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Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: The prevention of cardiovascular disease, including diastolic cardiac dysfunction with its high prevalence and ominous prognosis, is a therapeutic challenge for patients with type 2 diabetes. Both short and long-acting insulin analogues (AI) have been shown to reduce glucose variability and provide potential benefit for cardiovascular disease although the effects on cardiac function have not yet been evaluated. This long-term, prospective, randomized controlled trial in patients with type 2 diabetes (T2D) tested the hypothesis that a multiple daily injection regimen (MDI) with AI improves postmeal glucose excursions in comparison to human insulin (HI) and that the effects of AI improve diastolic cardiac function., Methods: For 36 months, MDI treatment in 109 T2D patients was adapted every 3 months (targets: fasting glucose ≤ 110 mg/dl, postmeal glucose ≤ 150 mg/dl) in both groups: AI (insulin detemir and insulin aspart, n = 61) and HI (NPH-insulin and regular HI, n = 48). Diastolic cardiac function (myocardial velocity E' using tissue Doppler imaging and the mitral inflow ratio E/A) and vascular function were assessed before and 2 h after a standardized breakfast (48 g carbohydrates). At baseline, both groups were comparable with regards to demographic, cardiac and metabolic data. Analysis of data included traditional statistics as well as the use of a multiple imputation technique shown in brackets [ ]., Results: At 36 months, the primary endpoint, postmeal glucose, decreased by 20 ± 62 mg/dl, p = 0.038 [p = 0.021] with AI and increased insignificantly with HI (inter-group p = 0.032 [p = 0.047]) to postmeal glucose levels of 161 ± 39 with AI vs. 195 ± 54 mg/dl with HI (inter-group p = 0.002 [p = 0.010]) whereas the levels of fasting glucose and HbA1c were comparable. With AI, postmeal E' improved by 0.6 ± 1.4 cm/s, p = 0.009 [p = 0.002] and fasting E' by 0.4 ± 1.4 cm/s, p = 0.069 [p = 0.013], however, E' remained unchanged with HI. These changes were consistent with those of the traditional parameter E/A., Conclusions: MDI with AI results in better postmeal glucose control compared to HI. The treatment with AI is associated with improved diastolic cardiac function. ClinicalTrials.gov (NTC00747409).

The changing demography of European populations mandates a vital role for internists in caring for patients in each level of healthcare. Internists in the tertiary or academic setting are highly ranked in terms of their responsibilities: they are clinicians, educators, researchers, role models, mentors and administrators. Contrary to the highly focused approach of sub-specialties, general internists working in academic settings can ensure that coordinated care is delivered in the most cost-conscious and efficient way. Moreover, internal medicine is one of the most appropriate specialties in which to teach clinical reasoning skills, decision-making and analytical thinking, as well as evidence based, patient oriented medicine. Internists deal with challenging patients of the new millennium with a high burden of chronic diseases and polypharmacy; practice personalised medicine with a wide scientific background and so they are the perfect fit to establish and implement new tools for scientific research. In conclusion, internal medicine is developing a new identity as a specialty in its own right. The European Federation of Internal Medicine supports the concept of academic internists and calls upon the member countries to construct academic (general) internal medicine departments in their respective countries. As 'internal medicine is the cornerstone of every national healthcare system', academic (general) internal medicine should strive to be the cornerstone of every integrated, patient-centred, modern medical care and training system., (Copyright © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Aims: To evaluate the efficacy and safety of twice-daily dosing of dapagliflozin and metformin, exploring the feasibility of a fixed-dose combination., Methods: In this 16-week, phase III, randomized, double-blind placebo-controlled study, adults who were receiving metformin administered twice daily (≥1500 mg/day) and had inadequate glycaemic control were randomized 1:1:1:1 to receive dapagliflozin twice daily (2.5 or 5 mg), placebo or dapagliflozin 10 mg once daily (which was included as a benchmark). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) level. Secondary endpoints included changes in fasting plasma glucose (FPG) level and body weight., Results: Four hundred adults were randomized to dapagliflozin (2.5 mg twice daily, 5 mg twice daily, 10 mg once daily) or placebo co-administered with metformin twice daily. At 16 weeks, the adjusted mean change in HbA1c from baseline was significantly reduced in the dapagliflozin 2.5 mg twice daily and 5 mg twice daily groups versus placebo (-0.52 vs. -0.30%, p = 0.0106 and -0.65% vs. -0.30%, p < 0.0001). There were also significantly greater improvements for dapagliflozin twice daily groups versus placebo in FPG body weight and achievement of HbA1c level of <7%. Efficacy outcomes for dapagliflozin twice daily were numerically similar to those for dapagliflozin once daily. Dapagliflozin twice daily was well tolerated., Conclusions: Dapagliflozin 2.5 or 5 mg twice daily added to metformin was effective in reducing glycaemic levels in patients with type 2 diabetes inadequately controlled with metformin alone. This study supports the development of a fixed-dose combination regimen., (© 2014 John Wiley & Sons Ltd.)

