Three different premixed combinations of biphasic insulin aspart - comparison of the efficacy and safety in a randomized controlled clinical trial in subjects with type 2 diabetes.

AIM: To evaluate clinical efficacy and safety of biphasic insulin aspart (BIAsp) 30 twice daily (b.i.d.) vs. BIAsp 50 or BIAsp 70 (high-mix regimens) thrice daily (t.i.d.) all in combination with metformin in a 36-week clinical trial in subjects with type 2 diabetes. METHODS: Efficacy measurements included haemoglobin A(1c) (HbA(1c)) and eight-point plasma glucose (PG); safety included adverse events (AEs) and hypoglycaemic episodes. The three treatment groups (approximately 200 subjects in each group) were well matched regarding sex ratio, ethnicity, age and body mass index. RESULTS: After 12 weeks, 43% and 54% in the BIAsp 50 and 70 groups, respectively, switched their dinner insulin to BIAsp 30. Both high-mix regimens were non-inferior to BIAsp 30 b.i.d., as measured by change in HbA(1c), and the BIAsp %50 regimen was superior. The odds for meeting the American Diabetes Association and The American Association of Clinícal Endocrinologist HbA(1c) targets of <7% and < or =6.5%, respectively, were significantly higher with the BIAsp 50 regimen than with BIAsp 30. A significantly lower PG level was achieved from lunch until 02:00 hours with both high-mix regimens compared with BIAsp 30 b.i.d. AEs were mild or moderate with all three regimens. Frequency of hypoglycaemic episodes was comparable for the BIAsp 50 and the BIAsp 30 b.i.d. regimens but was significantly higher with BIAsp 70 t.i.d. CONCLUSIONS: Glycaemic control improved with BIAsp 50 t.i.d. without higher incidence of hypoglycaemia compared with BIAsp 30 b.i.d.; with BIAsp 70 t.i.d. lower PG levels from lunch to 02.00 hours, but more hypoglycaemic episodes were obtained compared with BIAsp 30 b.i.d.

Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes.

AIMS: To show that a thrice daily meal-time biphasic insulin aspart (BIAsp) treatment regimen is as efficacious as a 4 times daily basal-bolus regimen with human isophane insulin (NPH) and insulin aspart (IAsp). METHODS: A multinational, randomised, open-label parallel-group trial in 394 patients with type 2 diabetes on a once or twice daily insulin regimen. Patients were randomised 1:1 to BIAsp or IAsp+NPH for 16 weeks. The BIAsp group was treated according to individual needs using BMI as a surrogate index of insulin resistance. Subjects administered BIAsp 70 (BMI< or =30 kg/m (2)) or BIAsp 50 (BMI>30 kg/m (2)) with breakfast and lunch and BIAsp 30 with dinner. The IAsp+NPH group injected IAsp at meals and NPH at bedtime as basal insulin. HbAlc levels after 16 weeks were compared between treatments using a predefined non-inferiority criterion of 0.4%. The incidence of hypoglycaemic episodes and adverse events was evaluated. RESULTS: Mean HbAlc (+/-SD) decreased from 9.1+/-0.7% to 7.8+/-1.0% with both treatments. Glycaemic control provided by BIAsp was non-inferior to that obtained by the IAsp+NPH (intention to treat ITT) population: diff, HbAlc -0.05%; 95% CI (-0.24; 0.14); per protocol (PP) population: diff, HbAlc -0.03%; 95% CI (-0.23; 0.16). Similar improvements in glycaemic control in both groups were confirmed by self-measured 8-point plasma glucose (PG) profiles, average and fasting PG concentrations, and average prandial PG increments. The incidence of adverse events and hypoglycaemic episodes was similar in the two treatment groups. CONCLUSIONS: A thrice daily meal-time BIAsp regimen is a suitable alternative to an intensified insulin regimen in people with inadequately controlled type 2 diabetes mellitus, and requires fewer daily injections than a basal-bolus therapy without compromising efficacy and safety.

