Darcy B. Carr

Oral Disposition Index Predicts the Development of Future Diabetes Above and Beyond Fasting and 2-h Glucose Levels

OBJECTIVE—We sought to determine whether an oral disposition index (DIO) predicts the development of diabetes over a 10-year period. First, we assessed the validity of the DIO by demonstrating that a hyperbolic relationship exists between oral indexes of insulin sensitivity and β-cell function. RESEARCH DESIGN AND METHODS—A total of 613 Japanese-American subjects (322 men and 291 women) underwent a 75-g oral glucose tolerance test (OGTT) at baseline, 5 years, and 10 years. Insulin sensitivity was estimated as 1/fasting insulin or homeostasis model assessment of insulin sensitivity (HOMA-S). Insulin response was estimated as the change in insulin divided by change in glucose from 0 to 30 min (ΔI0–30/ΔG0–30). RESULTS—ΔI0–30/ΔG0–30 demonstrated a curvilinear relationship with 1/fasting insulin and HOMA-S with a left and downward shift as glucose tolerance deteriorated. The confidence limits for the slope of the loge-transformed estimates included −1 for ΔI0–30/ΔG0–30 versus 1/fasting insulin for all glucose tolerance groups, consistent with a hyperbolic relationship. When HOMA-S was used as the insulin sensitivity measure, the confidence limits for the slope included −1 only for subjects with normal glucose tolerance (NGT) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) but not diabetes. On the basis of this hyperbolic relationship, the product of ΔI0–30/ΔG0–30 and 1/fasting insulin was calculated (DIO) and decreased from NGT to IFG/IGT to diabetes (P < 0.001). Among nondiabetic subjects at baseline, baseline DIO predicted cumulative diabetes at 10 years (P < 0.001) independent of age, sex, BMI, family history of diabetes, and baseline fasting and 2-h glucose concentrations. CONCLUSIONS—The DIO provides a measure of β-cell function adjusted for insulin sensitivity and is predictive of development of diabetes over 10 years.

β-Cell Loss and β-Cell Apoptosis in Human Type 2 Diabetes Are Related to Islet Amyloid Deposition

Amyloid deposition and reduced β-cell mass are pathological hallmarks of the pancreatic islet in type 2 diabetes; however, whether the extent of amyloid deposition is associated with decreased β-cell mass is debated. We investigated the possible relationship and, for the first time, determined whether increased islet amyloid and/or decreased β-cell area quantified on histological sections is correlated with increased β-cell apoptosis. Formalin-fixed, paraffin-embedded human pancreas sections from subjects with (n = 29) and without (n = 39) diabetes were obtained at autopsy (64 ± 2 and 70 ± 4 islets/subject, respectively). Amyloid and β cells were visualized by thioflavin S and insulin immunolabeling. Apoptotic β cells were detected by colabeling for insulin and by TUNEL. Diabetes was associated with increased amyloid deposition, decreased β-cell area, and increased β-cell apoptosis, as expected. There was a strong inverse correlation between β-cell area and amyloid deposition (r = -0.42, P < 0.001). β-Cell area was selectively reduced in individual amyloid-containing islets from diabetic subjects, compared with control subjects, but amyloid-free islets had β-cell area equivalent to islets from control subjects. Increased amyloid deposition was associated with β-cell apoptosis (r = 0.56, P < 0.01). Thus, islet amyloid is associated with decreased β-cell area and increased β-cell apoptosis, suggesting that islet amyloid deposition contributes to the decreased β-cell mass that characterizes type 2 diabetes.

Are We Optimizing Gestational Diabetes Treatment With Glyburide? The Pharmacologic Basis for Better Clinical Practice

Glyburides pharmacokinetics (PK) and pharmacodynamics have not been studied in women with gestational diabetes mellitus (GDM). The objective of this study was to assess steady‐state PK of glyburide, as well as insulin sensitivity, β‐cell responsivity, and overall disposition indices after a mixed‐meal tolerance test (MMTT) in women with GDM (n = 40), nonpregnant women with type 2 diabetes mellitus (T2DM) (n = 26), and healthy pregnant women (n = 40, MMTT only). At equivalent doses, glyburide plasma concentrations were ~50% lower in pregnant women than in nonpregnant subjects. The average umbilical cord/maternal plasma glyburide concentration ratio at the time of delivery was 0.7 ± 0.4. Insulin sensitivity was approximately fivefold lower in women with GDM as compared with healthy pregnant women. Despite comparable β‐cell responsivity indices, the average β‐cell function corrected for insulin resistance was more than 3.5‐fold lower in women with glyburide‐treated GDM than in healthy pregnant women. Women with GDM in whom glyburide treatment has failed may benefit from alternative medication or dosage escalation; however, fetal safety should be kept in mind.