Patient centred care is now considered the gold standard and there should be 'no decision about me, without me'. Internists who treat patients with complex multi-morbidities should consider patients' preferred outcomes, following a 'goal-oriented' principle. Perhaps the most important barrier to goal-oriented care is that medicine is deeply rooted in a disease-outcome-based paradigm. Rather than asking what patients want, the culture of modern medicine has prioritised optimal disease management according to guidelines and population goals. Doing what is right for the patient should be based on trust. Patients and internists must therefore meet as equals: 'I' and 'you' should be replaced by 'we'., (Copyright © 2014 European Federation of Internal Medicine. All rights reserved.)

The prevalence and prognostic importance of diastolic dysfunction in type 2 diabetes has only recently been appreciated. We tested the hypothesis that in insulin treated type 2 diabetes (D), carbohydrate consumption induces oxidative stress resulting in further impairment of diastolic function beyond structural myocardial stiffness. The effects of a pure carbohydrate breakfast (48 g) on oxidative stress and cardiac function were studied in the fasting and postmeal states in subjects without hypertension or overt cardiac disease (moderately well controlled D, n=21 and controls without D, n=20). Studied variables included systolic and early diastolic (E') myocardial velocities, traditional metabolic and hemodynamic parameters, serum nitrotyrosine, and sVCAM-1. In D compared to control subjects, the postmeal increase (∆) in glucose (1.44±2.78 vs. 0.11±0.72 mmol/l, p=0.04) and ∆nitrotyrosine (0.34±0.37 vs. -0.23±0.47 nM/l, p<0.001) were significantly higher. sVCAM-1 was higher in fasting and postmeal (p=0.02). E' was significantly lower in postmeal (7.3±1.3 vs. 9.6±1.3 cm/s, p<0.001) and fasting (p<0.001) whereas the rate pressure product was significantly higher (9 420±1 118 vs. 7 705±1 871 mm Hg/min, p<0.001). Multivariable regression models of the pooled data demonstrated that independent predictors for postmeal E' were ∆nitrotyrosine and septal thickness (R² 0.466) and for fasting E' age, ∆nitrotyrosine, and septal thickness (R² 0.400). In insulin requiring type 2 diabetes, carbohydrate consumption may induce oxidative stress that is associated with worsening diastolic function, indicating that this metabolic factor is an important determinant of diastolic dysfunction in the diabetic heart beyond the increase in structural myocardial stiffness., (© Georg Thieme Verlag KG Stuttgart · New York.)

Metformin is, if not contraindicated and if tolerated, usually preferred over other antidiabetic drugs for the first line treatment of type-2 diabetes. The particular decision on which antidiabetic agent to use is based on variables such as efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia, risk, and patient preferences. However, there is no guidance how to consider these in the selection of antidiabetic drug treatment. In this work, we aimed to summarize available evidence and tried to give pragmatic treatment recommendations from a clinical practice perspective.There are clear contraindications for some drugs in those with impaired renal and liver function and precautions in those with heart failure for the use of metformin (NYHA III-IV) and glitazones. On the other hand, GLP-1 analogs, DPP-4 inhibitors and acarbose are generally less critical and can be used in the majority of patients. We identified the following gaps with respect to the selection of antidiabetic drug treatment in patients with co-morbid disease conditions: 1) Guidelines fail to give advice on the use of specific antidiabetic drugs in patients with co-morbidity. 2) The literature is deficient in studies documenting antidiabetic drug use in patients with severely impaired renal function, diabetic retinopathy, cerebrovascular disease and systolic heart failure. 3) Further there are no specific data on patients with multiple of these co-morbid disease conditions. We postulate that differential use of antidiabetic drugs in patients with co-morbid disease constellations will help to reduce treatment related complications and might improve prognosis.

