A standard set of person-centred outcomes for diabetes mellitus: results of an international and unified approach.

AIMS: To select a core list of standard outcomes for diabetes to be routinely applied internationally, including patient-reported outcomes. METHODS: We conducted a structured systematic review of outcome measures, focusing on adults with either type 1 or type 2 diabetes. This process was followed by a consensus-driven modified Delphi panel, including a multidisciplinary group of academics, health professionals and people with diabetes. External feedback to validate the set of outcome measures was sought from people with diabetes and health professionals. RESULTS: The panel identified an essential set of clinical outcomes related to diabetes control, acute events, chronic complications, health service utilisation, and survival that can be measured using routine administrative data and/or clinical records. Three instruments were recommended for annual measurement of patient-reported outcome measures: the WHO Well-Being Index for psychological well-being; the depression module of the Patient Health Questionnaire for depression; and the Problem Areas in Diabetes scale for diabetes distress. A range of factors related to demographic, diagnostic profile, lifestyle, social support and treatment of diabetes were also identified for case-mix adjustment. CONCLUSIONS: We recommend the standard set identified in this study for use in routine practice to monitor, benchmark and improve diabetes care. The inclusion of patient-reported outcomes enables people living with diabetes to report directly on their condition in a structured way.

Correlates of psychological outcomes in people with diabetes: results from the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study.

AIMS: To assess country- and individual-level correlates of psychological outcomes, and differences among countries in the associations of individual characteristics with psychological outcomes among adults with diabetes. METHODS: The second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study assessed self-reported characteristics of people with diabetes in 17 countries, including 1368 adults with Type 1 diabetes and 7228 with Type 2 diabetes. In each country, a sample of 500 adults, stratified by diabetes type and treatment, completed a questionnaire incorporating the validated WHO-5 wellbeing index, the WHOQOL-BREF, and the five-item Problem Areas in Diabetes Scale, as well as the newly developed Diabetes Impact on Life Dimensions that assessed impact ranging from very positive to very negative, with no impact as the midpoint. Multilevel regression analyses identified significant (P < 0.05) independent correlates of psychological outcomes. RESULTS: There were significant variations in all outcomes across countries before adjustment for individual-level factors; adjustment reduced between-country disparities. Worse psychological outcomes were associated with more complications, incidence of hypoglycaemia, hypoglycaemic medication, perceived burden of diabetes, family conflict and experience of discrimination. Better psychological outcomes were associated with higher self-rated health, greater access to diabetes education and healthcare, and more psychosocial support from others. The associations of many factors with the outcomes were mediated by modifiable factors. The association of all factors with the outcomes varied across (interacted with) countries, highlighting the need for country-specific analyses. CONCLUSIONS: Improvements in modifiable risk factors (reductions in burden and increases in support) may lead to better psychological outcomes in adults with diabetes.

Diabetes Attitudes, Wishes and Needs second study (DAWN2™): cross-national comparisons on barriers and resources for optimal care--healthcare professional perspective.

AIMS: The second Diabetes Attitudes, Wishes and Needs (DAWN2) study sought cross-national comparisons of perceptions on healthcare provision for benchmarking and sharing of clinical practices to improve diabetes care. METHODS: In total, 4785 healthcare professionals caring for people with diabetes across 17 countries participated in an online survey designed to assess diabetes healthcare provision, self-management and training. RESULTS: Between 61.4 and 92.9% of healthcare professionals felt that people with diabetes needed to improve various self-management activities; glucose monitoring (range, 29.3-92.1%) had the biggest country difference, with a between-country variance of 20%. The need for a major improvement in diabetes self-management education was reported by 60% (26.4-81.4%) of healthcare professionals, with a 12% between-country variance. Provision of diabetes services differed among countries, with many healthcare professionals indicating that major improvements were needed across a range of areas, including healthcare organization [30.6% (7.4-67.1%)], resources for diabetes prevention [78.8% (60.4-90.5%)], earlier diagnosis and treatment [67.9% (45.0-85.5%)], communication between team members and people with diabetes [56.1% (22.3-85.4%)], specialist nurse availability [63.8% (27.9-90.7%)] and psychological support [62.7% (40.6-79.6%)]. In some countries, up to one third of healthcare professionals reported not having received any formal diabetes training. Societal discrimination against people with diabetes was reported by 32.8% (11.4-79.6%) of participants. CONCLUSIONS: This survey has highlighted concerns of healthcare professionals relating to diabetes healthcare provision, self-management and training. Identifying between-country differences in several areas will allow benchmarking and sharing of clinical practices.

