes fail to achieve targets for glycaemic control because of inappropriate use of insulin. Patients and health care professionals face many potential barriers to insulin initiation and intensification in primary care. These can be categorised as low motivation, lack of familiarity or experience and time constraints. CONCLUSION: Solutions should be tailored to different health care settings. Strategies include improving education and training, providing prescribing aids and increasing the efficiency of collaborative working and communications.

Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.

19 insulin-dependent diabetes mellitus (IDDM) patients participated in a randomized double-blind crossover investigation to investigate the impact of human C-peptide on skin microvascular blood flow. The investigation was also carried out with 10 healthy volunteers. Blood pressure, heart rate, blood sugar, and C-peptide levels were monitored during a 60-min intravenous infusion period of C-peptide (8 pmol kg-1 min-1) or saline solution (154 mmol liter-1 NaCl), and 30 min after stopping the infusion. During the same time period, capillary blood cell velocity (CBV), laser Doppler flux (LDF), and skin temperature were assessed in the feet. In the verum arm, C-peptide levels increased after starting infusion to reach a maximum of 2.3+/-0.2 nmol liter-1 after 45 min, but remained below 0. 15 nmol liter-1 during the saline treatment. Baseline CBV was lower in diabetic patients compared with healthy subjects (147+/-3.6 vs. 162+/-4.2 micron s-1; P < 0.01). During C-peptide administration, CBV in IDDM patients increased progressively from 147+/-3.6 to 167+/-3.7 micron s-1; P < 0.001), whereas no significant change occurred during saline infusion or in healthy subjects. In contrast to the CBV measurements, the investigation of LDF, skin temperature, blood pressure, heart rate, or blood sugar did not demonstrate any significant change during the study. Replacement of human C-peptide in IDDM patients leads to a redistribution in skin microvascular blood flow levels comparable to levels in healthy subjects by increasing the nutritive CBV relative to subpapillary arteriovenous shunt flow.

Improved diagnostic methods in the follow-up of medullary thyroid carcinoma by highly specific calcitonin measurements.

Calcitonin (CT) is an important tumor marker for medullary thyroid carcinoma (MTC). Recent CT assays chiefly recognize the monomeric form of CT (mCT). It was the objective of this study to examine the consequences of the higher specificity of the assay for interpretation of the postoperative CT values in MTC patients. The postoperative mCT concentration was measured in 214 patients with differentiated thyroid carcinoma (MTC excepted; non-MTC patients) to determine a reference range of mCT in totally thyroidectomized patients. Monomeric CT was also determined with a two-site chemiluminescence immunoassay (Nichols) in 94 healthy subjects and in 68 MTC patients. The mCT concentrations were below the detection limit in all examined completely thyroidectomized non-MTC patients. Basal and stimulated mCT values were also below the detection limit in 32 of the 68 MTC patients. The biochemical and imaging diagnosis of the latter patients did not give any indication of tumor recurrence. We conclude that completely thyroidectomized patients with non-MTC do not show any measurable mCT concentrations. In comparison with an unspecific CT-RIA, the more specific mCT determination by immunoluminometric assay permits a more precise differentiation between postoperative normal and pathological values and an earlier diagnosis of recurrent MTC.

Detection of sarcolectin-specific receptors like the cytokine macrophage migration inhibitory factor in rheumatoid nodules.

The objective of this study was the evaluation of the relation between the N-acetyl-neuraminic acid-binding endogenous lectin sarcolectin and the cytokine macrophage migration inhibitory factor (MIF) during development of rheumatoid nodules (RN) in seropositive rheumatoid arthritis (RA). Sarcolectin was purified and biotinylated. The binding patterns of this probe were analyzed in RN from patients with RA (n = 23) and compared with the distribution of antibodies with specificity for MIF, fibrin, fibronectin. In early RN, all areas of the inflammatory tissue displayed presence of receptors for sarcolectin. Macrophages were especially positive. In mature rheumatoid nodules binding of sarcolectin was restricted to the periphery of necrotic areas, to endothelial cells and perivascular connective tissue of marginal zones. Distribution patterns of MIF were similar but not identical. The histological staining characteristics demonstrate sarcolectin-binding receptors in RN that are altered upon disease progression. The finding suggests that specific interactions between this endogenous lectin and MIF may be involved in the course of RA.

