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OBJECTIVE Recent studies indicate that sodium-glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP), potentially counteracting the glucose-lowering potency, and stimulates lipid oxidation and lipolysis. However, the acute effects of SGLT-2 inhibition on hepatic glycogen, lipid, and energy metabolism have not yet been analyzed. We therefore investigated the impact of a single dose of dapagliflozin (D) or placebo (P) on hepatic glycogenolysis, hepatocellular lipid (HCL) content and mitochondrial activity (kATP). RESEARCH DESIGN AND METHODS Ten healthy volunteers (control [CON]: age 30 ± 3 years, BMI 24 ± 1 kg/m2, HbA1c 5.2 ± 0.1%) and six patients with type 2 diabetes mellitus (T2DM: age 63 ± 4 years, BMI 28 ± 1.5 kg/m2, HbA1c 6.1 ± 0.5%) were investigated on two study days (CON-P vs. CON-D and T2DM-P vs. T2DM-D). 1H/13C/31P MRS was performed before, 90–180 min (MR1), and 300–390 min (MR2) after administration of 10 mg dapagliflozin or placebo. EGP was assessed by tracer dilution techniques. RESULTS Compared with CON-P, EGP was higher in CON-D (10.0 ± 0.3 vs. 12.4 ± 0.5 μmol kg−1 min−1; P < 0.05) and comparable in T2DM-D and T2DM-P (10.1 ± 0.7 vs. 10.4 ± 0.5 μmol kg−1 min−1; P = not significant [n.s.]). A strong correlation of EGP with glucosuria was observed (r = 0.732; P < 0.01). The insulin-to-glucagon ratio was lower after dapagliflozin in CON-D and T2DM-D compared with baseline (P < 0.05). Glycogenolysis did not differ between CON-P and CON-D (−3.28 ± 0.49 vs. −2.53 ± 0.56 μmol kg−1 min−1; P = n.s.) or T2DM-P and T2DM-D (−0.74 ± 0.23 vs. −1.21 ± 0.33 μmol kg−1 min−1; P = n.s.), whereas gluconeogenesis was higher after dapagliflozin in CON-P compared with CON-D (6.7 ± 0.6 vs. 9.9 ± 0.6 μmol kg−1 min−1; P < 0.01) but not in T2DM. No significant changes in HCL and kATP were observed. CONCLUSIONS The rise in EGP after SGLT-2 inhibition is due to increased gluconeogenesis, but not glycogenolysis. Changes in glucagon and the insulin-to-glucagon ratio are not associated with an increased hepatic glycogen breakdown. HCL and kATP are not significantly affected by a single dose of dapagliflozin.

Implementation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) and the World Health Organization 2013 (WHO 2013) recommendations leads to an increased prevalence of gestational diabetes mellitus (GDM) due to more stringent criteria and early screening of women at high risk for diabetes in pregnancy (DIP) (1,2). IADPSG members now recommend that their GDM criteria should not be used in early pregnancy but have not provided alternative criteria (3). We have compared the characteristics of overweight/obese women early in pregnancy, with and without GDM using the new criteria, to assess whether those testing positive are metabolically distinct. Pregnant women with a BMI ≥29.0 kg/m2 underwent a 75-g oral glucose tolerance test in early pregnancy as part of enrollment into the DALI (Vitamin D And Lifestyle Intervention for GDM prevention) pilot and lifestyle Pan-European multicenter trials (4). GDM and DIP were diagnosed using WHO 2013 criteria. A high rate of GDM (237/1,035 or 22.9%: DIP 0.5%; total hyperglycemia in early pregnancy 23.4%) was found at a …