Self-monitoring of blood glucose and type 2 diabetes mellitus.

Self-monitoring of blood glucose (SMBG) in management of type 2 diabetes mellitus continues to be debated. However, SMBG is recognized as being useful (professional agreement) in three situations: sensitizing the type 2 diabetic patient to the advantages of diet control and physical exercise, determining and adapting the dosage of oral antidiabetic medication at the beginning of treatment or during a dosage change, and monitoring plasma glucose during intercurrent disease or during a treatment that may lead to acute blood glucose imbalance. However, the frequency, the timing of blood glucose monitoring, and the target blood glucose values remain poorly defined. It is well known that the postprandial period covers approximately 50% of the day, and several recent studies have shown the respective role of fasting, pre- and postprandial glucose levels in overall diurnal hyperglycemia in the type 2 diabetic and their respective contribution to the mean HbA1c level depending on how well blood glucose levels are controlled. Based on these studies, it is now possible to propose a SMBG scheme, specific to a given patient and for a defined therapeutic objective, taking the three physiological periods into account: postprandial, postabsorptive, and fasting. However, the optimal use of SMBG requires patient education and training. Using a specific, adapted, and optimal SMBG is only advantageous if the results are usable, and used, by the patient and healthcare professionals to improve the quality of blood glucose control (as shown by the HbAlc level) and the safety of intensified oral antidiabetic treatments (minimal risk of hypoglycemia).

Advantages to using capillary blood beta-hydroxybutyrate determination for the detection and treatment of diabetic ketosis.

Ketone body determination is indicated in all diabetic patients when the risk of ketotic decompensation exists. New methods of screening for ketosis, in particular capillary blood ketone body determination, provide analytical, technical and clinical advantages compared to the conventional ketonuria. It is proposed that a diabetic patient with hyperglycaemia (capillary blood glucose > 2.50 g.l(-1)) and capillary blood ketone bodies exceeding 0.5 mmol.l(-1) requires therapeutic management. For values greater than 3 mmol.l(-1) or in case of more serious clinical symptoms, hospitalisation is indicated, considering the high probability of ketoacidotic decompensation. The advantages of capillary blood ketone body determination including easy use, and rapid and objective results may improve management of the diabetic patient, especially in emergency situations. However, prescription by a physician of capillary blood ketone body determination should be offered to targeted populations that have a high risk of ketoacidotic decompensation, after providing education to patients that is above all aimed at preventing this metabolic complication. In this context of determining ketone bodies in capillary blood, the term "capillary blood ketone bodies" is therefore preferable to the term "capillary blood beta-hydroxybutyrate determination". Indeed, it appears more appropriate, simple, descriptive and significant both for health-care staff and for patients.

Hemorheological disturbances as a marker of diabetic foot syndrome deterioration.

Diabetes mellitus is associated with vascular abnormalities. Hemorheological variables as well as the transcutaneous oxygen pressure (TcPO2) were measured in 38 diabetic patients with critical limb ischemia to assess whether these variables could be of value to follow the deterioration in foot disease. Patients with previous history of foot ulcers or frank ulcers on presentation were followed for foot care. After a 12-month follow-up, they were divided into 2 subgroups based on the regression of foot disease: 30% of patients improved foot ischemia, i.e., healed or improved ulcer, while the remainder 70% deteriorated, i.e., impaired ulcer or underwent an amputation. RBC aggregation, plasma viscosity and fibrinogen level observed at baseline visit, were significantly higher in the patients who deteriorated. Blood viscosity values at both shear rates high and low were not significantly different between the 2 subgroups. TcPO2 was significantly lower in patients who deteriorated compared with those who improved. With regard to prognostic values, RBC aggregation parameters and fibrinogen level offered the highest positive predictive values (of 89%, 94%, and 88% respectively), comparable to that associated with TcPO2 (94%). Further analyses showed that combining markers of hemorheology with TcPO2 especially when TcPO2 value is in the range of 10-30 mmHg, may improve prognostic value for the management of the diabetic foot disease.

