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Die vorliegende Leitlinie nimmt Bezug auf die Indikation und praktische Umsetzung der Insulintherapie bei Typ 2 Diabetes, insbesondere auch im Hinblick auf die unterschiedlichen Formen der Insulintherapie.

Hyperglycemia significantly contributes to complications in patients with diabetes mellitus. While lifestyle interventions remain cornerstones of disease prevention and treatment, most patients with type 2 diabetes will eventually require pharmacotherapy for glycemic control. The definition of individual targets regarding optimal therapeutic efficacy and safety as well as cardiovascular effects is of great importance. In this guideline we present the most current evidence-based best clinical practice data for healthcare professionals.

Die Leitlinie nimmt Bezug auf die Diagnostik, einschlieslich begleitender Autoimmunerkrankungen, bei Typ 1 Diabetes mellitus, die Insulintherapie und die glykamischen Zielwerte.

Aims To characterize the prevalence of Type 2 diabetes between 1991 and 2013 in the UK and to determine whether corresponding glucose control and survival had changed in the diabetic population during this period. Methods For this retrospective cohort study, people diagnosed with Type 2 diabetes between 1991 and 2013 were identified from the Clinical Practice Research Datalink (CPRD) and the annual point prevalence calculated. Mean HbA1c by year was estimated. The Cox proportional hazards model was used to calculate the risk of all-cause mortality by year for incident cases of Type 2 diabetes treated with glucose-lowering therapy. Results Crude prevalence of diagnosed Type 2 diabetes increased from 1.32% [95% confidence interval (95% CI) 1.30% to 1.34%] in 1991 to 4.54% (4.52% to 4.56%) in 2013. Mean HbA1c for people with diagnosed Type 2 diabetes was 71 mmol/mol (8.6%) in 1991, 59 mmol/mol (7.5%) in 2003 and 58 mmol/mol (7.5%) in 2013. For diagnosed Type 2 diabetes treated with glucose-lowering therapy, when compared with 1991, the hazard ratio for all-cause mortality was 0.33 (0.27–0.41) in 2013. Conclusion The prevalence of diagnosed Type 2 diabetes trebled in the UK between 1991 and 2013. Improved survival in people with diagnosed Type 2 diabetes is likely to account, at least in part, for the increase in prevalence observed.

Aims: Clinical and observational studies have demonstrated increased risk of cardiovascular events and death associated with sulfonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulfonylureas. Our objective was therefore to compare all-cause mortality in diabetic patients treated first-line, glucose lowering therapy with either sulfonylurea or metformin monotherapy with that in matched individuals without diabetes. Materials and Methods: We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulfonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables. Results: We identified 78,241 subjects treated with metformin, 12,222 treated with sulfonylurea, and matched 90,463 cases without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7,498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1,000 person-years for metformin monotherapy and their matched controls, and sulfonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy, adjusted median survival time was 15% lower (survival time ratio = 0.85, 95%CI 0.81–0.90) than in matched individuals without diabetes, and adjusted median survival time was reduced by 38% (survival time ratio = 0.62, 0.58–0.66) in diabetic patients treated with sulfonylurea monotherapy. Conclusions: Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulfonylurea had markedly reduced survival than both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulfonylurea remains a continued concern.

Prevention of cardiovascular morbidity and mortality remains the key factor in the treatment of type 2 diabetes (T2DM). In the early phase of T2DM, multifactorial intervention is mandatory and glucose levels should be near normal, in particular in younger patients presenting with the highest cardiovascular risk. Anti-diabetic drugs without any risk for hypoglycaemia should be preferred in order to reduce clinical inertia and increase the long-term adherence to the treatment. In patients already presenting with cardiovascular disease, the best outcome may be expected with the triple oral therapy of metformin, pioglitazone, and empagliflozin, although a controlled prospective study versus insulin therapy is needed to confirm the expectation.

Der Typ-2-Diabetes ist eine komplexe Stoffwechselerkrankung, die mit einem deutlich erhohten Risiko fur kardiovaskulare Erkrankungen und bestimmte Krebserkrankungen einhergeht. Eine fruh einsetzende multifaktorielle Intervention ist notwendig, um die Prognose der Patienten zu verbessern. Die hochste Prioritat hat dabei die optimale Senkung des Low-density-Lipoprotein(LDL)-Cholesterins (Zielwert

