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.

Discrimination of Type 2 diabetic patients from healthy controls by using metabonomics method based on their serum fatty acid profiles.

Metabonomics, the study of metabolites and their roles in various disease states, is a novel methodology arising from the post-genomics era. This methodology has been applied in many fields, including work in cardiovascular research and drug toxicology. In this study, metabonomics method was employed to the diagnosis of Type 2 diabetes mellitus (DM2) based on serum lipid metabolites. The results suggested that serum fatty acid profiles determined by capillary gas chromatography combined with pattern recognition analysis of the data might provide an effective approach to the discrimination of Type 2 diabetic patients from healthy controls. And the applications of pattern recognition methods have improved the sensitivity and specificity greatly.

Intensive insulin therapy combined with metformin in obese type 2 diabetic patients.

Unlike other pharmacological therapies used in obese type 2 diabetic patients, metformin has been shown to improve glycemic control with lower insulin levels and not to involve weight gain. We therefore examined the effect of adjunct metformin in 13 severely obese type 2 diabetic patients (BMI 39.3 +/- 3.9 kg/m2) in suboptimal glycemic control pretreated with intensified insulin therapy. Patients were randomly assigned to either metformin or placebo treatment (double-blind) for 10 weeks and after a 2 week washout period received the opposite treatment, respectively, for 10 additional weeks. HbA1c decreased comparably during placebo (from 8.1 +/- 0.4 to 7.6 +/- 0.3%) and metformin (from 8.5 +/- 0.4 to 7.4 +/- 0.3%, p = 0.29 vs. placebo). Changes in fasting glucose levels were also not different between placebo (from 9.3 +/- 0.7 to 9.5 +/- 0.7 mM) and metformin (from 10.3 +/- 0.5 to 9.5 +/- 0.6 mM, p = 0.44 vs. placebo). Total exogenous insulin requirements decreased from 53 +/- 10 to 35 +/- 7 units during metformin treatment (p = 0.02 vs. placebo). Changes in fasting insulin levels during placebo and metformin treatments were not different (p = 0.11). Metformin had no effect on body weight and serum triglycerides but marginally decreased serum cholesterol levels (from 239 +/- 18 to 211 +/- 14 mg/dl, p = 0.005, p = 0.08 vs. placebo). During the oral glucose tolerance test no differences were observed in the areas under the curve for glucose and insulin while that for C-peptide showed a tendency to increase during metformin administration. We conclude that addition of metformin to insulin treatment in severely obese type 2 diabetic patients improves glycemia but not hyperinsulinemia in comparison to intensive insulin therapy alone. With adjunct metformin, approximately 30% less exogenous insulin is required. With respect to glycemia and lipids, adjunct metformin can be a reasonable treatment alternative in selected obese patients with type 2 diabetes already on intensive insulin therapy.

Type I hyperlipoproteinemia due to a novel loss of function mutation of lipoprotein lipase, Cys(239)-->Trp, associated with recurrent severe pancreatitis.

Lipoprotein lipase (LPL) is the major enzyme responsible for the hydrolysis of triglyceride-rich lipoproteins in plasma. The purpose of this study was to examine the molecular pathogenesis of type I hyperlipoproteinemia in a patient suffering from recurrent severe pancreatitis. Apolipoprotein (apo) CII concentration was normal as well as apo CII-activated LPL in an in vitro assay. In postheparin plasma neither LPL mass nor activity was detectable, whereas hepatic lipase activity was normal. Direct sequencing of all 10 exons of the LPL gene revealed that the patient was homozygous for a hitherto unknown mutation in exon 6, Cys(239)-->Trp. The mutation prevents the formation of the second disulfide bridge of LPL, which is an essential part of the lid covering the catalytic center. Consequently, misfolded LPL is rapidly degraded within the cells, causing the absence of LPL immunoreactive protein in the plasma of this patient. In conclusion, we have identified a novel loss of function mutation in the LPL gene (Cys(239)-->Trp) of a patient with type I hyperlipoproteinemia suffering from severe recurrent pancreatitis. After initiation of heparin therapy (10,000 U/day sc), the patient experienced no more episodes of pancreatitis, although heparin therapy did not affect serum triglyceride levels.

Long term effect of a structured inpatient diabetes teaching and treatment programme in type 2 diabetic patients: influence of mode of follow-up.