Blood rheology in patients with diabetes mellitus.

Blood rheology is now receiving increasing attention as an important potential contributory factor to diabetic angiopathy. This study was designed to provide evidence for and against early hemorheological abnormalities in diabetes mellitus (DM). For this purpose, blood viscosity, RBC aggregation, hematocrit, and plasma protein's levels of both fibrinogen and albumin were measured in 86 uncomplicated patients with DM (45 type 1 and 41 type 2). Patients with HbA1c < 7.5% were considered as having good glycemic control (GGC), while those with HbA1c > 8.5% as having poor glycemic control (PGC). Patients with type 1 DM showed normal blood viscosity at both shear rates high and low, while native hematocrit, fibrinogen, and RBC aggregation were significantly elevated and albumin significantly reduced when compared with healthy volunteers. Patients with type 2 DM showed more marked impairments associated with an increased low shear rate blood viscosity, when compared with patients with type 1 DM. Comparison between two subgroups of patients, both of which with type 1 DM and of similar disease duration of <5 yrs, with GGC or PGC showed that impaired blood rheology does depend on the quality of glycemic control. Differences were attenuated after a disease duration of >15 yrs. These findings suggest that early hemorheological impairments in patients with type 1 DM are dependent upon the glycemic control. In contrast, hemorheological impairments appear to be inevitable after a mean disease duration of 15 yrs even if there is a GGC. Aggravation of hemorheological abnormalities in patients with type 2 DM might depend upon the hemorheological effects of other metabolic abnormalities related to insulin resistance rather than the quality of glycemic control.

Blood rheology as a marker of venous hypertension in patients with venous disease.

During chronic venous insufficiency (CVI), several microvascular functional abnormalities, due to venous hypertension, develop. To look for blood rheological consequences of venous hypertension "VH", whole blood viscosity and its main determinants were measured in 11 normal controls and 36 patients with CVI exposed to a short-term experimental VH. Patients were subdivided into 2 groups according to the severity of their disease. Blood was taken from a foot vein before and after VH, which was induced by appling a pneumatic tourniquet to 100 mmHg for 15 minutes. Whole blood viscosity at low and high shear rates, red blood cell (RBC) aggregation, RBC rigidity, plasma viscosity and proteins as well as red and white blood cell (WBC) counts were recorded. Patients at baseline, i.e., before application of the tourniquet, showed several hemorheological abnormalities such as an increased RBC aggregation, increased low shear rate viscosity, and a significant elevation in plasma fibrinogen level. Patients with more severe CVI had more marked hemorheological changes. The short term VH in patients led to further aggravation of these changes. There were also at baseline lower values, however not significantly, of hematocrit and RBC count, suggesting that hemoconcentration is not a feature of CVI. These same parameters were slightly, however not significantly, increased after VH, indicating a fluid escape into the extravascular space. A significant fall in WBC count was also observed after VH, in keeping with the white cell trapping hypothesis. In conclusion, even a short-term VH is able to induce several hemorheological impairments, which are probably involved in the failure of the microcirculation and hence the initiation of tissue damage in patients with CVI.

Measurements of transcutaneous oxygen pressure and changes in blood rheology as markers of prognosis of critically ischemic limb in diabetes mellitus patients.

The aims of this study were to compare variations of the transcutaneous oxygen pressure (TcPO(2)) and blood rheology in diabetic patients. Diabetic patients with critical limb ischemia were compared with those who were either asymptomatic or had mild peripheral vascular disease (PVD). The results showed a significant decrease in TcPO(2) in patients with critical limb ischemia. Low shear rate blood viscosity, red blood cell (RBC) aggregation, plasma viscosity, and fibrinogen level were significantly higher in the group with critical severe limb ischemia. The group with critical limb ischemia was subdivided on the basis of clinical outcomes after 1 year and the prognostic values of these measurements examined. A TcPO(2) value of 10 mm Hg was associated with a positive predictive value of 94%. RBC aggregation index and fibrinogen levels offered positive predictive values of 89% and 88%, respectively, when cut off values were derived from means + 1 SD of same parameters in patients with asymptomatic or mild PVD. TcPO(2) is useful to follow the deterioration of diabetics with critical limb ischemia.