Diabet. Med. 29, 470–478 (2012) Abstract Aims Systemic concentrations of adhesion molecules and chemokines are associated with increased risk of cardiovascular complications. We compared these factors between patients with Type 2 diabetes vs. Type 1 diabetes or latent autoimmune diabetes in adults. Methods Serum concentrations of adhesion molecules sE-selectin, sICAM-1 and sVCAM-1, and chemokines CCL2, CCL3 and CCL4 were measured in 61 patients with latent autoimmune diabetes in adults, 90 with Type 1 diabetes, 465 with Type 2 diabetes and in 41 control subjects, using multiple regression models to adjust for possible confounders. Results Patients with Type 2 diabetes exhibited greater concentrations of adhesion molecules (P

Traditionally, patients with type 1 diabetes were regarded to be at an increased risk of fractures whereas type 2 diabetics were assumed to be protected from fractures since many of them have high bone mineral density. Nevertheless, several clinical studies consistently demonstrated that type 2 diabetes is a paradigm of a disease with an increased risk of fractures in the presence of high bone mass. The pathophysiology of decreased bone strength in diabetes mellitus is multifactorial: insulin deficiency, insulin resistance, osteoblast insufficiency, vitamin D deficiency, formation of advanced glycation end-products in bone, and microvascular complications appear to contribute. Drugs used for the treatment of type 2 diabetes also may influence bone fragility: thiazolidinedione use has been associated with an increased risk of fractures.

The medication-taking behaviour of patients may be key to avoiding the serious long-term micro- and macrovascular complications of Type 2 diabetes. However, the polypharmacy often required to achieve good metabolic control can be a significant barrier to adequate adherence. Reducing treatment complexity can be achieved through the use of single-tablet fixed-dose combinations of two oral hypoglycaemic agents. Studies to date suggest that this approach can significantly improve adherence over separate tablet dual therapy and has the potential to improve metabolic and clinical outcomes. A range of fixed-dose combination oral hypoglycaemic agents in several different dosage strengths are available and the strategies for optimal implementation of these options continue to evolve. This article describes the extent and consequences of poor adherence to oral hypoglycaemic agents in Type 2 diabetes and discusses the potential contribution of fixed-dose combinations to the provision of improved care.

In two girls (14 and 16 years) and one boy (19 years) with PLW-syndrome and pronounced obesity (240, 210 and 77% overweight) endocrine function tests were carried out. Growth hormone secretion was decreased but normalized after reduction of weight. Thyroxin levels as well as basal and TRH stimulated TSH concentrations were normal. HCG application in the boy induced no rise of the normal basal testosterone levels. Oral glucose tolerance test demonstrated an increased stimulation of insulin in two cases, no other symptoms of diabetes mellitus were found. In the LHRH test an insufficient rise of gonadotropins was found. However, after two weeks of pernasal application of an LHRH analogue (D-Leu6-des-Gly10-EA) the gonadotropin stimulation was distinctly improved and onset of puberty was induced in the male patient. These results are indicative of a hypothalamic disturbance in patients with PLW-syndrome.

We investigated the TRH induced TSH secretion and thyroid hormone concentrations in 14 type-II diabetics with secondary failure to oral hypoglycemic agents (mean age: 70.8 years, range: 55-77, mean duration of disease: 11 years +/- 7.9 SD, mean HbAlc: 10.1 +/- 1.6 SD) with normal body weight before and after insulin therapy. Results were compared with those of healthy control persons. Before insulin treatment T3 and fT3 concentrations were significantly lower in diabetics (p less than 0.05) compared to controls, rT3 was slightly elevated in diabetics. With improved metabolic control following insulin treatment T3 and fT3 slightly increased, whereas rT3 slightly decreased. Basal TSH concentrations and TRH induced TSH secretion were not altered in diabetics compared to controls and were not influenced by insulin therapy. The alterations of peripheral thyroid hormone concentrations seem to be caused by reduced peripheral deiodination of T4 to T3 with increased production of rT3. Pituitary thyrotroph function is normal in long-standing type-II diabetic patients with normal body weight.

