Search

Objective: To identify factors associated with declining beta-cell compensation for insulin resistance.Research Design and Methods: In a cohort of Hispanic women with recent gestational diabetes mellitus, oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and bioelectrical impedance measurements were performed at 15-month intervals for up to 5 years, or until fasting plasma glucose exceeded 140 mg/dl (7.8 mmol/l). Data were analyzed to identify predictors of declining beta-cell compensation for insulin resistance (the disposition index [DI]) and to examine the mechanism of weight gain and changes in circulating levels of selected adipokines and inflammatory markers on beta-cell compensation decline.Results: A total of 60 nondiabetic women had a median of four sets of OGTT + IVGTT during a median follow-up of 52 months. Fourteen of the women developed diabetes. None of the baseline characteristics were significantly predictive of a decline in DI. There were significant univariate associations between declining DI and weight gain (specifically fat gain), declining adiponectin and rising C-reactive protein. Multivariate analysis showed that the weight gain was the most significant factor associated with declining DI. The amount of association between weight gain and declining DI was explained 31% by changes in adiponectin and C-reactive protein and 40% by changes in insulin resistance.Conclusions: These results identify weight gain as the strongest factor associated with declining beta-cell compensation for insulin resistance in Hispanic women at high risk for type 2 diabetes. Such effect may be mediated through at least two effects: alterations in adipokine levels and increasing insulin resistance. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the effect of thiazolidinedione treatment on subclinical atherosclerosis progression in insulin-requiring patients with clinical characteristics suggesting type 2 diabetes. RESEARCH DESIGN AND METHODS: Eligible participants (n = 299) were randomized within strata of baseline common carotid artery (CCA) intima-media thickness (IMT) (<0.8 mm, >/=0.8 mm) to 400 mg troglitazone daily or placebo for 2 years. A general linear mixed-effects model was used to compare the rate of change in CCA-IMT between treatment groups. RESULTS: Overall, average rates of CCA-IMT change were not significantly different between troglitazone- and placebo-treated subjects (0.0030 +/- 0.021 vs. 0.0066 +/- 0.021 mm/year; P = 0.17). In the stratum of subjects with CCA-IMT >/=0.8 mm, troglitazone significantly reduced the progression of CCA-IMT relative to placebo (0.0013 +/- 0.022 vs. 0.0084 +/- 0.023 mm/year; P = 0.03). Fasting glucose, insulin, and HbA(1c) were significantly lower in troglitazone- versus placebo-treated subjects (P < 0.01). Whereas blood pressure significantly differed between treatment groups in the >/=0.8-mm stratum, there was no difference between treatment groups in the <0.8-mm stratum. CONCLUSIONS: Insulin sensitization and reduction in blood pressure may be contributory mechanisms by which troglitazone reduced subclinical atherosclerosis progression in this cohort of well-controlled insulin-dependent patients with clinical characteristics suggesting type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: We have tested whether the Pro12Ala variant of the peroxisome proliferator-activated receptor (PPAR)-gamma nuclear receptor involved in thiazolidinedione (TZD) action accounted for the failure of troglitazone to increase insulin sensitivity in nondiabetic Hispanic women with previous gestational diabetes treated in the Troglitazone in Prevention of Diabetes (TRIPOD) study.Research Design and Methods: Ninety-three women assigned to troglitazone had intravenous glucose tolerance tests at randomization and after 3 months of treatment with troglitazone, 400 mg/day, and were genotyped for the Pro12Ala variant of the PPAR-gamma gene. Subjects were divided into tertiles based on their change in minimal model insulin sensitivity (S(i)) during the first 3 months of troglitazone treatment.Results: The mean changes in S(i) in the bottom, middle, and top tertiles of S(i) response were -0.21 +/- 0.57, 0.91 +/- 0.26, and 2.58 +/- 1.32 min(-1) per microU/ml. 10(-4), respectively. Frequencies of the Ala/- genotype were 30, 22, and 26% in the same three tertiles (P = 0.77). Analysis of phenotypes by genotype revealed only small differences between the Pro/Pro and Ala/- groups, respectively, in baseline S(i) (2.76 +/- 0.19 vs. 2.33 +/- 0.33 x 10(-4) min(-1) per microU/ml; P = 0.27), the change in S(i) after 3 months of troglitazone treatment (1.19 +/- 0.17 vs. 0.93 +/- 0.30; P = 0.46), and the cumulative incidence of diabetes during a median follow-up of 30 months (13 vs. 17%; P = 0.66).Conclusions: Among young Hispanic women at high risk for type 2 diabetes, the Pro12Ala variant of the PPAR-gamma receptor gene did not explain the failure of approximately 1/3 of subjects to increase their insulin sensitivity when placed on troglitazone at a dose of 400 mg/day. [ABSTRACT FROM AUTHOR]