[Critical analysis of vascular explorations in diabetic complications]. / Analyse critique des explorations complémentaires vasculaires chez le diabétique.

Diabetes mellitus is the chief medical cause of amputation. The risk of amputation is 15-fold higher in diabetic subjects and 5 out of 6 amputees are diabetic. Among the three risk factors for amputation in diabetic patients-neuropathy, ischemia, and infection-ischemia is the most difficult to quantify. Thus, functional and/or distal foot arteriopathy may be present without any clinical symptoms long before trophic changes occur. Therefore additional vascular explorations, including measurement of systolic toe pressure, must be performed. Physical examination is sufficient to diagnose lower limb arterial disease when ankle pulses are missing, but severe foot ischemia may be present despite minimal clinical signs and normal ankle pulses. Mediacalcinosis alters ankle pressure. Toe pressure is the most reliable test for quantifying ischemia of the diabetic foot. Other investigations such as TcPO(2) measurement, laser-Doppler and capillaroscopy are useful for revealing early functional diabetic microangiopathy, but they can only be done and interpreted in specialized centers.

[Diabetic angiopathy: the role of microvascular exploration in routine practice. Consequences of a new algorithm for care of the diabetic foot]. / Vasculopathie diabétique: la place des explorations microcirculatoires en pratique quotidienne. Conséquences pour une nouvelle prise en charge du pied diabétique.

Diabetes mellitus is the chief medical cause of amputation. The risk of amputation is 15-fold higher in diabetic subjects and 5 out of 6 amputees are diabetic. There are three types of clinical presentation of diabetes-neurological, infectious and ischemic. In clinical practice, these three forms are often intertwined but the most frequent clinical sequence of events is neuropathy --> ulceration --> infection --> amputation. In this sequence, ischemia is not mentioned. The explanation is that the ischemic component of the diabetic foot is only recognized when ankle pulses are missing and when duplex scanning shows stenosis or occlusion of the main arterial trunks of the legs. This manner of diagnosing the ischemic component of diabetic foot is wrong as it fails to recognize the possibility of distal diabetic arteritis. Some experts in diabetology deny the existence of this arteritis which is obvious for those who measure systolic toe pressure. This distal arteritis is present in about 15% of all diabetic patients without trophic changes and in 35% of those with trophic changes. This foot arteritis is closely related to neuropathy. Toe pressure is not usually mentioned in text books or in consensus conferences concerning the diabetic foot. This is the main explanation for the calamitous number of amputations among diabetic patients. Nothing will change as long as physicians do not include toe pressure as a useful diagnostic tool in patients with diabetes. We present here a four-stage algorithm including toe pressure measurement for the management of the diabetic foot.

[Acrocyanosis: changing concepts and nosological limitations]. / Acrocyanose, évolution des concepts et limites nosologiques.

Acrocyanosis is undoubtedly the most commonplace acrosyndrome, both in terms of pathogenesis and prognosis. Patients experience functional impairment and an esthetic prejudice that must not be neglected. Adopting the nosological classifications described for Raynaud's syndrome, primary acrocyanosis must be distinguished from exceptional secondary phenomena that have a radically different clinical course. Primary acrocyanosis is generally observed in a young woman who appears thin or has recently lost weight. No paroxysmal episode (syncope, cyanosis, suspicious event involving the fingers) is found. The physical examination is negative and no complementary explorations are needed. Current pathophysiological hypotheses remain insufficient but suggest that vasospasticity rather than hemorheology is involved. The hypothesis that a thermoregulation disorder could be associated with weight loss deserves further study. Symptomatic care relies on dietary and hygiene counseling, emphasizing the importance of warm clothing. The psychological element must also be considered even in the most common forms.

Impaired hemorheological properties in diabetic patients with lower limb arterial ischaemia.