Background: Diabetes is frequently diagnosed in patients with cirrhosis and represents an important risk factor for morbidity and mortality. Pharmacological therapy is limited due to hepatotoxicity and the risk of hypoglycemia. Investigations on medical practice in this patient population, frequency of diabetes-associated complications and the impact of quality of metabolic control are rare., Aims and Methods: A retrospective analysis was performed to compare the effects of hypoglycemic treatment, the achieved glycemic control under therapy, the prevalence of typical cirrhosis-related or microangiopathic complications, and cardiovascular comorbidities between a group of diabetic patients with cirrhosis (n = 87) and a nondiabetic cirrhotic population (n = 198)., Results: The prevalence of diabetes in our cohort was 30.5%. Of all diabetic patients, 39.1% received therapy which might potentially result in serious side effects in patients with end-stage liver disease. The rate of ongoing alcohol abuse (28.7%) and noncompliance under medication (41.4%) was high. Only 28.7% of all diabetic subjects showed satisfactory (as defined by HbA1c ≤ 6.5%) glycemic control under therapy. Patients achieving satisfactory control experienced a lower rate of certain cirrhosis-related complications such as hepatic encephalopathy (HE) and hepatocellular carcinoma (HCC), arterial hypertension, and hypercholesterolemia. HE was significantly more frequent in diabetic than nondiabetic cirrhotic patients.

Aim: To examine factors associated with insulin injection omission/non-adherence on a global basis., Methods: Telephone survey of 1530 insulin-treated adults with self-reported diabetes (110 type 1 and 1420 type 2) in China, France, Japan, Germany, Spain, Turkey, UK or USA. Participants had a mean age of ∼60 years, ∼15 years duration of diabetes and ∼9 years duration of insulin treatment. Regression analysis assessed the independent associations (p < 0.05) of country, participant characteristics and treatment-related beliefs/perceptions with number of days in the past month that an insulin injection was missed or not taken as prescribed., Results: One third (35%) of respondents reported one or more days (mean: ∼3 days) of insulin omission/non-adherence. Insulin omission/non-adherence differed widely across countries (range = 20-44%); differences in days of insulin omission/non-adherence were maintained after adjustment for other risk factors. Most risk factors had similar relationships with insulin omission/non-adherence across countries (few interactions with country). Insulin omission/non-adherence was more frequent among respondents who were male, younger, had type 2 diabetes or more frequent hypoglycaemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/logistical barriers and difficulties with insulin adherence, were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing., Conclusions: The results of this large-scale study suggest that insulin omission/non-adherence is common and associated with several modifiable risk factors (including practical barriers, injection difficulties, lifestyle burden and regimen inflexibility). Additional efforts to address these risk factors might reduce the frequency of insulin omission/non-adherence and lead to improved clinical outcomes., (© 2012 Blackwell Publishing Ltd.)

Aims: Patients with type 2 diabetes are at high risk for developing heart failure. Evidence-based treatment recommendations with respect to the specific benefits or possible hazards of antidiabetic treatment are scarce., Methods and Results: In a systematic search we only identified randomized, controlled trials for thiazolidinediones. Further evidence is largely based on subgroup analyses of larger intervention studies in mostly systolic heart failure, on observational studies, or on registries. Acknowledging this lack of data, hyperglycaemia should be treated to appropriate guideline-recommended targets and hypoglycaemia avoided until this evidence becomes available. Thiazolidinediones should not be used because of an increased event rate in diabetic patients with established heart failure and a large increase in incident heart failure. All other glucose-lowering strategies might be used in patients with diabetes and heart failure, but specific precautions must be considered., Conclusions: The documented lack of data calls for specific trials, as diabetes and heart failure as well as their co-morbidities are highly prevalent and are becoming even more important with an increasing prevalence of obesity and an ageing population.

Aims: To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens., Methods: Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA., Results: One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives., Conclusions: Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

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.)