Objective: To compare effects of medications and laparoscopic gastric band surgery (LB) on α-cell function in dysglycemic youth and adults in the Restoring Insulin Secretion (RISE) Study protocols., Research Design and Methods: Glucagon was measured in three randomized, parallel, clinical studies: 1 ) 91 youth studied at baseline, after 12 months on metformin alone (MET) or glargine followed by metformin (G/M), and 3 months after treatment withdrawal; 2 ) 267 adults studied at the same time points and treated with MET, G/M, or liraglutide plus metformin (L+M) or given placebo (PLAC); and 3 ) 88 adults studied at baseline and after 12 and 24 months of LB or MET. Fasting glucagon, glucagon suppression by glucose, and acute glucagon response (AGR) to arginine were assessed during hyperglycemic clamps. Glucagon suppression was also measured during oral glucose tolerance tests (OGTTs)., Results: No change in fasting glucagon, steady-state glucagon, or AGR was seen at 12 months following treatment with MET or G/M (in youth and adults) or PLAC (in adults). In contrast, L+M reduced these measures at 12 months (all P ≤ 0.005), which was maintained 3 months after treatment withdrawal (all P < 0.01). LB in adults also reduced fasting glucagon, steady-state glucagon, and AGR at 12 and 24 months ( P < 0.05 for all, except AGR at 12 months [ P = 0.098]). Similarly, glucagon suppression during OGTTs was greater with L+M and LB. Linear models demonstrated that treatment effects on glucagon with L+M and LB were largely associated with weight loss., Conclusions: Glucagon concentrations were reduced by L+M and LB in adults with dysglycemia, an effect principally attributable to weight loss in both interventions., (© 2021 by the American Diabetes Association.)

Objective: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study., Research Design and Methods: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA 1c increase ≥0.5% from baseline)., Results: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 ( P = 0.008) and in 36% of youth versus 20% of adults at month 21 ( P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived β-cell responses predicted month 12 and month 21 glycemic worsening ( P < 0.01). Lower baseline OGTT-derived β-cell responses predicted month 21 worsening ( P < 0.05). In youth, higher baseline HbA 1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening ( P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening ( P < 0.05)., Conclusions: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline β-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults., (© 2021 by the American Diabetes Association.)

Objective: To determine whether β-cell hyperresponsiveness and insulin resistance in youth versus adults in the Restoring Insulin Secretion (RISE) Study are related to increased glucagon release., Research Design and Methods: In 66 youth and 350 adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (drug naive), we performed hyperglycemic clamps and oral glucose tolerance tests (OGTTs). From clamps we quantified insulin sensitivity (M/I), plasma fasting glucagon and C-peptide, steady-state glucagon and C-peptide at glucose of 11.1 mmol/L, and arginine-stimulated glucagon (acute glucagon response [AGR]) and C-peptide (ACPRmax) responses at glucose >25 mmol/L., Results: Mean ± SD fasting glucagon (7.63 ± 3.47 vs. 8.55 ± 4.47 pmol/L; P = 0.063) and steady-state glucagon (2.24 ± 1.46 vs. 2.49 ± 1.96 pmol/L, P = 0.234) were not different in youth and adults, respectively, while AGR was lower in youth (14.1 ± 5.2 vs. 16.8 ± 8.8 pmol/L, P = 0.001). Significant age-group differences in insulin sensitivity, fasting C-peptide, steady-state C-peptide, and ACPRmax were not related to glucagon. Fasting glucose and glucagon were positively correlated in adults ( r = 0.133, P = 0.012) and negatively correlated in youth ( r = -0.143, P = 0.251). In both age-groups, higher fasting glucagon was associated with higher fasting C-peptide (youth r = 0.209, P = 0.091; adults r = 0.335, P < 0.001) and lower insulin sensitivity (youth r = -0.228, P = 0.066; adults r = -0.324, P < 0.001). With comparable fasting glucagon, youth had greater C-peptide and lower insulin sensitivity. OGTT suppression of glucagon was greater in youth., Conclusions: Youth with IGT or recently diagnosed type 2 diabetes (drug naive) have hyperresponsive β-cells and lower insulin sensitivity, but their glucagon concentrations are not increased compared with those in adults. Thus, α-cell dysfunction does not appear to explain the difference in β-cell function and insulin sensitivity in youth versus adults., (© 2021 by the American Diabetes Association.)