Structured diabetes teaching and treatment programmes (STTP) are increasingly offered for patients with diabetes to improve metabolic control. We prospectively studied the long term-effect of STTP on metabolic control and knowledge of diabetes in patients with type 2 diabetes. In addition, differences in the mode of follow-up by a university diabetes centre (UDC) versus general practitioner (GP) were assessed. Of the 64 patients with type 2 diabetes (61 +/- 10 years old, diabetes duration 11 +/- 7 years) included in the study 52 could be reevaluated after 2 years. Of those, 31 were followed up by the UDC and 21 by their GPs who received detailed follow-up instructions from the UDC. In all patients, HbA1c decreased from 9.1 +/- 0.3% before the programme to 8.3 +/- 0.3% 2 years after the programme (P = 0.004), whereas body mass index increased from 28.8 +/- 0.8 to 30.3 +/- 0.9 kg/m2 (P < 0.001). Patients had a significantly better knowledge of diabetes and diet 2 years after the programme. For all parameters tested, none of the changes differed between patients managed by the UDC versus those managed by their GP. However, patients who chose follow-up by the UDC were more obese and had a better knowledge of diabetes. In conclusion, the STTP for patients with type 2 diabetes was effective in improving the long-term glycaemic control and knowledge of diabetes. Moreover, with precise therapeutic goals and follow-up instructions given to patient and GP this improvement was independent of the mode of outpatient follow-up.

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

Diabetes teaching program improves glycemic control and preserves perception of hypoglycemia.

Improvement of HbA1c is frequently accompanied by deteriorating awareness of hypoglycemia. We studied the effect of improved metabolic control on hypoglycemia perception in 33 type 1 diabetic patients during 3 months after an inpatient diabetes education program of 5 days. Patients were grouped according to the presence (H, n = 11) or the absence (N, n = 22) of a history of repeated severe hypoglycemia. To measure awareness of blood glucose (BG) and hypoglycemia, we calculated their accuracy of BG perception (error grid analysis) and sensitivity for BG levels < 3.9 mmol/l, respectively, during the first (I) and second (II) period of the 3 months using the method of BG estimation. HbA1c decreased from 8.0 +/- 0.3% before to 7.1 +/- 0.2% 3 months after the program (P < 0.001) with no difference between H and N. Neither accuracy of BG perception (40.6 +/- 3.8 (I) versus 43.6 +/- 4.1% (II), P = 0.25) nor sensitivity for low BG levels (49.1 +/- 4.2 (I) versus 54.9 +/- 4.9% (II), P = 0.12) changed significantly. Group H had a lower overall accuracy of BG estimation (P = 0.048) and a lower overall sensitivity for detecting BG levels < 3.9 mmol/l (P = 0.03) than group N. Group H was able to improve accuracy of BG estimation (H: 24.8 +/- 6.2 (I) versus 36.9 +/- 8.3% (II), P = 0.04) while group N was not (48.5 +/- 3.9 (I) versus 46.9 +/- 4.6% (II), P = 0.5). In conclusion, improvement of metabolic control after intensive diabetes education had no adverse effect on the perception of low BG levels. On the contrary, patients with a history of severe hypoglycemia improved their awareness of BG.

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting-enzyme gene and diabetic nephropathy in IDDM patients.

The insertion/deletion (I/D) polymorphism of the angiotensin-converting-enzyme (ACE) gene has been reported to be associated with diabetic nephropathy in IDDM. We studied the relationship between this polymorphism and diabetic nephropathy in 210 IDDM patients. Their DNA was analyzed by polymerase chain reaction to type for the presence (I) or absence (D) of the 287 bp fragment in intron 16 of the ACE gene. The relative frequency of the different genotypes was 33.8% (DD), 43.8% (ID), and 22.4% (II). There were no significant differences between the genotypes in age, body-mass-index, blood pressure, plasma total cholesterol and triglycerides. The prevalence of microalbuminuria or nephropathy was 23.9% in the DD, 16.3% in the ID, and 17% in the II genotypes. The higher percentage of microalbuminuria or nephropathy in the DD genotypes was due to an increasing frequency of DD genotypes in the IDDM patients with long diabetes duration. After matching for diabetic retinopathy, gender, and diabetes duration, there was no association between the ACEI/D polymorphism and diabetic nephropathy. In conclusion, these results suggest that the ACE DD genotype cannot be regarded as a risk factor for diabetic nephropathy, but may even be associated with diabetes duration and thus longevity in IDDM patients.

[Early detection of atherosclerosis with high resolution ultrasound exemplified by type II diabetic patients]. / Atherosklerose-Früherkennung mit hochauflösendem Ultraschall am Beispiel von Typ II-Diabetikern.