New aspects on biological activity of C-peptide in IDDM patients.

C-peptide, which is released from the pancreatic beta cells into the circulation in amounts equimolar with insulin, fulfills an important function in the assembly of the two-chain insulin structure, but has otherwise been considered to be biologically inactive. However, during the last few years several experimental and clinical studies have demonstrated that replacement of C-peptide in patients with insulin-dependent diabetes mellitus elicits several physiological effects. Thus, during short-term substitution of C-peptide (1-3 h) decreased glomerular hyperfiltration, augmented whole body and skeletal muscle glucose utilisation, improved autonomic nerve function and a redistribution of microvascular skin blood flow could be observed. In addition, replacement of C-peptide during a period of 1-3 months has been shown to improve renal function as well as autonomic and sensory nerve function in IDDM patients. The mechanisms behind these effects remain unclear, but recent investigations have indicated that an increase in Na+K+ATPase activity and a stimulation of the endothelial nitric oxide synthase may contribute to the observed physiological effects of C-peptide. Not only the intact C-peptide molecule, but also fragments from the C-terminal and mid-portion of the molecule have been shown to exert biological effects. Further research will be necessary to evaluate the underlying mechanism and the clinical impact of C-peptide replacement in IDDM patients.

Microvascular skin blood flow following the ingestion of 75 g glucose in healthy individuals.

It is expected that microvascular blood flow might be affected by blood glucose, blood insulin and C-peptide levels. In our investigation skin microvascular blood flow (LDF) was measured using laser doppler fluxometry at skin temperatures of 37 degrees C and 44 degrees C during a 75 g oral glucose load (OGT) or water in ten healthy volunteers (6 male, 4 female, age: 28.1+/-4.0) who had fasted overnight. The transcutaneous oxygen tension (tcPO2) was measured using a transcutaneous oxygen electrode at a temperature of 44 degrees C. The microvascular response to acetylcholine was investigated before the start of the ingestion period and after 30 minutes. In addition, the capillary blood cell velocity (CBV) was measured using dynamic capillaroscopy. During OGT an increase in LDF could be observed at 37 degrees C (180%, p < 0.005) but only a slight increase was observed at 44 degrees C (86%, n.s.). The microvascular response to acetylcholine increased by 164% (p < 0.05) and the TcPO2 values increased by 30% (p < 0.01) during the OGT investigation. No significant changes in the microvascular measurements could be observed during the water experiment. No significant changes could be observed in the CBV measurements in any phase of the investigation. Plasma C-peptide and insulin levels exhibited an association with the LDF measurements at 37 degrees C (r = 0.22, p < 0.05; r = 0.30, p < 0.05; respectively), whereas blood sugar values showed an association with the TcPO2 measurements (r = 0.39, p < 0.01). After the ingestion of glucose a sophisticated modulation of microvascular blood flow was found in healthy volunteers. Further studies are necessary to investigate the role of a disturbed postprandial blood sugar control, insulin and C-peptide secretion in the development of microvascular dysfunction, especially in IDDM.

Binding of monocytes from normolipidemic hyperglycemic patients with type 1 diabetes to endothelial cells is increased in vitro.