Objective: Exposure in utero to maternal obesity or gestational diabetes mellitus (GDM) is linked to a high risk for obesity in offspring. Animal studies suggest that these exposures disrupt the development of the hypothalamus, a brain region that regulates body weight, predisposing offspring to develop obesity. This study tested the hypothesis in humans that in utero exposure to maternal obesity and/or GDM is associated with alterations in the hypothalamic response to glucose and the altered hypothalamic response would predict greater increases in child adiposity 1 year later., Research Design and Methods: Participants were 91 children aged 7-11 years with and without in utero exposure to GDM. Maternal prepregnancy BMI and GDM exposures were determined from electronic medical records. Arterial spin labeling MRI was used to determine the child's hypothalamic blood flow response to oral glucose. Anthropometric measures were acquired in all children at their initial visit and again 1 year later in a subset of 44 children., Results: Children exposed to GDM diagnosed at ≤26 weeks' gestation had increased hypothalamic blood flow (a marker of hypothalamic activation) in response to glucose when compared with unexposed children, and results remained after adjustments for child age, sex, BMI, and maternal prepregnancy BMI. Maternal prepregnancy BMI was positively associated with the child's hypothalamic response to glucose. Greater hypothalamic response to glucose predicted greater increases in child's BMI 1 year later., Conclusions: Increased glucose-linked hypothalamic activation during childhood represents a possible mechanism by which exposure to maternal metabolic disorders during fetal development increases future risk for obesity., (© 2019 by the American Diabetes Association.)

Objective: Type 2 diabetes (T2D) results from progressive loss of β-cell function. The BetaFat study compared gastric banding and metformin for their impact on β-cell function in adults with moderate obesity and impaired glucose tolerance (IGT) or recently diagnosed, mild T2D., Research Design and Methods: Eighty-eight people aged 21-65 years, BMI 30-40 kg/m 2 , with IGT or diabetes known for <1 year, were randomized to gastric banding or metformin for 2 years. Hyperglycemic clamps (11.1 mmol/L) followed by arginine injection at maximally potentiating glycemia (>25 mmol/L) were performed at baseline, 12 months, and 24 months to measure steady-state C-peptide (SSCP) and acute C-peptide response to arginine at maximum glycemic potentiation (ACPRmax) and insulin sensitivity (M/I)., Results: At 24 months, the band group lost 10.7 kg; the metformin group lost 1.7 kg ( P < 0.01). Insulin sensitivity increased 45% in the band group and 25% in the metformin group ( P = 0.30 between groups). SSCP adjusted for insulin sensitivity fell slightly but not significantly in each group ( P = 0.34 between groups). ACPRmax adjusted for insulin sensitivity fell significantly in the metformin group ( P = 0.002) but not in the band group ( P = 0.25 between groups). HbA 1c fell at 12 and 24 months in the band group ( P < 0.004) but only at 12 months ( P < 0.01) in the metformin group ( P > 0.14 between groups). Normoglycemia was present in 22% and 15% of band and metformin groups, respectively, at 24 months ( P = 0.66 between groups)., Conclusions: Gastric banding and metformin had similar effects to preserve β-cell function and stabilize or improve glycemia over a 2-year period in moderately obese adults with IGT or recently diagnosed, mild T2D., (© 2018 by the American Diabetes Association.)

Objective: To examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring., Research Design and Methods: This retrospective birth cohort study included 333,182 singletons born in 1995-2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy., Results: A total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole ( P = 0.50) or with gestational age at GDM diagnosis ( P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications ( P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09-2.25) for exposure to T1D, 1.43 (1.29-1.60) for T2D, 1.26 (1.14-1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86-1.01) for GDM not requiring medications., Conclusions: The hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes., (© 2018 by the American Diabetes Association.)