Meta-analysis of individual patient data to assess the risk of hypoglycaemia in people with type 2 diabetes using NPH insulin or insulin glargine.

AIM: To estimate absolute and relative incidence rates of hypoglycaemia when using once-daily evening or morning regimens of insulin glargine (glargine) versus once-daily evening NPH insulin (NPH) using individual patient data (IPD). MATERIALS AND METHODS: Randomized controlled trials with accessible IPD and including white European people with type 2 diabetes (T2DM) using glargine or NPH once-daily (with oral glucose-lowering drugs) were identified. Two study pools were analysed: evening glargine versus evening NPH (pool 1); and morning glargine versus evening NPH (pool 2). The number-needed-to-treat to avoid hypoglycaemia was calculated for glargine versus NPH. RESULTS: In study pool 1 (n = 2711), the risk of nocturnal hypoglycaemia was approximately halved with glargine compared with NPH [odds ratios (OR): 0.44-0.52, p < 0.001-0.047]. This led to a significant reduction in anytime risk of symptomatic hypoglycaemia [plasma glucose (PG) <3.9 mmol/l, OR: 0.64, p = 0.018; PG <2.0 mmol/l, OR: 0.51, p < 0.001]. In study pool 2 (n = 470), although a strong numerical reduction in all types of nocturnal hypoglycaemia was observed (OR: 0.16-0.64), statistical significance was reached only for symptomatic hypoglycaemia with PG <3.9 mmol/l (p < 0.001). Eight (pool 1) or five (pool 2) people with T2DM needed to use glargine rather than NPH to avoid one person from experiencing a nocturnal symptomatic hypoglycaemic event within a median of about 25 weeks of starting insulin. CONCLUSIONS: This meta-analysis of open-label studies provides confidence that reductions of around 50% of risk for nocturnal hypoglycaemia can be achieved with using glargine instead of NPH.

Model based study on monitoring ketone bodies to improve safety in intensive insulin therapy.

AIM: The present study explores new signals (capillary 3betahydroxybutyrate - 3betaOHB) for improving the safety of a closed loop insulin infusion system (external wearable artificial pancreas). METHODS: Data collected during a clinical trial on diabetic subjects including a period of insulin deprivation were interpreted through mathematical models to simulate the effect of monitoring ketone bodies (capillary 3betaOHB, KB) compared to blood glucose in subjects on Continuous Subcutaneous Insulin Infusion (CSII) treatment. RESULTS: The estimation of model coefficients satisfactorily fits experimental data. The evaluation of dynamic changes of capillary 3betaOHB levels showed a more rapid response than blood glucose. CONCLUSIONS: The effect of the combination of monitoring of glucose and ketone bodies can consistently improve the safety and efficacy of the use of a closed loop system for glycemic control in dangerous situations like ketoacidosis. If a subcutaneous glucose-ketone bodies sensor were to become available in the near future it would be a key component of an external artificial pancreas.

Lower extremity amputation rates in people with diabetes as an indicator of health systems performance. A critical appraisal of the data collection 2000-2011 by the Organization for Economic Cooperation and Development (OECD).

AIMS: Critical appraisal of secondary data made available by the OECD for the time frame 2000-2011. METHODS: Comparison of trends and variation of amputations in people with diabetes across OECD countries. Generalized estimating equations to test the statistical significance of the annual change adjusting for major potential confounders. RESULTS: A total of 26 OECD countries contributed to the OECD data collection for at least 1 year in the reference time frame, showing a decline in rates of over 40 %, from a mean of 13.2 (median 9.4, range 5.1-28.1) to 7.8 amputations per 100,000 in the general population (9.9, 1.0-18.4). The multivariate model showed an average decrease equal to -0.27 per 100,000 per year (p = 0.015), adjusted by structural characteristics of health systems, showing lower amputation rates for health systems financed by public taxation (-4.55 per 100,000 compared to insurance based, p = 0.002) and non-ICD coding mechanisms (-7.04 per 100,000 compared to ICD-derived, p = 0.001). Twelve-year decrease was stronger among insurance-based financing systems (tax based: -0.16 per 100,000, p = 0.064; insurance based: -0.36 per 100,000; p = 0.046). CONCLUSIONS: In OECD countries, amputation rates in diabetes continuously decreased over 12 years. Still, in 2011, one amputation every 7 min could be directly attributed to diabetes. Although interesting, these results should be taken with extreme caution, until common definitions are improved and data quality issues, e.g., a different ability in capturing diabetes diagnoses, are fully resolved.