Increased endothelial binding and emigration of monocytes play a dominant role in the pathogenesis of atherosclerosis in diabetes mellitus. Previous studies revealed that hyperlipidemia correlates with monocyte binding in vitro. The aim of this study was to characterize the monocyte-endothelial interaction of leucocytes of hyperglycemic patients with type 1 diabetes but lacking hyperlipidemia. We isolated monocytes from healthy controls and normolipidemic type 1 diabetes patients with elevated levels of HbA1c and quantified monocyte binding by an immunoilluminometric cell adhesion assay. Purity of isolated monocytes was at least 98%. Endothelial binding of monocytes from patients with type 1 diabetes was found to be significantly increased compared to controls (19.2 +/- 3.9% vs. 14.9 +/- 3.5%). This difference of monocyte binding remained unchanged if the endothelial cells were stimulated with 27.7 mmol/l glucose for seven days prior to adhesion studies (31.5 +/- 4.9% in diabetes patients vs. 25.8 +/- 4.1% in controls) whereby monocyte binding markedly increased under these hyperglycemic conditions. Furthermore, an increased CD11b expression could be demonstrated on monocytes of normolipidemic hyperglycemic type 1 diabetes patients. Thus, we suggest that hyperglycemia per se may contribute to increased monocyte binding to endothelial cells by promoting leucocyte integrin expression. Recently performed studies of our group strengthen the hypothesis that this monocyte activation is mediated by stimulation of the beta-isoform of proteinkinase C.

The influence of advanced glycation endproducts (AGE) on the expression of human endothelial adhesion molecules.

Advanced glycation endproducts (AGEs) possibly play a dominant role in the pathogenesis of macrovascular disease in diabetes. Recent studies could demonstrate that glycated albumin (AGE-BSA) was able to stimulate vascular cell adhesion molecule-1 (VCAM.1) on endothelial cells. The aim of this study was to find out if AGE-BSA was not only able to enhance the expression of vascular cell adhesion molecule-1, but also of intercellular adhesion molecule-1 (ICAM-1) and E-Selectin on human endothelial cells. Stimulation of endothelial cells with AGE-BSA for six hours predominantly increased the expression of VCAM-1, but ICAM-1 and E-Selectin were also upregulated as shown by immunoilluminometric assay (ILMA).

Serum levels of substance P are decreased in patients with type 1 diabetes.

Morphological and immunohistochemical studies in diabetic subjects have shown a depletion of the neuropeptide substance P (SP) in the central and peripheral nervous system. This is the first study investigating serum levels of substance P in type 1 diabetes patients (n=50) and controls (n=75) by means of an enzyme immunoassay. The serum level of SP was significantly decreased in the diabetic group compared to the control group (10.12+/-0.29 vs. 12.25+/-0.38 pg/ml; p<0.0001). In diabetic patients, there was no correlation of substance P levels with age, serum creatinine, albuminuria, total cholesterol, HDL- or LDL-cholesterol, triglycerides, HbA1c, type or duration of diabetes and gender. Furthermore, there was no difference in serum levels of SP in patients with or without retinopathy, but SP was significantly decreased in patients with neuropathy (9.59+/-0.48 vs. 10.78+/-0.83 pg/ml; p=0.04). These data show that SP is decreased in serum of type 1 diabetes patients, especially in those with diabetic neuropathy. Subsequent and already ongoing prospective studies in well validated diabetic patients with neuropathy may characterize the impact of this neurogenic marker in the course of diabetic neuropathy.

Establishment of a quantitative RT-pCR for detection of vascular cell adhesion molecule-1 transcripts in endothelial cells after stimulation with advanced glycation endproducts.

Advanced glycation endproducts (AGE) are supposed to increase endothelial expression of adhesion molecules like vascular cell adhesion molecule-1 (VCAM-1) by inducing an intracellular stress with subsequent activation of nuclear transcription factor NF-kappa-B. Quantitative analysis of VCAM-1-transcription has not been demonstrated concerning this topic. Thus, the aim of this study was to establish quantitative reverse transcription polymerase chain reaction (RT-PCR) assays using a spacer gene in order to measure the amounts of specific mRNA for VCAM-1 in human umbilical vein endothelial cells (HUVEC) which were stimulated with AGE-albumin (AGE-BSA). A recombinant RNA-standard was synthesized and used as internal RT-PCR standard. The amount of VCAM-1-mRNA in unstimulated HUVEC was found to be 2.2 +/- 2.7 copies per cell. After stimulation with AGE-BSA, mRNA-levels were elevated to 38.9 +/- 10.9 copies per cell. Positive controls (stimulated with lipopolysaccharide) revealed mRNA-levels of 78.7 +/- 27.5 copies per cell. We conclude that quantitative RT-PCR using the spacer gene technique is a valid and reliable method for the measurement of small amounts of specific

Germline mutations in the MEN1 gene: creation of a new splice acceptor site and insertion of 7 intron nucleotides into the mRNA.