Endothelial cell activations and/or dysregulations of the coagulation system are crucial parameters for the prognosis of disease in patients with IDDM. Recent data suggest that expression of the adhesion molecules E-selectin and P-selectin are markers of endothelial cell activation and/or platelet activation and might modify immunologic responses after shedding from cell membranes. In patients with newly diagnosed IDDM only limited data on circulating selectins are available. This has prompted us to measure levels of soluble (s) forms of P-selectin and E-selectin in 18 patients with newly diagnosed IDDM and two years after the onset of insulin substitution therapy in comparison to 18 age-matched healthy control subjects. HbA1c and blood glucose levels were significantly higher in patients with new onset diabetes, compared to the same patients after two years of insulin therapy (HbA1c: 12 +/- 3% vs. 7.8 +/- 2%; p0.01; blood-glucose: 409 +/- 163 mg/dl vs. 131 +/- 23 mg/dl; p0.01), but no correlation between these metabolic parameters and soluble forms of E- and P-selectins were noted. Levels of sP-selectin decreased from 210 +/- 120 ng/ml in newly diagnosed IDDM patients to 127 +/- 75 ng/ml after two years of therapy (p0.01) and were similar to those of the control subjects (110 +/- 31 ng/ml). Serum concentrations of circulating E-selectin showed no differences in the three groups (newly diagnosed IDDM: 42 +/- 17 ng/ml; two years later: 43 +/- 19 ng/ml; control subjects: 41 +/- 14 ng/ml; n.s.). Increased levels of sP-selectin together with normal levels of sE-selectin at the onset of IDDM suggest enhanced platelet activation during the initial phase of the autoimmune process and return to baseline levels within two years of the disease.

SUMMARY Background: The thiazolidinediones pioglitazone and rosiglitazone have established efficacy in improving insulin sensitivity, glycaemic control, dyslipidaemia, hypertension and microalbuminuria in patients with type 2 diabetes. As specific agonists of peroxisome proliferator-activated receptor-c, thiazolidinediones have also demonstrated protective effects on a variety of atherosclerosis biomarkers and surrogate measures of cardiovascular disease. Aim: This paper reviews the evidence for pleiotropic effects on a variety of non-traditional atherosclerotic risk factors. Discussion: Thiazolidinediones attenuate circulating levels of pro-inflammatory mediators in patients with type 2 diabetes, including C-reactive protein, interleukin-6, CD40L, monocyte chemoattractant protein-1 and metalloproteinase9. These agents also increase levels of the vascular protective adipokine, adiponectin. The clinical significance of these findings is supported by evidence of improved endothelial dysfunction, reduced carotid intima media thickness and improvements in stenosis following coronary artery stent implantation in patients treated with thiazolidinediones. Limited data suggest that thiazolidinediones might also improve the circulating levels and functional activity of angiogenic endothelial progenitor cells, which independently predict the incidence of cardiovascular events and death. It should be noted that the US Food and Drug Administration and the European Medicines Agency have requested changes to the prescribing information for rosiglitazone to highlight the possibility of an increased risk with this agent in patients with ischaemic heart disease; on review, no such amendment was required for the pioglitazone prescribing information. Both agencies continue to suggest that the benefits of both thiazolidinediones outweight any possible detrimental effects. Further research remains to be conducted to elucidate the potentially differential vascular protective effects of thiazolidinediones. In the US, there are black box heart failure warnings for both agents. Conclusion: In light of the established importance of reducing cardiovascular risk in patients with type 2 diabetes, current evidence continues to support the use of pioglitazone within multifactorial risk management strategies.

Serum calcium determination of 11,588 hospitalized patients during a twelve-month period revealed hypercalcaemia in 74 (0.64%). Further clinical and biochemical investigation established primary hyperparathyroidism in 20 of them (27%), and in 15 (20%) a malignant tumour (with bone metastases in six) as the cause of the hypercalcaemia. Rarer causes were found in 11 patients (15%): diuretic medication (5), lithium treatment (3), immobilization (2) or hyperthyroidism (1). In the remaining 28 patients (38%) no cause of the hypercalcaemia could be established with certainty. In at least six patients, however, there were clinical pointers towards hyperparathyroidism in the absence of unequivocal biochemical findings. Leaving out of account borderline cases, one must reckon on a prevalence of hyperparathyroidism in 0.17% of an unselected group of hospitalized patients. Parathyroid hyperfunction must always be considered in the differential diagnosis because of its manifold clinical presentation.

Reflocheck, a new microprocessor-regulated apparatus determining blood sugar levels was tested in six laboratories. In the range of 20-450 mg/dl the apparatus gave precise results (co-efficient of variance 0.8%-6.4%), in good agreement with results by the hexokinase method. Reflocheck is an accurate and reliable instrument for the measuring of blood glucose levels.