Objective: Recent studies suggest that air pollution plays a role in type 2 diabetes (T2D) incidence and mortality. The underlying physiological mechanisms have yet to be established. We hypothesized that air pollution adversely affects insulin sensitivity and secretion and serum lipid levels., Research Design and Methods: Participants were selected from BetaGene (n = 1,023), a study of insulin resistance and pancreatic β-cell function in Mexican Americans. All participants underwent DXA and oral and intravenous glucose tolerance tests and completed dietary and physical activity questionnaires. Ambient air pollutant concentrations (NO2, O3, and PM2.5) for short- and long-term periods were assigned by spatial interpolation (maximum interpolation radius of 50 km) of data from air quality monitors. Traffic-related air pollution from freeways (TRAP) was estimated using the dispersion model as NOx. Variance component models were used to analyze individual and multiple air pollutant associations with metabolic traits., Results: Short-term (up to 58 days cumulative lagged averages) exposure to PM2.5 was associated with lower insulin sensitivity and HDL-to-LDL cholesterol ratio and higher fasting glucose and insulin, HOMA-IR, total cholesterol, and LDL cholesterol (LDL-C) (all P ≤ 0.036). Annual average PM2.5 was associated with higher fasting glucose, HOMA-IR, and LDL-C (P ≤ 0.043). The effects of short-term PM2.5 exposure on insulin sensitivity were largest among obese participants. No statistically significant associations were found between TRAP and metabolic outcomes., Conclusions: Exposure to ambient air pollutants adversely affects glucose tolerance, insulin sensitivity, and blood lipid concentrations. Our findings suggest that ambient air pollutants may contribute to the pathophysiology in the development of T2D and related sequelae., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: To assess associations between dietary intake and rates of change in insulin resistance and β-cell function in Hispanic women with prior gestational diabetes mellitus (GDM)., Research Design and Methods: Sixty-two nondiabetic Hispanic women with pregnancies complicated by GDM completed oral and intravenous glucose tolerance tests and bioelectrical impedance measurements of body fat every 12-15 months postpartum for up to 12 years. Self-reported dietary intake was collected at all visits by structured food frequency questionnaires developed for Hispanics. Mixed-effects models were used to assess the relationship between dietary intake and rates of change in metabolic outcomes during follow-up., Results: The median length of follow-up from the first postpartum evaluation was 8.0 years (interquartile range 4.5-10.8 years). At baseline, women were 32 ± 5.7 years old and had a median calorie intake of 2,091 kcal/day. Over the course of follow-up, dietary intake did not change significantly. Higher baseline calorie intake was associated with a faster decline in insulin sensitivity, measured by the insulin sensitivity index (SI) (P = 0.029), and β-cell compensation, measured by the disposition index (DI) (P = 0.027), over time. These associations remained after adjustment for baseline characteristics; changes in BMI, calorie intake, levels of physical activity; and additional pregnancies during the follow-up period. The median rates were -0.06 vs. -0.02 units/year for SI and -810 vs. -692 units/year for DI for women with baseline calorie intake above versus below the cohort median., Conclusions: High calorie intake is associated with a faster decline in insulin sensitivity and β-cell compensation in Hispanic women who are at high risk for type 2 diabetes, independent of adiposity., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Plasma adiponectin levels are reduced in type 2 diabetes mellitus (T2DM) and other insulin-resistant states. We examined whether plasma adiponectin levels at baseline and after pioglitazone treatment in impaired glucose tolerance (IGT) subjects were associated with improved insulin sensitivity (SI) and glucose tolerance status., Research Design and Methods: A total of 602 high-risk IGT subjects in ACT NOW were randomized to receive pioglitazone or placebo with a median follow-up of 2.4 years., Results: Pioglitazone reduced IGT conversion to diabetes by 72% in association with improved β-cell function by 64% (insulin secretion/insulin resistance index) and increased tissue sensitivity by 88% (Matsuda index). In pioglitazone-treated subjects, plasma adiponectin concentration increased threefold from 13 ± 0.5 to 38 ± 2.5 μg/mL (P < 0.001) and was strongly correlated with the improvement in SI (r = 0.436, P < 0.001) and modestly correlated with glucose area under the curve during oral glucose tolerance test (r = 0.238, P < 0.005) and insulin secretion/insulin resistance index (r = 0.306, P < 0.005). The increase in adiponectin was a strong predictor of reversion to normal glucose tolerance and prevention of T2DM. In the placebo group, plasma adiponectin did not change and was not correlated with changes in glucose levels. There was an inverse association between baseline plasma adiponectin concentration and progression to diabetes in the placebo group but not in the pioglitazone group., Conclusions: Baseline adiponectin does not predict the response to pioglitazone. The increase in plasma adiponectin concentration after pioglitazone therapy in IGT subjects is strongly related to improved glucose tolerance status and enhanced tissue sensitivity to insulin., (© 2014 by the American Diabetes Association.)

