Effect of insulin on fat metabolism during and after normal pregnancy.

Whereas development of resistance to the action of insulin on glucose metabolism during gestation has been recognized, it is presently not known whether there is also resistance to the action of insulin on lipid metabolism. We have, therefore, examined the effect of physiological hyperinsulinemia (during euglycemic-hyperinsulinemic clamping) on free fatty acid (FFA) turnover in seven nondiabetic overweight or obese women during and after pregnancy. Basal rates of FFA release, oxidation, and reesterification and basal plasma FFA concentrations were not significantly different from each other during the 2nd and 3rd trimester of pregnancy and postpartum. During euglycemic-hyperinsulinemic (approximately 500 pmol/l) clamping, however, lipolysis was significantly less inhibited during the 3rd trimester (from 7.0 +/- 0.9 to 4.9 +/- 0.9 micromol x kg(-1) x min(-1), -30%) than during the 2nd trimester (from 8.4 +/- 0.6 to 4.1 +/- 0.9 micromol x kg(-1) x min(-1), -51%) and postpartum (from 8.5 +/- 1.1 to 4.2 +/- 0.6 micromol x kg(-1) x min(-1), -51%). Similarly, fat oxidation was not inhibited at all (from 3.5 +/- 0.3 to 3.8 +/- 0.5 micromol x kg(-1) x min(-1)) during the 3rd trimester but was suppressed by 51% (from 3.9 +/- 0.2 to 1.9 +/- 0.3 micromol x kg(-1) x min(-1)) during the 2nd trimester and by 38% (from 2.6 +/- 0.7 to 1.6 +/- 0.5 micromol x kg(-1) x min(-1) postpartum. These data demonstrated that resistance to the action of insulin on lipolysis and on fat oxidation developed during late gestation and disappeared postpartum.

Leptin is present in human cord blood.

It has recently been reported that the ob gene receptor was expressed on human and murine hematopoietic stem cells and that the ob gene product leptin stimulated hemato- and lymphopoiesis at the stem cell level. These findings suggest a role for leptin in hemato- and lymphopoiesis during fetal development. There is at present no evidence, however, that leptin is synthesized and released by the fetus. To investigate this possibility, we have measured plasma leptin concentrations in the cord blood of 78 newborn infants. We found that leptin was present in all 78 infants in concentrations comparable with those found in adults (0.6-55.7 ng/ml). Overall, plasma leptin concentrations in the cord blood of infants correlated with birth weight (r = 0.74, P < 0.001). These observations show that leptin is synthesized and released by fetal fat cells. In addition, they are compatible with the concept that leptin may play a role in human fetal hematopoiesis.

Is self-monitoring of blood glucose necessary in the management of gestational diabetes mellitus?

There continues to be controversy regarding the role of blood glucose in the management of pregnant women with gestational diabetes mellitus (GDM), specifically with regard to the use of capillary versus venous samples, as well as the frequency and timing of blood glucose determinations. At the Third International Workshop Conference it was noted that "self-monitoring of capillary blood glucose has been useful in allowing the woman to participate in her own management," but its utility "in the mild GDM not requiring insulin, although reasonable and logical, has not been formally proved." This article reviews the existing evidence in the literature regarding the impact of self-monitoring of blood glucose on outcomes in pregnancies complicated by gestational diabetes. Data regarding the optimal timing, accuracy, costs, and psychosocial effects of self-monitored glucose determinations will also be explored.

The interrelationship between ethnicity and gestational diabetes in fetal macrosomia.

OBJECTIVE: To determine the possibility of an ethnic influence on the development of macrosomia (birth weight > 90th percentile for gestational age) in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: We prospectively followed all African-American and Latino women enrolled in the Temple diabetes-in-pregnancy program. GDM was diagnosed in 103 African-American and 36 Latino women during the study period (1991-1994) according to the criteria of Carpenter and Coustan. All women were treated according to our previously published protocols. Data were collected on gestational weight gain, previous history of macrosomia, body mass index (BMI), and level of maternal glycemic control. RESULTS: Insulin therapy was required in 53 women (37.5%) to maintain fasting blood glucose levels at < 95 mg/dl and 2-h postprandial levels at < 120 mg/dl. Macrosomia developed in 50% of the neonates of Latino women versus 19% of neonates of African-American women (relative risk 2.68; 95% confidence interval 1.57-4.59). Potential confounding factors were not significantly different between the Latino and African-American women: mean blood glucose 96.6 +/- 15.7 vs. 96.5 +/- 22.4 mg/dl; BMI 29.0 +/- 5.5 vs. 31.5 +/- 8.2 kg/m2; pregnancy weight gain 29.2 +/- 12.7 vs. 30.9 +/- 20.5 lb; and parity 1.8 +/- 1.5 vs. 1.6 +/- 1.4, respectively. CONCLUSIONS: We have demonstrated that Latino women with GDM are at higher risk for having macrosomic infants in comparison with African-American women. This ethnic variation in fetal growth may be due to varying influences of in utero growth promoters among these populations as well as underlying genetic factors.