New studies have demonstrated similarities in the complex pathomechanisms of diabetes mellitus type 1 (T₁D) and rheumatic diseases and in particular rheumatoid arthritis (RA). Common HLA gene complex characteristics and polymorphisms of inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) play a special role in both disorders. The metabolic syndrome, associated with insulin resistance and diabetes mellitus type 2 (T₂D), often shows criteria of a subclinical chronic inflammation. New forms of therapy with monoclonal antibodies against TNF-α, IL-1 and IL-6 have improved the management of patients with RA. Cytokine-induced inflammation also seems to be important in the pathogenesis and progression of T₁D and T₂D. Whether a therapy with the same monoclonal antibodies established in RA could also be successful in diabetes still has to be investigated in further studies. Both RA and T₁D are autoimmune disorders and show a cumulative incidence with further autoimmune diseases.

Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia., (© 2011 Blackwell Publishing Ltd.)

Diabetes and periodontitis are chronic diseases with an increasing prevalence in the German population. There is a bi-directional relationship between both diseases. Diabetes promotes the occurrence, the progression and the severity of periodontitis. Periodontitis complicates the glycemic control of diabetes, increases the risk of diabetes-associated complications and possibly even of its onset. In view of the existing evidence, that is still not sufficiently communicated within the medical community, an expert panel consisting of four diabetologists and four periodontists has addressed the following questions: What is the effect of diabetes mellitus on periodontitis and on periodontal therapy? What is the effect of periodontitis on diabetes mellitus? What are the practical consequences, that result for interdisciplinary treatment strategies? The treatment of periodontal infections should become an integral part of the management of diabetes, whereas glycemic control is a prerequisite for successful periodontal therapy.

Patients with hyperthyroidism tend to feel well and procrastinate the visit to the doctor and hence diagnosis of the disease. Among a whole variety of more or less distinct symptoms affecting many organs, cardiovascular disease is most prevalent and serious, because it relates to an increase in mortality of patients with hyperthyroidism. Recent epidemiological studies have clearly demonstrated that the disease already begins with the subclinical states of hyperthyroidism and, as a consequence, treatment should also be commenced early on. Novel insights into the mechanisms and actions of thyroid hormones at the pathophysiological level offer a potential for the development and future therapeutic use of selective hormone analogues. Despite the high frequency and importance of thyroid disorders, awareness appears to be decreasing and over-dosage of thyroid hormones in benign thyroid conditions is frequent. This review should emphasize that the thyroid gland affects the structure and function of a multitude of organs and, on the other hand, many symptoms and complaints, related to various organ systems, should raise suspicion of thyroid disease.

We report on a 46 year old patient with a history of paroxysmal atrial fibrillation who presented to our emergency room. Diagnostic evaluation showed elevated free peripheral thyroid hormone levels and thyrotropine (TSH) hormone within normal limits. Ultrasound of the thyroid was normal, and thyroid autoantibodies were found in the normal range. There was a positive family history for thyroid dysfunction. TSH-producing adenoma (TSHoma) of the pituitary gland - the main differential diagnosis - was excluded by cranial MRI and laboratory tests. Familial thyroid hormone resistance (Refetoff syndrome) was suspected and could be confirmed by detection of a pathogenic mutation within the beta-thyroidhormone receptor gene. After spontaneous conversion to sinusrhythm the patient was treated with a beta(1)-selective betareceptor blocker. Up to now, no specific treatment is available to correct the defective beta-thyroidhormone receptor.

Introduction: We determined the prevalence of anterior pituitary dysfunction in a multi-centre screening program across five German endocrine centres in patients rehabilitating from TBI (GCS<13)., Patients & Methods: 246 patients (39+/-14 yrs; 133 males, 12+/-8 months after TBI) underwent a series of baseline endocrine tests with central assessment of TSH, free T4, prolactin, LH, FSH, testosterone (m), estradiol (f), cortisol, GH, and IGF-I. If IGF-I was <-2 SDS dynamic testing was performed. GHD was defined according to BMI-dependent cut-off values for GH response to GHRH+arginine of <4.2, <8.0 and <11.5 ng/ml in obese, overweight and lean subjects, respectively, or <3 micro g/l in ITT. Hypocortisolism was suggested when basal cortisol was <200 nmol/l and confirmed by ITT (peak<500 nmol/l)., Results: In TBI patients some degree of impaired pituitary function was shown in 21% (n=52/246). Total, multiple and isolated deficits were present in 1%, 2% and 18%, respectively. 19% had an IGF-I of <-1 SDS, 9% of <-2 SDS. In 5% GHD was confirmed. 9% had hypogonadism. 4% had hypocortisolism and 1% of patients had confirmed ACTH-deficiency. 12% had TSH-deficiency., Summary: In summary, in this large series carried out on an unselected group of TBI survivors we have found hypopituitarism in every fifth patient with predominantly secondary hypogonadism and hypothyreosis. Regarding somatotrope insufficiency IGF-I is decreased in 50% of GHD patients., Conclusion: These findings strongly suggest that patients who suffer head trauma should routinely undergo endocrine evaluation., (J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart. New York.)