Objective: Individuals with impaired glucose tolerance (IGT) are at high risk for developing type 2 diabetes mellitus (T2DM). We examined which characteristics at baseline predicted the development of T2DM versus maintenance of IGT or conversion to normal glucose tolerance., Research Design and Methods: We studied 228 subjects at high risk with IGT who received treatment with placebo in ACT NOW and who underwent baseline anthropometric measures and oral glucose tolerance test (OGTT) at baseline and after a mean follow-up of 2.4 years., Results: In a univariate analysis, 45 of 228 (19.7%) IGT individuals developed diabetes. After adjusting for age, sex, and center, increased fasting plasma glucose, 2-h plasma glucose, G0-120 during OGTT, HbA1c, adipocyte insulin resistance index, ln fasting plasma insulin, and ln I0-120, as well as family history of diabetes and presence of metabolic syndrome, were associated with increased risk of diabetes. At baseline, higher insulin secretion (ln [I0-120/G0-120]) during the OGTT was associated with decreased risk of diabetes. Higher β-cell function (insulin secretion/insulin resistance or disposition index; ln [I0-120/G0-120 × Matsuda index of insulin sensitivity]; odds ratio 0.11; P < 0.0001) was the variable most closely associated with reduced risk of diabetes., Conclusions: In a stepwise multiple-variable analysis, only HbA1c and β-cell function (ln insulin secretion/insulin resistance index) predicted the development of diabetes (r = 0.49; P < 0.0001).

Objective: To examine the association between self-reported physical activity (PA) and diabetes-related quantitative traits., Research Design and Methods: The observational cohort was 1,152 Mexican American adults with dual-energy X-ray absorptiometry, oral and intravenous glucose tolerance tests, and self-reported dietary and PA questionnaires. PA was categorized into three mutually exclusive groups according to the U.S. Department of Health and Human Services PA guidelines for Americans: low (vigorous <75 min/week and moderate <150 min/week), moderate (vigorous ≥75 min/week or moderate ≥150 min/week), and high (vigorous ≥75 min/week and moderate ≥150 min/week). Trends in PA groups were tested for association with metabolic traits in a cross-sectional analysis., Results: The participants' mean age was 35 years (range, 18-66 years), mean BMI was 29.6 kg/m(2), and 73% were female. Among them, 501 (43%), 448 (39%), and 203 (18%) were classified as having low, moderate, and high PA, respectively. After adjustment for age, a higher PA was significantly associated with lower 2-h glucose, fasting insulin, and 2-h insulin and greater β-cell function (P = 0.001, 0.0003, 0.0001, and 0.004, respectively). The association did not differ significantly by sex. Results were similar after further adjustment for age, sex, BMI, or percent body fat., Conclusions: An increasing level of PA is associated with a better glucose and insulin profile and enhanced β-cell function that is not explained by differences in BMI or percent body fat. Our results suggest that PA can be beneficial to β-cell function and glucose regulation independent of obesity.

Objective: To investigate the effect of nonhormonal contraception (NHC), combination oral contraception (COC), and depo-medroxyprogesterone acetate (DMPA) on lipids and blood pressure in women with recent gestational diabetes mellitus (GDM)., Research Design and Methods: An observational cohort of 972 nondiabetic, normotensive, postpartum Latino women who elected NHC (n = 448), COC (n = 430), or DMPA (n = 94) were followed for at least one subsequent metabolic evaluation on the same contraception. Baseline and follow-up measures included glucose tolerance testing, fasting serum LDL and HDL cholesterol, triglycerides, and systolic (SBP) and diastolic (DBP) blood pressure. Patterns of changes in lipids and blood pressure were evaluated by comparing slopes over follow-up time using random coefficient linear mixed-effects models., Results: Median follow-up times were 20, 12, and 11 months in the NHC, COC, and DMPA groups. The DMPA users gained significantly more weight (4.3 +/- 6.9 kg/year) compared with NHC and COC users (1.2 +/- 4.7 and 0.7 +/- 6.0 kg/year, respectively; P < 0.0001). Patterns of change in LDL cholesterol, triglycerides, and DBP were not significantly different among groups. HDL cholesterol change differed only between COC and NHC groups (adjusted slopes: 1.0 vs. -1.6 mg x dl(-1) x year(-1), respectively; P < 0.0001). SBP change differed only between COC and DMPA groups (adjusted slopes: 1.3 vs. -1.7 mmHg/year, respectively; P = 0.01)., Conclusions: These results, derived predominantly from the initial 1-2 years of treatment in Hispanic women, demonstrate that DMPA was associated with greater weight gain than NHCs or COCs. Other differences in blood pressure and lipid effects were very small. These findings should be taken into account when advising women with recent GDM about their contraceptive choices.