Diabetes and hypertension frequently coexist, and their combination provides additive increases in the risk of life-threatening cardiovascular events. Recent guidelines agree (JN-VII) on the need for early, aggressive reduction of blood pressure, with a goal of < 130/80 mmHg, in patients with diabetes. The mechanism responsible for the increased sensitivity of diabetics to hypertension is not known, but may involve attenuated nocturnal decrease (non-dipping) of blood pressure. Treatment of hypertension in type 2 diabetes provides dramatic cardiovascular benefit. Aggressive blood pressure control may be the most important factor in preventing adverse outcomes in patients with type 2 diabetes. Target diastolic blood pressures of less than 80 mm Hg and systolic targets less than 135 mm Hg appear optimal. All classes of antihypertensive agents are effective in reducing blood pressure in patients with diabetes, and all show evidence of a concomitant reduction in cardiovascular risk. Although there is evidence that agents that interrupt the renin-angiotensin system system may be superior in both the nephroprotection and cardioprotection, however the data are not totally conclusive. However, most diabetics and especially diabetic patients with nephropathy will require combination therapy ("antihypertensive cocktail") to reach goal blood pressure. Hypertensive patients have a significantly increased risk for the development of type 2 diabetes, and antihypertensive drugs can also significantly influence the risk for that. While diuretics and ss-blockers have a prodiabetic effect, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may prevent diabetes more effectively than the metabolically neutral calcium channel blockers.

Patients with hypopituitarism have an increased mortality from cardiovascular events. Reduced nocturnal blood pressure decline (non-dipping) and impaired glucose tolerance are considered as cardiovascular risk factors. To evaluate the role of these risk factors in patients with hypopituitarism we determined the 24-hour blood pressure regulation and glucose tolerance status in hypopituitary patients with and without growth hormone (GH) deficiency. Sixty-one hypopituitary subjects 5 +/- 3 years after brain surgery because of macroadenoma, 61 patients with type 2 diabetes mellitus (T2DM), and 20 healthy controls were included. Forty-four hypopituitary patients were GH deficient and 28 of these on GH treatment. Non-dipping was observed in 41 % (n = 7) of hypopituitary subjects with normal GH release, in 46 % (n = 13) of patients on GH therapy, and in 69 % (n = 11) of untreated GH deficient patients. Untreated GH deficient patients had a higher systolic night/day ratio (1.00 +/- 0.03) compared to non GH deficient (0.92 +/- 0.02; p < 0.02) and GH treated hypopituitary patients (0.93 +/- 0.01; p < 0.02). The rate of non-dipping in hypopituitarism was comparable to that in T2DM. Pathologic glucose tolerance was diagnosed in 30 % of the hypopituitary patients. The prevalence of non-dipping was independent of glucose metabolism in hypopituitary patients. All controls had normal night time blood pressure fall and glucose metabolism. The high prevalence of nocturnal non-dipping and glucose intolerance detected in this cohort might contribute to the increased cardiovascular risk of hypopituitary patients.

Aims Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients. Methods Liver testing results performed in four 1-year, randomized, double-blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed. Results Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (≥ 87%) compared with patients receiving metformin (≥ 80%) or gliclazide (≥ 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%). Conclusions During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.

Background This 52-week, randomized, double-blind study compared the efficacy and safety of metformin plus pioglitazone with the established combination of metformin plus gliclazide in type 2 diabetes mellitus. Methods Patients with poorly controlled type 2 diabetes (HbA1c ≥ 7.5% to ≤11.0%) received either pioglitazone 15 mg o.d. (titrated up to 45 mg; n = 317) or gliclazide 80 mg o.d. (titrated up to 320 mg; n = 313) and metformin at the pre-study dose. HbA1c, fasting plasma glucose (FPG), insulin, lipids and the urinary albumin/creatinine ratio were measured. Results There were no significant differences in HbA1c (1% decrease in both groups) and FPG between groups. There was a decrease in fasting insulin in the pioglitazone group compared to an increase in the gliclazide group (p < 0.001). There were significantly greater improvements in triglycerides and HDL-cholesterol in the metformin plus pioglitazone group compared to the metformin plus gliclazide group (p < 0.001). Mean LDL-cholesterol decreased with metformin plus gliclazide and increased with metformin plus pioglitazone (p < 0.001); however, this increase was considerably less marked than that in HDL-cholesterol. The mean urinary albumin/creatinine ratio was reduced by 10% in the metformin plus pioglitazone group compared to an increase of 6% in the metformin plus gliclazide group (p = 0.027). The incidence of adverse events was comparable between groups and both combinations were well tolerated. Conclusions Compared to the established combination of metformin plus gliclazide, this study indicates potential benefits of addition of pioglitazone to metformin in terms of improvements in microalbuminuria and specific abnormalities associated with diabetic dyslipidemia. Copyright © 2004 John Wiley & Sons, Ltd.

