Serenella Burzacca

Platelet Resistance to Nitrates in Obesity and Obese NIDDM, and Normal Platelet Sensitivity to Both Insulin and Nitrates in Lean NIDDM

OBJECTIVE Previous studies in our laboratory showed that the platelet anti-aggregating effect exerted by insulin, mediated by a nitric oxide (NO)-induced increase of guanosine-3′,5′-cyclic monophosphate (cGMP), is lost in the insulin-resistant of obesity and obese NIDDM. It is not clear 1) whether the alterations observed in obese NIDDM patients are attributable to the obesity-related insulin resistance or to diabetes per se and 2) whether insulin-resistant states present a normal or a blunted response to NO. This study has been conducted to investigate 1) the platelet sensitivity to insulin in lean NIDDM and 2) the platelet sensitivity to an NO donor, glyceryl trinitrate (GTN), in obesity and in both lean and obese NIDDM. RESEARCH DESIGN AND METHODS We determined 1) ADP-induced platelet aggregation and platelet cGMP content in platelet-rich plasma (PRP) obtained from 11 lean NIDDM patients, after a 3-min incubation with insulin (0, 240, 480, 960, 1,920 pmol/l) and 2) ADP-induced platelet aggregation and platelet cGMP content in PRP obtained from 9 obese subjects, 11 lean and 8 obese NIDDM patients, and 18 control subjects, after a 3-min incubation with 0, 20, 40, and 100 μmol/l GTN. RESULTS Insulin dose-dependently decreased platelet aggregation in lean NIDDM patients (P = 0.0001): with 1,920 pmol/l of insulin, ADP ED50 was 141.5 ± 6.4% of basal values (P = 0.0001). Furthermore, insulin increased platelet cGMP (P = 0.0001) from 7.5 ± 0.2 to 21.1 ± 3.7 pmol/109 platelets. These results were similar to those previously described in healthy subjects. GTN reduced platelet aggregation in all the groups (P = 0.0001) at all the concentrations tested (P = 0.0001), but GTN IC50 values were much higher in insulin-resistant patients: 36.3 ± 5.0 μmol/l in healthy control subjects, 26.0 ± 6.0 μmol/l in lean NIDDM patients (NS vs. control subjects), 123.6 ± 24.0 μmol/l in obese subjects (P = 0.0001 vs. control subjects), and 110.1 ± 19.2 μmol/l in obese NIDDM patients (P = 0.0001 vs. control subjects). GTN dose-dependently increased platelet cGMP in all the groups (P = 0.0001 in control subjects, lean NIDDM patients, and obese subjects; P = 0.04 in obese NIDDM patients). Values reached by obese subjects and obese NIDDM patients, however, were lower than those reached by control subjects (with 100 μmol/l of GTN, P = 0.001 and P = 0.0001, respectively). In healthy control subjects and in obese subjects, the insulin:glucose ratio, used as an indirect measure of insulin sensitivity, was positively correlated to GTN IC50 (r = 0.530, P = 0.008), further suggesting that the sensitivity to NO is reduced in the presence of insulin resistance. CONCLUSIONS The insulin anti-aggregating effect is preserved in lean NIDDM; platelet sensitivity to GTN in preserved in lean NIDDM but is reduced in the insulin-resistant states of obesity and obese NIDDM. Resistance to nitrates, therefore, could be considered another feature of the insulin-resistance syndrome.

Occurrence of low blood glucose concentrations during the afternoon in type 2 (non-insulin-dependent) diabetic patients on oral hypoglycaemic agents : importance of blood glucose monitoring

SummaryThe European NIDDM Policy Group states that the lowest target for good control of Type 2 (non-insulin-dependent) diabetic patients is a blood glucose level 4.4 mmol/l, both fasting and postprandially. The aim of this study is to evaluate the occurrence and temporal distribution of values under this target in the clinical records of 463 Type 2 diabetic patients, treated by diet or diet and oral hypoglycaemic agents, monitored for at least 2 years. The protocol includes blood glucose measurements after overnight fasting (08.00 hours), 120–150 min after breakfast (11.00 hours) and 120 and 240 min after lunch (14.00 and 16.00 hours). At least one blood glucose concentration of less than 4.4 mmol/l was presented by 42% of the patients. The only difference between patients showing and not showing glycaemic levels under this target was the higher percentage on oral hypoglycaemic agents in the first group (68.4% vs 56.9%, p=0.016). We considered 299 blood glucose profiles containing at least one value of less than 4.4 mmol/l, observing that a) 46.9% of profiles from patients treated by diet alone and 68.7% of profiles from patients treated both by diet and oral hypoglycaemic agents presented the lowest blood glucose concentration at 16.00 hours (p=0.002). b) No correlation existed between fasting blood glucose and values at 16.00 hours in profiles from diet-treated patients, whereas a negative correlation was present in patients on diet and oral hypoglycaemic agents, indicating that an excess of oral agents, administered to correct fasting hyperglycaemia. was the cause of the low glycaemic values in the afternoon. c) 37.9% of profiles on a diet and 83.3% of profiles on diet and oral agents showed fasting glucose concentrations >6.7 mmol/l, the upper limit of good control according to the European NIDDM Policy Group. This indicates that fasting hyperglycaemia does not exclude the occurrence of low glucose values throughout the day and that it is necessary to monitor blood glucose profiles.