Objective: To investigate the impact of a long-acting injectable progestin, depo-medroxyprogesterone acetate (DMPA), compared with combination oral contraceptives (COCs) on the risk of diabetes in Latino women with prior gestational diabetes mellitus (GDM)., Research Design and Methods: An observational cohort study of 526 Hispanic women with prior GDM who were not diabetic in their postpartum visit during January 1987 to October 1997 and who elected DMPA (n = 96) or COCs (n = 430) as initial contraception were followed for a maximum of 9.2 years with a median follow-up of approximately 12 months. Oral glucose tolerance tests were performed and choice of contraception method was recorded at each visit as part of routine clinical care., Results: Annual diabetes incidence rates were 19% in the DMPA group and 12% in the COC group, with an unadjusted hazard ratio (HR) of 1.58 (95% CI 1.00-2.50; P = 0.05) for DMPA compared with COCs. Adjustment for baseline imbalances reduced the HR to 1.18 (0.67-2.28; P = 0.57). Additional adjustment for weight gain during follow-up, which was on average 1.8 kg higher in the DMPA group (P < 0.0001), reduced the HR to 1.07. DMPA interacted with baseline serum triglyceride levels and, separately, with breast-feeding to increase the diabetes risk., Conclusions: DMPA use was associated with an increased risk of diabetes that appeared to be explained by three factors: 1) use in women with increased baseline diabetes risk, 2) weight gain during use, and 3) use with high baseline triglycerides and/or during breast-feeding.

Objective: To compare the degree of insulin resistance in women with gestational diabetes mellitus (GDM) who do and do not develop preeclampsia., Research Design and Methods: We conducted a prospective cohort study of initially normotensive women with GDM who underwent oral glucose tolerance tests (OGTTs), intravenous glucose tolerance tests (IVGTTs), and glucose clamp studies in the early third trimester (n = 150) and 15 months postpartum (n = 89). After delivery, the women were categorized as nonpreeclamptic or preeclamptic (systolic blood pressure [SBP] > or = 140 mmHg, diastolic blood pressure [DBP] > or = 90 mmHg, and at least >1+ proteinuria or >300 mg/24 h). Metabolic parameters between the groups were compared by chi2 or Fisher's exact tests and ANOVA with P < 0.05 as significant., Results: A total of 29 women (19%) developed preeclampsia, which was mild in 21 and severe in 8 women. At entry, there were no differences in age, weight indexes, and glycemic measures between the nonpreeclamptic and preeclamptic groups. Those with preeclampsia were significantly taller (61.5 +/- 2.4 vs. 60.1 +/- 2.3 in, P = 0.003), were more often nulliparous (38 vs. 16%, P = 0.01), and had higher entry SBP (112 +/- 10 vs. 103 +/- 6.9 mmHg, P < 0.0001) and DBP (64 +/- 9 vs. 59 +/- 5 mmHg, P = 0.002). No significant differences between the groups were found in any measures of the OGTT glucose levels, insulin sensitivity index, glucose effectiveness, acute response to glucose, or disposition index, nor were there any differences found in the euglycemic clamp measures of basal or steady-state levels of glucose, insulin, free fatty acid, hepatic glucose output, peripheral glucose clearance, C-peptide, or glucagon. At 15 months postpartum, blood pressure levels remained significantly higher in the preeclamptic group (n = 19) compared with the nonpreeclamptic group (n = 70). No differences in any glycemic or insulin resistance measures were found., Conclusions: Women with GDM were uniformly insulin resistant. Those who developed preeclampsia, when compared with those who remained nonpreeclamptic, were not more insulin resistant in either the third trimester or 15 months postpartum. However, women who developed preeclampsia had blood pressure levels that were significantly higher, although still in the normal range, than those of women who remained nonpreeclamptic.

