Home monitoring of blood glucose: new approach to management of insulin-dependent diabetic patients in Great Britain.

The history of home monitoring of blood glucose by diabetic patients at St. Thomas' Hospital in London is reviewed. Initial successful experience with pregnant diabetic patients was extended to cover those with retinopathy and, subsequently, to all insulin-treated patients. Experience showed overwhelming preference by patients for blood glucose monitoring over urine tests and demonstrated improvement in blood glucose control. Experience in children 13 and older was equally (if not more) enthusiastic as in adults. Self-monitoring revealed many elementary mistakes in insulin therapy, which, when corrected, led to marked improvement in diabetic control with reduced frequency and severity of hypoglycemic attacks. Initial studies were made with Dextrostix and Eyetone. The need for a simple patient-oriented blood glucose machine was identified, and Glucochek was designed to meet it. Evaluation of Glucochek was satisfactory, and it was well liked by patients. It seems likely that blood glucose monitoring will replace urine tests in the majority of diabetic patients.

Non-insulin-dependent diabetes: 10-year outcome in relation to initial response to diet and subsequent sulfonylurea therapy.

Thirty-eight non-insulin-dependent diabetic patients within 130% of desirable body weight were given a 100-g oral glucose tolerance test (OGTT) at diagnosis and after at least 1 mo of dietary treatment with energy and carbohydrate restriction. Thirteen "responders" showed an improvement in fasting blood glucose, glucose tolerance, and insulin secretion, with near-normalization of plasma, lactate, pyruvate, free fatty acids, glycerol, and ketone bodies. There were no significant changes in the 25 "non-responders." The responders were, at diagnosis, heavier than the non-responders (75.5 versus 64.3 kg, P less than 0.01). Twenty non-responders subsequently completed a prospective controlled study of glibenclamide, chlorpropamide, and placebo lasting for 16 mo with OGTTs at the end of each 4-mo treatment phase. The results showed that there were no significant differences between the metabolic effects of glibenclamide and chlorpropamide. On active treatment, insulin levels rose coincident with a fall in fasting blood glucose and an improvement in glucose tolerance and near-normalization of plasma lactate, pyruvate, free fatty acids, glycerol, and ketone bodies, all of which relapsed to initial values after placebo. Ten years after the initial study, 29 of the original patients were traced and reviewed and the outcome related to their earlier tests. Twenty-two percent of the responders and 70% of the non-responders were now on insulin (P less than 0.02); the initial insulin response to OGTT at the end of the diet treatment was significantly lower in those subsequently treated with insulin (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Conversion of thyroxine to 3,3',5'-triiodothyronine in the guinea pig placenta: in vivo studies.

Studies of placental inner-ring deiodination of T4 were carried out in pregnant guinea pigs, by in situ placental perfusion. When [131I]T4 and [125I]rT3 were administered to the mother, the ratio of fetal side to maternal side [131I]rT3 was more than 10 times greater than the corresponding ratio for [125I]rT3. When radiolabeled T4 was supplied to the fetal side of the placenta in perfusion fluid, and the perfusate recycled through the placental circuit, there was a progressive increase in labeled rT3 concentration in the perfusate. These results indicate that the guinea pig placenta actively deiodinates both maternal and fetal T4 in the inner ring in vivo. We found evidence of very little outer ring deiodination of either T4 or rT3. The quantitative contribution of placental deiodination of maternal T4 to circulating rT3 in the fetus appears to be small; however, placental deiodination of fetal T4 (about 0.5 nmol/kg fetal BW X day) could contribute significantly to fetal rT3 levels. Our observations are consistent with the hypothesis that placental inner-ring deiodination of T4 plays a part in the regulation of fetal iodothyronine metabolism.

The effect of recombinant human growth hormone on glucose and leucine metabolism in Cushing's syndrome.