The MEN1 tumor predisposition syndrome is caused by mutations in the MEN1 gene on human chromosome 11q13. We screened MEN1 gene exons 1-10 and flanking intron sequences from four different MEN1 families for mutations. In three families, heterozygous germline mutations within the exons were found, two of these representing novel mutations. In another family, all clinically affected members were heterozygous for a point mutation Gright curved arrow A within intron 4. Sequence analysis of cDNA from lymphocytes of the affected patients revealed that the intron mutation created a new acceptor splice site, leading to the inclusion of 7 bp of intronic sequence into the mRNA. The resulting frameshift generates a premature stop in codon 271. Intron borders should thus be screened for mutations in MEN1 diagnostics and cDNA sequence analysis is helpful in identifying pathophysiological consequences of intron mutations.

The influence of local capsaicin treatment on small nerve fibre function and neurovascular control in symptomatic diabetic neuropathy.

Topical treatment with capsaicin cream has been shown to be successful in the treatment of different symptomatic nerve disorders like diabetic neuropathy. Conflicting data exist on the effect of capsaicin on nerve function and neurovascular control especially in patients with diabetic neuropathy. The aim of this pilot study was to investigate the impact of topical capsaicin application on small nerve fibre function and neurovascular control. Capsaicin cream was applied to the feet of 13 patients with symptomatic diabetic neuropathy over a period of 8 weeks. Before and during the treatment period, we investigated the total symptoms score, the vibration, thermal (heat and cold) and pain perception thresholds, and the neurovascular responses to heat and acetylcholine stimuli. In addition, the serum plasma levels of substance P, a neurotransmitter of nociceptor C-fibres, were measured. A significant improvement in total symptoms score was observed during topical capsaicin treatment (18.3+/-3.2 vs. 14.3+/-3.3; p<0.05). An improvement in the heat perception threshold was also found (12.7+/-0.4 degrees C vs. 11.4+/-0.7 degrees C: p<0.05), while other sensory nerve fibre functions remained unchanged. No significant change in neurovascular control was observed, neither after mild thermal injury nor after stimulation with acetylcholine. Serum substance P levels increased after initiation of topical capsaicin treatment (72.9+/-5.8 pg/ml vs. 81.7+/-5.0 pg/ml; p<0.05), but returned to baseline levels during further treatment (77.4+/-8.3 pg/ml: n.s.). In conclusion, topical treatment with capsaicin cream over a period of 8 weeks in patients with symptomatic diabetic neuropathy is effective without adverse effects on nerve fibre function or neurovascular control.

Comparison of immunoassays for the detection of anti-GAD65 autoantibodies in patients with diabetes mellitus.

