Clinical laboratory values during diabetic pregnancies.

BACKGROUND: Physiological pregnancy can affect routine laboratory tests, e.g., the erythrocyte sedimentation rate increases above the reference range for healthy non-pregnant adults and little is known about whether diabetes and pregnancy together can cause additional changes that require monitoring of blood-tests. OBJECTIVE: The purpose of this study was to investigate changes in clinical chemistry and haematological laboratory test results during pregnancies of type 1 diabetics and to compare the results with changes during normal pregnancies. METHODS: We studied 25 type 1 diabetic women with standard clinical chemistry and haematological blood-tests during pregnancy. RESULTS: Haemoglobin, haematocrit, and erythrocyte number decreased until the 3rd trimester and leucocytes and platelets did not change significantly. The erythrocyte sedimentation rate increased by over 200%. Protein and albumin decreased until the 3rd trimester to below the reference range. Urea did not change, creatinine decreased and uric acid increased within the reference range. AST and ALT remained within the reference range. Alkaline phosphatase and leucine aminopeptidase increased until above the reference range. Cholesterol and triglycerides increased until the third trimester above results from normal pregnancies. CONCLUSION: A wide range of biochemistry and haematology laboratory values changed during diabetic pregnancy comparable to physiological pregnancies. No additional routine laboratory-testing during diabetic pregnancies compared with physiological pregnancies is required.

Association of increased intramyocellular lipid content with insulin resistance in lean nondiabetic offspring of type 2 diabetic subjects.

Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.

Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients.

To test the hypothesis that recurrent short-term hypoglycemic episodes may impair hormonal counterregulation, symptom awareness, and neurophysiological function during subsequent hypoglycemia, we examined two groups of IDDM patients (n = 18), neither of whom exhibited signs of autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed three days apart with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' awareness of and response to hypoglycemia was evaluated. In the intervention group (n = 11), three short-term hypoglycemic episodes preceded the second clamp study. Counterregulatory hormones increased significantly during hypoglycemia, but adrenaline (P < 0.03), cortisol (P < 0.01), and ACTH (albeit not significant) showed a blunted response after repetitive hypoglycemic events. In this group, the perception of hypoglycemic symptoms was significantly reduced and was most evident for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and warmness (P < 0.03). The deterioration of neurophysiological function, as assessed from the middle latency auditory evoked potentials, was more pronounced in the intervention group (latency shift of the Pa component, P < 0.05). These data suggest that alterations of neuroendocrine counterregulation, symptom perception, and certain aspects of cerebral function may occur as a consequence of recurrent short-term hypoglycemic episodes. These adaptation phenomena may contribute to the increased incidence of severe hypoglycemia in IDDM patients on intensive insulin therapy.

Platelet prostacyclin binding in coronary artery disease.

Reduced responsiveness of platelets to prostacyclin, reported in vitro in patients with coronary artery disease, has been thought to be a factor predisposing toward coronary thrombosis and vasospasm as a result of enhanced in vivo release of cyclic endoperoxides and thromboxane A2 by the platelets. In this study, specific binding of prostacyclin to intact platelets was determined in patients with coronary artery disease by direct binding studies using 9-3H-prostacyclin sodium salt. In addition, the inhibitory effect of prostacyclin on primary aggregation induced by adenosine diphosphate and cyclic adenosine monophosphate (cyclic AMP) accumulation stimulated by prostacyclin was examined. Twenty patients with angiographically documented coronary artery disease and stable angina, 8 patients with acute myocardial infarction, 14 healthy volunteers and 10 patients with normal angiograms were studied. In patients with stable angina, binding capacity and affinity of platelet prostacyclin binding sites and prostacyclin-induced cyclic AMP accumulation were not different from those of control subjects. In patients with acute myocardial infarction, however, binding capacity of platelet prostacyclin receptors was significantly reduced (0.69 +/- 0.45 versus 1.35 +/- 0.37 pmol/10(9) platelets, p = 0.001) and the postreceptor response, represented by platelet responsiveness to prostacyclin and prostacyclin-induced cyclic AMP synthesis, was impaired. Because all patients with myocardial infarction were receiving intravenous heparin and nitroglycerin, which might interfere with platelet prostacyclin binding, competition experiments were performed in vitro. Neither heparin (3 to 250 IU/ml) nor nitroglycerin (0.8 to 22 microM) displaced specifically bound 9-3H-prostacyclin. L-Epinephrine in concentrations up to 10 microM also exhibited no competition with specific platelet prostacyclin binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Catecholamine response during human and pork insulin-induced hypoglycemia in IDDM patients.