Cushing's syndrome is characterized by central obesity and muscle wasting. As GH is anabolic, it may be able to counteract the loss of body protein. To evaluate the potential therapeutic use of GH preoperatively, eight patients with Cushing's syndrome received sc injections of recombinant human GH (0.07 U/kg.day) for 7 days. Whole body leucine and glucose turnover were measured after an infusion of [1-13C]leucine and [6,6-2H2]glucose before (day 0) and after 2 and 7 days of GH treatment. Compared with the value on day 0, there was a significant increase on days 2 and 7 in insulin (P < 0.005 and P < 0.001), C peptide (P < 0.01 and P < 0.005), insulin-like growth factor I (P < 0.001), and glucose concentrations (P < 0.01 and P < 0.005) and a decrease in the leucine concentration (P < 0.005). There was no significant change in glucose production rate, glucose MCR, leucine production rate (a measure of protein degradation), or nonoxidative leucine disappearance rate (a measure of protein synthesis). The leucine MCR was increased after 7 days (P < 0.05), and the clearance of leucine into protein (nonoxidative leucine disappearance rate/leucine concentration) was increased (P < 0.05) after 2 and 7 days of GH treatment. This is consistent with GH stimulating the availability of amino acid transporters. GH may, therefore, have a therapeutic role in the preoperative treatment of Cushing's syndrome.

Effect of long-term inhibition of gonadotrophin secretion by the gonadotrophin-releasing hormone agonist, buserelin, on sex steroid secretion and ovarian morphology in polycystic ovary syndrome.

In order to investigate the effect of long-term suppression of the gonadotrophin axis in polycystic ovary syndrome, eight affected subjects were given s.c. infusions of gonadotrophin-releasing hormone (GnRH) agonist buserelin for 12 weeks. Hormone measurement and ultrasound studies were carried out weekly, from 6 weeks before to 12 weeks after administration of buserelin. An overnight dexamethasone-suppression test was carried out before and after treatment. Maximal suppression of LH to below the lower limit of that in normal subjects occurred after 6 weeks of treatment with buserelin. Plasma testosterone and androstenedione fell to normal levels during the infusion but reached pretreatment levels during the follow-up period. There was no effect of buserelin on plasma dehydroepiandrosterone sulphate or sex hormone-binding globulin. Ovarian size decreased significantly during the infusion with the disappearance of cysts in six subjects. After cessation of buserelin therapy, there was rapid and spontaneous ovulation which occurred within 3 weeks in all subjects. The results suggest that treatment with this GnRH agonist facilitates ovulation in this condition.

The assessment of gestational age and litter size in the guinea pig using a radiographic method.

The gestational age and litter size in the guinea pig can be accurately assessed by taking an x-ray of the animal. From a measurement of the fetal head length on the x-ray plate a fetal weight can be calculated using previously accumulated data, included here. The gestational age can be assessed from this weight to within +/- two days, using the fetal growth data of Draper (1920), Eckstein, McKeown and Record (1955) and Ibsen (1928). The litter size can be readily ascertained from the x-ray plate.

Serum lipid, lipoprotein and apolipoprotein changes in gestational diabetes mellitus: a cross-sectional and prospective study.

AIMS: To compare serum lipid, lipoprotein and apolipoprotein concentrations during and six to 12 months after pregnancy in control and diabetic women. METHODS: The serum lipid, lipoprotein and apolipoprotein concentrations were measured in 20 women with gestational diabetes mellitus (GDM) and 22 women with normal glucose tolerance (controls) during the third trimester of pregnancy and six to 12 months after delivery. RESULTS: During pregnancy the women with GDM had higher serum triglyceride (mean (95% confidence interval (CI)), 2.91 (2.22-3.51) v 2.1 (1.75-2.52)) but lower low density lipoprotein (LDL) cholesterol concentrations compared with controls (mean (SD), 3.08 (1.2) v 4.01 (1.1). Total cholesterol, high density lipoprotein (HDL) cholesterol and apolipoprotein concentrations were not significantly different between the two groups. After pregnancy, total cholesterol, HDL cholesterol, triglyceride, and apolipoprotein A1 and B decreased in a parallel manner, resulting in lower concentrations, comparable between the two groups. LDL cholesterol concentrations decreased after pregnancy in the controls (mean (SD), 4.01 (1.1) v 2.69 (0.6)) but not in those with GDM (3.08 (1.2) v 2.72 (0.7)). The change in lipid concentrations was not related to change in weight. CONCLUSION: Development of diabetes during pregnancy induces a state of dyslipidaemia characterised by elevated triglyceride concentrations, as seen in other insulin resistance states. However, GDM seems to blunt the increase in LDL cholesterol during pregnancy and this requires further investigation. Whether the changes in lipoprotein metabolism in GDM are significant for the health status of the mother and the foetus requires further study.