Core Standards of the EUBIROD Project. Defining a European Diabetes Data Dictionary for Clinical Audit and Healthcare Delivery.

BACKGROUND: A set of core diabetes indicators were identified in a clinical review of current evidence for the EUBIROD project. In order to allow accurate comparisons of diabetes indicators, a standardised currency for data storage and aggregation was required. We aimed to define a robust European data dictionary with appropriate clinical definitions that can be used to analyse diabetes outcomes and provide the foundation for data collection from existing electronic health records for diabetes. METHODS: Existing clinical datasets used by 15 partner institutions across Europe were collated and common data items analysed for consistency in terms of recording, data definition and units of measurement. Where necessary, data mappings and algorithms were specified in order to allow partners to meet the standard definitions. A series of descriptive elements were created to document metadata for each data item, including recording, consistency, completeness and quality. RESULTS: While datasets varied in terms of consistency, it was possible to create a common standard that could be used by all. The minimum dataset defined 53 data items that were classified according to their feasibility and validity. Mappings and standardised definitions were used to create an electronic directory for diabetes care, providing the foundation for the EUBIROD data analysis repository, also used to implement the diabetes registry and model of care for Cyprus. CONCLUSIONS: The development of data dictionaries and standards can be used to improve the quality and comparability of health information. A data dictionary has been developed to be compatible with other existing data sources for diabetes, within and beyond Europe.

A comparative study of the activity of biosynthetic human insulin and pork insulin using the glucose clamp technique in normal subjects.

The activity of biosynthetic human insulin (BHI) has been compared with that of pork insulin using the glucose clamp technique in normal subjects. After a baseline period, insulin was infused at 0.02 U/kg/h for 2 h, then 0.032 U/kg/h for 2 h, and finally 0.05 U/kg/h for 2 h. Glucose was clamped at baseline values using a glucose-controlled insulin infusion system (Biostator) and the amount of glucose infused to maintain normoglycemia calculated for each insulin dose for the two insulins. C-peptide levels decreased with both insulins, suggesting suppression of endogenous insulin secretion. Serum insulin levels attained were the same for both insulins. There were no significant differences in either total glucose infused or glucose infused during the last 30 or 60 min at each insulin dose for the two insulins. Intermediary metabolite responses to the infusion of the two insulins were similar. We conclude that in normal human beings, BHI shows identical metabolic activity with pork insulin.

Comparison of the activity and pharmacokinetics of porcine insulin and human insulin (Novo) as assessed by the glucose clamp technique in normal and diabetic man.

Using the glucose clamp technique, human insulin (Novo) and natural porcine insulin were found to have identical potency in terms of glucose delivery in the second hour of i.v. infusion at low (0.02 U/kg/h; 265 +/- 25 versus 232 +/- 35 mg/min, respectively) and high (0.05 U/kg/h; 467 +/- 47 versus 452 +/- 41 mg/min, respectively) doses in normal man. Insulin metabolic clearance rates, serum in vivo half-life, and rate of onset of action were also similar. In insulin-dependent diabetic subjects, whose blood glucose levels were also held constant by feedback glucose infusion, the free insulin profiles after s.c. injection of neutral soluble human insulin and porcine insulin (0.2 U/kg) were identical, and similar to those after conventional and highly purified bovine insulin preparations. Glucose requirement to maintain normoglycemia for the first 5 h after injection was 49.6 +/- 8.2 g for conventional bovine insulin, 50.4 +/- 10.0 g for highly purified bovine, 40.5 +/- 6.9 g for human insulin, and 50.6 +/- 12.4 g for porcine insulin (NS by analysis of variance). No difference in insulin activity was detected when glucose requirement was expressed in terms of the prevailing free insulin concentration. Responses of blood intermediary metabolite levels were indistinguishable between all insulins in both studies.

