Clinical benefits of switching to insulin degludec irrespective of previous basal insulin therapy in people with Type 1 or Type 2 diabetes: evidence from a European, multicentre, retrospective, non-interventional study (EU-TREAT).

AIMS: To investigate whether the benefits of switching to insulin degludec observed in the European retrospective chart review study EU-TREAT were dependent on the previous basal insulin used. METHODS: People with Type 1 or Type 2 diabetes were switched to insulin degludec from other basal insulins ≥6 months before data collection. Participants were stratified into three groups based on their previous basal insulin: insulin glargine 100 units/ml (Type 1: n=888; Type 2: n=259); insulin detemir (Type 1: n=726; Type 2: n=415); and neutral protamine Hagedorn (Type 1: n=53; Type 2: n=95). Their glycaemic control and hypoglycaemia incidence at 6 and 12 months post-switch vs pre-switch was then evaluated. RESULTS: Significant HbA1c reductions were achieved in all previous basal insulin groups for participants with Type 1 diabetes [insulin glargine 100 units/ml: -2.08 mmol/mol (-0.19%); insulin detemir: -2.40 mmol/mol (-0.22%)] and those with Type 2 diabetes [insulin glargine 100 units/ml: -5.90 mmol/mol (-0.54%); insulin detemir: -6.01 mmol/mol (-0.55%); neutral protamine Hagedorn: -2.73 mmol/mol (-0.25%)] at 6 months, except for the relatively small neutral protamine Hagedorn group in those with Type 1 diabetes [-1.75 mmol/mol (-0.16%)], where statistical significance was not reached. At 6 months in the Type 1 diabetes group, switching to insulin degludec from insulin glargine 100 units/ml resulted in significantly lower hypoglycaemia rates across all hypoglycaemia categories; for the insulin detemir group, this significance was also observed for severe and nocturnal non-severe hypoglycaemia, while the low number of people in the neutral protamine Hagedorn group resulted in nonsignificant reductions in hypoglycaemia rates. At 6 months in the people with Type 2 diabetes, switching to insulin degludec resulted in significantly lower rates of hypoglycaemia across all categories for all groups. Similar outcomes were observed at 12 months. CONCLUSIONS: Switching to insulin degludec from other basal insulins can improve glycaemic control and/or reduce hypoglycaemia risk in people with diabetes (although there was a nonsignificant reduction in HbA1c and hypoglycaemia rates for the neutral protamine Hagedorn group in Type 1 diabetes) under routine care.

Composite efficacy parameters and predictors of hypoglycaemia in basal-plus insulin therapy--a combined analysis of 713 type 2 diabetic patients.

AIMS: We aimed to identify predictors of hypoglycaemia in patients with poorly controlled type 2 diabetes treated with a single daily bolus of insulin glulisine on top of insulin glargine and oral antidiabetic drugs (basal-plus regimen). METHODS: We retrospectively analysed four large basal-plus trials including 713 patients (47% female) with type 2 diabetes, mean age of 59.9 ± 9.5 years and diabetes duration of 11 ± 7.0 years. Predictors for symptomatic, severe and nocturnal hypoglycaemia were identified by multivariate logistic regression analyses, calculation of odds ratios (ORs) and Wald 95% confidence intervals (CIs). RESULTS: Mean numbers of hypoglycaemic events per year were 4.64 ± 11.4 (symptomatic < 60 mg/dl), 0.59 ± 2.28 (nocturnal) and 0.03 ± 0.22 (severe). A total of 44.5% of patients reached the composite endpoint of glycated haemoglobin (HbA1c) <7.0% plus no severe hypoglycaemia, and 26.7% reached the composite of HbA1c <7.0% plus no symptomatic hypoglycaemia. Predictors of nocturnal and symptomatic hypoglycaemia were female gender (OR 1.82; 95% CI 1.07-3.11 and OR 1.89; 95% CI 1.31-2.78), diabetes duration >10 versus <5 years (OR 2.61; 95% CI 1.03-6.59 and OR 2.01; 95% CI 1.15-3.51) and higher basal insulin dose (per unit of increase) (OR 1.01; 95% CI 1.00-1.03 and OR 1.01; 95% CI 1.00-1.02). Conversely, a higher body mass index (BMI) (27-30 vs. <27 kg/m(2) and >30 vs. <27 kg/m(2) ) conferred a reduced risk of symptomatic hypoglycaemia with an OR of 0.53 (95% CI 0.31-0.90) and an OR of 0.61 (95% CI 0.39-0.97). CONCLUSIONS: Female gender, a long diabetes duration and higher basal insulin dose were predictors of hypoglycaemia, while protection was provided by BMI > 30. These results may help to successfully establish basal-plus insulin regimen in individual patients on their transition from basal-only to basal-bolus treatment.