Longitudinal study of carbohydrate metabolism in healthy obese pregnant women.

OBJECTIVE: To longitudinally characterize changes in insulin sensitivity in obese women during and after pregnancy. RESEARCH DESIGN AND METHODS: Six glucose-tolerant obese women underwent a 4-h euglycemic-hyperinsulinemic (500-600 pmol/l) clamping during the second (22.5 +/- 2 weeks [mean +/- SD]) and third trimester (36.8 +/- 0.9) of pregnancy and again 15.6 +/- 1.4 weeks after delivery. Rates of total body glucose turnover (with [6.6-2H2]glucose) and oxidation (with indirect calorimetry) were measured. RESULTS: There were no significant changes with respect to the action of insulin on rates of glucose disappearance (GRd), carbohydrate oxidation, or endogenous glucose production (EGP), comparing the second trimester of pregnancy with the nonpregnant (postpartum) state. The third trimester, however, was characterized 1) by reductions in insulin-stimulated GRd (-28%, P < 0.05, compared with the second trimester and -40%, P < 0.05, compared with postpartum); 2) by even larger reductions in insulin-stimulated carbohydrate oxidation (-46%, P < 0.05, compared with the second trimester and -54%, P < 0.02, compared with postpartum); and 3) by reduction of insulin suppression of EGP (-39% compared with -79% at the second trimester and -77% postpartum, P < 0.01). CONCLUSIONS: Glucose-tolerant obese women developed peripheral was well as hepatic insulin resistance during the third trimester of pregnancy. These alterations were reversed after delivery and appeared to be adaptive mechanisms to cope with the increased demand for glucose of the growing fetus.

Effect of dietary fat and food consistency on gastroparesis symptoms in patients with gastroparesis.

BACKGROUND: Nutrition therapy for gastroparesis focuses on reducing meal size, fiber, fat intake, and increasing liquids intake relative to solid foods. Evidence to support these dietary interventions has been anecdotal. The aim of this study was to determine the effect of fat intake and solid/liquid meal consistency on symptoms in gastroparesis. METHODS: Twelve patients with gastroparesis were studied on four separate days receiving one of four meals each day in a randomized order: high-fat solid, high-fat liquid, low-fat liquid, and low-fat solid meal. At each visit, eight gastrointestinal symptoms were rated from 0 (none) to 4 (very severe) every 15 min, before and for 4 h after meal ingestion. KEY RESULTS: There was an increase in the total symptom score in the following order: high-fat solid > low-fat solid > high-fat liquid > low-fat liquid. For the high-fat solid meal, symptoms remained elevated throughout the 4 h postprandial period. Severity of nausea more than doubled after the high-fat solid meal, whereas the low-fat liquid meal caused the least increase in nausea. CONCLUSIONS & INFERENCES: A high-fat solid meal significantly increased overall symptoms among individuals with gastroparesis, whereas a low-fat liquid meal had the least effect. With respect to nausea, low-fat meals were better tolerated than high-fat meals, and liquid meals were better tolerated than solid meals. These data provide support for recommendations that low-fat and increased liquid content meals are best tolerated in patients with symptomatic gastroparesis.

Free fatty acids and insulin resistance during pregnancy.

The purpose of this study was to determine whether elevation of plasma free fatty acids (FFA) in early pregnancy would cause alterations in insulin-stimulated glucose disposal similar to those occurring in late gestation. Seven glucose-tolerant women underwent 4-h euglycemic hyperinsulinemic (1 mU/kg.min) clamping during the early second trimester of pregnancy (14-17 weeks) on 2 consecutive days, receiving either lipid (Liposyn II; 1.5 mL/min) and heparin (0.4 U/kg.min; L/H) or saline/glycerol (2.25 g/h; S/G) infusions. Rates of total body glucose disposal (6,6-2H2 glucose) and of carbohydrate and fat oxidation (indirect calorimetry) were determined at hourly intervals. Blood glucose was clamped at about 85 mg/dL. Plasma FFA increased from 290 +/- 50 to 1000 +/- 139 mumol/L during L/H infusion and decreased from 351 +/- 60 to 35 +/- 11 mumol/L during S/G infusion. L/H infusion inhibited insulin stimulation of total body glucose disposal by 28% compared with S/G infusion (from 6.7 +/- 0.7 to 4.9 +/- 0.6 mg/kg.min; P < 0.01). L/H infusion increased fat oxidation from 0.73 +/- 0.04 to 1.26 +/- 0.2 mg/kg.min (P < 0.05) and decreased carbohydrate oxidation from 2.0 +/- 0.2 to 1.6 +/- 0.2 mg/kg.min (P < 0.05). Endogenous glucose production decreased equally by approximately 70% during L/H and S/G infusions. These data showed that elevating plasma FFA levels during early pregnancy inhibits total body glucose uptake and oxidation. We conclude that elevation of plasma FFA can contribute to the peripheral insulin resistance commonly observed during late pregnancy.