Recent studies have demonstrated that a combination of GAD-antibody assays and IA-2 autoantibody assays show a high diagnostic specificity for Type 1 diabetes. For this reason there is increasing interest in the use of GAD-antibody measurement for Type 1 risk assessment. Since a number of different assays have been published and documented in the literature, the aim of this study was to evaluate four different anti-GAD test systems that are commercially available in Germany. We tested the anti-GAD prevalences in five patient groups with the different immunoassays and compared them with the values obtained by an immunoprecipitation test (IP-Test). All assays correlated well with the IP-test and showed high sensitivity and specificity in the group of patients with recent onset Type 1 diabetes and the control group. The groups tested consisted of 20 subjects with recent onset Type 1 diabetes (< 6 weeks) (sensitivity 70-90%), nine subjects with a Type 1 duration of more than 2 years (sensitivity 11-33%), 21 patients with pluriglandular insufficiency (sensitivity 28.5-47.5%), 10 patients with Type 2 (specificity: 90-100%), and 14 healthy control subjects (specificity: 93-100%). Our data show a high level of sensitivity and specificity of the tested, commercially available, assays. Since almost every laboratory should be able to establish one of these assays, this may facilitate the possibility of further large scale population studies with the aim of investigating GAD-antibody prevalences in screening for Type 1 diabetes. Increased measurement of the diabetes-associated antibodies will be helpful in the differential diagnosis of gestational diabetes mellitus (GDM) and latent autoimmune diabetes of the adult (LADA).

Assessment of some important anatomical variations and dangerous areas of the paranasal sinuses by computed tomography in children.

The purpose of this study is to determine important variations and areas of risk for major complications in paranasal computed tomography (CT). We also made specific measurements for individual differences. This study consisted of 64 children (128 sides). Eleven participants had coronal and axial, and the remaining 53 only coronal CT. The distance of the anterior ethmoidal artery (AEA) and the lamina cribrosa to the inferior turbinate and the orbital roof, and the depth of the lamina cribrosa were measured. The percentages of some of the variations were as follows: upper attachment of uncinate process 25%, freely coursing AEA 43%, aerated anterior clinoids 8%, optic canal bulging 6% and extreme medially coursing carotid canal 3%. The frequencies of some of these variations and the existence of Onodi cells were significantly smaller than compared with adults. Specific measurements varied individually. In conclusion, children deserve more attention while evaluating CT, due to their tiny bony structures.

Expression patterns of complex glycoconjugates and endogenous lectins during fetal development of the viscerocranium.

Experimental evidence suggests that carbohydrates and their corresponding receptors (endogenous lectins) decode biological information. Therefore, the expression of complex oligosaccharides--the potential ligand part of this recognition system--during chondrogenesis and osteogenesis was determined in the viscerocranium of fetal rats by mapping the staining patterns of exogenous lectins. Results were compared with the expression of bone- and/or cartilage-specific core proteins and the binding profiles of neoglycoconjugates. These synthetic tools make possible the localization of sugar-ligand-binding sites. The spatial and temporal distribution patterns of glycoconjugates were highly dynamic and demonstrated a clear correlation with characteristic morphological modifications. The glycobiological characterization of precartilage mesenchymal cells revealed distinct differences compared to prospective bone anlagen. Especially the binding of the exogenous lectin from Griffonia simplicifolia II, that selectively visualized prechondral aggregations, reveals that regulation of early chondral growth is at least phenomenologically correlated with a relatively atypical oligosaccharide composition terminating with N-acetylglucosamine.

Cholesterol granuloma of the maxillary sinus: six cases from the same region.

It is common to find cholesterol granuloma in the mastoid antrum and air cells of the temporal bone, but it is very rare in paranasal sinuses. In the development of this pathology, the key factor is the presence of a closed cavity containing exudate and blood. Six cases of cholesterol granuloma of the maxillary sinus are presented from six years' study in our hospital. According to the main symptoms, clinical findings, and radiological appearance (except the destruction of the antrum wall in some patients), the pathology was similar to chronic maxillary sinusitis. All the patients were treated with radical operative techniques. In this study, we reviewed the literature and our cases, and could not detect any findings to explain why this pathology had occurred frequently in our district. We strongly recommend that investigations should be carried out on all specimens obtained from paranasal sinus surgery, because the cholesterol granuloma in the maxillary antrum could be mistaken for chronic sinusitis.

Current strategies for controlling postprandial hyperglycaemia.

