The impact of risk factors and more stringent diagnostic criteria of gestational diabetes on outcomes in central European women.

OBJECTIVES: In the face of the ongoing discussion on the criteria for the diagnosis of gestational diabetes (GDM), we aimed to examine whether the criteria of the Fourth International Workshop Conference of GDM (WC) select women and children at risk better than the World Health Organization (WHO) criteria. DESIGN AND SETTING: This was a prospective longitudinal open study in five tertiary care centers in Austria. PATIENTS AND OUTCOME MEASURES: The impact of risk factors, different thresholds (WC vs. WHO), and numbers of abnormal glucose values (WC) during the 2-h, 75-g oral glucose tolerance test on fetal/neonatal complications and maternal postpartum glucose tolerance was studied in 1466 pregnant women. Women were treated if at least one value according to the WC (GDM-WC1) was met or exceeded. RESULTS: Forty-six percent of all women had GDM-WC1, whereas 29% had GDM-WHO, and 21% of all women had two or three abnormal values according to WC criteria (GDM-WC2). Eighty-five percent of the GDM-WHO were also identified by GDM-WC1. Previous GDM [odds ratio (OR) 2.9], glucosuria (OR 2.4), preconceptual overweight/obesity (OR 2.3), age 30 yr or older (OR 1.9), and large-for-gestational age (LGA) fetus (OR 1.8) were the best independent predictors of the occurrence of GDM. Previous GDM (OR 4.4) and overweight/obesity (OR 4.0) also independently predicted diabetes postpartum. GDM-WC1 had a higher rate of obstetrical complications (LGA neonates, neonatal hypoglycemia, cesarean sections; P < 0.001) and impaired postpartum glucose tolerance (P < 0.0001) than GDM-WHO. CONCLUSION: These results suggest the use of more stringent WC criteria for the diagnosis of GDM with the initiation of therapy in case of one fasting or stimulated abnormal glucose value because these criteria detected more LGA neonates with hypoglycemia and mothers with impaired postpartum glucose metabolism than the WHO criteria.

Asymmetrical dimethylarginine is related to renal function, chronic inflammation and macroangiopathy in patients with Type 2 diabetes and albuminuria.

AIMS: Patients with Type 2 diabetes mellitus (T2DM) and micro- and macroalbuminuria are at increased cardiovascular risk. The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in renal failure and could promote atherosclerosis. To determine the relationship between ADMA, renal albumin excretion rate (AER) and cardiovascular risk, we studied 103 T2DM patients. METHODS: ADMA, symmetrical dimethylarginine (SDMA) and L-arginine were determined by high-performance liquid chromatography in plasma from 36 normo-, 40 micro- and 27 macroalbuminuric patients with T2DM (age 64 +/- 11 years; 38 women) who had comparable age, sex and metabolic parameters. Forty-six patients had macrovascular disease (MVD). RESULTS: ADMA was significantly increased in patients with micro- and macroalbuminuria [median 0.61 (interquartile range 0.55-0.70) micromol/l and 0.62 (0.50-0.79) micromol/l, respectively] compared with those with normoalbuminuria [0.55 (0.48-0.63) micromol/l; both P < 0.05]. SDMA was elevated in micro- and macroalbuminuria [0.57 (0.42-0.80) micromol/l and 0.64 (0.50-0.96) micromol/l] compared with normoalbuminuric subjects [0.44 (0.37-0.53) micromol/l; both P < 0.01]. Patients with increased AER and MVD had higher ADMA and SDMA compared with those without MVD (both P < 0.001). L-arginine was comparable between all groups. ADMA correlated significantly with high-sensitivity C-reactive protein (hsCRP) and glomerular filtration rate (GFR) but not with the extent of albumin excretion, body mass index, fasting glucose, HbA(1c) or plasma lipids. CONCLUSIONS: Increased ADMA in T2DM patients with albuminuria is linked to cardiovascular disease and is associated with renal dysfunction and subclinical inflammation.

Preprandial vs. postprandial insulin lispro-a comparative crossover trial in patients with Type 1 diabetes.