Objective: Recent evidence suggests that poor glycemic control is significantly associated with the development of macrovascular complications of diabetes. Studies have indicated that C-reactive protein (CRP) is an important risk factor for cardiovascular disease. The purpose of this study was to determine the relation between CRP and HbA(1c) in a large national sample of individuals with diabetes., Research Design and Methods: A nationally representative sample of noninstitutionalized U.S. adults aged 17 years and over with nongestational diabetes was derived from the National Health and Nutrition Examination Survey III (1988-1994) (n = 1,018). Respondents with diabetes were stratified by HbA(1c) level. The main outcome measure was elevated (>0.30 mg/dl) CRP., Results: In unadjusted analyses, respondents with diabetes who had elevated HbA(1c) levels (> or =9.0%) had a significantly higher percent of elevated CRP than people with low (<7%) HbA(1c) levels (P < 0.001). In adjusted regression analysis, after controlling for age, race, sex, smoking, length of time with diabetes, insulin, and BMI, HbA(1c) was significantly associated with an increased likelihood of elevated CRP for HbA(1c) >9.0% (OR 2.15, 95% CI 1.07-4.32) and for HbA(1c) >11.0% (4.40, 1.87-10.38). Higher HbA(1c) also predicted elevated CRP in the regression model when HbA(1c) was analyzed as a continuous variable (1.20, 1.07-1.34)., Conclusions: In this study, the likelihood of elevated CRP concentrations increased with increasing HbA(1c) levels. These findings suggest an association between glycemic control and systemic inflammation in people with established diabetes.

Objective: To compare management based on maternal glycemic criteria with management based on relaxed glycemic criteria and fetal abdominal circumference (AC) measurements in order to select patients for insulin treatment of gestational diabetes mellitus (GDM) with fasting hyperglycemia., Research Design and Methods: In a pilot study, 98 women with fasting plasma glucose (FPG) concentrations of 105-120 mg/dl were randomized. The standard group received insulin treatment. The experimental group received insulin if the AC, measured monthly, was > or =70th percentile and/or if any venous FPG measurement was >120 mg/dl. Power was projected to detect a 250-g difference in birth weights., Results: Gestational ages, maternal glycemia, and AC percentiles were similar at randomization. After initiation of protocol, venous FPG (P = 0.003) and capillary blood glucose levels (P = 0.049) were significantly lower in the standard group. Birth weights (3,271 +/- 458 vs. 3,369 +/- 461 g), frequencies of birth weights >90th percentile (6.3 vs 8.3%), and neonatal morbidity (25 vs. 25%) did not differ significantly between the standard and experimental groups, respectively. The cesarean delivery rate was significantly lower (14.6 vs. 33.3%, P = 0.03) in the standard group; this difference was not explained by birth weights. In the experimental group, infants of women who did not receive insulin had lower birth weights than infants of mothers treated with insulin (3,180 +/- 425 vs. 3,482 +/- 451 g, P = 0.03)., Conclusions: In women with GDM and fasting hyperglycemia, glucose plus fetal AC measurements identified pregnancies at low risk for macrosomia and resulted in the avoidance of insulin therapy in 38% of patients without increasing rates of neonatal morbidity.

The effects of subsequent states of excess hormone exposure, for example, subsequent pregnancy, hormonal contraception, and hormonal replacement therapy, on the development of diabetes in women with prior gestational diabetes were assessed. Current literature examining the effect of parity, hormonal contraception, and hormonal replacement therapy in healthy women and women with previous gestational diabetes and current diabetes was reviewed. Subsequent pregnancy in women with prior GDM appears to triple the risk of subsequent diabetes. Low-dose progestin and estrogen combination oral contraceptives do not appear to clinically increase the risk of diabetes. Hormonal replacement therapy appears to provide the greatest reduction in coronary artery disease to women at greatest risk, i.e., those who have developed diabetes. Careful follow-up and metabolic surveillance should be provided when prescribing hormonal contraception or replacement therapy. In women with prior gestational diabetes, exposure to repeat pregnancy poses a greater risk for subsequent diabetes than does either an exposure to low-dose progestin and estrogen combination oral contraceptives or to postmenopausal hormonal therapy, both of which do not appear to increase the risk of diabetes.

