Impact of type 1 diabetes and its duration on wall-to-lumen ratio and blood flow in retinal arterioles.

BACKGROUND: Subclinical damage to both the small and large vessels may contribute to the development and progression of cardiovascular disease. Scanning laser Doppler flowmetry (SLDF), an established method used to measure retinal microcirculation, has been successfully applied in hypertensive and post-stroke patients. METHODS: Retinal microcirculation was assessed in 158 patients with type 1 diabetes and 38 age-matched healthy controls. The diabetics were divided into 3 groups: group A with diabetes duration <12 months, group B with diabetes with 1-10 years, and group C >10 years of diabetes. Retinal capillary structure and perfusion were evaluated using a Heidelberg retina flowmeter and automatically analyzed with full-field perfusion imaging. RESULTS: Age and BMI were comparable in all the diabetic patients and the controls (mean age 24.8 ± 4.7 years, mean BMI 22.9 ± 4.1). In the univariate analyses, RCF (retinal capillary flow) was significantly higher in group A (297 ± 121 arbitrary units [AU]) vs group B (236 ± 52 AU; p = 0.007) and group C (236 ± 70 AU; p = 0.008) and comparable to that of the controls (p = 0.46). Additionally, the WLR (Wall-to-Lumen Ratio) was highest in group C compared to the other diabetic subgroups and controls (p = 0.001). Multivariate regression analyses including age, BMI, sex, HbA1c, smoking, systolic blood pressure, and diabetes duration as covariates, showed, that only diabetes duration was significantly associated with WLR variations, whereas HbA1c was significantly linked to retinal capillary flow levels. CONCLUSIONS: New-onset diabetes is associated with an increase in RCF, which then gradually decreased with the duration of the disease. Structural changes of the retinal arterioles estimated via WLR are evident later in the course of diabetes, especially when the disease duration exceeded 10 years.

Above 40% of Polish children and young adults with type 1 diabetes achieve international HbA1c target - results of a nationwide cross-sectional evaluation of glycemic control: The PolPeDiab HbA1c study.

BACKGROUND: Youth with type 1 diabetes (T1D) (16-18 y.o.) present worst disease control of all age groups and need structured interventions. Those should be based on unbiased, national-scale outcomes, which have not yet been successfully assessed in Poland. OBJECTIVE: To evaluate the glycemic control in young patients with T1D in Poland. METHOD: All pediatric diabetes care centers and the nine largest centers for adults with T1D were invited to this cross-sectional study, conducted in March 2018. Eligibility was defined as age ≤ 30 years and diabetes duration ≥1 year. Blinded samples of capillary blood and clinical questionnaires were sent to coordinating center, where HbA1c was measured by high-pressure liquid chromatography. RESULTS: Nine adult and 25/28 pediatric centers participated, providing data for 1255 patients (50.8% males), mean age 12.3 years (95%CI:12.1-12.6) for children and 23.2 years (22.9-23.6) for adults; mean diabetes duration 7.1 years (6.8-7.3). This covered ~8% of pediatric population and 2% of 18-30-years-olds with T1D. Mean HbA1c was comparable between children and adults (57 mmol/mol [7.4%], 95%CI:56-57 mmol/mol [7.3-7.4%] vs. 57 mmol/mol [7.4%], 95%CI:56-60 mmol/mol [7.3-7.6%], p = 0.1870). Overall, 45.2% of patients achieved ISPAD target (<53 mmol/mol [<7.0%]). During the month preceding the study, 0.9% of patients experienced severe hypoglycemia and 0.4% suffered ketoacidosis. HbA1c was related to the method of insulin therapy, continuous glucose monitoring use and body weight (p < 0.0001). CONCLUSIONS: In Polish children and young adults with T1D glycemic control expressed as HbA1c is promising in the light of ISPAD guidelines. Our results confirm the known associations between better glycemic control and the use of new technologies and maintaining optimal body weight.

Subclinical macroangiopathic target organ damage in type 1 diabetes mellitus patients.