The rheological properties of blood play an important role in the regulation of blood flow resistance in vessels. Numerous data show evidence for an impaired hemorheological characteristic in diabetes mellitus. The aim of this study was to investigate whether chronic severe leg ischaemia in diabetes may be associated with further hemorheologic impairment. To do this, whole blood viscosity, erythrocyte aggregation/disaggregation, plasma viscosity and proteins were measured in 32 healthy control subjects, in 32 diabetic patients without micro- and macroangiopathy, in 21 diabetic patients with chronic tissue hypoxia of lower limbs and in 23 diabetic patients with severe leg ischaemia. The diabetic patients with leg hypoxia and leg ischaemia were selected according to their value of transcutaneous oxygen pressure (TcPO2) measured on dorsal side of the foot in supine position. The TcPO2 value was within 10-30 mmHg or less than 10 mmHg in patients with chronic hypoxia and severe ischaemia, respectively. Results in diabetic patients without micro- and macroangiopathy showed an increased erythrocyte aggregation associated with an increased fibrinogen level while albumin levels were decreased. Both diabetic patients with chronic hypoxia and those with severe ischaemia exhibited similarly more aggravated hemorheological disturbances including an increased whole blood viscosity at low shear rate, an increased erythrocyte hyperaggregation, increased plasma viscosity, increased fibrinogen level, decreased albumin level and decreased hematocrit. In conclusion, the hemorheological disturbances are present even in diabetic patients without clinically detectable micro- and/or macroangiopathy. The fact that the extent of disturbances was similar in the two later diabetic groups, emphasizes that the hemorheological disturbances are not the consequences of chronic hypoxia and/or severe ischaemia but are likely among factors promoting the maldistribution of blood flow in nutritive capillaries as evidenced by decreased TcPO2 in patients with chronic leg hypoxia or severe leg ischaemia.

Effect of naftidrofuryl on platelet aggregation in plasma from aspirin treated patients: an in vitro study.

This study concerns an in vitro evaluation of the effect of naftidrofuryl on platelet aggregation in plasma of 15 diabetic patients, who were being treated with aspirin, and who were suffering from chronic arterial disease of the lower limbs. Platelet aggregation, induced either spontaneously or by aggregating agents, was measured in platelet-rich plasma (PRP). The results show that serotonin (5-HT)- and adenosine 5'-diphosphate (ADP)-induced platelet aggregation significantly decreased after addition of naftidrofuryl. Decreases were achieved with naftidrofuryl at a low dose (0.06 microM) and became more marked with naftidrofuryl at higher concentrations. In contrast, naftidrofuryl did not appear to modify routinely spontaneous platelet aggregation. These results show an in vitro antiaggregating effect of naftidrofuryl on platelets of aspirinized patients. However, the clinical interest of a such coadministration of naftidrofuryl and aspirin in patients, has still to be confirmed in a double blind randomized trial.

[Diabetes mellitus and fibrinogen. Hemorrheological and microcirculatory consequences]. / Diabète sucré et fibrinogène. Conséquences hémorhéologiques et microcirculatoires.

Fibrinogen level, erythrocyte aggregation and transcutaneous oxygen pressure (TcPO2) were measured in the two populations of 32 healthy volunteer subjects and 119 diabetic patients without any clinical sign of micro and/or macroangiopathy. Measured parameters were studied according to both the long term glycemic control (HbA1C) and the type of diabetes. Results showed a significant elevation of plasma fibrinogen in all diabetic patients even when they had good glycemic control. Hyperfibrinogenemia appeared to be related to both long term glycemic control and type of diabetes. Hyperfibrinogenemia in studied diabetic patients was associated with a tendency to erythrocyte hyperaggregation. Indeed, this hyperaggregation like fibrinogen level, seem to be related to both HbA1C level and the type of diabetes. In contrast, the TcPO2 was found to be significantly decreased in all patients irrespective to either HbA1C or the type of diabetes. Besides, TcPO2 was not correlated with fibrinogen nor erythrocyte aggregation. In conclusion, the decrease in TcPO2 as observed here, does not directly depend upon the type of diabetes, or the HbA1C level, i.e the quality of mid and/or long term glycemic control.