Ethnic differences in lipid and lipoprotein metabolism in pregnant women of African and Caucasian origin.

AIMS: To investigate differences in serum lipid, lipoprotein and apolipoprotein concentrations in pregnant women of different ethnic origin. METHODS: Serum lipid, lipoprotein and apolipoprotein concentrations were measured in 232 women (114 Caucasians, 118 Africans/Afro-Caribbeans), who presented consecutively for screening for gestational diabetes in the third trimester of pregnancy. RESULTS: African/Afro-Caribbean pregnant women had lower serum concentrations of total cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoprotein B and higher high density lipoprotein cholesterol and Lp(a) lipoprotein concentrations compared with Caucasian women. Apolipoprotein A1 concentrations were similar in the two groups. The differences were not attributable to differences in weight, age, parity, or postload plasma glucose levels. CONCLUSION: Ethnic origin is an important determinant of serum lipid, lipoprotein and apolipoprotein concentrations during pregnancy.

Serum lipids, lipoproteins and apolipoproteins in pregnant non-diabetic patients.

AIMS: To investigate the effect of pregnancy on serum concentrations of lipids, lipoproteins, and apolipoproteins. METHODS: Fasting serum concentrations of total cholesterol, triglyceride, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), apolipoproteins AI, AII, and B, and lipoprotein (a) were measured in 178 women with normal glucose tolerance in the second and third trimesters of pregnancy and in a control group of 58 non-pregnant women of similar age. Data were analysed using the unpaired t test and by one-way analysis of variance. RESULTS: The pregnant women had significantly higher concentrations of total cholesterol, triglyceride, LDL cholesterol, HDL cholesterol, and apolipoproteins AI and B (p < 0.001) and apolipoprotein AII (p = 0.003) than the control women. The ratio of apolipoprotein B:apolipoprotein AI was significantly higher in the pregnant women than in the controls (p < 0.001), but the total cholesterol:HDL cholesterol ratio was not significantly different. No significant difference was found in the concentration of lipoprotein (a). CONCLUSIONS: Hyperlipidaemia is common in the second half of pregnancy. This may be a purely physiological response to pregnancy or it may be indicative of pathology in some women. These results warrant a follow up study to investigate whether the hyperlipidaemic response to pregnancy is variable and if so, whether it can predict future hyperlipidaemia in a manner analogous to that of impaired glucose tolerance during pregnancy, predicting non-insulin dependent diabetes in later life.

Placental transfer and uptake of 2-deoxyglucose in control and diabetic rats.