PURPOSE: We have summarized key studies regarding the assessment of subclinical macroangiopathic target organ damage (TOD) in type 1 diabetes mellitus (T1DM). RESULTS: Although chronic complications resulting from hyperglycemia, in particular macroangiopathies, are still the first cause of death in T1DM, there has been growing recognition of the role of hypoglycemia in cardiovascular morbidity and mortality. Subclinical TOD diagnosis ensures early implementation of the complex management aiming at either partial reversal of these complications or at least its downturn. To better identify patients with early TODs, several non-invasive diagnostic techniques are employed, including the ultrasonographic assessment of the intima-media thickness (IMT), computed tomography (CT) for coronary artery calcium (CAC) scores, and pulse wave velocity (PWV) measurement for arterial stiffness evaluation. Various studies reported that T1DM patients present an increased IMT. An increasing IMT fairly correlates with the cardiovascular (CV) events risk even after the adjustment to age, diabetes duration, quality of glucose control as well as the presence of hypertension, and chronic complications. Another, well established marker of the organ damage - CAC score is recommended by ACC/AHA guidelines to assess the overall CV risk in T1DM. Also, the arterial stiffness evaluation with PWV may further improve CV risk prediction, which has been reported in multiple studies including the Framingham Heart Study. CONCLUSIONS: There is shortage of data from prospective studies which could confirm the benefits of early treatment initiation based on the presence of the subclinical organ damage in T1DM. Most evidence comes from T2DM trials, where effective preventive measures were identified i.e.: smoking cessation, reasonable blood glucose control, efficacious hypertension treatment, and dyslipidemia management, as well as renoprotection. There is still a field for further research to see if routine assessment of asymptomatic vascular damage and early implementation of aggressive treatment would reduce mortality excess from CVD in T1DM.

Cerebral and skin microcirculatory dysfunction in type 1 diabetes.

INTRODUCTION: An increase in cerebral pulsatility index (PI), measured by transcranial Doppler, reflects the presence of cerebral microangiopathy. A decrease in distance between skin capillaries (DISTANCE) and an increase in the ratio between the area of capillaries and total area of examined skin (COVERAGE), revealed by capillaroscopy, reflects skin microangiopathy. However, little is known about the association between the cerebral and skin microvasculature function in patients at risk of microcirculatory dysfunction. AIM: To assess PI of the middle cerebral artery by transcranial Doppler and the DISTANCE and COVERAGE of the nailfold capillaries by quantitative capillaroscopy in patients with type 1 diabetes and control subjects without diabetes, and to investigate relationships between these parameters. MATERIAL AND METHODS: The study group consisted of 51 patients with type 1 diabetes (median age: 37.5 years) and 23 volunteers free from chronic diseases (median age: 37.9 years). RESULTS: Median PI was higher in patients than in control subjects (0.82 vs. 0.75; p < 0.01). Median DISTANCE was lower in patients than in control subjects (220.9 µm vs. 239.7 µm; p = 0.03), while median COVERAGE was higher in patients than in control subjects (20.4% vs. 18.3%; p = 0.01). No correlations between PI and DISTANCE or COVERAGE were found, but PI was correlated with patients' age and diabetes duration. CONCLUSIONS: In spite of simultaneous presence of cerebral and skin microangiopathy, we found no association between cerebral and skin microvasculature dysfunction. This seems to indicate independent progression of microcirculatory injury in cerebral and peripheral vascular beds.

Inhibitors of sodium-glucose transport protein 2: A new multidirectional therapeutic option for heart failure patients.

Several mechanisms have been suggested to explain positive cardiovascular effects observed in studies with sodium-glucose co-transporter 2 (SGLT2) inhibitors. The reduction in glucose reabsorption in proximal tubuli induced by SGLT2 inhibitors increases urinary glucose and sodium excretion resulting in increased osmotic diuresis and consequently in decreased plasma volume, followed by reduced preload. In addition, the hemodynamic effects of SGLT2 inhibition were observed in both hyper and euglycemic patients. Due to the complex and multidirectional effects induced by SGLT2 inhibitors, this originally antidiabetic group of drugs has been successfully used to treat patients with heart failure as well as for subjects with chronic kidney disease. Moreover, their therapeutic potential seems to be even broader than the indications studied to date.

Angiogenin in middle-aged type 1 diabetes patients.

BACKGROUND: Angiogenin levels are increased in children and adolescent patients with type 1 diabetes, regardless of the extent of diabetic microangiopathy. However, little is known about the angiogenin concentrations in adults with type 1 diabetes. Thus we studied its level in middle aged subjects with the presence of diabetic nephro-, retino and neuropathy. METHODS: We investigated the data of 57 (age 39±6.6 years, 45.6% of males) patients with type 1 diabetes and 38 age-matched control subjects without diabetes (age 37.1±5.9 years, 42.1% of males), including medical histories, evidences of microangiopathy and serum angiogenin concentrations. RESULTS: Serum angiogenin level was lower in patients with type 1 diabetes [384.2(190.4-999.8) ng/ml] compared to controls [460.4(230.6-708.2) ng/ml], p=0.04. In patients with overt diabetic nephropathy the angiogenin level was higher when compared to patients without nephropathy [568.2(269.6-999.8) vs 369.4(190.4-999.8) ng/ml, p=0.01]. There were no differences between angiogenin levels in subgroups of patients distinguished by the presence of other microvascular complications or other concomitant vascular risk factors despite cigarette smoking [smokers: 516.2(294.4-999.8) vs. non-smokers: 372.1(190.4-924.8) ng/ml, p=0.01]. CONCLUSIONS: Regardless of the presence of diabetic microangiopathy, angiogenin level in middle-aged type 1 diabetes patients is lower than in controls. The presence of overt nephropathy and smoking habit in middle-aged patients with type 1 diabetes are associated with higher angiogenin level.