Tissular oxygenation and venoarteriolar reflex disturbances in diabetes mellitus: vasoregulator effect of Buflomedil.

The present study was designed to investigate whether the Veno-Arteriolar Reflex (VAR) mediated via a local nervous reflex mechanism may be used as a microvascular approach to predict the effect of vasoactive drugs in diabetic patients. The vasoactive drug we studied here was Buflomedil. The effect of a single infusion of 400 mg of Buflomedil was examined on VAR and on transcutaneous oxygen pressure (TcPO2). Investigations were performed in 42 diabetic patients. The VAR was assessed on dorsal foot and dorsal big toe by measuring changes in skin blood flux induced by lowering the leg. TcPO2 was measured on dorsal foot. Before Buflomedil infusion, patients were characterized by a loss of the VAR in comparison to healthy volunteers. The loss of the VAR was associated to significant decreases in TcPO2 values. Buflomedil infusion led to significant increases in VAR at the two sites of measurement and also in TcPO2 values. These findings indicate that the VAR can be used as a sensitive microvascular test, as it allows to detect the effect of Buflomedil. Furthermore, our findings demonstrate that the Buflomedil-induced improvement in VAR is identical in the two diabetic groups with or without complications. This result emphasizes the benefit of Buflomedil not only in diabetics with microangiopathy or those suffering from a peripheral vascular disease for reducing pain or healing trophic lesions, but also in those patients without any clinically detectable macro- or microangiopathy in order to prevent or to reduce as long as possible the risk of developing diabetes related complications by the normalization of functional microangiopathy.

Haemorheological consequences of hyperglycaemic spike in healthy volunteers and insulin-dependent diabetics.

The present study has been designed to examine the role of a hyperglycaemic spike of short duration as a factor possibly involved in haemorheological microcirculatory and (or) haemostatic dysfunctions in ten insulin-dependent diabetes mellitus patients (IDDM) and five healthy volunteers. The hyperglycaemic spike was induced by glucose infusion via GCIIS Biostator. Blood viscosity, erythrocyte aggregation, erythrocyte deformability, plasma viscosity and proteins' levels, cell counts, and transcutaneous oxygen pressure were investigated during normoglycaemic period and at the end of a 1 h hyperglycaemic spike. Hyperglycaemia induced in IDDM patients significant decreases in erythrocyte aggregation, in blood and plasma viscosities and in both fibrinogen and albumin levels. The number of platelets was significantly decreased as a result of the hyperglycaemic spike. There was no significant change induced by the hyperglycaemic spike in healthy volunteers. These findings show that a hyperglycaemic spike of 280 mg/dl (15.6 mmol/l) of short duration in IDDM patients causes numerous significant changes in both blood components and rheological behaviour. These changes were accompanied by a significant decrease in transcutaneous oxygen tension indicating an impaired tissue oxygenation during the hyperglycaemia.

Evaluation of haemorheological and microcirculatory disturbances in chronic venous insufficiency: activity of Daflon 500 mg.