OBJECTIVE Ways to prevent gestational diabetes mellitus (GDM) remain unproven. We compared the impact of three lifestyle interventions (healthy eating [HE], physical activity [PA], and both HE and PA [HE+PA]) on GDM risk in a pilot multicenter randomized trial. RESEARCH DESIGN AND METHODS Pregnant women at risk for GDM (BMI ≥29 kg/m2) from nine European countries were invited to undertake a 75-g oral glucose tolerance test before 20 weeks' gestation. Those without GDM were randomized to HE, PA, or HE+PA. Women received five face-to-face and four optional telephone coaching sessions, based on the principles of motivational interviewing. A gestational weight gain (GWG) RESULTS Among the 150 trial participants, 32% developed GDM by 35–37 weeks and 20% achieved GWG CONCLUSIONS An antenatal HE intervention is associated with less GWG and lower fasting glucose compared with PA alone. These findings require a larger trial for confirmation but support the use of early HE interventions in obese pregnant women.

OBJECTIVE—Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence of angiopathies. Gestational diabetes mellitus (GDM) is an early manifestation of type 2 diabetes in pregnant women. It is usually confined to the time of gestation, but carries an increased risk to develop type 2 diabetes later in life. RESEARCH DESIGN AND METHODS—From consecutive Caucasian pregnant women (n = 250) referred for oral glucose tolerance testing, the Hp phenotype was determined. Significance of distribution and odds ratios (ORs) associated with Hp phenotype were calculated for women with GDM (n = 110) and women with normal glucose tolerance (n = 140). RESULTS—Frequency of GDM in Hp phenotype classes increased with the number of Hp2 alleles (P < 0.001). ORs for GDM in women heterozygous and homozygous for Hp2 were 2.7 (95% CI 1.06–6.84) and 4.2 (1.67–10.55), respectively. CONCLUSIONS—Hp phenotype is an apparent risk factor for the development of GDM in our study population. This might be due to the low antioxidative potential of Hp2 compared with Hp1.

OBJECTIVE—Women with prior gestational diabetes mellitus (pGDM) are at increased risk of developing type 2 diabetes and associated vasculopathy. Because increased fat mass and inflammatory processes are angiopathic risk factors, the relationship between insulin sensitivity, parameters of subclinical inflammation, and plasma concentrations of adipocytokines was investigated in pGDM both at 3 months and 12 months after delivery. RESEARCH DESIGN AND METHODS—Insulin sensitivity (through a frequently sampled intravenous glucose tolerance test) and plasma concentrations of ultrasensitive C-reactive protein (CRP), adiponectin, plasminogen activator inhibitor (PAI)-1, tumor necrosis factor-α, leptin, and interleukin-6 were measured in 89 pGDM (BMI 26.9 ± 0.5 kg/m2, age 32 ± 0.5 years) and in 19 women with normal glucose tolerance during pregnancy (NGT) (23.7 ± 0.9 kg/m2, 31 ± 1.3 years). RESULTS—pGDM showed lower (P < 0.0001) plasma adiponectin (6.7 ± 0.2 μg/ml) than NGT (9.8 ± 0.6 μg/ml) and a decreased (P < 0.003) insulin sensitivity index (Si) and disposition index (P < 0.03), but increased plasma leptin (P < 0.003), PAI-1 (P < 0.002), and CRP (P < 0.03). After adjustment for body fat mass, plasma adiponectin remained lower in pGDM (P < 0.004) and correlated positively with Si (P < 0.003) and HDL cholesterol (P < 0.0001) but negatively with plasma glucose (2-h oral glucose tolerance test [OGTT]) (P < 0.0001), leptin (P < 0.01), CRP (P < 0.007), and PAI-1 (P < 0.0001). On regression analysis, only HDL cholesterol, postload (2-h OGTT) plasma glucose, and Si remained significant predictors of plasma adiponectin, explaining 42% of its variability. Of note, adiponectin further decreased (P < 0.05) only in insulin-resistant pGDM despite unchanged body fat content and distribution after a 1-year follow-up. CONCLUSIONS—Lower plasma adiponectin concentrations characterize women with previous GDM independently of the prevailing insulin sensitivity or the degree of obesity and are associated with subclinical inflammation and atherogenic parameters.