Background: People with diabetes mellitus on insulin therapy increasingly prefer insulin pens over syringes and vials. Different types of pen needles are available for insulin pens, e.g., "thin-wall" needles, which have the same outer diameter but a relatively lager inner diameter compared to needles produced with a "regular-wall.", Methods: We conducted a multicenter open-label, single-arm study in patients (n = 97) with diabetes mellitus using insulin pens. The aim of our study was to evaluate pen user habits as well as to assess patient's appraisals and ratings considering two different types of 31-gauge pen-needles, so-called "thin-wall" needles or "regular-wall" needles." Patients twice underwent a 2-week intervention period, starting with a "regular-wall period" followed by a "thin-wall-period." After each period patients filled in questionnaires., Results: In total, 97 diabetes patients (48% female; mean age, 56 years; range, 20-70 years) completed the study. Patients reported significantly less pain, less bleeding, less skin irritation, less injection strain, less residual insulin leakage from the needle tip after injection, and less needle occlusion when using "thin-wall needles" (P < 0.001). A higher proportion of patients expressed an overall preference for the "thin-wall" needles (78%) compared to the "regular-wall" needles (8%) (P < 0.001)., Conclusions: Pen and pen needle handling, preparation, and execution of injections should be a part of repeated diabetes education and be re-evaluated on a regular basis. The "thin-wall" 31-gauge needle was found to be more user-friendly and consequently preferred by the patients. Additional larger-scale trials using blinded and randomized study designs are needed to validate these findings.

Background: Patients with liver cirrhosis develop frequently disturbances of glucose metabolism e. g. glucose intolerance or hepatogenous diabetes which are caused by the hepatocellular functional loss and insulin resistance due to chronic liver disease., Discussion: Until now there are no recommendations comparable to guidelines on the diagnosis of and therapy for hepatogenic diabetes. Regarding basic treatment a sufficient daily energy and protein supply should be guaranteed since the majority of patients with liver cirrhosis are malnourished. The risk of hypoglycaemia must be considered carefully under pharmacological treatment of hepatogenous diabetes. Biguanide and PPAR gamma agonists are contraindicated due to side effects in liver cirrhosis. Suitable oral antidiabetics are glinides and short-acting sulfonylureas. If a sufficient diabetes adjustment does not succeed by oral antidiabetics a prandial insulin therapy using short-acting insulins or rapid-acting insulin analogues should be applied., Conclusion: Optimisation of diabetic metabolic conditions is not only important to avoid typical diabetic late complications but also cirrhosis-associated complications, e. g., gastrointestinal bleeding, hepatic encephalopathy or the occurrence of hepatocellular carcinoma.

In people with type 2 diabetes (T2DM), hyperglycemia has a negative impact on cardiac function and cardiovascular risk. Beneficial effects of improved postprandial glycemic control have been shown for cardiovascular risk only. To demonstrate these beneficial effects on myocardial function, we investigated well-controlled T2DM patients on three insulin regimens with different impact on postprandial glucose control. For 24 months, 61 T2DM participants in a randomized study had either conventional therapy (CT) with human premixed insulin b.d. (n=20), intensified therapy (ICT) with Lispro at meals and NPH at bedtime (n=24), or supplementary therapy (SIT) with human regular insulin at meals (n=17). Metabolism and cardiovascular function were assessed before and 2 hours after a standardized carbohydrate breakfast (48 g) using tissue Doppler to measure diastolic myocardial function (E'). Age, BMI, dose of insulin, cardiovascular disease, and medication were comparable between the groups. Hb1Ac was comparable with CT, ICT, and SIT (6.6+/-0.6, 6.2+/-0.6, and 6.4+/-0.7%) and so was fasting glucose. Post-meal glucose increment was 60+/-45 mg/dl with CT, but 15+/-52 and 8+/-58 mg/dl with ICT and SIT (p<0.006). E' was significantly lower (p<0.03) with CT (6.8+/-1.0 cm/s) vs. ICT (7.7+/-1.6) and SIT (7.8+/-1.2 cm/s), and correlated with post-meal glucose (r=-0.2644, p<0.046). Intima-media thickness and arterial stiffness parameters were higher in CT (p<0.04). In T2DM patients, the long-term insulin regimens CT, ICT, and SIT achieved overall good metabolic control with significant differences, however, in postprandial glucose increments. The regimens achieving better post-meal glucose control were associated with better myocardial/vascular function.