Background Progressive β-cell failure is a characteristic feature of type 2 diabetes; consequently, β-cell secretagogues are useful for achieving sufficient glycaemic control. The European GUIDE study is the first large-scale head-to-head comparison of two sulphonylureas designed for once-daily administration used under conditions of everyday clinical practice. Design Eight hundred and forty-five type 2 diabetic patients were randomized to either gliclazide modified release (MR) 30‐120 mg daily or glimepiride 1‐6 mg daily as monotherapy or in combination with their current treatment (metformin or an α-glucosidase inhibitor) according to a double-blind, 27-week, parallel-group design. Efficacy was evaluated by HbA1c and safety by hypoglycaemic episodes using the European Agency definition. Results HbA1c decreased similarly in both groups from 8·4% to 7·2% on gliclazide MR and from 8·2% to 7·2% on glimepiride. Approximately 50% of the patients achieved HbA1c levels less than 7%, and 25% less than 6·5%. The mean difference between groups of the final HbA1c was −0·06% (noninferiority test P < 0·0001). No hypoglycaemia requiring external assistance occurred. Hypoglycaemia with blood glucose level < 3 mmol L −1 occurred significantly less frequently (P = 0·003) with gliclazide MR (3·7% of patients) compared with glimepiride (8·9% of patients). The distribution of the sulphonylurea doses was similar in both groups. Conclusions This study provides new insights into therapeutic strategies using sulphonylureas. It shows that gliclazide MR is at least as effective as glimepiride, either as monotherapy or in combination. The safety of gliclazide MR was significantly better, demonstrating approximately 50% fewer confirmed hypoglycaemic episodes in comparison with glimepiride.

Aims Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. Methods Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. Results Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. Conclusions Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.

Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes.We used retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables.We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy [survival time ratio (STR) = 1.0], adjusted median survival time was 15% lower (STR = 0.85, 95% CI 0.81-0.90) in matched individuals without diabetes and 38% lower (0.62, 0.58-0.66) in diabetic patients treated with sulphonylurea monotherapy.Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

LADA or type 1.5 diabetes is a slowly progressive form of autoimmune diabetes of adults and represents a considerable proportion (about 5-10%) of all diabetic patients. Associations with high risk HLA genotypes and autoimmune phenomena (GAD, IA2, ICA) show similarities with type 1 diabetes, but phenotypical characteristics of these patients do not allow the correct identification without screening of GAD antibodies. The relatively low antibody titers against islet-cell antigens in LADA patients may be sign of a less aggressive form of autoimmune diabetes and could be responsible for the long non-insulin requirement phase of this diabetes type. Similar as in prediabetic relatives of type 1 diabetic patients the risk for beta cell failure in adult "type 2 diabetic" patients increases with the number of antibodies positive. Consequently, low titers of GAD--in particular in elderly patients--do not predict a progressive and rapid loss of beta-cell failure, when associations with high risk genotypes or other islet-cell antibodies are lacking. Patients with LADA share insulin resistance with type 2 diabetic patients, but display a more severe defect in stimulated beta-cell capacity than patients with classical type 2 diabetes. With respect to features of the metabolic syndrome, patients with LADA have lower BMI, blood pressure and triglyceride levels compared with classical type 2 diabetes patients. Early identification of LADA patients will be mandatory, when effective immune interventions are available for prevention of the beta-cell destructive process and insulin requirement of these patients.

Grundlagen: Im letzten Jahrzehnt konnten die Ergebnisse der kombinierten Pankreas-Nieren-Transplantation entscheidend verbessert werden. Methodik: Anhand einer Ubersicht wird eine Wertung der Pankreas- und Nieren-Transplantation aus der Sicht des Internisten und Diabetologen versucht. Ergebnisse: Bei simultaner Pankreas -und Nierentransplantation konnte eine Insulinfreiheit sowie weitgehende normale Hb-A lc-Werte nach 1 Jahr in 82% und nach 3 Jahren in 78 % der Falle erreicht werden. Auch die Uberlebensrate der Patienten konnte nach kombinierter Pankreas-Nieren-Transplantation dramatisch verbessert werden. Exzellente Ergebnisse nach Inselzelltransplantation wurden aus Edmonton berichtet, wobei dies auf die neue Form der nichtdiabetogenen Immunsuppression und die hohe Zahl an transplantierten Inseln (10 000 pro kg Korpergewicht) zuruckzufuhren sein durfte. Schlusfolgerungen: Die Fortschritte auf dem Gebiet der Pankreastransplantation sind sowohl auf eine verbesserte chirurgische Operationstechnik wie auch auf eine Optimierung der Immunsuppression zuruckzufuhren. Fortschritte auf dem Gebiet der Inselzellisolierung und die Entwicklung neuer die Abstosung verhindernder Medikamente lassen hoffen, das die Inselzelltransplantation in weiterer Zukunft eine realistische Therapieoption fur Patienten mit Typ-1-Diabetes darstellen wird. Endziel ist die Induktion einer spenderspezifischen Immuntoleranz, die es erlauben soll eine Xenotransplantation von tierischen Inselzellen in menschilche Empfanger zu erreichen.

