C. Lowy

Association of gestational diabetes with abnormal maternal vascular endothelial function

Objective To evaluate vascular endothelial function in isolated small arteries from women with gestational diabetes.

SERUM-GROWTH HORMONE AND GLUCOSE INTOLERANCE IN RENAL FAILURE

Abstract Serum-growth-hormone (G.H.) measurements during oral glucose-tolerance tests were done on forty-one patients with chronic renal failure, seven patients with nephrotic syndrome, and fifty controls. Of the patients with chronic renal failure, 54% had impaired glucose tolerance (2-hour blood-sugar greater than 120 mg. per 100 ml.) and G.H. levels were raised in 49%, but not significantly among those with impaired glucose tolerance. In chronic renal failure, the Serum-G.H. level correlated directly with the serum creatinine and inversely with serum-albumin. It is suggested that protein malnutrition may be an important factor determining the raised levels of G.H. in renal failure.

Measurement of glucose metabolism and insulin secretion during normal pregnancy and pregnancy complicated by gestational diabetes

SummaryGestational diabetes affects 2–3% of pregnant women and is associated with foetal complications including macrosomia and an increased likelihood of developing diabetes in later life. We have therefore studied seven women with gestational diabetes and five control women both during the third trimester of pregnancy and again 2–3 months post-partum, using the minimal model analysis of the frequently sampled labelled ([6, 6-2H2]-glucose) intravenous glucose tolerance test. Glucose tolerance (glucose Kd) was significantly reduced in the women with gestational diabetes compared with the normal pregnant women both in pregnancy (1.16±0.11 vs 1.78±0.23%/min; p<0.05) and post-partum (1.47±0.22 vs 2.59±0.43%/min; p<0.05) and increased significantly in the control women after delivery (p<0.05). Glucose effectiveness was not significantly different between the women with gestational diabetes and the control group either during or after pregnancy. Insulin sensitivity was significantly lower during pregnancy than after delivery in the women with gestational diabetes (p<0.05). There was no significant difference in basal insulin secretion in the two groups during pregnancy or post-partum. However, during pregnancy the control subjects significantly increased (p<0.001) their insulin secretion over a period of 20 min in response to an intravenous glucose tolerance test (96.2±42.7 pmol/kg) compared with post-partum values (58.3±25.2 pmol/kg) while in the women with gestational diabetes insulin secretion was similar in pregnancy (65.5±9.3 pmol/kg) and after delivery (57.7±15.7 pmol/kg). These data suggest that the glucose intolerance in gestational diabetes compared to normal pregnancy is due to reduced insulin sensitivity and an impaired ability in gestational diabetes to increase insulin secretion in response to glucose.

Adverse effect of obesity on red cell membrane arachidonic and docosahexaenoic acids in gestational diabetes

Aims/hypothesisGestational diabetes is a metabolic disorder affecting 2–5% of women and is a predictor of obesity, Type 2 diabetes mellitus and cardiovascular disease. Insulin resistance, a characteristic of gestational diabetes and obesity, is correlated with the fatty acids profile of the red cell and skeletal muscle membranes. We investigated the plasma and red cell fatty acid status of gestational diabetes. The effect of obesity on membrane fatty acids was also examined.MethodsFasting blood obtained at diagnosis was analysed for the fatty acids in plasma choline phosphoglycerides and red cell choline and ethanolamine phosphoglycerides.ResultsThere were reductions in arachidonic acid (controls 10.74±2.35 vs gestational diabetes 8.35±3.49, p<0.01) and docosahexaenoic acid (controls 6.31±2.67 vs gestational diabetes 3.25±2.00, p<0.0001) in the red cell choline phosphoglycerides in gestational diabetes. A similar pattern was found in the ethanolamine phosphoglycerides. Moreover, the arachidonic and docosahexaenoic acids depletion in the red cell choline phosphoglycerides was much greater in overweight/obese gestational diabetes (arachidonic acid=7.49±3.37, docosahexaenoic acid=2.98±2.18, p<0.01) compared with lean gestational diabetes (arachidonic acid=10.03±2.74, docosahexaenoic acid=4.18±1.42).Conclusion/interpretationApparently normal plasma choline phosphoglycerides fatty acids profile in the gestational diabetic women suggested that membrane lipid abnormality is associated specifically with perturbation in the membrane. The fact that the lipid abnormality is more pronounced in the outer leaflet of the membrane where most of receptor binding and enzyme activities take place might provide an explanation for the increased insulin resistance in gestational diabetes and obesity.