Effects of Pregnancy on CYP3A and P‐glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study

The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P‐glycoprotein (P‐gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1–2 weeks at 28–32 weeks gestation, and the same order was repeated at 6–10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography–mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/Funbound (593 ± 237 l/min vs. 345 ± 103 l/min; P = 0.007), digoxin CLRenal, unbound (272 ± 45 ml/min vs. 183 ± 37 ml/min; P < 0.002) and digoxin CLsecretion, unbound (109 ± 34 ml/min vs. 58 ± 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P‐gp activities during pregnancy.

Pharmacokinetics of Metformin during Pregnancy

Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 ± 243 ml/min, P < 0.01) and late pregnancy (625 ± 130 ml/min, P < 0.01) compared with postpartum (477 ± 132 ml/min). These changes reflected significant increases in creatinine clearance (240 ± 70 ml/min, P < 0.01 and 207 ± 56 ml/min, P < 0.05 versus 165 ± 44 ml/min) and in metformin net secretion clearance (480 ± 190 ml/min, P < 0.01 and 419 ± 78 ml/min, P < 0.01 versus 313 ± 98 ml/min) in mid and late pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (<5 ng/ml) and 1263 ng/ml. The daily infant intake of metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was <0.5% of the mother’s weight-adjusted dose. Our results indicate that metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Postpartum Depression:

Postpartum depression (PPD) affects at least 10% to 15% of postpartum women, including more than 600,000 American mothers in 2003 alone. Dramatic changes in the hypothalamic-pituitary-adrenal (HPA) system in the transition from pregnancy to postpartum coupled with research on the psychobiology of depression provided the foundation for this study. The purpose of this study was to compare the reactivity and regulation of the HPA axis components, adrenocorticotropic hormone (ACTH) and cortisol, in depressed and nondepressed postpartum women. A comparative, longitudinal study design was used with 22 normal, healthy, nondepressed pregnant women. Physiologic and postpartum depression data were collected at 6 and 12 weeks postpartum at a university clinical research center. Maximal treadmill exercise stimulated plasma ACTH and serum cortisol levels which were measured before, during, and after 20 min of exercise. Postpartum depression was measured with the Postpartum Depression Screening Scale. Lag within-subject ACTH levels predicting cortisol regression slopes were significantly different between the depressed and nondepressed groups at both 6 and 12 weeks. The depressed group showed no relationship between their ACTH and cortisol levels, with higher ACTH and lower cortisol levels when compared with the nondepressed group. The expected regulated relationship with cortisol levels rising in response to rising ACTH levels was found in the non-depressed group. These findings indicate that the HPA axis was dysregulated in the depressed group, but regulated in the nondepressed group at 6 and 12 weeks postpartum. This pattern of higher ACTH levels to stimulate less cortisol is similar to patterns found in women with early life stresses.

Treatment of hypertension in pregnancy: effect of atenolol on maternal disease, preterm delivery, and fetal growth.

OBJECTIVE To assess the impact of antihypertensive therapy initiated early in pregnancy on maternal and fetal outcomes. METHODS A retrospective review of patients treated in early pregnancy with atenolol was conducted. Therapy was directed by measurements of cardiac output. Fetal growth was analyzed with reference to prior pregnancy outcome, treatment inconsistent with standards present at the end of the study period, and year of treatment. Data were analyzed by paired and unpaired t‐test, analysis of variance for multiple comparisons, and linear regression. RESULTS Two hundred thirty‐five pregnancies at risk for preeclampsia were studied. Ten percent (n = 22) received additional therapy with furosemide; 20% (n = 48) with hydralazine. Six and one half percent had treatment inconsistencies. Fifty‐five percent had greater than 100 mg of proteinuria at baseline. One patient developed severe preeclampsia. Only 2.1% delivered before 32 weeks; 4.7% delivered before 34 weeks. Low percentile birth weight was strongly associated with a prior pregnancy with intrauterine growth restriction (P = 0.001), treatment inconsistency (P < .001), and a pregnancy earlier in our treatment experience (P < .001). Percentile birth weight increased from the 20th at the beginning of the study period to the 40th by the end (P = 0.002). CONCLUSION Early intervention with antihypertensive therapy was associated with a low rate of severe maternal hypertension and preterm delivery. The failure to adjust therapy in response to an excessive fall in cardiac output or increase in vascular resistance was associated with reduced fetal growth.