Placental glucose transfer and sequestration were investigated in anesthetized control and streptozotocin-diabetic rats by perfusing the fetal side of one placenta in situ while infusing a mixture of [3H]D-glucose (to measure net transfer after metabolism) and [14C]2-deoxyglucose (to estimate tissue sequestration) into the maternal circulation. No difference was found between transfer ratios (perfusate/simultaneous maternal plasma ratio) of [3H]D-glucose (0.35 +/- 0.06, mean +/- SD) and [14C]2-deoxyglucose (0.36 +/- 0.06) in control rats. Ratios were reduced (P < .001) to the same extent in diabetic rats ([3H]D-glucose, 0.13 +/- 0.06; [14C]2-deoxyglucose, 0.15 +/- 0.07). Placental glucose utilization, estimated by the quantity of [14C]2-deoxyglucose-6-phosphate present, was increased from 66 nmol.min-1.g-1 in control to 595 nmol.min-1.g-1 (P < .001) in diabetic rats. Transfer to the perfusion fluid of unlabeled D-glucose was increased (P < .001) in diabetic rats (2.32 mumol/mL) compared with control rats (0.77 mumol/mL) due to elevated (P < .001) maternal plasma glucose levels. Upon phosphorylation, 2-deoxyglucose becomes trapped within the placenta, and therefore these results indicate that all the glucose destined for direct transfer to the fetus is protected from phosphorylation while traversing the placenta, and that diabetes appears to increase placental glucose utilization, but does not induce futile cycling of glucose in an attempt to protect the fetus from an excessive influx of glucose from the mother in the rat.

Insulin secretory response to oral glucose load, diabetic microangiopathy and diabetic control: a study in non-insulin dependent diabetics.

To study the importance of the residual insulin secretion for the degree of diabetic control and for the development of microangiopathy 55 patients with non-insulin-dependent diabetes mellitus (NIDDM) were studied. A 1 hr oral glucose tolerance test was performed at diagnosis and 5-10 yr later. At diagnosis all patients were free of microangiopathy, at reassessment 24 patients had evidence of microangiopathy, i.e. retinopathy, neuropathy or nephropathy, alone or in combination. The glucose induced increments of insulin levels (delta IRI) at reassessment correlated inversely with the degree of diabetic control, measured by Haemoglobin A1 (r = -0.466, p less than 0.01), and with the mean fasting blood glucose throughout the follow up period (r = -0.491, p less than 0.01). delta IRI at diagnosis was similar in patients with and without microangiopathy, and at reassessment, although lower in the microangiopathy group (11.2 +/- 2.1 vs. 16.4 +/- 2.1 microunits/ml, p less than 0.1). The difference between the 2 groups did not reach statistical significance. When patients were separated into those treated with diet alone and those treated with oral antidiabetic agents, delta IRI at reassessment was significantly lower in patients on oral agents (10.5 +/- 1.9 vs. 17.2 +/- 2.2 microunits ml, p less than 0.01), but the prevalence of microangiopathy was not different between 2 groups (37% and 52%, respectively). These findings show that in patients with NIDDM the residual beta cell function is important for the degree of diabetic control, but a direct relationship between the degree of insulin deficiency and the presence of diabetic microangiopathy is not established.

The pituitary-adrenal axis in idiopathic retinal vasculitis.

AIMS: To determine whether patients with idiopathic retinal vasculitis have altered production of cortisol and dehydroepiandrosterone sulphate (DHEA-S), and whether differences in these variables occur between those who are sensitive (SS) and resistant (SR) to steroids. METHODS: 20 patients with retinal vasculitis (off treatment) and 10 control subjects were prospectively recruited. Morning cortisol and DHEA-S levels were measured, and cortisol secretion rates and short synacthen tests (SST) carried out in patients before treatment, when on prednisolone 20 mg/day, and in controls. RESULTS: There were no differences in any variables between patients and controls. For retinal vasculitis patients pretreatment, the SST was lower in SR patients (p=0.02). More of the SR patients had ischaemic retinal vasculitis ( p<0.001). CONCLUSIONS: Cortisol and DHEA-S are not involved in the pathogenesis of retinal vasculitis. SR in retinal vasculitis may be associated with a defective hypothalamic-pituitary-adrenal axis.

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.

Arachidonic and docosahexaenoic acids are strongly associated in maternal and neonatal blood.