In patients with diabetes mellitus glycosylated haemoglobin (HbA1c), which reflects mean glycaemic values in the previous 3 months, is typically used as a clinical measure of blood glucose control. However, it does not always correlate satisfactorily with postprandial blood glucose excursions, which may occur only for a few hours and be insufficient to alter HbA1c formation. Thus, postprandial glucose peaks may have a significant impact on diabetic complications but not be monitored sufficiently from HbA1c measurements. Epidemiological studies have shown stronger correlations for incidence of cardiovascular events with postprandial glucose levels than with preprandial levels. Results from the UKPDS suggest that HbA1c had to be reduced below 7 per cent to ameliorate macrovascular outcomes. In patients with type 2 diabetes there is a loss of the first phase insulin response so a logical treatment strategy is to use a rapid-acting insulin analogue. Rapid-acting insulin analogues have a greater effect on postprandial glucose levels than regular human insulin. This is due to the faster absorption and higher insulin peak in blood, but also due to the increased ability of rapid-acting analogues to suppress hepatic glucose release. In clinical practice, preprandial injection of rapid-acting insulin reveals significant advantages including treatment flexibility, lack of weight gain, stable insulin doses and reduction of hypoglycaemic episodes. These effects are more pronounced if this type of therapy is used early in the course of the disease. Thus rapid-acting insulin analogues are being increasingly used as first-line therapy with multiple daily injection in patients with type 2 diabetes.

Role of C-Peptide in the regulation of microvascular blood flow.

During the recent years, the role of C-peptide, released from the pancreatic beta cell, in regulating microvascular blood flow, has received increasing attention. In type 1 diabetic patients, intravenous application of C-peptide in physiological concentrations was shown to increase microvascular blood flow, and to improve microvascular endothelial function and the endothelial release of NO. C-peptide was shown to impact microvascular blood flow by several interactive pathways, like stimulating Na(+)K(+)ATPase or the endothelial release of NO. There is increasing evidence, that in patients with declining beta cell function, the lack of C-peptide secretion might play a putative role in the development of microvascular blood flow abnormalities, which go beyond the effects of declining insulin secretion or increased blood glucose levels.

[Short-acting insulin analogs--critical assessment of meta-analyses]. / Kurzwirksame Insulinanaloga--Kritische Bewertung metaanalytischer Betrachtungen.

Short-acting insulin analogs have for nearly ten years been prescribed for type 1 and 2 diabetes mellitus. There is extensive scientific and practical evidence of their being better than normal insulin. For this reason these insulins have been recommended in the guidelines of most leading specialist societies. In everyday practice they are an important component of the therapeutic portfolio which can produce an improvement in insulin treatment, especially of selective cases. On the other hand, there is growing economic pressure, especially in Germany, affecting their use. However, it must be critically asserted that those meta-analyses on insulin analogs, which have been commissioned by insurance companies or governmental organisations, do not do justice to their advantage. Current meta-analyses of short-acting insulin analogs exclude decisive advantages of insulin analogs from their analyses and compare highly heterogeneous groups. They do not distinguish between differing incidences of hypoglycemia associated with different HbA1c values as well as between conventional and intensive treatment. Furthermore positive data and positive major studies are excluded, while approval studies or trials with completely different aims are cited. Short study duration is also often neglected. As a result, the International Diabetes Federation (IDF) has rejected the Cochrane Review for 2005 for methodological reasons. Also, no recommendations can be derived from the recommendations of of the Institut für Qualitätssicherung und Wirtschaftlichkeit in der Medizin (IQWiG: Institute for Quality Assurance and Cost Effectiveness in Medicine). After critical assessment of meta-analyses the IDF concluded in its guidelines that insulin analogs should generally be used.

[Obesity: when does the internist recommend surgery?]. / Adipositas--Wann sieht der Internist die Indikation zur Operation?

Obesity is a chronic disease with a poor therapeutical outcome. Well-defined education of the patient and conservative treatment are the basics of therapy. Nevertheless, one should always be aware of the possibility of surgical intervention. In the following, the diagnostical and therapeutical procedures concerning obesity will be described in order to allow a reasonable indication of surgical intervention.