The metabolic management of gestational diabetes mellitus (GDM) during pregnancy traditionally has focused on maintenance of circulating maternal glucose concentrations in all patients within a range that is associated with a low rate of perinatal morbidity, especially morbidity related to excessive fetal growth and macrosomia. Clinical data reviewed elsewhere in this supplement provide guidelines for glycemic targets that appear to eliminate the excess risk to the fetus. However, because only a minority of infants are at risk for perinatal morbidity over the range of glycemia generally encountered in patients with GDM, attainment of those strict glycemic targets in all women with GDM requires implementation of self-monitoring of glucose and exogenous insulin therapy in many pregnancies that are not at risk. In this article, we review management approaches that take into account not only maternal glycemia, but also fetal growth and metabolic parameters in selecting GDM pregnancies for intensive metabolic therapy. The approaches can reduce the number of women with mild GDM who require self-monitoring of glucose and/or exogenous insulin therapy, thereby providing the potential to improve cost-effectiveness of antepartum management of GDM.

Objective: To determine whether the use of oral hypoglycemic agents during early pregnancy is associated with a risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes mellitus (NIDDM) independent of maternal metabolic control., Research Design and Methods: From a prospectively collected data-base of pregnancies complicated by diabetes at a large urban medical center, we identified 332 consecutive infants born to women with NIDDM who did not participate in a preconceptional diabetes care program. Stepwise logistical regression was used to identify maternal characteristics that were independently associated with risks of major and minor congenital malformations in infants., Results: Overall, 56 (16.9%) of the 332 infants were born with congenital anomalies (11.7% major anomalies and 5.1% minor anomalies). Analysis of data from subgroups of women who were treated with diet therapy, exogenous insulin, or sulfonylurea compounds during the first 8 weeks of gestation did not reveal statistically significant differences in major or minor malformation rates among the three groups. Stepwise logistic regression analysis revealed two maternal characteristics that were independently associated with major malformations in infants: maternal HbA1c at initial presentation for care (direct relationship; P = 0.0007) and the maternal age at onset of diabetes (inverse relationship; P = 0.009). The risk of major malformations was unrelated to the mode of antidiabetic therapy during early pregnancy. No relationship was found between maternal glycemia or treatment modality and rates of minor congenital anomalies., Conclusions: These data indicate that, in the absence of special preconceptional care, NIDDM is associated with a risk for major congenital anomalies that is in the range reported for pregnancies complicated by insulin-dependent diabetes mellitus. Moreover, the risk in individual patients appears to be related to maternal glycemic control rather than to the mode of antidiabetic therapy during early pregnancy.

Objective: To determine whether fetal ultrasound early in the third trimester can identify Latina with mild gestational diabetes mellitus (GDM) whose fetuses are at risk for macrosomia and, if so, whether maternal insulin therapy can reduce that risk., Research Design and Methods: Study subjects included 303 consecutive women with GDM and a fasting serum glucose level < 5.8 mM on diet therapy who had a fetal ultrasound between 29 and 33 weeks gestation. Of the women, 98 (32%) had a fetal AC > or = 75th percentile for gestational age, and 59 women completed a randomized trial of diet therapy (n = 29) or diet plus twice daily insulin (n = 30). Maternal nutrient levels were assessed by meal tolerance testing (MTT) before and during therapy and by capillary glucose monitoring four to seven times a day. Birth weights corrected for gestational age and neonatal glycemia and skin folds were the primary outcome variables compared between treatment groups., Results: Diet and diet-plus-insulin groups were well matched for maternal age, prepregnancy relative weight, weight gain during pregnancy, and glycemia at entry. Insulin therapy reduced maternal capillary (P < 0.005) and MTT (P < 0.001) glucose levels and prevented a diet-associated rise in MTT triglyceride levels (P < 0.002). Gestational age at delivery was similar in insulin- and diet-treated groups (39.6 +/- 0.2 vs. 39.5 +/- 0.2 weeks). Birth weights (3,647 +/- 67 vs. 3,878 +/- 84 g; P < 0.02), the prevalence of large-for-gestational age infants (13 vs. 45%, P < 0.02), and neonatal skin-fold measurements at three sites (P < 0.005) were reduced in the insulin-treated group. Rates of transient neonatal hypoglycemia were low in both treatment groups (14 and 18%, respectively) and did not differ significantly between groups., Conclusions: Fetal ultrasound early in the third trimester identified women with mild GDM whose infants were at high risk for fetal macrosomia in the absence of standard glycemic criteria for insulin therapy. Insulin treatment reduced the macrosomia, indicating that fetal ultrasound can be used to guide metabolic therapy in pregnancies complicated by mild GDM.