Objective: Perinatal morbidity and mortality are increased in pregnancies complicated by untreated or undetected gestational diabetes mellitus (GDM), but there is little agreement on how to screen for or diagnose the condition. We evaluated a sensitive diagnostic strategy for GDM. Methods: We conducted an oral glucose tolerance test (oGTT) with 75 g of glucose in 1621 unselected pregnant women between 24 and 28 weeks' gestation. Patients with a positive screening test underwent a second, diagnostic oGTT. A diagnosis of GDM was made if serum glucose exceeded one of the following limits: 100 mg/dL at fasting, 160 mg/dL at 1 hour, 140 mg/dL at 2 hours, and 120 mg/dL at 3 hours. Results: A total of 97 of the 1621 (6.0%) women met the diagnosis of GDM, 61 had impaired glucose tolerance (positive screening test but negative diagnostic test). Women with intermediate glucose tolerance were similar in age and BMI to 104 women with normal glucose tolerance and had serum glucose and insulin levels during oGTT between those of women with GDM and women with normal glucose tolerance. The neonatal outcome in women with (treated) GDM was similar to that in women with normal glucose tolerance, whereas in (untreated) women with IGT birth weight and the rate of macrosomia tended to be higher. Conclusion: Our data support the concept of a continuum of glucose tolerance during pregnancy. A diagnostic strategy aiming at detecting even minor alterations of glucose tolerance (mild GDM) yielded good neonatal results and appears to be clinically useful.

The sulphonylurea receptor-1 (SUR-1) regulates glucose-induced insulin secretion by controlling K+-ATP channel activity of the pancreatic beta-cell membrane. In this study, we investigated the putative role of a T/G-polymorphism (exon 33, codon 1369; S1369A) in the adenosine diphosphate-sensing nucleotide-binding fold-2 (NBF-2) of the SUR-1 on glucose-induced insulin secretion during an oral glucose tolerance test in pregnant women (PW; n=182). Compared to PW with the T/T genotype, statistically significant elevated C-peptide concentrations were found 60 min after glucose intake in PW with the T/G and G/G genotype (T/T 9.0+/-0.4 ng/ml vs T/G 10.8+/-0.4 ng/ml or G/G 10.8+/-0.7 ng/ml, p=0.01). Furthermore, compared to PW with T/T genotype the deltaC-peptide (60/0 min) was significantly enhanced in PW with T/G or G/G genotype (T/T 6.7+/-0.3 vs T/G 8.9+/-0.4 or G/G 8.9+/-0.7, p=0.0009). A significant correlation of C-peptide concentrations with blood glucose (BG) 60 min after glucose intake was only found in PW with the T/T genotype (r=0.6, p0.0004). Similarly, a significant correlation of insulin concentrations with BG 60 min after glucose intake was observed in PW with T/T genotype (r=0.5, p0.0001) and T/G genotype (r=0.24, p0.03) but not in PW with G/G genotype (r=0.01, p=0.9). From our data we conclude that in PW with the alanine substitution in the NBF-2 region, the insulin response of the pancreatic beta-cell after glucose intake is enhanced and does not correlate with actual BG levels.

Summary Aims There is increasing evidence suggesting that leptin plays a major role in the regulation of energy homeostasis, as well as in the neuroendocrine and reproductive systems. Leptin is synthesized in the human placenta. The aim of this study was to relate serum leptin levels during pregnancy to glucose tolerance, body mass index (BMI) and specific metabolic variables, such as specific insulin and proinsulin. Methods A 2-h 75 g oral glucose tolerance test was performed in 221 pregnant women at 22–29 weeks of gestation (median 25th week). Serum leptin was measured using a radioimmunoassay. In 49 women, sequential leptin measurements were performed (during pregnancy and post partum (median 5 months)). Results During pregnancy serum leptin was significantly related to body weight (r = 0.49), BMI (r = 0.51), fasting immunoreactive insulin (r = 0.46), specific insulin (r = 0.43) and proinsulin (r = 0.29) (all P-values

OBJECTIVE To compare the therapeutic effects of the α-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.