AIMS: Administration of bolus insulin after eating may be a useful therapeutic option for some patients. This 6-month, crossover study compared metabolic effects of routine use of preprandial vs. postprandial injection of bolus insulin lispro. METHODS: Thirty-one patients with Type 1 diabetes injected insulin lispro either preprandially or postprandially for a 3-month period followed by the alternate regimen for a further 3 months. HbA1c, fructosamine and eight-point self-determined blood glucose profiles were measured and analysed using an anova model appropriate for a crossover design. RESULTS: Mean HbA1c decreased slightly from baseline with preprandial (-0.15 +/- 0.41%) and increased slightly with postprandial (0.11 +/- 0.48%) insulin lispro so that there was a significant (P = 0.008) difference between treatments in final HbA1c level. Mean fructosamine also decreased slightly with preprandial (-15 +/- 31 micro mol/l) but was almost unchanged (1 +/- 39 micro mol/l) with postprandial insulin lispro. Overall daily blood glucose was not different (P = 0.312) for preprandial compared with postprandial administration. However, mean preprandial glucose was lower (7.5 +/- 2.01 vs. 6.6 +/- 1.22 mmol/l; P = 0.026), whereas mean postprandial glucose was higher (7.7 +/- 1.8 vs. 8.7 +/- 2.1 mmol/l; P = 0.031) with postprandial insulin lispro administration. Mean blood glucose excursions were higher with postprandial compared with preprandial insulin lispro, indicating greater daily fluctuations. No difference in incidence of hypoglycaemia was observed with the two treatment regimens. CONCLUSIONS: Postprandial insulin lispro administration appeared to be an acceptable treatment regimen and may be of benefit in certain situations. However, the benefits of postprandial administration may have to be balanced against poorer glycaemic control with continuous long-term use.

A serine/alanine polymorphism in the nucleotide-binding fold-2 of the sulphonylurea receptor-1 (S1369A) is associated with enhanced glucose-induced insulin secretion during pregnancy.

The sulphonylurea receptor-1 (SUR-1) regulates glucose-induced insulin secretion by controlling K+-ATP channel activity of the pancreatic beta-cell membrane. In this study, we investigated the putative role of a T/G-polymorphism (exon 33, codon 1369; S1369A) in the adenosine diphosphate-sensing nucleotide-binding fold-2 (NBF-2) of the SUR-1 on glucose-induced insulin secretion during an oral glucose tolerance test in pregnant women (PW; n=182). Compared to PW with the T/T genotype, statistically significant elevated C-peptide concentrations were found 60 min after glucose intake in PW with the T/G and G/G genotype (T/T 9.0+/-0.4 ng/ml vs T/G 10.8+/-0.4 ng/ml or G/G 10.8+/-0.7 ng/ml, p=0.01). Furthermore, compared to PW with T/T genotype the deltaC-peptide (60/0 min) was significantly enhanced in PW with T/G or G/G genotype (T/T 6.7+/-0.3 vs T/G 8.9+/-0.4 or G/G 8.9+/-0.7, p=0.0009). A significant correlation of C-peptide concentrations with blood glucose (BG) 60 min after glucose intake was only found in PW with the T/T genotype (r=0.6, p<0.0004). Similarly, a significant correlation of insulin concentrations with BG 60 min after glucose intake was observed in PW with T/T genotype (r=0.5, p<0.0001) and T/G genotype (r=0.24, p<0.03) but not in PW with G/G genotype (r=0.01, p=0.9). From our data we conclude that in PW with the alanine substitution in the NBF-2 region, the insulin response of the pancreatic beta-cell after glucose intake is enhanced and does not correlate with actual BG levels.

Proinsulin in pregnant women with normal glucose tolerance or mild gestational diabetes mellitus.

Pregnancy is characterized by peripheral insulin resistance, which is physiologically compensated by an increase in insulin secretion. Type 2 diabetes and impaired glucose tolerance (IGT) have been associated with an inappropriate increase in insulin precursors, namely proinsulin. The aim of this study was to determine levels of proinsulin (PI), specific insulin (SI) and the proinsulin-to-specific insulin (PI/SI) ratio in consecutive pregnant women (n = 209) with normal glucose tolerance (NGT), as assessed by a 2h oral glucose tolerance test, and with mild gestational diabetes (GDM), in comparison to 32 healthy, non-pregnant women. Furthermore, we related these variables to surrogate markers of insulin resistance and insulin secretion. We found no significant differences in the levels of PI and the PI/ SI ratio between pregnant and non-pregnant women (PI: 5.0 +/- 3.6 vs. 4.8 +/- 3.5 pmol/L, p = NS), and between pregnant women with mild GDM and NGT (PI: 5.4 +/- 2.4 vs. 4.9 +/- 3.9 pmol/L, p = NS). SI was elevated in women with mild GDM (112.2 +/- 47.3 vs. 94.8 +/- 43.0 pmol/L in NGT, p=0.02). PI was related to fasting glucose (r = 0.17, p < 0.02), but not post-load glucose levels, and to fasting insulin [specific insulin: r = 0.67, p = 0.0001; total immunoreactive insulin (IRI): r = 0.69, p = 0.0001], as well as post-load insulin levels (IRI at 120 min: r = 0.18, p < 0.03). The PI/SI ratio showed no association with fasting or post-load glucose or insulin levels. Pregnant women presented with a metabolic pattern suggestive of enhanced insulin resistance, namely increased fasting and post-load insulin levels. In women with mild GDM, fasting and post-load hyperglycemia, as well as an additional increase in insulin resistance was found. Group differences weakened when accounting for differences in body weight. The data of the present study suggest that in normal pregnancy as well as mild GDM metabolic alterations including enhanced insulin resistance and hyperglycemia do not result in an increase in circulating levels of proinsulin, both in absolute terms and relative to levels of specific insulin, as indicated by the proinsulin-to-specific insulin ratio.