Clinical update on insulin pump therapy in combination with continuous glucose monitoring.

In recent years, the treatment of type 1 diabetes has changed significantly. An important diagnostic and therapeutic support tool is the continuous glucose monitoring (CGM) showing its best performance when used in combination with an insulin pump therapy. Before the availability of CGM the consideration of glucose regulation and therapeutic success was based solely on selectively measured blood glucose levels and HbA1c. In contrast to the blood glucose measurements CGM measures in the interstitial fluid and opens a new dimension of diabetes therapy, we call it "glucose dynamics". The knowledge of the continuous glucose course and its trends has proved to be a highly relevant additional parameter which in practical terms has a particularly stabilizing influence on blood glucose profiles. CGM therefore offers the option of a fine-tuning of metabolic control by experienced heath care professionals and the patient, making blood glucose control in general and unplanned activities and problems in everyday life better controllable. However, despite the tremendous potential of CGM in combination with a pump therapy the basic settings of an effective pump therapy are crucial. Particularly the right basal insulin coverage as the first step is the key issue for success. With support of CGM there is an enormous potential to facilitate the adjustment and optimization of insulin pump therapy.

[SGLT2 inhibition: an effective therapeutic approach in the treatment of diabetes mellitus?]. / SGLT2-Inhibition: Ein wirksames Therapieprinzip des Diabetes mellitus?

Since end of 2012 a new therapeutical approach for the treatment of type 2 diabetes is available in Germany. It relies on the modulation of glucose re-absorption in the kidney by inhibition of so called Sodium Glucose Linked Transporters (SGLT) thereby leading to therapeutical glucosuria. Putting the kidney in the centre of therapeutical approach of glucose regulation is unfamiliar for physicians. Therefore, it is helpful to elucidate the underlying renal mechanisms and to present the advantages and disadvantages of this new therapeutic class.

Oxidative stress after a carbohydrate meal contributes to the deterioration of diastolic cardiac function in nonhypertensive insulin-treated patients with moderately well controlled type 2 diabetes.

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.

Clinical manifestations and treatment options in patients with cirrhosis and diabetes mellitus.

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.

Risk of diabetic foot ulceration during treatment with insulin glargine and NPH insulin.

OBJECTIVE: To evaluate the effect of the long-acting basal insulin analog glargine compared with neutral protamine Hagedorn (NPH) insulin on the incidence of diabetic foot ulceration (DFU) in patients with diabetes in Germany. METHOD: A retrospective cohort study was performed using a representative German database (IMS Disease Analyzer) of patients with type 2 diabetes, who started a basal insulin therapy with either insulin glargine or NPH insulin, between July 2000 and September 2007, and continued this therapy for at least 24 months, and whose data were continuously documented.The occurrence of DFU was recorded beginning in the third year after therapy initiation and Kaplan-Meier curves were generated and compared using log-rank tests. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for the incidence of DFU. RESULTS: Patients who fulfilled the inclusion criteria (n=23 395) had started either on insulin glargine (n=9638) or on NPH insulin (n= 13 757).After adjustment for demographic and clinical variables, it was demonstrated that the relative risk to diabetes patients of developing DFS is 64% lower with insulin glargine than with NPH insulin therapy (HR=0.6 I; p=0.0405). CONCLUSION: The results suggest that, compared with NPH insulin, insulin glargine therapy significantly reduces the risk of DFS in patients with diabetes under real life conditions. Prospective long-term trials are needed to confirm these secondary data analysis results. DECLARATION OF INTEREST: There were no external sources of funding for this study.The authors have no conflicts of interest to declare.