The influence of epidural analgesia on cesarean delivery rates: A randomized, prospective clinical trial

OBJECTIVE The effects of epidural analgesia on the progress of labor are controversial. The objective of this study was to determine the effect of epidural analgesia on cesarean delivery rates in a population of patients randomly assigned to receive either epidural analgesia or intravenous opioids for intrapartum pain relief. STUDY DESIGN From January 1995 to May 1996, 318 spontaneously laboring, term, nulliparous patients were randomly assigned to receive either intravenous opioids or epidural analgesia for pain relief. Labor was managed according to the principles of active management of labor. Cesarean delivery was performed for obstetric indications. Data analysis was conducted on an intent-to-treat basis. A subanalysis was subsequently performed on patients who were compliant with the allocated form of treatment. RESULTS One hundred sixty-two patients were randomly assigned to receive intravenous meperidine and 156 were randomly assigned to receive epidural analgesia. Maternal age, gravidity, race, gestational age, and cervical dilatation at admission and at first analgesic dose did not differ between the groups. Intent-to-treat data analysis revealed no significant difference in the cesarean delivery rate between the 2 groups, being 13.6% in the opioid group and 9.6% in the epidural group (relative risk 0.70, 95% confidence interval 0.38-1.31, P >.05). Cesarean delivery rates for the indication of dystocia also did not differ, being 10.5% in the opioid group and 5.8% in the epidural group (relative risk 0.56, 95% confidence interval 0.26-1.21, P >.05). Subanalysis of the data from patients who were compliant with the allocated form of treatment revealed that patients in the epidural group (n = 147) were 3 times more likely to have an active phase duration >/=8 hours and were 10 times more likely to require >/=2 hours in the second stage of labor than were those in the opioid group (n = 78). There were no significant differences in cesarean delivery rates in this subanalysis, being 7.7% in the opioid group and 8.8% in the epidural group (relative risk 1.15, 95% confidence interval 0.45-2.91, P >. 05). The cesarean delivery rates for dystocia were also similar in the subanalysis, being 3.8% in the opioid group and 5.5% in the epidural group (relative risk 1.42, 95% confidence interval 0.39-5. 22, P >.05). CONCLUSION Epidural analgesia provides safe and effective intrapartum pain control and may be administered without undesirable effects on labor outcome.

Pharmacokinetics and pharmacodynamics of atenolol during pregnancy and postpartum

Preexisting hypertension complicates 5% of all pregnancies. The objective of this study was to evaluate steady‐state atenolol pharmacokinetics and pharmacodynamics (n = 17) during the second trimester (2nd T), third trimester (3rd T), and 3 months postpartum. Pregnancy as compared to 3 months postpartum (nonpregnant control) resulted in significant (P < .05) changes, including the following: 42% (2nd T) and 50% (3rd T) increase in creatinine clearance, 38% (2nd T) and 36% (3rd T) increase in atenolol renal clearance, 12% (2nd T) and 11% (3rd T) decrease in atenolol half‐life, 20% (2nd T) and 28% (3rd T) increase in cardiac output, 15% (2nd T) and 23% (3rd T) increase in resting heart rate, and 22% (2nd T) and 21% (3rd T) decrease in total peripheral resistance in subjects on steady‐state oral atenolol for treatment of hypertension in pregnancy. In conclusion, the renal clearance of atenolol along with creatinine clearance is increased during pregnancy. However, this does not translate into an increase in apparent oral clearance of atenolol, possibly related to the high variability in bioavailability. Atenolol administration did not appear to change the pattern of the increase in cardiac output and the decrease in total peripheral resistance, which normally occurs during pregnancy.

An examination of β‐cell function measures and their potential use for estimating β‐cell mass

A characteristic and dominant feature of type 2 diabetes is a reduction in β‐cell function that is associated with a decrease in β‐cell volume. A decline in the first‐phase insulin response following intravenous glucose administration can be demonstrated as the fasting glucose concentration increases. This response is completely absent before the glucose threshold that defines diabetes has been reached and at a time when β‐cells are clearly still present, implying that a functional β‐cell lesion has to exist independent of β‐cell loss. Surgical or chemical reductions of up to 65% of β‐cell volume demonstrate that functional adaptation of the normal β‐cell prevents a rise in fasting glucose or reduction in first‐phase insulin response. However, the ability of glucose to potentiate the β‐cell’s response to non‐glucose secretagogues is reduced and is more closely associated with the reduction in β‐cell volume. The future, in terms of prevention and treatment of type 2 diabetes, lies in the ability to prevent and revert both β‐cell loss and dysfunction. However, until β‐cell volume can be quantified reliably and non‐invasively, we will need to rely on the ability of glucose to potentiate insulin release as the best surrogate estimate of the number of β‐cells.