Although cardiovascular and cerebrovascular morbidity and mortality in type 2 diabetic patients is closely related to urinary albumin excretion rate (UAER), the causative mechanisms are not yet identified. The aim of our study was to define the circadian variation of blood pressure (BP) in 72 type 2 diabetic patients (mean age 60 years, mean diabetes mellitus duration: 12 years) in comparison with 41 nondiabetic controls with essential hypertension (mean age 58 years) by using ambulatory blood pressure measurement. Thirty diabetic patients had normal UAER (30 mg/24 h), 27 had microalbuminuria (30 to 300 mg/24 h), and 15 had persistent proteinuria (300 mg/24 h). Systolic blood pressure during both nighttime and daytime was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls and patients with normal UAER. During nighttime even type 2 diabetic patients with microalbuminuria had significantly elevated systolic blood pressure compared to controls with essential hypertension. We also observed a correlation of nocturnal blood pressure to UAER (systolic: r = 0.32, P.007 and diastolic: r = 0.24, P.04). Nondipping (defined as a reduction of nocturnal BP10%) was observed in 80% of the macroalbuminuric, 74% of the microalbuminuric, but only in 43% of the normoalbuminuric type 2 diabetic patients and in 37% of the controls (P.04). Since a loss of circadian variation of BP is closely related to vascular complications in nondiabetics, our findings may indicate an important relationship between nondipping of BP and the high morbidity and mortality rate in diabetic patients with increased UAER.

A representative number of prospective studies clearly indicate that cardiovascular morbidity and mortality is significantly increased in type-2 diabetic patients in comparison with non-diabetic control subjects. The cardiovascular death rate is 4.4 fold increased in those diabetic patients presenting none of the classical risk factors (hypertension, hypercholesterinemia or smoking) compared with age-matched control subjects (MRFIT). A decreased survival rate after myocardial infarction, congestive heart failure and an increased occurrence of silent ischemia are responsible for the poor prognosis of type-2 diabetic patients. Recent studies indicate that haemostatic abnormalities and endothelial dysfunction are important risk factors for coronary events in diabetic as well as in nondiabetic patients. In newly diagnosed type-2 diabetic patients a similar prevalence of myocardial infarction and angina compared to previously known type-2 diabetes was found. The long prediabetic period and clustering of risk factors may be very relevant for the high prevalence of cardiovascular disease already at diagnosis of type-2 diabetes. More recent studies performed in Scotland and Verona demonstrated a mortality risk approximately only 50% higher than in nondiabetic subjects. The reduction in the mortality risk could reflect an improvement in diabetes prognosis from the 1960s to the 1980s. Recent observations in type-2 diabetic patients from Finland indicate that glycemic control is an important predictor for coronary heart disease morbidity and mortality. However incidence of coronary heart disease is only low in those patients presenting with a HbAlc value below 6.0%. More information will be available after analysis of the United Kingdom prospective diabetes study. (UKPDS).

Immunointervention studies with immunosuppressive drugs (Cyclosporin A, Azathioprine) in type-1 diabetic patients after clinical diagnosis demonstrated that improvement of beta-cell function is not sufficient and longlasting. Since 80 - 90 % of the beta-cell mass are already destroyed at onset of type-1 diabetes, intervention studies with nicotinamide and insulin (parenteral or oral) were undertaken in the early phase of type-1 diabetes. However, immunomodulation is restricted to familial cases of type-1 diabetes (only 10% of all cases), since prediction of the disease is not possible in the general population. It cannot be excluded that the described immunintervention may only postpone but not hinder the manifestation of type-1 diabetes. Interventions with tolerance induction by BCG or GAD are promising, but did not yet result in prevention of type-1 diabetes in humans. Finally, the most effective strategy would be primary prevention by vaccination or exposure prophylaxis. Should type-1 diabetes prove to be a disease that is provoked through molecular mimicry, i.e. an immunization by an environmental antigen, then strategies to avoid contact with the environmental trigger (f.e. cow's milk protein) or to vaccinate against it (f.e. Coxsackie virus protein P2-c) could be adopted. If all these interventions are not effective in the long term run, research should be concentrated on molecular approaches after improvement in gene transfer technology.

Type 2 diabetes is a complex metabolic disease associated with a high risk of vascular disease and certain entities of cancer. An early starting multifactorial intervention is mandatory in order to improve the prognosis of the patients. Of highest priority is the lowering of LDL-cholesterol (Target value 100 mg/dl or 70 mg/dl when vascular complications are present) and of the very often increased blood pressure values (target values 130-135/80 mm Hg). A successful blood glucose lowering therapy is often only possible when antidiabetic drugs are used in combination. The antidiabetic therapy has to be individualized concerning the HbA1target value and the selection of the antidiabetic drugs in relation to age of the patients and presence or absence of co-morbidities. Severe events of hypoglycemia should be avoided, since these are associated with an increased cardiovascular risk and mortality.