Spatially varying properties of the vocal ligament contribute to its eigenfrequency response.

The vocal ligament is known to have nonlinear variation in geometry, yet this is rarely considered in empirical or computational studies. This paper investigates the effects of a nonlinear variation of the anterior-to-posterior geometry and the corresponding spatial variation in elastic modulus on the fundamental frequency of vibration for the vocal ligament. Uniaxial tensile tests were performed on a vocal ligament specimen dissected from an excised 60-year-old male larynx. Digital image correlation (DIC) was used to obtain the spatial deformation field for the entire ligament specimen. DIC results revealed that the tensile deformation was very heterogeneous, with the least amount of deformation occurring in the region of smallest cross-sectional area. The elastic modulus was calculated locally and was found to be approximately 10 times higher at the midpoint of the vocal ligament than in the anterior and posterior macula flavae regions. Based on the spatially varying material properties obtained, finite element models (isotropic and transversely isotropic) were created to investigate how the effects of varying cross-section, heterogeneous stiffness, and anisotropy could affect the fundamental frequency of vibration. It was found that the spatial cross-section variation and the spatially varying anisotropy (i.e. modulus ratio) are significant to predictions of the vibration characteristics. Fundamental frequencies predicted with a finite element model are discussed in view of rotatory inertia and contribution of transverse shear deformation.

Differences in exhaled gas profiles between patients with type 2 diabetes and healthy controls.

AIMS: Recent advances in analytical technology allow the detection of several hundred volatile organic compounds (VOCs) in human exhaled air, many of which reflect unidentified endogenous pathways. This study was performed to determine whether a breath gas analysis using proton transfer reaction-mass spectrometry (PTR-MS) could serve as a noninvasive method to distinguish between patients with type 2 diabetes mellitus and healthy controls. METHODS: Breath and room air samples were measured from 21 patients with insulin-treated type 2 diabetes and 26 healthy controls. VOCs in the mass range of 20-200 atomic mass units were analyzed using PTR-MS. RESULTS: We identified eight masses characteristic of endogenous VOCs that showed significant differences in the gas profiles of patients with type 2 diabetes and healthy control subjects. Using these VOCs for linear discriminant analysis, the sensitivity and specificity were found to be 90% and 92%, respectively. CONCLUSIONS: These results suggest that it is possible to separate patients with diabetes mellitus type 2 from healthy controls by multivariate analysis of exhaled endogenous VOCs. This is a first step towards the development of a noninvasive test using breath gas of at-risk persons and making it an attractive option for large-scale testing of at-risk populations. However, the establishment of exhaled volatiles as metabolic markers requires additional confirmatory investigations.

[A 46-year-old patient with atrial fibrillation, elevated thyroid hormones and normal thyrotropine]. / Vorhofflimmern, erhöhte Schilddrüsenhormone und nicht supprimiertes TSH bei einem 46-jährigen Patienten.

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.

Optimized postprandial glucose control is associated with improved cardiac/vascular function - comparison of three insulin regimens in well-controlled type 2 diabetes.

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.

Comparison of insulin glargine versus NPH insulin in people with Type 2 diabetes mellitus under outpatient-clinic conditions for 18 months using a basal-bolus regimen with a rapid-acting insulin analogue as mealtime insulin.

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.

[Augmentation of myocardial function by improved glycemic control in patients with type 2 diabetes mellitus]. / Verbesserung der Myokardfunktion durch verbesserte Stoffwechselkontrolle bei Typ-2-Diabetes.

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.

Global myocardial perfusion and diastolic function are impaired to a similar extent in patients with type 2 diabetes mellitus and in patients with coronary artery disease--evaluation by contrast echocardiography and pulsed tissue Doppler.