Kinetics and metabolic activity of biosynthetic NPH insulin evaluated by the glucose clamp technique.

The glucose clamp technique has been used to evaluate the metabolic activity of NPH biosynthetic insulin in diabetic subjects free from anti-insulin antibodies. After overnight blood glucose normalization with a glucose-controlled insulin infusion system (Biostator), an s.c. injection of NPH insulin was given in the abdominal region. The insulin dose (0.236 +/- 0.05 U/kg body wt) was related to the usual intermediate-acting insulin requirement in the morning. Glucose was clamped at 100 mg/dl by a feedback i.v. glucose infusion. The end of the action of s.c. injected insulin considered conventionally to be the time of the spontaneous rise of blood glucose to 110 mg/dl. Free insulin levels were higher and the length of action was longer after NPH porcine than after NPH biosynthetic human insulin (BHI) (area under the free insulin curve: porcine 1423 +/- 556 mU/L/h; BHI 1045 +/- 338 mU/L/h, P less than 0.05; length of action: porcine 16.0 +/- 3.2 h; BHI 13.7 +/- 0.9 h, P less than 0.05); the glucose requirement was higher after porcine (76.8 +/- 13.5 g) than after BHI (58.5 +/- 14.6 g) without reaching statistical significance. However, the metabolic activity of the bioavailable insulin (index of plasma free insulin activity) was similar for the two insulins (porcine 381 +/- 77.4, BHI 342.8 +/- 54.2 mU/L/g of glucose/h). We conclude that a difference in pharmacokinetics exists between NPH BHI and porcine NPH insulin, which makes the latter metabolically more active. The different behavior does not seem to be related to the insulin molecule itself but could be a consequence of the unequal content of protamine in the two pharmacologic preparations.

The relationship between physicians' self-reported target fasting blood glucose levels and metabolic control in type 2 diabetes. The QuED Study Group--quality of care and outcomes in type 2 diabetes.

OBJECTIVE: To investigate the relationship between beliefs of physicians relative to intensive metabolic control in type 2 diabetes and levels of HbA1c obtained in a sample of their patients. RESEARCH DESIGN AND METHODS: Physicians' beliefs were investigated through a questionnaire sent to a sample of self-selected clinicians participating in a nationwide initiative aimed at assessing the relationship between the quality of care delivered to patients with type 2 diabetes and their outcomes. At the same time, physicians were asked to collect clinical data on a random sample of their patients, stratified by age (<65 vs. > or = 65 years). Mean HbA1c levels in the study population were thus evaluated according to target fasting blood glucose (FBG) used by their physicians. RESULTS: Of 456 physicians, 342 (75%) returned the questionnaire. Among the responders, 200 diabetologists and 99 general practitioners (GPs) recruited 3,297 patients; 2,003 of whom were always followed by the same physician and 1,294 of whom were seen by different physicians in the same structure on different occasions. Only 14% of the respondents used target FBG levels < or = 6.1 mmol/l, whereas 38% pursued values >7.8 mmol/l, with no statistically significant difference between diabetologists and GPs. The analysis of the relationship between FBG targets and metabolic control, restricted to those patients always seen by the same physician, showed a strong linear association, with mean HbA1c values of 7.0 +/- 1.6 for patients in the charge of physicians pursuing FBG levels < or = 6.1 mmol/l and 7.8 +/- 1.8 for those followed by physicians who used target values >7.8 mmol/l. After adjusting for patients' and physicians' characteristics, the risk of having HbA1c values > 7.0% was highly correlated with physicians' beliefs. Patients followed by different physicians in the same unit showed a risk of inadequate metabolic control similar to that of patients followed by physicians adopting a nonaggressive policy. CONCLUSIONS: Doctors adopt extremely heterogeneous target FBG levels in patients with type 2 diabetes, which in turn represent an important independent predictor of metabolic control. To improve patient outcomes, physicians-centered educational activities aimed at increasing the awareness of the potential benefits of a tight metabolic control in patients with type 2 diabetes are urgently needed.

Circulating catecholamine and glucagon responses to insulin-induced blood glucose decrement in a patient with pheochromocytoma.