Systemic pro- and anti-inflammatory cytokines are associated with both type 1 and type 2 diabetes, while their role in latent autoimmune diabetes in adults (LADA) is unclear. Therefore, we compared cytokine concentrations in patients with LADA, type 1 or type 2 diabetes and healthy individuals to test the hypothesis that differences of cytokine concentrations between all groups are attributable to diabetes type and BMI.The pro-inflammatory cytokines IL-6 and TNF-α, and the anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10 were measured in 90 participants with type 1 diabetes, 61 with LADA, 465 with type 2 diabetes and 41 control participants using multiple regression models adjusted for BMI, sex, age, blood pressure and diabetes duration.Patients with type 2 diabetes had higher concentrations of systemic IL-1RA, IL-6 and TNF-α cytokines than patients with either LADA or type 1 diabetes (p 0.0001 for all differences). Cytokine concentrations in controls were lower than those in all diabetes types (p 0.04). Increased BMI was positively associated with higher systemic cytokine concentrations in all diabetes types (p 0.0001). Despite the association of cytokines with anthropometric data, differences between diabetes forms persisted also after adjusting analysis for the confounders BMI, age, sex, disease duration and blood pressure (p 0.04).Although body mass associates positively with pro- and anti-inflammatory cytokine levels, patients with type 2 diabetes have higher cytokine levels independent of the prevailing BMI. LADA and type 1 diabetes could not be distinguished by systemic cytokines.

Background: Type 2 diabetes is a leading cause of chronic kidney disease (CKD). The purpose of the Individual Risk-Profiling and Treatment in Diabetes Management (IRIDIEM) study was to evaluate the characteristics of CKD and associated comorbidities in patients with type 2 diabetes and CKD. Methods: IRIDIEM was conducted as a cross-sectional survey in 109 centres in 11 countries and included 1,205 patients aged ≧50 years with type 2 diabetes for ≧5 years and CKD stage 2–4. Results: 50% of patients were in CKD stage 4; 42% had CKD stage 3, and 4% were in CKD stage 2. Concomitant risk factors for cardiovascular disease and/or progression of CKD included hypertension (92% of patients), proteinuria (74%), hypercholesterolaemia (65%), and hypertriglyceridaemia (44%). Only 64% of patients with hypertension had received antihypertensive medication. Anaemia was present in 34% of patients and increased markedly with advanced CKD stages. Of patients with documented anaemia, only 19% had received epoetin and only 7% had received iron treatment. Conclusion: IRIDIEM documents the need to improve adherence to current best practice guidelines for management of cardiorenal risk factors including earlier initiation of antihypertensive treatment, lipid and anaemia management in this high-risk patient population.

No conclusive data are available about the long-term effect of insulin treatment in type 2 diabetic patients failing to maximal doses of sulfonylureas and caloric restriction. In total 160 non-obese type 2 diabetic patients with secondary failure were substituted with insulin using a diabetic teaching and care program. From these 160 patients 40 died within the observation period of five years; 102 patients had a complete five year follow-up, whereas the remaining 18 patients did not come to regular follow-up visits. Metabolic control parameters improved significantly in the 102 patients with the complete five year follow-up. Postprandial plasma glucose (16.0 mM vs 10.9 mM; p < 0.0001) and HbA1c values (8.7% vs 7.1%, p < 0.0001) decreased significantly from the state before to five years after insulin substitution. In addition, plasma lipid levels could be significantly lowered under insulin therapy (cholesterol 6.2 +/- 1.5 mM vs 5.4 +/- 3.6 mM, p < 0.0002; triglycerides 2.8 +/- 1.6 mM vs 2.4 +/- 2.1 mM, p < 0.01). However, we observed a significant weight gain (mean: 10.6 kg) associated with insulin application during the five year follow-up. Thus, the body-mass-index decreased from 28.9 at onset of type 2 diabetes to 24.5 (p < 0.0001) at time of secondary failure and increased again to 28.5 (p < 0.0001) at five years after onset of insulin treatment. Furthermore, small increases of plasma creatinine from 88.4 microM to 115 microM, as well as systolic (19.3 kPa to 20.7 kPa) and diastolic (10.7 kPa to 11.3 kPa) blood pressures were observed.(ABSTRACT TRUNCATED AT 250 WORDS)