Lymphocytic adenohypophysitis: magnetic resonance imaging features of two new cases and a review of the literature

Lymphocytic adenohypophysitis can cause pituitary expansion and hypopituitarism closely mimicking the features of a pituitary adenoma. Discrimination between these two conditions is of importance since, despite the similarity of their presentation, there are significant differences in pathophysiology. In contrast to pituitary adenoma, lymphocytic adenohypophysitis occurs almost exclusively in young women in relation to pregnancy, there is a preference for destruction of ACTH and TSH secreting cells and computed tomographic scanning shows uniform contrast enhancement in a proportion of cases. There is, as yet, no proven specific non‐surgical treatment. There are anecdotal reports of a beneficial effect of steroids but there is also evidence that spontaneous resolution may occur. We have reviewed the literature and report two new cases of lymphocytic adenohypophysitis both of whom exhibited early striking diffuse homogeneous contrast enhancement on magnetic resonance imaging scanning which we suggest may be a diagnostic feature of this condition.

Urine insulin in normal subjects

Abstract Immunochemical insulin is measurable in urine by the double-antibody assay procedure. Its excretion per hour correlates with the mean serum level and its “clearance” does not vary with changes in serum insulin concentrations. In 28 normal subjects the “insulin clearance”, measured during an oral GTT, was low (mean 0.42 ml./min.; range 0.23–0.87 ml./min.) and varied with the “creatinine clearance” and less with urinary albumin. This low “clearance” suggests that either serum insulin is bound to a larger protein or polymerized, or that it is avidly reabsorbed by the renal tubules after glomerular filtration. The log-mean basal (overnight) urine insulin level in 28 normal subjects was 215 μU/hr. (range 89–499). During the 2 hr. following 50 Gm. oral dextrose the level rose to a log-mean of 834 μU/hr. (range 330–2370).

Type 1 diabetes compromises plasma arachidonic and docosahexaenoic acids in newborn babies

The activity of Δ6- and Δ5-desaturase, enzymes required for the synthesis of AA and DHA, are impaired in human and experimental diabetes. We have investigated whether neonates of type 1 diabetic women have compromised plasma AA and DHA at birth. Cord blood was obtained from healthy babies born to mothers with (n=31) and without (n=59) type 1 diabetes. FA composition of plasma choline phosphoglycerides (CPG), TG, and cholesterol esters (CE) was assayed. The neonates of the diabetics had lower levels of AA (20∶4n−6, P<0.0001), adrenic acid (22∶4n−6, P<0.01), Σn−6 metabolites (P<0.0001), docosapentaenoic acid (22∶5n−3, P<0.0001), DHA (22∶6n−3, P<0.0001), Σn−3 (P<0.0001), and Σn−3 metabolites (P<0.0001) in CPG compared with the corresponding babies of the nondiabetic mothers. Similarly, they had lower levels of AA (P<0.05), Σn−6 metabolites (P<0.05), DHA (P<0.0001), and Σn−3 metabolites (P<0.01) in plasma CE. There was also a nonsignificant reduction of AA and DHA in TG in the babies of the diabetic group. The current investigation indicates that healthy neonates born to mothers with type 1 diabetes have highly compromised levels of AA and DHA. These nutrients are of critical importance for neurovisual and vascular system development. In poorly controlled maternal diabetes, it is conceivable that the relative “insufficiency” of AA and DHA may exacerbate speech and reading impairments, behavioral disorders, suboptimal performance on developmental tests, and lower IQ, which have been reported in some children born to mothers with type 1 diabetes mellitus. Further studies are needed to understand the underlying mechanism for this biochemical abnormality and its implications for fetal and infant development.