AIM: Endothelial Dysfunction (ED) is an early functional marker and Intima-Media-Thickness (IMT) an early morphological parameter of atherogenesis. Is there a simple, non-invasive routine method for the identification of atherosclerosis including the detection of the early functional endothelial impairment seen for example in Type 2 diabetic patients? METHODS: Using high resolution ultrasound we studied peripheral endothelial function expressed as flow-associated dilation (FAD %) and endothelial independent vasodilation after administration of 400 micrograms glycerol trinitrate (postnitro %) of the brachial artery as well as IMT of the common carotid artery in 25 Type 2 diabetic patients and their matched controls. RESULTS: (mean +/- SD): The diabetic patients showed a remarkable ED (FAD%: 3.8 +/- 3.3 vs. 6.9 +/- 4.4%, p = 0.01) and an already increased IMT (0.72 +/- 0.14 vs. 0.62 +/- 0.10 mm, p < 0.01). The similar postnitro % in diabetic patients and controls suggests normal dilating capacity of the studied vessels in the diabetic patients (postnitro %: 14.3 +/- 9.4 vs. 14.9 +/- 8.5%, p = ns). CONCLUSION: With a combination of these three sonomorphological parameters it is possible to document the stage of atherosclerosis including endothelial dysfunction in Type 2 diabetic patients.

Glucose turnover in humans in the basal state and after intravenous glucose: a comparison of two models.

This study investigated the ability of two models to represent glucose kinetics in the basal steady state and during an intravenous glucose tolerance test (IVGTT). Six young nonobese male subjects were studied after an overnight fast. Two bolus injections of [U-13C]glucose were given 150 min apart, the first without and the second together with concomitant injection of unlabeled glucose. [3-3H]glucose was constantly infused throughout the study and served to provide an independent means for evaluation of system responses. A linear time-invariant three-compartmental model and the two-compartment time-variant model proposed by Caumo and Cobelli were used to interpret measured time courses of [U-13C]glucose and to reconstruct endogenous glucose production and glucose removal. The ability of the two models to describe the glucose tracer time course was comparable. Simulation studies showed that the two-compartmental time-variant system better predicted measured [3-3H]glucose concentration profiles than did the three-compartmental time-invariant model. However, endogenous glucose production and the integral of excess glucose removal over basal during the IVGTT derived from the two models were almost identical.

Long-term changes of body weight and cardiovascular risk factors after weight reduction with group therapy and dexfenfluramine.

The aim of this work was to investigate the long-term changes of body weight and cardiovascular risk factors after weight reduction with dexfenfluramine (dF) compared to placebo (pI) and additional group therapy. There was a 3 year follow-up of obese patients after 1 year double-blind, randomized treatment with 30mg dF or pI and group therapy. The work was carried out at the outpatient clinic of University Hospital, Tübingen. Forty-eight (24 dF, 24 pI) patients were investigated with more than 120% of ideal body weight. Body weight, blood pressure, blood glucose, serum cholesterol and triglycerides were measured. During 1 year of treatment body weight fell by 11.2% (dF) and 9.1% (pI) (P < 0.001 for time, n.s. for dF/pI), systolic blood pressure by 7.3 and 9.9 mm Hg (P = 0.044/n.s.). There were no significant changes of serum cholesterol, triglycerides, and blood glucose. At the follow-up of 22 (11/11) patients 3 years later, the dF group had regained more than the lost weight; the placebo group had lost 2.4% of the initial body weight. Serum cholesterol (dF + 0.64/pI + 0.65 mmol/l, P = 0.010/n.s.), triglycerides (+0.74/+0.59 mmol/l, P = 0.002/n.s.), and blood glucose (+0.56/+0.81mmol/l, P < 0.001/n.s.) increased significantly. Systolic blood pressure increased slightly, diastolic blood pressure did not change significantly. Without appropriate prevention of weight regain even combined weight reduction therapy over a period of one year results in weight regain and deterioration of cardiovascular risk factors.

Rudimentary second stomach as adrenal incidentaloma.

We present the case of an adrenal incidentaloma of considerable size which turned out to be a stomach-like diverticular mass, probably a malformation arising from the embryonic foregut. We discuss whether results possibly obtained by extensive and costly investigative techniques would have changed the management.

Spontaneous gas-forming bacterial myonecrosis caused by group B streptococci and peptostreptococci.