BACKGROUND: The red cell membrane fatty acid composition has frequently been used as an index of essential fatty acid (EFA) nutrition. After birth there is a decline in plasma arachidonic acid (AA) and docosahexaenoic (DHA) acids in babies fed on conventional formula which contains only the parent linoleic and alpha-linolenic acids. In human studies, the red cell phosphoglyceride composition appears to be more constant than that of plasma. In infants fed fish oil without AA, the AA proportions fall in the plasma but much less so in the red cells. This result might be considered to mean that there is no need for preformed AA. On the other hand, in a study where the levels of AA fell there was reduction of infant growth. Indeed, where cell membrane composition does change there is often an associated alteration in physiological functions of membranes. We therefore felt it worth investigating the balance between AA and DHA in a physiological situation where plasma levels are known to change, namely in pregnancy. PURPOSE: The aim of the study was to investigate a relationship between blood phosphoglyceride AA and DHA in pregnant women and neonates. SUBJECTS: Health pregnant women from London, England (n=193) and their term babies (n=45); healthy pregnant women from Seoul, South Korea (n=40) and their term babies (n=40); and preterm neonates (n=72) from London. METHOD: Blood samples were taken from British and Korean pregnant women during the third trimester, and from term and preterm babies at birth. These samples were taken for routine monitoring purposes in Korea and were a part of a study on pregnancy outcome for which ethical permission was granted from the East London and The City Health Authority and Lambeth, Southwark and Lewisham Health Authority. Approval was also obtained from the Ethical Committee of the Asan Medical Centre, Seoul, South Korea. RESULTS: AA and DHA correlated in plasma choline phosphoglycerides (CPG) of the British mothers (r=0.52 P<0.0001). The correlation coefficients and significance were much stronger in the red cell CPG and even more so in the term and preterm infant red cell CPGs ( r=0.75, 0.80 and 0.88, respectively). Similarly, AA and DHA correlated in red cell CPGs of the Korean women and their term babies. There was also a significant relationship between the two fatty acids in red cell ethanolamine phosphoglycerides in the mothers and their babies. Both linoleic (LA) and alpha-linolenic acids (ALA) were inversely associated with AA and DHA in some of the phosphoglyceride fractions of the mothers and babies. CONCLUSIONS: Although AA and DHA have different primary dietary origins, there were significant relationships between AA and DHA in the phosphoglycerides of the red cell membrane. This finding seems surprising if the red cell composition is determined by diet. These results suggest a physiological mechanism which attempts to maintain an appropriate balance between AA and DHA. It is plausible that there is an optimum balance between AA and DHA for membrane stability, deformability, enzyme and receptor function. SPONSORSHIP: The British Diabetic Association, March of Dimes Birth Defects Foundation and The Christopher H.R. Reeves Charitable Trust. European Journal of Clinical Nutrition (2000) 54, 50-56

Bidirectional placental transfer ('leak') of L-glucose in control and diabetic rats.

The placental transfer of D- and L-glucose was investigated in anaesthetised non-diabetic and streptozotocin-induced diabetic rats. Maternal to fetal transfer was determined by perfusing the fetal side of one placenta in situ whilst infusing a mixture of D-[3-3H]glucose and L-[1-14C]glucose into the maternal circulation. Back-transfer from the fetal to maternal circulation was assessed by determining the uptake of the radiolabelled glucoses from the perfusion fluid during a single passage through the placenta on the fetal side. Maternal diabetes resulted in a reduced utero-placental blood flow but an increased bidirectional transfer of D-glucose. Non-specific maternal to fetal placental transfer of L-glucose was greater in diabetic rats than in controls, and the loss of L-glucose during placental perfusion on the fetal side was, again, greater in diabetic than in control rats. This increased bidirectional 'leak' of glucose possibly reflects a functionally compromised placenta, caused by its formation in a diabetic milieu, and may explain the greater fetal-maternal glucose ratios found in diabetic rats relative to controls.

Difference in prevalence of gestational diabetes and perinatal outcome in an innercity multiethnic London population.