The relation between human fetal growth and fetal blood levels of insulin-like growth factors I and II, their binding proteins, and receptors.

OBJECTIVE: To determine the relation between normal human fetal growth and the levels of insulin-like growth factors (IGF-I, IGF-II), their receptors, and IGF binding protein-3 (IGFBP-3) in both the maternal and fetal compartments. METHODS: Serum samples were obtained from normal pregnant women (n = 52) and their fetuses (n = 32) via funipuncture at 21-34 weeks' gestation (mean 29 +/- 4.3) and from term neonates (n = 20) between 38-41 weeks (mean 39 +/- 0.9). Neonates were divided into two groups: the "large" group, whose weights were above the mean for gestational age, and the "small" group, whose weights were below the mean. Aliquots of amniotic fluid (AF) and serum samples were analyzed for levels of IGF-I, IGF-II, and IGFBP-3. Type 1 IGF receptors were assayed from placental extracts of first-trimester elective abortions and from term deliveries. RESULTS: Fetal IGF-I serum levels remained stable throughout most of pregnancy until 34 weeks' gestation (56 +/- 30 ng/mL). Thereafter, IGF-I increased significantly until term (79 +/- 8 ng/mL) (P < .05). Fetal IGF-II levels were relatively unchanged from 23 weeks to term except for a significant increase at 34 weeks. Fetal serum levels of IGFBP-3 averaged 0.8 +/- 0.05 microgram/mL up to 30 weeks' gestation and then increased slightly toward term, at 0.96 +/- 0.05 micrograms/mL. At term, the levels of IGF-I and IGF-II in the AF were not different from the levels in the neonatal serum, but were lower (P < .005) than those in maternal blood. All placental tissue obtained from first-trimester terminations of pregnancy assayed positive for IGF type 1 receptors. There was a direct correlation between neonatal weight and the levels of IGF-I (P < .02), but not with the levels of IGF-II. There were no significant correlations between newborn weights and IGFBP-3, or maternal serum levels of IGF-I and IGF-II. Amniotic fluid IGF-I and IGF-II levels were almost similar to fetal serum levels. CONCLUSION: These data demonstrate the presence of type 1 receptors and the bioavailability of IGF-I, IGF-II, and IGFBP-3 throughout pregnancy. Insulin-like growth factor-I is shown to be adjunctively and directly associated with fetal size in normal pregnancies. The precise role that IGFs play in deviant fetal growth or whether IGFs can be used to treat reduced fetal growth remains unknown and awaits further investigation.

Diabetes mellitus in pregnancy. What are the best treatment options?

Diabetes mellitus complicates somewhere between 1 and 20% of all pregnancies worldwide. Women with all types of diabetes, including type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus, and gestational diabetes mellitus, as well as their infants, are at increased risk for a number of different complications. However, achieving and maintaining euglycemia throughout gestation has been demonstrated to reduce the risk of adverse outcome for both the mother and her offspring. Traditional management approaches use a combination of diet, exercise, intensive insulin regimens and multiple self monitored blood glucose determinations. There are a number of newer agents available to treat diabetes mellitus; however, their safety in pregnancy has not been thoroughly tested. Although the oral hypoglycaemic drugs are not customarily used during gestation in most of the US and Europe they have had considerable use in South Africa. Animal and human studies of the teratogenic effects of these drugs have yielded conflicting data and it is difficult to distinguish between the teratogenic effects of poor maternal metabolic control and the agents themselves. This article also addresses the current state of the knowledge regarding the drug safety of a variety of medications for conditions, including hypertension and preterm labour, commonly encountered in the management of the pregnant women with diabetes mellitus.

The role of free radicals and membrane lipids in diabetes-induced congenital malformations.