OBJECTIVE: To evaluate the catecholamine response during human and pork insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS: Ten insulin-dependent diabetes mellitus (IDDM) patients without any signs of autonomic neuropathy received either human or pork insulin in a randomized crossover fashion on 2 nonconsecutive days. The glucose clamp technique was applied to achieve stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM. RESULTS: The effect of both types of insulin on glucose metabolism and circulating catecholamines was almost identical. There was a sharp rise of both epinephrine (P less than 0.05) and norepinephrine (P less than 0.02) during hypoglycemia, which did not depend on the type of insulin applicated. Symptom awareness increased significantly during the decrease of blood glucose concentration. Only during developing hypoglycemia (3.3-mM plateau), was this effect more pronounced (cumulative symptom score 2 vs. 26, P less than 0.05) with pork insulin. CONCLUSIONS: AN attenuated catecholamine secretion seems not to be the putative mechanism of a reduced awareness of human insulin-induced hypoglycemia.

Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM.

OBJECTIVE: To test the hypothesis that impaired counterregulatory hormone response and symptom perception, induced by recurrent hypoglycemic episodes over 2 days, may be improved by short-term (2-day) avoidance of hypoglycemia. RESEARCH AND DESIGN: We examined two groups of insulin-dependent diabetes mellitus (IDDM) patients (n = 16), none of whom exhibited signs of peripheral or autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed applying stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol/l, at which the patients' awareness of and responses to hypoglycemia were evaluated. In the intervention group (n = 11), three short-term hypoglycemic ( < 2.2 mmol/l) episodes (days 1-3) preceded the first clamp study (day 4), whereas the second clamp study (day 6) followed a 2-day interval of strict avoidance of hypoglycemia. A control group (n = 5) was introduced to detect adaptation effects caused by the study procedure per se. RESULTS: This short-term avoidance of hypoglycemia caused improvement of the impaired counterregulatory hormone response during insulin-induced hypoglycemia involving adrenaline (P < 0.05), adrenocorticotrophic hormone (P < 0.03), and cortisol (P < 0.05). Improvement of hypoglycemia symptom awareness encompassed overall symptom perception (multiple analysis of variance, P < 0.04) and the automatic symptoms of heart pounding (P < 0.05) and sweating (P < 0.05). CONCLUSIONS: The previously reported compromised neuroendocrine counterregulation and symptom awareness, occurring as a consequence of repetitive hypoglycemic episodes over 2 days, may be improved by a single 2-day interval of strict avoidance of hypoglycemia

Pain intensity and blood pressure reactions during a cold pressor test in IDDM patients.

OBJECTIVE: To determine the contribution of altered pain perception to the impaired blood pressure reactions during a cold pressor test in diabetic patients. Reduced blood pressure increases have been observed in diabetic patients during a cold pressor test and have been attributed to an impaired efferent sympathetic function. RESEARCH DESIGN AND METHODS: We investigated pain intensities and blood pressure reactions simultaneously during a cold pressor test in 30 IDDM patients (diabetes duration 12 +/- 6 years, HbA1c 7.5 +/- 1.4%) and in 30 normal control subjects with comparable sex distribution, age, height, BMI, physical fitness, and smoking habits. RESULTS: Initial pain intensities and respective time courses did not differ between the two groups. The initial blood pressure response was significantly smaller in diabetic patients (P < 0.002). Correlations of diastolic blood pressure increases in diabetic patients with initial pain intensity, standard cardiovascular reflex tests, age, clock time, smoking habits, disease duration, and actual blood glucose concentrations did not reach statistical significance. Pain intensity and diastolic blood pressure increases, however, were correlated to HbA1c concentrations in diabetic patients. CONCLUSIONS: Impaired pain perception is not the cause of the impaired reactions of blood pressure in diabetic patients during the cold pressor test, leaving very early deterioration of either cerebral processing of pain stimuli, cardiac function, efferent sympathetic nerves, or decreased vascular reactivity as possible explanations.

Neurophysiological impairments in IDDM patients during euglycemia and hypoglycemia.

OBJECTIVE: To test the hypothesis that latencies of evoked potentials in IDDM patients are delayed compared with healthy control subjects during euglycemia, and that insulin-induced hypoglycemia causes further latency delays of evoked potentials to occur. RESEARCH DESIGN AND METHODS: We recruited 23 IDDM patients (27.9 +/- 1.6 yr of age, HbA1c 6.7 +/- 0.3%, without sensory or autonomic neuropathy) and 26 unequivocally healthy subjects who were carefully matched for sex, age, and body mass index to serve as the control group (18 men and 8 women, 28.4 +/- 1.6 yr of age, 22.6 +/- 0.7 kg/m2), for a controlled, prospective study. Sequential euglycemic-hypoglycemic clamps were performed with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' and healthy control subjects' neurophysiological functions were evaluated. The methodological armamentarium included the measurement of brainstem auditory, middle-latency auditory, and somatosensory evoked potentials that assessed conduction velocity in corresponding neural structures and information processing in the midbrain and auditory cortex. RESULTS: Multiple analysis of variance revealed a significant overall difference of brainstem auditory evoked potential latencies during euglycemia between the study group and healthy control group (F = 3.41, P < 0.03), which was mainly attributable to latency delays of wave III (F = 6.60, P < 0.02), V (F = 9.19, P < 0.01), and interpeak latency I-V (F = 2.82, P < 0.07). Repeated analysis of variance measures detected a significant latency delay of the major wave Pa of the middle-latency auditory evoked potentials during hypoglycemia (F = 4.4, P < 0.02), which rapidly returned to normal after reinstitution of euglycemia. CONCLUSIONS: In IDDM patients, chronic, structural CNS changes already appear at the brainstem level during euglycemia. Functional, reversible CNS changes, however, seem to emerge during acute deviation from glucose homeostasis in more rostral brain regions.