"Old School" Islet Purification Based on the Unit Gravity Sedimentation as a Rescue Technique for Intraportal Islet Transplantation-A Case Report.

Here, we present a case that required a supplemental "old school" islet purification for a safe intraportal infusion. Following pancreas procurement from a brain-dead 26-year-old male donor (body mass index: 21.9), 24.6 ml of islet tissue was isolated after continuous density gradient centrifugation. The islet yield was 504,000 islet equivalent (IEQ), distributed among the following three fractions: 64,161 IEQ in 0.6 ml of pellet, 182,058 IEQ in 10 ml, and 258,010 IEQ in 14 ml with 95%, 20%, and 10% purity, respectively. After a 23-h culture, we applied supplemental islet purification, based on the separation of tissue subfractions during unit gravity sedimentation, a technique developed over 60 years ago ("old school"). This method enabled the reduction of the total pellet volume to 11.6 ml, while retaining 374,940 IEQ with a viability of over 90%. The final islet product was prepared in three infusion bags, containing 130,926 IEQ in 2.6 ml of pellet, 108,079 IEQ in 4 ml of pellet, and 135,935 IEQ in 5 ml of pellet with 65%, 40%, and 30% purity, respectively, and with the addition of unfractionated heparin (70 units/kg body weight). Upon the islet infusion from all three bags, portal pressure increased from 7 to 16 mmHg. Antithrombotic prophylaxis with heparin was continued for 48 h after the infusion, with target activated partial thromboplastin time 50-60 s, followed by fractionated heparin subcutaneous injections for 2 weeks. ß-Cell graft function assessed on day 75 post-transplantation was good, according to Igls criteria, with complete elimination of severe hypoglycemic episodes and 50% reduction in insulin requirements. Time spent within the target glucose range (70-180 mg/dl) improved from 42% to 98% and HbA1c declined from 8.7% to 6.7%. Supplemental "old school" islet purification allowed for the safe and successful utilization of a robust and high-quality islet preparation, which otherwise would have been discarded.

The IMPROVE study--a multinational, observational study in type 2 diabetes: data from the Polish cohort.

INTRODUCTION: Observational studies are valuable tools for assessing the applicability of results from randomised controlled trials to broader patient populations. They are especially important in chronic diseases such as diabetes, as they can provide a comprehensive picture of the safety and effectiveness of a particular therapy across cultures and phenotypes. MATERIAL AND METHODS: Patients with type 2 diabetes who required insulin and whose physician had decided to initiate biphasic insulin aspart 30 (BIAsp 30) were eligible. A total of 4117 type 2 diabetic patients were recruited to the study in Poland, and 809 primary and secondary care physicians were involved. The aim of this study was to assess the safety and effectiveness of BIAsp 30 treatment in type 2 diabetes in routine clinical practice. RESULTS: Baseline glycaemic control was poor in the Polish cohort enrolled in the IMPROVE(TM) study, with a mean HbA(1c) value of 9.0 +/- 1.7%. A very high proportion of patients were thus at risk of macrovascular and microvascular complications. A twice-daily regimen for the start of BIAsp 30 therapy was the most common choice, including 72.2% of patients at baseline. HbA(1c) was significantly reduced by 1.66% for the total cohort and by 3.07% and 1.55% in the pre-study no-therapy or oral antidiabetic drug group respectively (p < 0.001). The rates (episodes per subject year) of overall major hypoglycaemia were 0.012 and 0.12 at follow-up and final visits respectively. For minor hypoglycaemia rates of 5.12 per subject per year at follow-up visit and 4.54 episodes per subject per year at final visit were recorded. CONCLUSIONS: BIAsp 30 appears to be an effective and flexible treatment approach and can be safely intensified to achieve glycaemic control in a majority of patients with type 2 diabetes.

Statin Use and Cognitive Impairment in Patients With Type 1 Diabetes: An Observational Study.