Plasma AA and DHA levels are not compromised in newly diagnosed gestational diabetic women

Objective: The polyunsaturated fatty acids, arachidonic (AA) and docosahexaenoic (DHA), are vital structural and functional components of the neural, vascular and visual systems. There is increased demand for these fatty acids during pregnancy. Diabetes impairs the synthesis of both AA and DHA. We have investigated the possibility that pregnancy-induced diabetes compromises the levels of plasma AA and DHA in newly diagnosed expectant mothers.Design: Cross-sectional study.Setting: London, UK.Subjects and methods: Venous blood was obtained from 44 women with gestational diabetes mellitus (GDM) and from the same number of nondiabetics, during the third trimester. Fatty acid composition of plasma choline phosphoglycerides (CPG), triglycerides (TG) and cholesterol esters (CE) was analysed.Results: The GDM women had higher levels of AA (20:4n-6; P<0.0001) and AA/linoleic acid ratio (20:4n-6/18:2n-6; P<0.01) in the CPG, and linoleic acid (LA; P<0.0001), total n-6 (P<0.01), DHA (P<0.05) and n-3 metabolites (P<0.05) in TG compared to their nondiabetic counterparts. Similarly, AA (P<0.0001), osbond acid (22:5n-6; P<0.05), total n-6 metabolites (P<0.0001), AA/LA (P<0.0001) and n-6 metabolites/LA (P<0.01) were higher in the CE of the GDM women. There was no difference in the levels of DHA in CPG and CE between the two groups (P>0.05).Conclusions: The results of this study do not provide evidence that the activity of delta-6 or delta-5 desaturases, which are vital for the synthesis of AA and DHA, is compromised by pregnancy-induced diabetes. However, since the samples were taken at diagnosis, it is conceivable that the duration of the diabetes was too short to have a discernable adverse effect on the levels of AA and DHA in plasma lipids.Sponsorship: Diabetes UK, March of Dimes Birth Defect Foundation, and the Mother and Child Foundation.

Liver triacylglycerols and free fatty acids in streptozotocin-induced diabetic rats have atypical n-6 and n-3 pattern

In diabetes there is a decrease in membrane arachidonic (AA) and docosahexaenoic (DHA) acids and a concomitant increase in linoleic (LA) and alpha-linolenic (ALA) acids. This metabolic perturbation is thought to be due to impaired activity of Delta(6)- and Delta(5)-desaturases. Triacylglycerols are the major lipid pool in plasma and liver tissue and have a significant influence on fatty acid composition of membrane and circulating phospholipids. Data on the distribution of n-6 and n-3 polyunsaturated fatty acids of triacylglycerols in diabetes are sparse. We investigated whether streptozotocin-induced diabetes in Sprague-Dawley rats alters fatty acid composition of triacylglycerols and free fatty acids of liver tissue. The animals were fed a breeding diet prior to mating, during pregnancy and lactation. On days 1-2 of pregnancy, diabetes was induced in 10 of the 25 rats. Liver was obtained at post partum day 16 for analysis. Relative levels of LA (P=0.03), dihomo-gamma-linolenic acid (DHGLA) (P=0.02), AA (P=0.049), total n-6 (P=0.02), ALA (P=0.013), eicosapentaenoic acid (EPA) (P=0.004), docosapentaenoic acid (22:5n-3, DPA) (P=0.013), DHA (P=0.033), n-3 metabolites (P=0.015) and total n-3 (P=0.011) were significantly higher in the triacylglycerols of the diabetics compared with the controls. Similarly, liver free fatty acids of the diabetics had higher levels of LA (P=0.0001), DHGLA (P=0.001), AA (P=0.001), n-6 metabolites (P=0.002), total n-6 (P=0.0001), ALA (P=0.003), EPA (P=0.015), docosapentaenoic (22:5n-3, P=0.003), DHA (P=0.002), n-3 metabolites (P=0.005) and total n-3 (P=0.001). We conclude that impaired activity of desaturases and/or long chain acyl-CoA synthetase could not explain the higher levels of AA, DHA and n-6 and n-3 metabolites in the diabetics. This seems to be consistent with an alteration in the regulatory mechanism, which directs incorporation of polyunsaturated fatty acids either into triacylglycerols or phospholipids.

Fetal erythrocyte membrane lipids modification: preliminary observation of an early sign of compromised insulin sensitivity in offspring of gestational diabetic women.

Aims  Intrauterine exposure to diabetes is a significant determinant of the development of obesity and early onset of Type 2 diabetes mellitus in the offspring. Both conditions are characterized by insulin resistance and the latter is associated with reduced membrane arachidonic and docosahexaenoic acids. Hence, we investigated if the membrane arachidonic and docosahexaenoic acids are depressed in the cord blood of babies born to women with gestational diabetes.