In order to establish the prevalence of gestational diabetes mellitus (GDM) among ethnic groups residing in the catchment area of one hospital in central London and to assess both the mode of delivery and the baby outcome, we studied retrospectively 703 women selected for screening for GDM during the years 1991 and 1992. While the prevalence of GDM was approximately 2% overall, within the ethnic groups a significant difference was found with Asians and Africans/Afrocaribbeans being four and two times more likely to have GDM, respectively, than Caucasians (P < 0.001). Both maternal obesity and the diagnosis of GDM influenced the time and the mode of delivery, but perinatal mortality and morbidity did not differ significantly between women with GDM and women with normal glucose tolerance. An association between the GTT glucose area and the gestational age and ethnicity adjusted birth weight was observed in women with normal glucose tolerance test, but was absent in the GDM pregnancies, providing indirect evidence that dietary treatment, with or without insulin treatment, altered the maternal milieu in the latter sufficiently to modify fetal growth.

Hyperglycaemia; a risk factor for hypertension.

The epidemiological evidence for an association between diabetes mellitus and ischaemic heart disease is reviewed briefly. The relationship between blood sugar after challenge and blood pressure is described, with particular reference to studies in populations of U.S. and Jamaican adults and Dutch children.

Maternal diabetes and its cell membrane abnormalities as they affect the foetus: implications for the mother and birth defects.

My brief is to discuss maternal diabetes and its implications for birth defects. The perinatal mortality in Britain has fallen in the last 70 years from 60 per 1000 live births to less than 10. For the baby of the diabetic mother there has been a more dramatic decrease from 249 per thousand live births reported by Peel and Oakley in 1949 to approximately 30 in the Swedish cohort in 1993. However even in countries such as Sweden with one of the lowest figures there is still a three fold higher perinatal mortality for the baby of the diabetic mother compared with the background population. There has been a much less dramatic decrease in the incidence of congenital malformations. Peel and Oakley reported an incidence of 6.9% in 1949, and Hanson from Sweden in 1993 reported only a marginally lower incidence of 6.1%. Recent observations indicate that gestational diabetes (GDM) may be associated with increased incidence of fetal malformation and perinatal mortality. The most frequent and significant morbidity is fetal macrosomia, which in turn is associated with increased risk of birth injuries and asphyxia, (Persson and Hanson. 1998). Detection and definition of congenital malformation vary but in spite of this and the much better maternal diabetic control, congenital malformation today forms a major cause of the perinatal morbidity and mortality.

Relationship between red cell membrane fatty acids and adipokines in individuals with varying insulin sensitivity.

BACKGROUND/OBJECTIVES: Plasma leptin and adiponectin, and membrane phospholipid fatty acid composition are implicated into the mechanism of insulin resistance but no clear pattern has emerged. Hence, this study examined these variables in subjects presenting to the diabetic clinic for a diagnostic glucose tolerance test. SUBJECTS/METHODS: Body composition, glucose, glycated hemoglobin, insulin, leptin, adiponectin, and red cell and plasma phospholipid fatty acids were assessed from 42 normal and 28 impaired glucose tolerant subjects. Insulin sensitivity was determined by homeostatic model assessment. RESULTS: The plasma phosphatidylcholine fatty acid composition of the impaired glucose tolerant subjects was similar to that of normal subjects. However, the impaired glucose tolerant subjects had significantly lower linoleic (P<0.05), eicosapentaenoic (P<0.05) and docosahexaenoic (P<0.01) acids in the red cell phosphatidylcholine and phosphatidylethanolamine compared with the normal subjects. Moreover, red cell phosphatidylcholine docosahexaenoic acid correlated positively with adiponectin (r=0.290, P<0.05) but negatively with leptin (r=-0.252, P<0.05), insulin (r=-0.335, P<0.01) and insulin resistance (r=-0.322, P<0.01). Plasma triglycerides, leptin and glucose combined predicted about 60% of variation in insulin level whereas insulin was the only component that predicted the membrane fatty acids. CONCLUSIONS: We postulate that membrane phospholipids fatty acids have an indirect role in determining insulin concentration but insulin has a major role in determining membrane fatty acid composition.