OBJECTIVE: We aimed to assess a wide range of cognitive functions in patients with type 1 diabetes (DM1) compared with healthy control subjects and to evaluate the effects of statins on cognitive functions in DM1 patients. MATERIALS AND METHODS: The sample studied consisted of 55 DM1 patients (80.0% with hyperlipidemia, 20% with statin treatment) and 36 age-matched control subjects (77.8% with hyperlipidemia) without diabetes or statin use. Their cognitive functions (attention, memory, and executive functions) were evaluated with the trail making test, controlled oral word association test (COWAT), Rey-Osterrieth complex figure test, brain damage test (diagnosticum für cerebralschädigung, DCS), Wisconsin card sorting test (WCST), and digit span and block design tests from the revised Wechsler adult intelligence scale. RESULTS: Cognitive performance was impaired in DM1 patients when compared with the control group with regard to semantic verbal fluency (COWAT_animals), visual learning (DCS), conceptual-level responses, executive functions (WCST random errors), and WCST trials to complete the first category. Subgroups of DM1 patients distinguished on the basis of statin therapy did not differ with regard to verbal fluency (COWAT_animals), visual learning (DCS), conceptual-level responses, executive functions (WCST random errors), and WCST trials to complete the first category. Multivariate analysis also does not show the impact of statin therapy on cognitive functioning regardless of the duration of education, microangiopathic evidence, the presence of hyperlipidemia, or antihypertensive therapy. CONCLUSIONS: We find impairment of cognitive functions in DM1 patients when compared with control subjects without diabetes. However, we show neither the effect of statins nor the significant influence of metabolic control, microangiopathic complications, or the presence of hyperlipidemia on cognitive functions in DM1 patients.

Diabetic symmetric polyneuropathy is associated with increased aortal stiffening but not cerebral angiopathy in type 1 diabetes.

INTRODUCTION: Diabetic symmetric polyneuropathy (DSP) and cerebral microangiopathy are common complications of type 1 diabetes (T1DM). However, little is known about associations between DSP, cerebral microcirculation and macrovascular injury in T1DM. We aimed to assess relationships between those complications. MATERIAL AND METHODS: We examined 42 patients (25 females; mean age 37.1±5.6years) with T1DM (mean disease duration 20.6±6.1years). DSP was diagnosed with the use of quantitative vibration sensory testing (QVST) and Michigan Neuropathy Screening Instrument (MNSI). Cerebral microvasculature was evaluated with measurements of vasomotor reactivity reserve (VMR) and pulsatility index (PI) of middle cerebral artery, macroangiopathic injury by measuring intima-media complex thickness (IMT) in the common carotid artery and carotid-femoral pulse-wave velocity (PWV). RESULTS: Patients with DSP (33.3%) showed higher PWV than those without DPS (10.5 vs 9.1m/s; P=0.03); no differences concerning VMR, PI or IMT existed. There were correlations between PWV and vibration perception thresholds (VPT) (r=0.44; P=0.004) and MNSI score (r=0.43; P=0.003); VPT showed impact on PWV (beta 0.34; P<0.03). CONCLUSIONS: DSP is associated with systemic macroangiopathy, reflected by increased carotid-femoral PWV, but not with the cerebral macro- and microangiopathy.

Self-monitoring of blood glucose in diabetes: from evidence to clinical reality in Central and Eastern Europe--recommendations from the international Central-Eastern European expert group.

Self-monitoring of blood glucose (SMBG) is universally considered to be an integral part of type 1 diabetes management and crucial for optimizing the safety and efficacy of complex insulin regimens. This extends to type 2 diabetes patients on intensive insulin therapy, and there is also a growing body of evidence suggesting that structured SMBG is beneficial for all type 2 diabetes patients, regardless of therapy. However, access to SMBG can be limited in many countries in Central and Eastern Europe. A consensus group of diabetes experts from 10 countries in this region (with overlapping historical, political, and social environments)--Bulgaria, Croatia, Czech Republic, Hungary, Poland, Romania, Serbia, Slovakia, Slovenia, and Ukraine--was formed to discuss the role of SMBG across the spectrum of patients with diabetes. The group considered SMBG to be an essential tool that should be accessible to all patients with diabetes, including those with non-insulin-treated type 2 diabetes. The current article summarizes the evidence put forward by the consensus group and provides their recommendations for the appropriate use of SMBG as part of individualized patient management. The ultimate goal of these evidence-based recommendations is to help patients and providers in Central and Eastern Europe to make optimal use of SMBG in order to maximize the efficacy and safety of glucose-lowering therapies, to prevent complications, and to empower the patient to play a more active role in the management of their diabetes.

Multicenter, open-label, non-randomized, non-interventional observational study of safety of treatment initiation with a biphasic insulin aspart.