The effects of thiazolidinediones on cardiac function are controversial in humans with type 2 diabetes (T2DM) and in animals. Given the high prevalence and prognostic relevance of diastolic myocardial dysfunction in T2DM, we tested the hypothesis that by reducing oxidative stress rosiglitazone, but not glimepiride, may improve diastolic function. This randomised cross-over study investigated 12 metformin-treated T2DM patients without cardiovascular disease before and after 16 weeks of additional therapy with rosiglitazone (8 mg daily) or glimepiride (3 mg daily). Systolic and diastolic myocardial velocity (E') were assessed with tissue Doppler. In spite of similar non-significant lowering of glycosylated haemoglobin (HbA1C), rosiglitazone, but not glimepiride, significantly improved E' (p=0.04), reduced malondialdehyde (p=0.028), lowered high-sensitivity C-reactive protein (hsCRP) (p=0.019), and increased adiponectin (p=0.002). For rosiglitazone, multivariate regression analysis revealed malondialdehyde reduction as an independent determinant of treatment-induced improvement in E'. The rosiglitazone-induced improvements of diastolic function and oxidative stress may be of prognostic relevance in choosing therapy for T2DM patients without overt heart disease.

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiovascular outcome in patients with type 2 diabetes mellitus (T2DM). Myocardial diastolic function (Ve) is a known marker of cardiovascular prognosis. It could potentially indicate the effects of preventive therapy if evaluated by tissue Doppler. We tested the hypothesis that treatment with the ACE inhibitor ramipril has beneficial effects on Ve. In this study, 16 subjects on insulin therapy (eight receiving 10 mg ramipril/day compared to eight matched controls who were not treated with an ACE inhibitor) were followed up for a period of nine months. Myocardial and vascular function were assessed by tissue Doppler and ultrasound. In the ramipril group, Ve improved significantly after nine months of treatment (7.8+/-0.9 cm/s to 8.6+/-0.9 cm/s, p<0.04). Systolic blood pressure and intima media thickness (IMT) demonstrated a trend towards improvement. In controls, Ve remained unchanged and there was a trend towards deterioration in stiffness index beta (p<0.07). In conclusion, the observed improvement of myocardial diastolic function with ramipril in patients with T2DM is an encouraging result. It might contribute to the overall improvement that has been observed with hard cardiovascular end points.

Aims: To assess the effects of a structured in-patient diabetes training programme in people with Type 2 diabetes mellitus on a basal-bolus regimen using insulin glargine or NPH insulin and rapid-acting insulin analogues with respect to glycaemic control, weight development and incidence of hypoglycaemia in an outpatient-clinic setting., Patients and Methods: This was a prospective, non-randomized, single centre, comparative observational study including 119 subjects. Pre-study treatment was a basal-bolus regimen with NPH insulin and a rapid-acting insulin analogue. Subjects either continued with NPH insulin (n=56) or were switched over to insulin glargine (n=63) at the discretion of the investigator (aiming at equal numbers in each group). Patients then attended routine out-patient follow up visits for 18 months., Results: HbA1c in the insulin glargine group improved statistically significant by -0.49%; [95%CI, -0.26, -0.71; p<0.001; HbA1c at endpoint 6.95+/-0.71%], whereas in the NPH group the reduction by -0.12% [95%CI, -0.31, 0.06; p=0.189; HbA1c at endpoint 7.22+/-0.74%] was statistically not significant. After 18 months of treatment the difference between treatment groups was 0.37% (p<0.015). Mean weight gain was significantly higher in the NPH group than in the glargine group (2.1 vs. 0.25 kg; p=0.025). A lower risk of hypoglycaemia in the glargine group (0.50 vs. 0.71 episodes/patient/month) did not reach statistical significance (p=0.081)., Conclusions: Following a structured in-patient diabetes training programme glycaemic control in people with Type 2 diabetes mellitus on a basal-bolus regimen improved significantly only with insulin glargine suggesting that training alone may not be sufficient to further improve metabolic control in relatively well controlled patients on NPH insulin. Therefore, in addition to a structured training programme also the insulin regimen should be optimized, e.g. by introduction of an insulin analogue.