OBJECTIVE—The relationship between splanchnic glucose uptake (SGU) after oral glucose administration and metabolic control in type 1 diabetic patients is controversial. We estimated SGU as well as peripheral glucose uptake and the time required for glucose absorption by a validated method, the oral glucose (OG) clamp, in type 1 diabetic patients with different levels of long-term glycemic control. RESEARCH DESIGN AND METHODS—An OG clamp (which combines a hyperinsulinemic clamp [120 mU · m−2 · min−1] with an OR load [75 g] during steady-state glucose uptake) was performed in eight type 1 diabetic patients with good metabolic control (DG) (HbA1c 6.1 ± 0.2%, BMI 23.1 ± 0.7 kg/m2), eight type 1 diabetic patients with poor metabolic control (DP) (HbA1c 8.5 ± 0.3%, BMI 25.4 ± 1.4 kg/m2), and eight healthy matched control subjects (C) (HbA1c 5.1 ± 0.1%, BMI 25 ± 1.3 kg/m2) to determine SGU, glucose uptake, and glucose absorption. RESULTS—Glucose uptake calculated from 120 to 180 min during the clamp was 9.13 ± 0.55 mg · kg−1 · min−1 in C, 8.18 ± 0.71 mg · kg−1 · min−1 in DG, and 7.42 ± 0.96 mg · kg−1 · min−1 in DP (NS). Glucose absorption was 140 ± 6 min in C, 156 ± 4 min in DG, and 143 ± 7 min in DP (NS). The respective calculated SGU was 14.5 ± 5.6% in C, 17.8 ± 3.1% in DG, and 18.8 ± 4.2% in DP (NS) and did not correlate with HbA1c values. CONCLUSIONS—Peripheral glucose uptake, SGU after oral glucose administration, and the glucose absorption time were not different in type 1 diabetic patients independent of glycemic control when compared with healthy subjects.

OBJECTIVE Alterations in maternal lipid metabolism could affect fetal programming and the susceptibility for atherosclerosis in the offspring; therefore, we studied differences in lipid profiles of pregnant women with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 173 diabetic pregnancies were studied prior to conception (V0), at each trimester (V1–V3), and after delivery and were compared with 137 healthy women at V3. RESULTS During gestation, the increase in serum lipid concentrations was less pronounced in type 2 diabetic subjects. At V3, the lipid levels of type 1 diabetic women with normal glucose tolerance were similar but significantly higher then those of type 2 diabetic women. Elevated triglycerides and low HDL cholesterol at V3 were significant predictors for large-for-gestational-age (LGA) newborns. CONCLUSIONS Our data suggest smaller changes in serum lipid concentrations during pregnancy in type 2 diabetic mothers. Additionally, we found a positive association between maternal triglycerides and LGA infants independently of chronic glycemic control.

The insulin-mimetic adipocytokine visfatin has been associated with insulin resistance in some studies and is regulated by glucose. We hypothesized that glucose-induced changes in plasma visfatin are different in women with gestational diabetes mellitus (GDM). Plasma visfatin concentrations were studied in 10 women with GDM and 10 age-matched healthy women in pregnancy week 24-28 during a standard oral glucose tolerance test (OGTT). Women with GDM had lower systemic visfatin concentrations than controls (1.9±0.8 ng/ml vs 5.2±4.4 ng/ml, respectively, p