In a gastrectomized woman with an adrenal pheochromocytoma we observed hypertensive crisis in association with postprandial hypoglycemic episodes. To assess whether hypoglycemia could be responsible for the hypertensive crises, we measured circulating catecholamines and glucagon during an insulin-induced blood glucose decrement carried out by an artificial endocrine pancreas. When the blood glucose level reached 36 mg/dl, a severe hypertensive crisis occurred. At this time, circulating catecholamines increased 2-fold (norepinephrine, from 2200 to 3568 pg/ml; epinephrine, from 950 to 1750 pg/ml), while no changes in glucagon were observed. Our observation suggests that in patients with pheochromocytoma, hypoglycemia may trigger a marked release of catecholamines independent of glucagon secretion. This response probably is mediated by activation of the sympathetic nervous system. Our results also suggest that the pancreatic A-cell response to blood glucose decrement is totally suppressed in patients with pheochromocytoma by the chronically high levels of circulating catecholamines. Thus, hypoglycemia may be added to the list of other well known factors which may provoke hypertensive emergencies in patients with pheochromocytoma.

Counterregulatory hormones during moderate, insulin-induced, blood glucose decrements in man.

To verify whether a significant increase in levels of counterregulatory hormones occurs in the course of mild blood glucose decrements, we infused regular insulin iv over 65 min in two groups of healthy volunteers (group A, n= 7; group B, n = 6) at a constant rate (group A, 0.05 U/kg; group B, 0.025 U/kg). All subjects were connected to an artificial endocrine pancreas (Biostator) for continuous blood glucose (BG) monitoring. Plasma insulin, glucagon, and GH were determined by specific RIAs. Plasma norepinephrine, epinephrine, and cortisol were measured by sensitive fluorimetric methods. A moderate fall in BG occurred from 91 +/- 1.5 mg/dl (mean +/- SEM) to a nadir of 56 +/- 4.5 mg/ml at 45 min in group A and from 81 +/- 2.5 to a nadir of 64 +/- 4.9 mg/dl at 45 min in group B. In both groups A and B, the increases in plasma glucagon and catecholamine levels, which remained strictly in the physiological range, appeared concomitant and were significant at 45 min (P less than or equal to 0.05 vs. basal), while the increases in plasma cortisol and GH concentrations were clearly delayed. The increments for all counterregulatory hormones (expressed as the area to minutes ratio) except GH, were significantly greater in group A than in group B ( P less than or equal to 0.01). There was a significant correlation between these increases, including that of GH and the BG decrease, calculated in all subjects investigated. These results suggest that the mechanisms involved for the release of counterregulatory hormones such as glucagon, catecholamines, cortisol, and GH are very sensitive to a moderate decrease in BG concentration and that there is a close relationship between this hormonal response and the degree of the BG decrements obtained.

Pharmacology and clinical experience with repaglinide.

Repaglinide (NovoNorm((R))) is a novel oral antidiabetic agent, the first of a new class of insulin secretagogues known as the prandial glucose regulators to be approved for use in patients with Type 2 diabetes. Prandial glucose regulation is aimed at restoring the first-phase insulin response that follows consumption of a meal, which is missing in patients with Type 2 diabetes. After repaglinide administration, the resulting insulin profile reflects that of healthy individuals more closely, providing tighter glycaemic control and reducing the risk of hypoglycaemic events. Repaglinide is quickly absorbed and rapidly eliminated through biliary excretion, making it suitable for use in patients with renal impairment. It appears in the bloodstream within 15 to 30 min of dosing, stimulating short-term insulin release from the pancreatic beta-cells by binding to a unique site on the beta-cell membrane. Rapid elimination ensures that postprandial insulin levels quickly return to preprandial levels as the high prandial glucose level subsides. Repaglinide is given on a 'one meal, one tablet; no meal, no tablet' basis. It is particularly effective in patients who have not previously been treated with an oral antidiabetic agent, significantly reducing glycosylated haemoglobin (HbA(1c)) levels by 1.6%. It also offers increased mealtime flexibility and safety, compared with other oral antidiabetic agents. As a result of the short plasma half-life and lack of accumulation of repaglinide with repeated dosing, the risk of between-meal and nocturnal hypoglycaemia is substantially reduced compared with other oral antidiabetic agents. Repaglinide acts synergistically with metformin, consistently improving glycaemic control in patients who were insufficiently controlled by metformin alone. Results from recent studies have shown similar synergistic effects with neutral protamine Hagedorn (NPH)-insulin or troglitazone.