We present the case of a patient who spontaneously developed a severe gas-forming infection involving the voluntary muscles of both thighs. The organisms responsible were group B beta-haemolytic streptococci together with peptostreptococci. Following surgical and medical treatment, the patient fully recovered. No predisposing factors, in particular no disease causing immunocompromise, could be identified.

Exercise and insulin requirements.

In order to facilitate the management of sports and work for insulin injecting diabetic patients we analyzed 6 different situations: 1) In the morning before injecting insulin stepwise increasing bicycle ergometry until exhaustion with a duration of less than one half hour may be performed without previous reduction of insulin or additional oral carbohydrates. Maximal work load can thus be determined with ECG monitoring. After insulin injection we advise our patients to estimate their reaction by calculating with exercise units. One exercise unit equals 20 minutes of half maximal exercise or one hour of 30% maximal exercise. 2) Performing one exercise unit the diabetic will have to anticipate a blood glucose reduction of -60 mg/dl. In order to maintain normal blood glucose levels he will have to reduce the regular insulin bolus 3) in the morning by -3,3 IU or 4) by -1.7 IU in the evening or he should 5) take +12 g of oral glucose (quickly absorbable carbohydrates). 6) A reduction of basal rate (CSII) or NPH insulin (ICT) is not advisable for exercise up to 3 hours. On the basis of these mean values every diabetic patient has to monitor blood glucose during exercise and adapt the measures to his individual reactions.

Influence of strenuous exercise on albumin excretion.

Renal albumin excretion rate was 7.3 mg/24 h (SEM 0.5, range 0.6-21.0) in 66 healthy subjects. This rate increased markedly during and shortly after strenuous exercise on a bicycle ergometer (before: 5.5 +/- 0.6 micrograms/min; during and just after: 16.9 +/- 2.2 micrograms/min; P less than 0.001; n = 30). However, albumin excretion/24 h was not significantly higher during 24 h with a period of strenuous exercise than during 24 h without such exercise (10.3 +/- 0.9 mg/24 h vs 8.5 +/- 0.7 mg/24 h).

Enzyme-linked immunosorbent assay for urinary albumin at low concentrations.

We describe an enzyme-linked immunosorbent assay (ELISA) for urinary albumin. It requires only commercially available reagents, can detect as little as 16 micrograms of albumin per liter, and analytical recovery ranges from 92 to 116%. The assay is simple, rapid, and inexpensive. Albumin excretion was 6.2 (SD 4.1) mg/24 h in healthy subjects (n = 40), 14.7 (SD 7.2) mg/24 h in albumin-test-strip-negative Type I diabetics (n = 11), and 19.7 (SD 16.2) mg/24 h in patients with essential hypertension (n = 12).

Hormonal and metabolic changes in starving obese patients during exhaustive physical exercise.

Exhaustive graded exercise leads to changes of hormones, carbohydrate, and lipid metabolism in normal controls and obese patients after prolonged starvation. Concomitant with a large increase of plasma catecholamines, insulin concentration is reduced and blood glucose levels slowly increase. More glucose is made available by glycogenolysis and gluconeogenesis than can be oxidized in the mitochondria. Lactate associated metabolic acidosis appears. Starving obese patients in the basal state have reduced blood glucose concentrations, but their initial values for free glycerol, free fatty acids, and ketone bodies are much higher than in normal controls. This is caused by the starvation induced lipolysis. With exhaustive exercise adrenaline, noradrenaline, and free glycerol increase. In contrast, free fatty acids and ketone bodies decrease, because they are consumed as fuel. Prolonged starvation changes basal values of hormones and metabolites, but it does not change the quality of exercise-induced shifts in these values when compared with those of the normal controls.

Definition of clinically relevant lactic acidosis in patients with internal diseases.

In order to define clinically relevant lactic acidosis, 12 biochemical variables, eight clinical symptoms and signs, leading diagnoses, and mortality were evaluated prospectively in approximately 2,000 unselected patients with internal diseases, consecutively admitted to the hospital. Patients with incomplete data sets were not considered. Of those patients who repeatedly were admitted to the hospital during the time of the study, only the first admission was included for statistical analysis. In addition to 11 definitions of lactic acidosis given in the literature, sequential cluster analyses of the biochemical variables were used to estimate the incidence of lactic acidosis in 1,467 patients. Depending upon which definition was used, 0.5-3.8% of all patients were classified as suffering from lactic acidosis, with a mortality rate ranging from 30-88%. From this study it is concluded that a limit of less than or equal to 7.35 for pH and of greater than 5-6 mmol/L for the concentration of lactate in whole blood will minimize false-negative or false-positive classifications.