OBJECTIVE To compare total retinal blood flow in diabetic patients with no or mild nonproliferative diabetic retinopathy and healthy control subjects and to investigate in patients whether there is a difference between retinal blood flow before morning insulin and under normoglycemic conditions using a glucose clamp. RESEARCH DESIGN AND METHODS Twenty patients with type 1 diabetes with no or mild diabetic retinopathy were included in this open parallel-group study, and 20 healthy age- and sex-matched subjects were included as control subjects. Retinal blood flow was assessed by combining velocity measurements using laser Doppler velocimetry and diameter measurements using a commercially available dynamic vessel analyzer. Measurements were performed before and during a euglycemic clamp. RESULTS Total retinal blood flow was higher in diabetic patients (53 ± 16 μl/min) than in healthy subjects (43 ± 16 μl/min; P = 0.034 between groups). When plasma glucose in diabetic patients was reduced from 9.3 ± 1.7 to 5.3 ± 0.5 mmol/l (P < 0.001) retinal blood flow decreased to 49 ± 15 μl/min (P = 0.0003 vs. baseline). Total retinal blood flow during the glucose clamp was not significantly different from blood flow in normal control subjects (P = 0.161). CONCLUSIONS Type 1 diabetic patients with no or only mild diabetic retinopathy have increased retinal blood flow before their morning insulin dosage. Blood flow is reduced toward normal during euglycemic conditions. Retinal blood flow may fluctuate significantly with fluctuating plasma glucose levels, which may contribute to the microvascular changes seen in diabetic retinopathy.

OBJECTIVE There is growing evidence that osteocalcin, an osteoblast-derived protein locally acting on bone formation, can increase insulin secretion as well as insulin sensitivity and thus prevent the development of obesity and diabetes in experimental animals. In humans, osteocalcin has been reported to be decreased in patients with type 2 diabetes. Because gestational diabetes mellitus (GDM) can serve as a model of pre–type 2 diabetes, the aim of this study was to investigate osteocalcin in GDM. RESEARCH DESIGN AND METHODS Osteocalcin measurement and an oral glucose tolerance test were performed in 78 pregnant women (26 women had GDM and 52 women had normal glucose tolerance [NGT] during pregnancy; women were matched for age and BMI) and in 34 women postpartum. RESULTS During pregnancy osteocalcin was significantly higher in the women with GDM than in the women with NGT (15.6 ± 6.4 vs. 12.6 ± 4.0 ng/ml; P < 0.015), whereas no difference was observed between the two groups at 12 weeks postpartum (36.2 ± 10.2 vs. 36.2 ± 13.0 ng/ml), when osteocalcin was found to be increased compared with the level in the pregnant state in all women (+145 ± 102% in GDM vs. +187 ± 119% in NGT; P < 0.0001). Moreover, osteocalcin showed a significant correlation with basal and total insulin secretion in the whole study group (R = 0.3, P < 0.01). CONCLUSIONS In GDM osteocalcin was higher and thus less restrained than in women with NGT during pregnancy and furthermore correlated with insulin secretion parameters. Therefore, it could be hypothesized that osteocalcin can enhance insulin secretion in insulin-resistant states; alternatively an effect of hyperinsulinemia on osteocalcin secretion cannot be excluded.

There is considerable and growing interest in neutraceutical products for the treatment of diabetes (1). Recently, it has been shown that caiapo, the extract of white-skinned sweet potato ( Ipomoea batatas ), improves glycemic control in rodents by reducing insulin resistance (2). The aim of our study was to assess the effect of caiapo on glucose metabolism and its tolerability and mode of action in male Caucasian type 2 diabetic patients in a randomized, double-blind prospective study in parallel groups controlled with placebo. A total of 18 male type 2 diabetic patients (age: 58 ± 8 years; weight: 88 ± 3 kg; BMI: 27.7 ± 2.7 kg/m2; means ± SEM) treated by diet alone were randomized to receive placebo or 2 (low dose) or 4 g (high dose) caiapo (four tablets each containing 168 or 336 mg powdered white-skinned sweet potato [ I. batatas ], respectively) before breakfast, lunch, and dinner for 6 weeks. The study protocol was approved by the Ethics Committee of the University of Vienna, and informed consent was obtained from all patients before inclusion into the study. Safety parameters (hematology and blood chemistry, including hepatic enzymes and urinanalysis) were controlled before and at the end of the study, and patients were asked to report any adverse events. Patients were seen weekly during the 6-week trial, and fasting blood glucose was measured. Each subject underwent a frequently sampled intravenous glucose tolerance test (FSIGT) …