OBJECTIVE: The incidence of major congenital malformations is approximately 6-9% in pregnancies complicated by diabetes mellitus. This incidence is 3-4-fold higher than that in the general population. Congenital malformations are now ranked as the leading cause of death in the offspring of women with diabetes. The precise mechanism(s) by which these anomalies are induced is unknown. It is also not clear what predisposes women to deliver malformed infants, which infants are at risk, and why some are spared even when exposed to presumably high risk conditions. The purpose of this report is to determine, from the literature, the primary etiologic factors associated with diabetes-induced embryopathy and its prevention. METHODS: A review of the current literature regarding malformations in diabetic pregnancies was conducted to elucidate dominant concepts in the pathogenic mechanism(s) of these anomalies and to discuss current and future strategies for their prevention. RESULTS: Numerous investigators have demonstrated that hyperglycemia has a teratogenic effect during organogenesis. However, the exact mechanisms involved have not been completely elucidated. Dietary supplementation of deficient substrates (arachidonic acid or myo-inositol), either in vitro or in vivo, has been shown to reduce the incidence of diabetes-related malformations in offspring of diabetic pregnant animals. In addition, free oxygen radical-scavenging enzymes and antioxidants aimed at reducing the excess load of radicals also result in a reduced malformation rate. Clinical evidence has demonstrated that the teratogenic effects of hyperglycemia may be obviated by maintaining euglycemia throughout organogenesis. Numerous studies have demonstrated that participation in a preconception care program can reduce the incidence of malformations in women with diabetes to the background rate. Unfortunately, less than 10% of women with diabetes currently enter these programs. CONCLUSIONS: Diabetic embryopathy remains the single most common lethal problem affecting diabetic pregnancies today. Although preconception planning and glycemic control can reduce the incidence of malformations, it is often difficult to get women to attend such programs and to achieve and maintain euglycemia. The use of dietary supplements, which presumably would override the teratogenic effects of aberrant metabolic fuels, holds great promise for the future as a prophylaxis against diabetic embryopathy.

Glucose monitoring and insulin therapy during pregnancy.

Excellent blood glucose control is necessary to reduce the excess fetal morbidity and mortality associated with the diabetic pregnancy. This article outlines the roles of glucose monitoring and insulin therapy in intensive treatment regimens during gestation. The discussion includes recommended monitoring frequency, glycemic standards, types of insulin and mechanism of action, goals and timing of insulin therapy, as well as the complications of insulin therapy.

Prenatal diagnosis and prevention of diabetic embryopathy.

This article emphasizes the need for early biochemical and sonographic evaluation of pregnancies complicated by diabetes mellitus. Methods available for the prenatal diagnosis and prevention of diabetes-associated malformations are described.

Diabetic retinopathy in pregnancy.

Diabetic retinopathy is the most common chronic complication associated with diabetes mellitus. It affects 20% to 30% of diabetic women in the reproductive age group. This article reviews the course and treatment of pregnancy complicated by diabetic retinopathy.

Management of hypoglycemia and diabetic ketoacidosis in pregnancy.

The article discusses the incidence and management of hypoglycemia and diabetic ketoacidosis (DKA) in pregnancy. Additional topics addressed are the incidence of hypoglycemia, pathophysiology, diagnosis and management of hypoglycemia in pregnancy, fetal monitoring with short- and long-term fetal sequelae, and prevention of hypoglycemic recurrences. Subsequently, attention is focused on the diagnosis and management of hyperglycemia and DKA in pregnancy.

To screen or not to screen for gestational diabetes mellitus. The clinical quagmire.

Although there continues to be a lack of agreement about the most appropriate way to screen for GDM, screening remains the standard of care in this country. Universal screening of all pregnant women maximizes sensitivity but has significant financial implications because of its increased costs. Additional studies are needed that apply cost-analysis to various screening protocols to identify cost-effective screening strategies.

Metabolic fuel mixtures and diabetic embryopathy.

The incidence of congenital anomalies remains the major cause of morbidity and mortality among the offspring of diabetic women. Animal and human studies indicate that these malformations occur early in pregnancy and are influenced by the abnormal maternal metabolic milieu. This article reviews the recent advances in understanding the pathogenesis of diabetic embryopathy. A possible pathway to explain the various diabetic-related fuel aberration is presented.

Self-monitoring of blood glucose in gestational diabetes.