BACKGROUND: Type 2 diabetes mellitus is characterized by hyperglycaemia. Incidence and progression of microvascular complications have been shown to undergo reduction with lowered glucose levels. METHODS: This is an open-label, non-randomized, non-interventional, observational study of safety and efficacy of BiAsp 30, enrolling 2223 patients with type 2 diabetes mellitus. Patients previously treated with oral antidiabetic drugs and/or human insulin were recruited, provided they had been hospitalized for at least 3 days. Data were collected during a single multi-stage visit lasting up to 6 days, during the patient's hospitalization period. A mild hypoglycaemic episode was defined as blood glucose measurement < 56 mg/dL (3.1 mmol/L). A severe hypoglycaemia was hypoglycaemic episode requiring assistance of another person. RESULTS: The total number of hypoglycaemic episodes decreased over time of follow-up. The intensity of severe hypoglycaemic episodes decreased by almost a third from day to day (IRR = 0.64, 95%, p < 0.001). However, intensity of mild hypoglycaemic episodes was the same over the subsequent days of follow-up (IRR = 0.97, p > 0.1). Mean blood glucose concentration decreased from 202.0 mg/dL to 157.8 mg/dL after 3 days and to 138.3 mg/dL after 6 days (p < 0.001). CONCLUSION: This study highlights the safety, efficacy and ease of initiation of insulin BiAsp 30 therapy for treatment of type 2 diabetes mellitus.

Decreased reactivity of skin microcirculation in response to L-arginine in later-onset type 1 diabetes.

OBJECTIVE: The aim of our study was to evaluate the vasodilatory effect of l-arginine infusion on the skin microcirculation and to assess the relationship between this effect and the presence of microangiopathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Capillaroscopy was performed before and after l-arginine infusion in 48 diabetic patients (26 women and 22 men; age, 39.8 ± 6.3 years) and 24 volunteers free of any chronic disease (13 women and 11 men; age, 38.0 ± 6.7 years). The skin microcirculation reactivity, as expressed by the percentage of area covered by capillaries (coverage) and the distance between capillaries (distance), and the relationship between microcirculation reactivity and the presence of microangiopathic complications were assessed. RESULTS: The distance before l-arginine infusion was significantly lower in patients than in controls (221 [153-311] vs. 240 [185-356] µm; P = 0.02) and did not differ after l-arginine infusion (223.5 [127-318] vs. 242.5 [181-341] µm; P = 0.27). The difference between the coverage values obtained before and after l-arginine infusion (Δcoverage) was significantly different from zero in the control group but not in the diabetes group. Patients with later onset of diabetes were characterized by decreased skin microcirculation reactivity when compared with patients with earlier onset of diabetes (-1.18 [-5.07 to 11.60] vs. 1.36 [-6.00 to 8.06]; P = 0.02) despite the higher prevalence of retinopathy in patients with earlier onset of diabetes (64% vs. 26%; P = 0.02). CONCLUSIONS: Skin microvascular reactivity is impaired in patients with later onset of type 1 diabetes. Capillaroscopy with l-arginine infusion is useful for the identification of skin microangiopathy in type 1 diabetes.

Cerebrovascular reactivity, intima-media thickness, and nephropathy presence in patients with type 1 diabetes.

OBJECTIVE: Cerebrovascular reactivity impairment was reported as a marker of cerebral microangiopathy in long-term type 1 diabetes. Intima-media complex thickening reflects early stages of macroangiopathy in type 1 diabetes. The analysis of the relationship between these variables and other microangiopathic complications might serve as a beneficial indicator for early prophylaxis in these patients. RESEARCH DESIGN AND METHODS: Vasomotor reactivity reserve (VMRr) and breath-holding index (BHI) of the middle cerebral artery were measured with transcranial Doppler in 59 patients (median age 32.0 years, range 20-51, 36 females) with type 1 diabetes, without history of cerebrovascular events, and 30 healthy control subjects (median age 31.5 years, range 25-39, 15 females). The relationships between the presence of selected vascular complications of type 1 diabetes and biochemical parameters, intima-media thickness (IMT), and VMRr and BHI in patients were analyzed. RESULTS: VMRr and BHI were lower in patients with type 1 diabetes when compared with healthy subjects (81.5 vs. 100%, P < 0.01, and 1.6 vs. 2.2, P = 0.04, respectively), whereas IMT was significantly higher in patients then in healthy control subjects (0.36 vs. 0.30 mm, P = 0.001). However, no association of IMT with VMRr was found. We found a significant reduction of VMRr and BHI in patients with diabetic nephropathy. CONCLUSIONS: The presence of diabetic nephropathy, but not IMT, can be regarded as an indicator of cerebral microangiopathy severity in patients with type 1 diabetes.