A Comparison of the Predictive Power for Overall Blood Glucose Control of a ‘Good’ Fasting Level in Type 2 Diabetic Patients on Diet Alone or with Oral Agents

The European NIDDM Policy Group classifies both fasting and post‐prandial blood glucose concentrations into ‘good’, ‘acceptable’, and ‘poor’ categories. The aim of the present study was to evaluate whether a ‘good’ fasting blood glucose concentration in Type 2 diabetic patients on diet or diet + oral hypoglycaemic agents is able to predict ‘good’ blood glucose values throughout the day, and therefore to discover whether or not it is necessary to perform blood glucose profiles in Type 2 diabetic patients when their fasting value is ‘good’. Capillary blood glucose profiles (n = 417) were measured in 287 Type 2 diabetic patients, on diet alone (279 profiles), or on diet + tablets (138 profiles). We observed that 66% of profiles on diet and 44% of profiles on diet + tablets had only ‘good’ blood glucose concentrations (p < 0.001). Eleven percent of profiles on diet and 30% of profiles on diet + tablets included ‘poor’ blood glucose concentrations (p < 0.001). Despite matched fasting blood glucose concentrations (diet 5.69 ± 0.04 (±SE) vs tablets 5.75 ± 0.05 mmol I−1), levels were higher in the diet + tablet treated patients at all later time‐points (p < 0.01–0.001). HbA1c was significantly higher in tablet‐treated patients than in patients on diet alone (6.6 ± 0.1 vs 5.9 ± 0.1%, p < 0.001), and correlated with the mean blood glucose concentration (r = 0.43, p< 0.001) but not with the fasting glucose concentrations. We conclude that a ‘good’ fasting blood glucose concentration is more predictive of good overall control in patients on diet alone than in patients on diet plus oral agents.

Blood glucose pre-prandial baseline decreases from morning to evening in type 2 diabetes: role of fasting blood glucose and influence on post-prandial excursions

Background  To know the relationships between pre‐ and postprandial blood glucose (BG), i.e. BG profile shape, is a requisite for an appropriate therapy for type 2 diabetic patients. In non diabetic subjects, pre‐breakfast, pre‐lunch and pre‐dinner BG are similar, so that BG postprandial excursions are superimposed on a stable BG preprandial baseline. We aimed to clarify: (a) whether BG preprandial baseline is stable also in type 2 diabetes and (b) whether fasting BG (FBG) influences the slope of BG preprandial baseline and the relationships between pre‐ and postprandial BG.

Moderate Exercise Increases Platelet Function in Type I Diabetic Patients Without Severe Angiopathy and in Good Control

OBJECTIVE The aim of this study was to investigate whether a 45-min moderate exercise, performed postprandially with a timing that partially prevented the risk of hypoglycemia, was able to modify platelet function in patients affected by insulin-dependent (type I) diabetes mellitus without severe late complications and in a good metabolic control. RESEARCH DESIGN AND METHODS We submitted 6 male type I diabetic patients (27.2 ± 3.4 yr; body mass index, 21.4 ± 0.6 kg/m2; HbA1c, 7.6 ± 0.9%) on a daily three-insulin injection regimen, without severe late complications of diabetes, to a 45-min moderate exercise (about 50% of maximal oxygen consumption) with a cycle ergometer, beginning 180 min after breakfast and 195 min after a subcutaneous shot of regular insulin. Serial venous blood samples were conducted to measure plasma glucose, free insulin, counterregulatory hormones (glucagon, growth hormone, cortisol, and catecholamines), platelet sensitivity to ADP, platelet activating factor and collagen, and plasma concentrations of the platelet-specific protein beta-thromboglobulin (a marker of the platelet release reaction in vivo). RESULTS Exercise was accompanied by a decrease of plasma glucose (from 5.9 ± 1.2 to 4.6 ± 1 mmol/L, P = 0.067) and free insulin (from 180 ± 36 to 114 ± 30 pmol/L, P = 0.003), and by a significant increase of growth hormone (from 5 ± 1 to 15 ± 4 μg/L, P = 0.045), cortisol (from 240 ± 30 to 406 ± 69 nmol/L, P = 0.018), epinephrine (from 1005 ± 240 to 5143 ± 1753 pmol/L, P = 0.077), and norepinephrine (from 5.04 ± 1.08 to 13.48 ± 2.98 nmol/L, P = 0.009). Platelet sensitivity to the agonists and plasma concentrations of β-thromboglobulin increased during the exercise period. In particular, ADP ED50 reached during exercise 61 ± 16% of basal values (P = 0.048), platelet activating factor ED50 reached 73 ± 11% (P = 0.043), and collagen ED50 reached 68 ± 9% (P = 0.008). β-Thromboglobulin rose from 24 ± 2 to 32 ± 3 μg/L (P = 0.007). CONCLUSIONS Moderate exercise enhances platelet function in type I diabetic patients without severe angiopathy and in a good metabolic control.

STUDIES ON THE EFFECT OF DOPAMINE ON THE HUMAN PLATELET RESPONSE

1. The present study investigated the in vitro effect of dopamine on platelet responses in healthy subjects.

Phenothiazines inhibit collagen-induced thromboxane B2 synthesis and increase forskolin anti-aggregating effects in human platelets

1. The aim of the present study was to investigate the effects of phenothiazine compounds chlorpromazine and trifluoperazine on human platelet response to collagen and sodium arachidonate. 2. The results demonstrated that phenothiazines inhibit collagen-induced platelet aggregation and thromboxane B2 synthesis in a dose-dependent way and increase the antiaggregating properties of forskolin. 3. Phenothiazines at high concentrations decreased the platelet aggregation in response to arachidonate, without a significant reduction of thromboxane B2 production. 4. The data provides evidence that phenothiazine effects could involve calmodulin-dependent enzymatic activities.

CALCIUM‐CHANNEL BLOCKING AGENTS VERAPAMIL AND DILTIAZEM ARE INHIBITORS OF VASOPRESSIN‐INDUCED HUMAN PLATELET ACTIVATION

1. This study investigated the influences of calcium‐channel blocking agents verapamil and diltiazem on platelet responses induced by arginine vasopressin (AVP) and lysine vasopressin (LVP).