Numerous studies have clearly demonstrated a significant association between maternal glycemic control and adverse outcomes in pregnancies complicated by gestational diabetes. However, despite our understanding of the importance of stringent glucose control in the management of these pregnancies, the definition of optimal glycemic control and monitoring protocols have yet to be firmly established. This article reviews current evidence regarding the efficacy of self-monitoring of blood glucose in the management of gestational diabetes. The role of various self-monitoring protocols and their impact on outcome is also explored. Areas where further investigations are needed in terms of glucose assessment are highlighted.

Diabetes-related complications of pregnancy.

Diabetes mellitus is a major medical complication of pregnancy and is associated with an increased risk of maternal and perinatal morbidity and mortality. Although recent advances have improved outcomes dramatically, the increased incidence of congenital malformations remains a significant problem. In the past, it was believed that pregnancy worsened microvascular complications, and women with vasculopathy were counseled to avoid or terminate pregnancies. Recent evidence suggests that normalization of blood glucose levels and current management strategies can lead to improved outcomes even in women with vasculopathy. Today, with the exception of coronary artery disease, women with diabetes may be counseled toward a more favorable outcome. This article discusses preconception planning and contemporary treatment methods.

Bodyweight in patients with idiopathic gastroparesis: roles of symptoms, caloric intake, physical activity, and body metabolism.

BACKGROUND: Most gastroparetic patients are underweight probably because of frequently experienced early satiety, nausea, and vomiting. Some gastroparesis (GP) patients, however, are overweight, for reasons that are not well understood. The aim of this study was to evaluate the factors that influence bodyweight such as resting energy and exercise-related expenditure, symptoms of early satiety, nausea and vomiting, and caloric intake in patients with idiopathic GP and in healthy controls. METHODS: Thirty-nine healthy controls and 29 subjects with idiopathic GP were studied. Resting energy expenditure (indirect calorimetry), body composition (bioelectrical impedance), dietary intake (Block Food Frequency Questionnaire), symptoms (Patient Assessment of Upper GI Symptoms), and physical activity (Paffenbarger exercise survey) were assessed. KEY RESULTS: Both median caloric intake (1242 vs 1804 kcal; p = 0.005) and caloric expenditure (486 vs 2172 kcal; p < 0.01) were significantly lower in patients with GP as compared to controls although BMI (25.8 ± 5.8 vs 24.3 ± 4.0 kg/m²) and resting energy expenditure (1327 ± 293 vs 1422 ± 243 kcal) were similar. On the other hand, the 12 GP patients who had gained weight (GW) since diagnosis had lower symptom severity (12.9 ± 4.4 vs 19.3 ± 6.3; p < 0.05), consumed more calories (1342 vs 1134 kcal; p = 0.08) and expended less calories for activity per week (406 vs 644 median kcal; p = 0.45) compared to the 17 GP patients who had lost weight or remained weight neutral (LW). CONCLUSIONS & INFERENCES: Patients with GP, although in energy balance, consumed and expended less calories than healthy controls. A subgroup of patients with GP who were less symptomatic, gained weight because of increased caloric intake and reduced energy expenditure.

A randomized comparison of a commercially available portion-controlled weight-loss intervention with a diabetes self-management education program.

OBJECTIVE: This study examined the efficacy of a commercially available, portion-controlled diet (PCD) on body weight and HbA1c over 6 months in obese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: One-hundred participants with a mean±s.d. age of 55.6±10.6 year, body weight of 102.9±18.4 kg and HbA1c of 7.7±1.3% were randomly assigned to a 9-session group lifestyle intervention that included a PCD or to a 9-session group program of diabetes self-management education (DSME). Participants in the two groups were prescribed the same goals for energy intake (1250-1550 kcal per day) and physical activity (200 min per week). RESULTS: While both groups produced significant improvements in weight and HbA1c after 6 months of treatment, PCD participants lost 7.3 kg [95% confidence interval (CI): -5.8 to -8.8 kg], compared with 2.2 kg (95% CI: -0.7 to -3.7 kg) in the DSME group (P<0.0001). Significantly more PCD than DSME participants lost 5% of initial weight (54.0% vs 14.0%, P<0.0001) and 10% (26.0% vs 6.0%, P<0.0001). HbA1c declined by 0.7% (95% CI: -0.4 to -1.0%) in the PCD group, compared with 0.4% (95% CI: -0.1 to -0.7%) in DSME (P<0.026). Across both groups, larger weight losses were associated with greater reductions in HbA1c (r=0.52, P<0.0001). CONCLUSIONS: These findings demonstrate that a commercially available portion-controlled meal plan can induce clinically meaningful improvements in weight and glycemic control in obese individuals with type 2 diabetes. These data have implications for the management of obesity in primary care, as now provided by the Centers for Medicare and Medicaid Services.