Healthy subjects ingested 2 H 2 O and after 14, 22, and 42 h of fasting the enrichments of deuterium in the hydrogens bound to carbons 2, 5, and 6 of blood glucose and in body water were determined. The hydrogens bound to the carbons were isolated in formaldehyde which was converted to hexamethylenetetramine for assay. Enrichment of the deuterium bound to carbon 5 of glucose to that in water or to carbon 2 directly equals the fraction of glucose formed by gluconeogenesis. The contribution of gluconeogenesis to glucose production was 47 Ϯ 4% after 14 h, 67 Ϯ 4% after 22 h, and 93 Ϯ 2% after 42 h of fasting. Glycerol's conversion to glucose is included in estimates using the enrichment at carbon 5, but not carbon 6. Equilibrations with water of the hydrogens bound to carbon 3 of pyruvate that become those bound to carbon 6 of glucose and of the hydrogen at carbon 2 of glucose produced via glycogenolysis are estimated from the enrichments to be ف 80% complete. Thus, rates of gluconeogenesis can be determined without corrections required in other tracer methodologies. After an overnight fast gluconeogenesis accounts for ف 50% and after 42 h of fasting for almost all of glucose production in healthy subjects. ( J. Clin. Invest. 1996. 98:378-385.)
Historically, insulin resistance during pregnancy has been ascribed to increased production of placental hormones and cortisol. The purpose of this study was to test this hypothesis by correlating the longitudinal changes in insulin sensitivity during pregnancy with changes in placental hormones, cortisol, leptin, and tumor necrosis factor (TNF)-␣. Insulin resistance was assessed in 15 women (5 with gestational diabetes mellitus [GDM] and 10 with normal glucose tolerance) using the euglycemic-hyperinsulinemic clamp procedure, before pregnancy (pregravid) and during early (12-14 weeks) and late (34 -36 weeks) gestation. Body composition, plasma TNF-␣, leptin, cortisol, and reproductive hormones (human chorionic gonadotropin, estradiol, progesterone, human placental lactogen, and prolactin) were measured in conjunction with the clamps. Placental TNF-␣ was measured in vitro using dually perfused human placental cotyledon from five additional subjects. Compared with pregravid, insulin resistance was evident during late pregnancy in all women (12.4 ؎ 1.2 vs. 8.1 ؎ 0.8 10 ؊2 mg ⅐ kg ؊1 fat-free mass ⅐ min ؊1 ⅐ U ؊1 ⅐ ml ؊1 ). TNF-␣, leptin, cortisol, all reproductive hormones, and fat mass were increased in late pregnancy (P < 0.001). In vitro, most of the placental TNF-␣ (94%) was released into the maternal circulation; 6% was released to the fetal side. During late pregnancy, TNF-␣ was inversely correlated with insulin sensitivity (r ؍ ؊0.69, P < 0.006). Furthermore, among all of the hormonal changes measured in this study, the change in TNF-␣ from pregravid to late pregnancy was the only significant predictor of the change in insulin sensitivity (r ؍ ؊0.60, P < 0.02). The placental reproductive hormones and cortisol did not correlate with insulin sensitivity in late pregnancy. Multivariate stepwise regression analysis revealed that TNF-␣ was the most significant independent predictor of insulin sensitivity (r ؍ ؊0.67, P < 0.0001), even after adjustment for fat mass by covariance (r ؍ 0.46, P < 0.01). These observations challenge the view that the classical reproductive hormones are the primary mediators of change in insulin sensitivity during gestation and provide the basis for including TNF-␣ in a new paradigm to explain insulin resistance in pregnancy. Diabetes 51:2207-2213, 2002
The definition of clinically significant hypoglycemia remains one of the most confused and contentious issues in contemporary neonatology. In this article, some of the reasons for these contentions are discussed. Pragmatic recommendations for operational thresholds, ie, blood glucose levels at which clinical interventions should be considered, are offered in light of current knowledge to aid health care providers in neonatal medicine. Future areas of research to resolve some of these issues are also presented.
. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 285: E906-E916, 2003; 10.1152/ajpendo.00117.2003.-The current study was undertaken to examine metabolic and body composition correlates of fatty liver in type 2 diabetes mellitus (DM). Eighty-three men and women with type 2 DM [mean body mass index (BMI): 34 Ϯ 0.5 kg/m 2 ] and without clinical or laboratory evidence of liver dysfunction had body composition assessments of fat mass (FM), visceral adipose tissue (VAT), liver and spleen computed tomography (CT) attenuation (ratio of liver to spleen), muscle CT attenuation, and thigh adiposity; these assessments were also performed in 12 lean and 15 obese nondiabetic volunteers. Insulin sensitivity was measured with a euglycemic insulin infusion (40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 ) combined with systemic indirect calorimetry to assess glucose and lipid oxidation, and with infusions of [ 2 H2]glucose for assessment of endogenous glucose production. A majority of those with type 2 DM (63%) met CT criteria for fatty liver, compared with 20% of obese and none of the lean nondiabetic volunteers. Fatty liver was most strongly correlated with VAT (r ϭ Ϫ0.57, P Ͻ 0.0001) and less strongly but significantly associated with BMI (r ϭ Ϫ0.42, P Ͻ 0.001) and FM (r ϭ Ϫ0.37, P Ͻ 0.001), but only weakly associated with subcutaneous adiposity (r ϭ Ϫ0.29; P Ͻ 0.01). Fatty liver was also correlated with subfascial adiposity of skeletal muscle (r ϭ Ϫ0.44; P Ͻ 0.01). Volunteers with type 2 DM and fatty liver were substantially more insulin resistant those with type 2 DM but without fatty liver (P Ͻ 0.001) and had higher levels of plasma free fatty acids (P Ͻ 0.01) and more severe dyslipidemia (P Ͻ 0.01), a pattern observed in both genders. Plasma levels of cytokines were increased in relation to fatty liver (r ϭ Ϫ0.34; P Ͻ 0.01). In summary, fatty liver is relatively common in overweight and obese volunteers with type 2 DM and is an aspect of body composition related to severity of insulin resistance, dyslipidemia, and inflammatory markers.
A method is introduced for estimating the contribution of gluconeogenesis to glucose production. 2H20 is administered orally to achieve 0.5% deuterium enrichment in body water. Enrichments are determined in the hydrogens bound to carbons 2 and 6 of blood glucose and in urinary water. Enrichment at carbon 6 of glucose is assayed in hexamethylenetetramine, formed from formaldehyde produced by periodate oxidation of the glucose. Enrichment at carbon 2 is assayed in lactate formed by enzymatic transfer of the hydrogen from glucose via sorbitol to pyruvate. The fraction gluconeogenesis contributes to glucose production equals the ratio of the enrichment at carbon 6 to that at carbon 2 or in urinary water. Applying the method, the contribution of gluconeogenesis in healthy subjects was 23-42% after fasting 14 h, increasing to 59-84% after fasting 42 h. Enrichment at carbon 2 to that in urinary water was 1.12±0.13. Therefore, the assumption that hydrogen equilibrated during hexose-6-P isomerization was fulfilled. The 3H/14C ratio in glucose formed from [3-3H,3-'4C]lactate given to healthy subjects was 0.1 to 0.2 of that in the lactate. Therefore equilibration during gluconeogenesis of the hydrogen bound to carbon 6 with that in body water was 80-90% complete, so that gluconeogenesis is underestimated by 10-20%. Glycerol's contribution to gluconeogenesis is not included in these estimates. The method is applicable to studies in humans of gluconeogenesis at safe doses of 21H20. (J. Clin. Invest. 1995. 95:172-178.)