Hormonal and metabolic responses in brittle diabetic patients during feedback intravenous insulin infusion.

Twenty-four hour profiles of blood hormones and intermediary metabolites were obtained in seven 'brittle' diabetic subjects during their usual insulin therapy and during feedback intravenous insulin infusion from an artificial pancreas (GCIIS). The results were compared to those in matched stable diabetics and normal controls. Although routine insulin doses were higher in the brittle group than in the stable group (164 +/- 32 (mean +/- SE) vs. 58 +/- 8 U/day, P less than 0.005) during routine therapy, plasma free insulin levels were equal (35 +/- 12 vs. 31 +/- 6 mU/l). In the brittle group feedback i.v. insulin infusion reduced daily requirements to normal levels (80 +/- 13 U/day, P less than 0.025; stable group 71 +/- 4 U/day, NS). On routine therapy blood glucose levels were not different in the two groups (brittle 10.5 +/- 1.6, stable 10.8 +/- 0.6 mmol/l) and were similarly corrected by the GCIIS (6.9 +/- 0.3 and 6.9 +/- 0.3 mmol/l, respectively). Blood lactate and pyruvate levels were markedly abnormal in the brittle group during routine therapy (lactate: brittle group 1.93 +/- 0.27 mmol/l, stable group 0.91 +/- 0.07 mmol/l, P less than 0.025), and this abnormality was not corrected by the GCIIS (1.75 +/- 0.32 and 0.88 +/- 0.08 mmol/l, P less than 0.005). Abnormalities were also found in profiles of blood alanine and glycerol, and serum cortisol. Blood ketone body levels did not differ between the two groups of patients. The results suggest a defect in insulin delivery from subcutaneous tissue into the plasma. These patients have a characteristic metabolic abnormality, unresponsive to short-term normoglycaemia, either as the result of long-term disturbance of diabetic control, or as a marker for the underlying hormonal or biochemical abnormality.

Epidemiology and determinants of blood glucose self-monitoring in clinical practice.

The aim of this study was to describe the epidemiology of self-monitoring of blood glucose and to identify specific characteristics of those subgroups of diabetic patients treated with insulin that are most likely to monitor their blood glucose according to medical recommendations. Data were collected on 1384 insulin-treated patients, enrolled from 35 diabetic outpatient clinics and 49 general practitioners' offices between December 1993 and June 1994. Seventeen Italian regions out of 20 were included in the study. Our data show that 418 (31%) diabetic patients treated with insulin had never practised blood glucose self-monitoring. In addition, only 242 patients (18.2%) self-monitored their glycemia with a mean frequency of at least once a day (29.7% among insulin-dependent diabetes mellitus (IDDM) and 13.9%, among insulin-treated non-insulin-dependent diabetes mellitus (NIDDM-IT) patients). Patients' characteristics associated with a higher probability of practising blood glucose self-monitoring were age below 50 years, being treated at a diabetic outpatient clinic, hypertension, need of three or more insulin injections per day, history of hypoglycemic episodes, ability to self-manage insulin doses. Our study calls for vigorous efforts aimed at promoting the incorporation of clearly-defined educational programs at each level of care, in order to improve the motivation and self-care of diabetic patients. Furthermore, studies are necessary to identify subgroups of diabetic patients that truly need to self-monitor blood glycemia, and to assess the efficacy of the practice of self-monitoring of blood glucose in improving metabolic control and reducing acute and long-term diabetic complications.

Cardiovascular risk factors in type 2 diabetes: the role of hyperglycaemia.