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.

[How much do inpatient treated diabetics know about their disease?]. / Wie viel wissen stationär behandelte Diabetiker über ihre Erkrankung? Eine empirische Untersuchung in einem städtischen Klinikum in München.

AIM OF STUDY: The aim of the study was to find to find out which factors are able to predict the disease-specific knowledge of in-patient diabetic patients and to characterize this group of patients. METHODS: The disease-specific knowledge of diabetic patients of a Hospital in Munich, Germany (department of diabetology) was tested using a general questionnaire and a specific diabetes knowledge test. All data manipulation and statistical calculations were conducted with the statistical software package SAS (version 9.1). RESULTS: On average type-1-diabetics achieved 73% of the possible points in the knowledge test, type-2-diabetics achieved 68% of total points. In bivariate analyses, using logistic regression, existence of diabetes related complications was a significant predictor of poor knowledge (OR = 4.36; 95%-KI: 1.38-13.77) in type-1-diabetics. Other factors, e. g. lack of diabetes education were associated with low test results but reached no statistical significance (OR = 6.13; 95%-KI: 0.67-56.42). In multivariate logistic regression (female) gender was a significant risk factor for low test results (OR = 7.66; 95%-KI: 1.18-49.8). In type-2-diabetics lack of diabetes education (OR = 3.86; 95%-KI: 1.51-9.84), low self-assessment of information about diabetes (OR = 3.90; 95%-KI: 1.36-11.21) and lack of knowledge about diabetes diet (OR = 4.06; 95%-KI: 1.60-10.28) were predictors of poor test results. The existence of diabetes related complications was associated with poor test results but showed no statistical significance in multivariate analysis (OR = 2.99; 95%-KI: 0.85-10.43). CONCLUSIONS: There is a group of diabetic inward-patients that is less informed about diabetes and shows knowledge deficits in testing. These patients often lack diabetes education and show an unfavourable course of the disease, already having diabetes related complications. Type-2-diabetes patients who feel that they have poor information about their disease actually achieve lower results in knowledge testing. Efforts to assure diabetes education for these patients are essentially necessary.

The codon 17 polymorphism of the CTLA4 gene in type 2 diabetes mellitus.

Several studies have demonstrated an association of CTLA4 (IDDM12) alanine-17 with type 1 diabetes, but CTLA4 variants have not yet been investigated in type 2 diabetes. The CTLA4 exon 1 polymorphism (49 A/G) was analyzed in 300 Caucasian patients with type 2 diabetes and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. CTLA4 alleles were defined by PCR, single-strand conformational polymorphism, and restriction length fragment polymorphism analysis using BBV:I. The distribution of alleles as well as the genotypic and phenotypic frequencies were similar among patients and controls [AA, 42 vs. 39%; AG, 47 vs. 46%; GG, 11 vs. 15%, P = not significant (n.s.); A/G, 65/35% vs. 62/38%, P = n.s.; alanine/threonine 92/58% vs. 85/61%, P = n.s.]. However, detailed analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation (46.8 +/- 0.8 vs. 49.5 +/- 0.8 yr, mean +/- SEM), lower body mass index (21.4 +/- 0.5 vs. 24.4 +/- 0.5 kg/m(2), P = 0.042), and basal C-peptide level (0.33 +/- 0.07 vs. 0.53 +/- 0.07nmol/L), as well as earlier start of insulin treatment (5.8 +/- 1.2 vs. 8.7 +/- 0.6 yr) and higher portion of patients on insulin (71 vs. 61%). Patients with the AA genotype were significantly less likely to develop microangiopathic lesions (P < 0.0005). No differences were found for hypertension or family history of type 2 diabetes. In conclusion, CTLA4 alanine-17 does not represent a major risk factor for type 2 diabetes. Additional studies on larger groups and different ethnic groups are warranted to clarify the association of the GG genotype with faster ss-cell failure and the lower rate of microvascular complications in AA carriers.