The use of2H2O in estimating gluconeogenesis’ contribution to glucose production (%GNG) was examined during progressive fasting in three groups of healthy subjects. One group ( n = 3) ingested2H2O to a body water enrichment of ≈0.35% 5 h into the fast. %GNG was determined at 2-h intervals from the ratio of the enrichments of the hydrogens at C-5 and C-2 of blood glucose, assayed in hexamethylenetetramine. %GNG increased from 40 ± 8% at 10 h to 93 ± 6% at 42 h. Another group ingested2H2O over 2.25 h, beginning at 11 h ( n = 7) and 19 h ( n = 7) to achieve ≈0.5% water enrichment. Enrichment in plasma water and at C-2 reached steady state ≈1 h after completion of2H2O ingestion. The C-5-to-C-2 ratio reached steady state by the completion of 2H2O ingestion. %GNG was 54 ± 2% at 14 h and 64 ± 2% at 22 h. A 3-h [6,6-2H2]glucose infusion was also begun to estimate glucose production from enrichments at C-6, again in hexamethylenetetramine. Glucose produced by gluconeogenesis was 0.99 ± 0.06 mg ⋅ kg−1 ⋅ min−1at both 14 and 22 h. In a third group ( n = 3) %GNG reached steady state ≈2 h after2H2O ingestion to only ≈0.25% enrichment. In conclusion, %GNG by 2 h after2H2O ingestion and glucose production using [6,6-2H2]glucose infusion, begun together, can be determined from hydrogen enrichments at blood glucose C-2, C-5, and C-6. %GNG increases gradually from the postabsorptive state to 42 h of fasting, without apparent change in the quantity of glucose produced by gluconeogenesis at 14 and 22 h.
OBJECTIVE -We examined whether selected indexes of insulin sensitivity derived from an oral glucose tolerance test (IS OGTT ) or fasting glucose/insulin levels (IS QUICKI and IS HOMA ) can be used to predict insulin sensitivity in women before and during pregnancy. RESEARCH DESIGN AND METHODS -A 2-h euglycemic-hyperinsulinemic clamp(5 mmol/l glucose, 40 mU ⅐ m Ϫ2 ⅐ min Ϫ1 insulin) and a 120-min oral glucose tolerance test (75 g load pregravid, 100 g pregnant) were repeated on 15 women (10 with normal glucose tolerance [NGT] and 5 with gestational diabetes mellitus [GDM]) pregravid and during both early (12-14 weeks) and late (34 -36 weeks) pregnancy. An index of insulin sensitivity derived from the clamp (IS CLAMP ) was obtained from glucose infusion rates adjusted for change in fat-free mass and endogenous glucose production measured using [6,6-2 H 2 ]glucose.RESULTS -Univariate analysis using combined groups and periods of pregnancy resulted in significant correlations between IS CLAMP and IS OGTT (r 2 ϭ 0.74, P Ͻ 0.0001), IS QUICKI (r 2 ϭ 0.64, P Ͻ 0.0001), and IS HOMA (r 2 ϭ 0.53, P Ͻ 0.0001). The IS OGTT provided a significantly better correlation (P Ͻ 0.0001) than either IS QUICKI or IS HOMA. Multivariate analysis showed a significant group effect (P Ͻ 0.0003) on the prediction model, and separate equations were developed for the NGT (r 2 ϭ 0.64, P Ͻ 0.0001) and GDM (r 2 ϭ 0.85, P Ͻ 0.0001) groups. When subdivided by period of pregnancy, the correlation between IS CLAMP and IS OGTT pregravid was r 2 ϭ 0.63 (P ϭ 0.0002), during early pregnancy was r 2 ϭ 0.80 (P Ͻ 0.0001), and during late pregnancy was r 2 ϭ 0.64 (P ϭ 0.0002).CONCLUSIONS -Estimates of insulin sensitivity from the IS OGTT during pregnancy were significantly better than from fasting glucose and insulin values. However, separate prediction equations are necessary for pregnant women with NGT and women with GDM. Diabetes Care 24:1602-1607, 2001A number of standard clinical procedures are available for evaluating maternal insulin sensitivity during pregnancy, including the euglycemichyperinsulinemic clamp, the oral glucose tolerance test (OGTT), the intravenous glucose tolerance test, the Minimal Model, and various derivations of fasting glucose and insulin levels. The euglycemic-hyperinsulinemic clamp is considered by many the "gold standard" among these procedures (1). Although the clamp method can provide a precise measure of insulin sensitivity under physiological conditions, it is a relatively complicated and labor-intensive procedure and is not suitable for large-scale clinical or epidemiological studies. Therefore, a simple but valid estimate of insulin sensitivity is desirable to monitor and possibly reduce the potential adverse effects associated with hyperinsulinemia and/or hyperglycemia during pregnancy.In a recent report, Matsuda and DeFronzo (2) validated an index of insulin sensitivity estimated from glucose and insulin levels during an OGTT (IS OGTT ) against the clamp procedure. Katz et al. (3) have also validated an index of insul...
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