Background: In patients with type 2 diabetes mellitus diastolic dysfunction is a frequent manifestation of myocardial disease with poor prognosis. The hypothesis that better glycemic control results in improved myocardial function was tested using tissue Doppler., Methods: During a short-term (3 weeks) and a long-term (52 weeks) study, metabolic control and myocardial function were evaluated in 33 and 50 patients, respectively, with type 2 diabetes. Systolic (Vs) and diastolic (Ve) myocardial velocity were assessed by tissue Doppler. In the short-term study, antidiabetic therapy was intensified in 25 patients (Int3) and compared to those eight individuals with unchanged therapy (Con3), similarly to the long-term study with Int52 (n = 39) and Con52 (n = 11)., Results: In Int3, fasting serum glucose was reduced by 69+/-47 mg/dl (p < 0.01) compared to baseline and was associated with an increase of Ve from 8.0 +/- 1.6 to 8.8 +/- 1.6 cm/s (p < 0.01) and Vs from 6.2 +/- 1.1 to 6.6 +/- 1.3 cm/s, p < 0.04. In Con3, serum glucose and myocardial velocities were unchanged. In Int52, fasting serum glucose was reduced by 20 +/- 43 mg/dl (p < 0.017) compared to baseline and was associated with an increase of Ve from 7.6 +/- 1.3 to 8.3 +/- 1.7 cm/s (p < 0.002) and a similar trend in Vs (p < 0.07). In Con52, serum glucose and myocardial velocities remained unchanged. Evaluating pooled data, the changes of diastolic myocardial velocity correlated significantly with the changes of serum glucose (r = 0.49, p < 0.004 short- and r = 0.45; p < 0.002 long-term study, respectively)., Conclusion: In patients with type 2 diabetes subclinical diastolic myocardial dysfunction, measured as diastolic myocardial velocity by tissue Doppler, improves with better glycemic control.

Aims/hypothesis: Using modern echocardiography, we quantified the extent of global myocardial function and perfusion abnormalities in patients with type 2 diabetes and compared this with the hypothetically similar extent of impairments in patients with coronary artery disease (CAD)., Subjects and Methods: This case-control study (66 patients) compared four age-matched groups: control, type 2 diabetic, CAD, and diabetic subjects with CAD (DCAD) and left ventricular ejection fraction >50%. CAD patients had 1-2 vessel disease. Diastolic and systolic myocardial velocities were assessed with pulsed tissue Doppler. Global myocardial perfusion was assessed with contrast echocardiography as indices of capillary blood volume and myocardial blood flow at maximal vasodilatation. In CAD and DCAD patients, functional and perfusion parameters were additionally assessed in the territory with a normal coronary angiogram reading, providing a model for comparison with the global data from control and diabetic patients., Results: Comparing diabetic with control subjects, myocardial velocity at early diastole was impaired (8.8+/-1.8 vs 10.1+/-1.7 cm/s; p=0.02) and correlated inversely with age, HbA(1c) and pulse pressure (R (2)=0.761). Capillary blood volume (16.6+/-5.0 vs 24.4+/-4.9%) and blood flow (56+/-35 vs 114+/-40) were decreased (p=0.001). In CAD patients, myocardial velocity at early diastole was similarly decreased (p=0.02). CAD and DCAD patients were receiving more cardiovascular preventive therapy for the same extent of impaired global perfusion as in the less extensively treated diabetes group without CAD (p<0.002), but had superior perfusion of the 'normal' coronary territory than that group (p<0.05)., Conclusions/interpretation: In patients with diabetes, global diastolic function and myocardial capillary blood volume and blood flow are impaired to the same extent as in patients with CAD. These impairments could form the basis of new therapeutic concepts.