Macrovascular complications are the most important causes of morbidity, mortality and disability in people with Type 2 diabetes mellitus. Although other known risk factors for macrovascular disease (e.g. dyslipidaemia, hypertension, obesity) often co-exist, diabetes itself is an important risk factor for accelerated development of atherosclerosis. Hyperglycaemia, hyperinsulinaemia and insulin resistance may each play a major role in the onset and development of atherosclerotic disease, which causes arterial wall dysfunction, haematological disturbances and lipid abnormalities through two mechanisms: oxidative stress and non-enzymatic glycation. Hyperglycaemia induces damage to the endothelium through activation of mitogen-activated protein kinase, protein kinase C and transcription factor nuclear factor (NF)-kappaB and through increased levels of pro-adhesion proteins such as intracellular adhesion molecule (ICAM)-1. The arterial wall tone is shifted towards vasoconstriction by hyperglycaemia, which is also associated with vascular smooth muscle cell proliferation and increased intimal wall thickness. Alteration of the coagulation system towards thrombophilia is observed in Type 2 diabetes and a series of lipid abnormalities that facilitate the development of atherosclerosis is evident. In Type 2 diabetes, undiagnosed disease and unrecognized postprandial hyperglycaemia are becoming the most relevant issues in reducing the risk of vascular complications and cardiovascular mortality; improved glycaemic control may reduce the incidence of macrovascular complications.

Time delay compensation for closed-loop insulin delivery systems: a simulation study.

Closed loop insulin therapy certainly represents the best possible approach to insulin replacement. However, present limitations preclude wider application of the so-called artificial pancreas. Therefore, a thorough understanding of these limitations is needed to design better systems for future long-term use. The present simulation study was design: to obtain better information on the impact of the measurement delay of currently available closed-loop devices both during closed-loop insulin delivery and blood glucose clamp studies, and to design and test a time delay compensator based on the method originally described by O.J. Smith. Simulations were performed on a Compaq Deskpro 486/25 personal computer under MS-DOS operating system using Simnon rel. 3.00 software. There was a direct relationship between measurement delay and amount of insulin delivered, i.e., the longer the delay the higher the insulin dose needed to control a rise in blood glucose; the closed-loop response in presence of a time delay was qualitatively impaired both during insulin delivery and blood glucose clamp studies; time delay compensation was effective in reducing the insulin dose and improving controller stability during the early phase of clamp studies. However, the robustness of a Smith's predictor-based controller should be carefully evaluated before implementation in closed-loop systems can be considered.

Wearable system for acquisition, processing and storage of the signal from amperometric glucose sensors.

A wearable device for the acquisition, processing and storage of the signal from needle-type glucose sensors has been designed and developed as part of a project aimed at developing a portable artificial pancreas. The device is essential to assess the operational characteristics of miniaturized sensors in vivo. It can be connected to sensors operating at a constant potential of 0.65 Volts, and generating currents in the order of 10(-9) Amp. It is screened and equipped with filters that permit data recording and processing even in the presence of electrical noise. It can operate with sensors with different characteristics (1-200 nA full scale). The device has been designed to be worn by patients, so its weight and size have been kept to a minimum (250 g; 8.5 x 14.5 x 3.5 cm). It is powered by rechargeable Ni/Cd batteries allowing continuous operation for 72 h. The electronics consists of an analog card with operational amplifiers, and a digital one with a microprocessor (Intel 80C196, MCS-96 class, with internal 16-bit CPU supporting programs written in either C or Assembler language), a 32 Kb EPROM, and an 8 Kb RAM where the data are stored. The microprocessor can run either at 5 or 10 Mhz and features on-chip peripherals: an analog/digital (A/D) converter, a serial port (used to transfer data to a Personal Computer at the end of the 72 h), input-output (I/O) units at high-speed, and two timers. The device is programmed and prepared to operate by means of a second hand-held unit equipped with an LCD display and a 16-key numeric pad.(ABSTRACT TRUNCATED AT 250 WORDS)

[Adrenergic activity and glycometabolic compensation in patients with diabetes mellitus]. / Attività adrenergica e compenso glicometabolico in pazienti con diabete mellito.

In an assessment of the degree of adrenergic activity in the course of diabetes mellitus, plasma levels and urinary excretion of norepinephrine and epinephrine were determined in 20 normal subjects and 47 diabetics: 11 in good control (group I), 23 in poor control (group II), 13 with frank ketoacidosis (group III). The study was repeated in groups II and III once good glycometabolic control had been achieved. Slightly above normal catecholamine levels were noted in group I, while there was a marked increase in group II. Group III shaved an enormous increase by comparison with the other two groups. After medical treatment values in group III fell to within the group I range. The conclusion is drawn that a close relationship exists between adrenergic acitivity and the degree of control of diabetes. The sympathetic nervous system, therefore, interferes in the course of diabetes with blood sugar control via numerous, complex mechanisms.