Relative hypoleptinaemia in women with mild gestational diabetes mellitus.

AIMS: There is increasing evidence suggesting that leptin plays a major role in the regulation of energy homeostasis, as well as in the neuroendocrine and reproductive systems. Leptin is synthesized in the human placenta. The aim of this study was to relate serum leptin levels during pregnancy to glucose tolerance, body mass index (BMI) and specific metabolic variables, such as specific insulin and proinsulin. METHODS: A 2-h 75 g oral glucose tolerance test was performed in 221 pregnant women at 22-29 weeks of gestation (median 25th week). Serum leptin was measured using a radioimmunoassay. In 49 women, sequential leptin measurements were performed (during pregnancy and post partum (median 5 months)). RESULTS: During pregnancy serum leptin was significantly related to body weight (r = 0.49), BMI (r = 0.51), fasting immunoreactive insulin (r = 0.46), specific insulin (r = 0.43) and proinsulin (r = 0.29) (all P-values <0.0001). In women with mild gestational diabetes (GDM, n = 55), leptin levels were lower compared to women with normal glucose tolerance (n = 166) after adjusting for BMI and fasting insulin (26.9 vs. 19.4 ng/ml, P = 0.0001). Leptin was significantly higher during pregnancy compared to post partum (mean +/- SE: 24.3+/-1.5 vs. 19.6+/-1.6 ng/ml, P = 0.0003), even after adjustment for changes in BMI and changes in fasting insulin (P = 0.013). CONCLUSIONS: Leptin levels are elevated in pregnancy. Women with mild GDM presented with relative hypoleptinaemia compared to women with normal glucose tolerance.

Trp64Arg polymorphism of the beta3-adrenergic receptor gene in pregnancy: association with mild gestational diabetes mellitus.

A missense mutation of the beta3-adrenergic receptor gene (Trp64Arg) has been associated with obesity and increased capacity to gain weight in nonpregnant populations. Furthermore, the mutation is a potential modifying factor in the etiology of impaired glucose tolerance and type 2 diabetes. We studied the relation of the beta3-adrenergic receptor genotype to glucose tolerance during pregnancy, a state of physiological insulin resistance. In 179 pregnant women (mean age, 28.5 +/- 0.4 yr), a 2-h oral glucose tolerance test was performed between gestational weeks 20 and 31. The beta3-adrenergic receptor genotype was assessed using restriction fragment length polymorphism. The frequency of the Arg64 allele was 9.15%. In women with mild gestational diabetes (n = 70), as defined by 60 min postload glucose values, the Trp64Arg genotype was more frequent than in women with normal glucose tolerance (n = 109; 26% vs. 11%; P = 0.01). Furthermore, the Trp64Arg polymorphism was associated with increased weight gain during pregnancy (baseline to gestational weeks 20-31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test. The results of the present study extend current knowledge about the association of the Trp64Arg beta3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The association with mild gestational diabetes suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance.

Gastric emptying in Type II (non-insulin-dependent) diabetes mellitus before and after therapy readjustment: no influence of actual blood glucose concentration.

AIMS/HYPOTHESIS: Hyperglycaemia that is induced short-term slows gastric emptying in healthy subjects and patients with diabetes mellitus. Little information is available on the impact of longer-lasting, naturally occurring blood glucose increases and their reduction to euglycaemic values. We studied the relation between gastric emptying and pre-prandial and postprandial blood glucose concentrations in patients with Type II (non-insulin-dependent) diabetes mellitus and secondary failure to respond to oral hypoglycaemic treatment (a) before readjusting hypoglycaemic therapy and (b) 1 week thereafter. METHODS: We studied 9 female and 1 male patient (age 60-78 years, BMI 21.9-32.5 kg/m2, diabetes duration 3-33 years, HbA1c 8.8-13.2%). Gastric emptying of a radiolabelled semisolid 1168 kJ meal was recorded scintigraphically. RESULTS: Blood glucose concentration pre-prandial and postprandial was considerably lower subsequent to than before therapy readjustment in all patients (fasting, 7.9 mmol/l+/-1.5 SD vs 11.7+/-1.7 mmol/l; 60 min postprandial, 11.7+/-2.0 vs 15.4+/-2.2 mmol/l). By contrast, gastric emptying was unchanged (residual radioactivity in stomach 50 min postprandial 65.7+/-14.1% vs 66.5+/-12.9%). There was no relation between emptying and either fasting blood glucose concentration or its postprandial increase. CONCLUSION/INTERPRETATION: The data do not support a major impact of actual, longer-lasting, naturally occurring blood glucose concentrations upon the rate of gastric emptying in patients with Type II diabetes.