The use of Daflon 500 mg has been shown to improve venous tone, microvascular permeability, lymphatic activity, and microcirculatory nutritive flow. This study aimed to assess the effects of Daflon 500 mg at a daily dose of 2 tab/day on microcirculatory, haemorheologic parameters, white blood cell counts and neutrophil activation in patients suffering from chronic venous insufficiency (CVI). This was a single-centre double-blind placebo-controlled study comparing two parallel groups of CVI patients who were treated for 2 months with Daflon 500 mg (n = 39) or placebo (n = 38). Evaluations were performed before treatment (D0) and at the end of treatment (D60). Blood samples were drawn from a foot vein before and at the end of a 15-min period of venous hypertension provoked by a cuff inflated to 100 mm Hg. Red blood cell (RBC) deformability was determined by the initial flow rate filtration technique using a Hanss haemorheometer. RBC aggregation was evaluated by a Myrenne aggregometer based on analysis of transmitted light through a blood sample during flow. RBC disaggregation was evaluated by Sefam erythro-aggregometer based on analysis of the backscattered light through a blood sample in a Couette flow. Microcirculatory parameters were assessed by means of laser Doppler fluxmetry and transcutaneous oxymetry measurements and consisted of continuous records of blood flux (BF) and TcPO2 before and during 15 min of venous hypertension. Results are expressed as absolute values at baseline (before stasis) and at the end of stasis, before and after 2 months of treatment. Univariate analysis showed a significant reduction of the stasis-induced RBC aggregation index (Daflon 500 mg: -0.07+/-0.20; placebo: 0.04+/-0.18; mean +/- SD; p = 0.03). Multivariate analysis identified a subset of 5 variables (RBC aggregation, RBC count, microcirculatory BF, amplitude and frequency of vasomotion) that produced a good discrimination model between the two treatments. Linear combination of these 5 variables in 48 patients with complete data showed a significant difference (p < 0.001) between the groups. These changes suggest a protective effect of Daflon 500 mg on the deleterious influence of stasis on microcirculatory (BF) and hemorheologic (RBC aggregation) parameters in CVI patients in comparison to patients receiving placebo.

The autoregulation of the skin microcirculation in healthy subjects and diabetic patients with and without vascular complications.

The skin microvascular autoregulatory capacity was investigated in healthy volunteers and diabetic patients without or with vascular complications. To assess this capacity, skin blood flux (SBF) of different areas was examined during different procedures of venous stasis, standing position, and passive lowering of the leg. SBF was evaluated by laser doppler fluxmetry. There was, in healthy control subjects, the same degree of vasoconstriction, i.e., the same reduction in SBF irrespective of the site of measurement and the procedure used. In diabetic patients, the vasoconstriction elicited in the finger pulp by venous stasis was normal. By contrast, the vasoconstrictor responses to standing or lowering of the leg were impaired. In fact there was, in some patients, an increased SBF instead of a decreased one during standing or lowering of the leg. Impaired vasoconstrictor responses to standing or lowering of the leg was observed even in patients without complications; the impairment, however, was more marked in patients with complications. Thus, the inability of the diabetic skin microvasculature to respond normally to postural changes may be an important factor initiating the development of foot complications. The contribution of local and central reflexes to microvascular autoregulation in diabetic patients and control subjects was also discussed.

Role and limits of glycemic regulation in the pathogenesis of diabetic microangiopathy.

The relationship between either an acute or a chronic hyperglycemia and functional microcirculatory disturbances was studied in insulin-dependent diabetic (IDD) patients in comparison to healthy volunteers. Acute hyperglycemia, provoked in 10 IDD patients, was accompanied by an increase in laser doppler skin blood flux while transcutaneous oxygen pressure (TcPO2) decreased. These changes, accompanied by that in the concentration of moving blood cells indicate that acute hyperglycemia results in a vasodilation in favour of non-nutritive microvascular shunts. The effect of chronic hyperglycemia was studied in 36 IDD patients who had a duration of diabetes of less than 5 years and had no clinical signs of micro- and macroangiopathy. In these patients, erythrocyte aggregation, plasma viscosity and fibrinogen concentration were increased and transcutaneous oxygen pressure reduced, compared with the levels seen in healthy subjects. More marked impairments were observed in patients with poor glycemic control. This suggests that chronic hyperglycemia involves functional disturbances which will contribute to the development of the vascular complications of diabetes. In 34 patients with poorly controlled diabetes who received intensive insulin therapy for 36 months, these changes were reversed in patients in whom good glycemic control was achieved within 2 months, but not in those in whom glycemic control remained poor. It is concluded that disturbances in blood flow and TcPO2 occur early in diabetes, and are consequences of poor glycemic control. These disturbances can be reversed or normalized if glycemic control is improved by intensive treatment.