Effect of hypoglycemia on beta-adrenergic sensitivity in normal and type 1 diabetic subjects.

OBJECTIVE: The purpose of this study was to assess the potential role of reduced tissue sensitivity to catecholamines in the pathogenesis of hypoglycemia unawareness in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: The effect of a single episode of hypoglycemia on beta-adrenergic sensitivity was studied in 10 type 1 diabetic patients with apparently normal awareness of hypoglycemia (age 29 +/- 5 years, diabetes duration 13 +/- 8 years, HbA1c 7.3 +/- 0.9%) and 10 age-matched healthy control subjects. Beta-adrenergic sensitivity was measured with the isoproterenol test after a hyperinsulinemic euglycemic clamp and after a hyperinsulinemic hypoglycemic clamp. Beta-adrenergic sensitivity was expressed as the dose of intravenous isoproterenol that increased the heart rate by 25 beats/min (IC25). RESULTS: During hypoglycemia, diabetic subjects had an impaired plasma epinephrine response compared with that of the control subjects (16.7 +/- 5.0 vs. 40.1 +/- 6.8 ng/ml, P = 0.02). In control subjects, the IC25 was lower after hypoglycemia than after euglycemia (0.83 +/- 0.22 vs. 1.13 +/- 0.21 microg, P = 0.02) indicating an increase in beta-adrenergic sensitivity. In diabetic subjects, on the other hand, the IC25 was greater after hypoglycemia than after euglycemia (1.00 +/- 0.26 vs. 0.65 +/- 0.14 microg, P = 0.04), indicating a decrease in beta-adrenergic sensitivity. CONCLUSIONS: In normal subjects, a single episode of hypoglycemia increases beta-adrenergic sensitivity. In diabetic subjects, in contrast, hypoglycemia reduces beta-adrenergic sensitivity. These results provide evidence that in type 1 diabetic patients, some maladaptation of tissue sensitivity to catecholamines contributes to the development of hypoglycemia unawareness. A unifying hypothesis is presented for the pathogenesis of hypoglycemia unawareness in type 1 diabetic patients incorporating the concepts of both a reduced catecholamine response and reduced adrenergic sensitivity

Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity.

OBJECTIVE: The oral glucose tolerance test (OGTT) has often been used to evaluate apparent insulin release and insulin resistance in various clinical settings. However, because insulin sensitivity and insulin release are interdependent, to what extent they can be predicted from an OGTT is unclear. RESEARCH DESIGN AND METHODS: We studied insulin sensitivity using the euglycemic-hyperinsulinemic clamp and insulin release using the hyperglycemic clamp in 104 nondiabetic volunteers who had also undergone an OGTT. Demographic parameters (BMI, waist-to-hip ratio, age) and plasma glucose and insulin values from the OGTT were subjected to multiple linear regression to predict the metabolic clearance rate (MCR) of glucose, the insulin sensitivity index (ISI), and first-phase (1st PH) and second-phase (2nd PH) insulin release as measured with the respective clamps. RESULTS: The equations predicting MCR and ISI contained BMI, insulin (120 min), and glucose (90 min) and were highly correlated with the measured MCR (r = 0.80, P < 0.00005) and ISI (r = 0.79, P < 0.00005). The equations predicting 1st PH and 2nd PH contained insulin (0 and 30 min) and glucose (30 min) and were also highly correlated with the measured 1st PH (r = 0.78, P < 0.00005) and 2nd PH (r = 0.79, P < 0.00005). The parameters predicted by our equations correlated better with the measured parameters than homeostasis model assessment for secretion and resistance, the delta30-min insulin/delta30-min glucose ratio for secretion and insulin (120 min) for insulin resistance taken from the OGTT. CONCLUSIONS: We thus conclude that predicting insulin sensitivity and insulin release with reasonable accuracy from simple demographic parameters and values obtained during an OGTT is possible. The derived equations should be used in various clinical settings in which the use of clamps or the minimal model would be impractical.