Lack of effect of subtherapeutic vitamin D treatment on glycemic and lipid parameters in Type 2 diabetes: A pilot prospective randomized trial.

BACKGROUND: Epidemiological studies suggest a higher prevalence of metabolic syndrome and its components among individuals with vitamin D deficiency. The aim of the present study was to determine whether vitamin D treatment improves glucose control and insulin sensitivity in Type 2 diabetes mellitus (T2DM). METHODS: Subjects with T2DM and serum 25-hydroxyvitamin D (25(OH)D) concentrations <25 ng/mL were randomized to receive 400 IU (Group 1) or 1200 IU (Group 2) cholecalciferol for 4 months. Fasting plasma glucose, glycosylated hemoglobin (HbA1c), Quantitative Insulin Sensitivity Check Index (QUICKI), serum lipid levels and serum adiponectin were measured at baseline and at 4 months. RESULTS: Mean 25(OH)D levels increased in both groups (from 17.6±1.5 to 25.5±1.8 ng/mL in Group 1 and from 15.6±1.4 to 27.4±2.4 ng/mL in Group 2; P≤0.001 vs baseline for each group). No significant differences were noted in fasting plasma glucose, HbA1c, QUICKI, serum adiponectin, and lipid levels compared with baseline within groups or between the two groups. CONCLUSIONS: In the present pilot study, conventional vitamin D treatment at a level improving, but not optimizing, serum 25(OH)D did not improve glycemia, insulin sensitivity, or lipid profile. However, diabetes and lipids were relatively well controlled at baseline. Future studies should be designed to achieve optimal concentrations of serum 25(OH)D (at least >32 ng/mL) and should include subjects showing more abnormal parameters of glycemia, lipid, and insulin sensitivity at baseline.

Interactions among peroxisome proliferator activated receptor-gamma, insulin signaling pathways, and steroidogenic acute regulatory protein in human ovarian cells.

CONTEXT AND OBJECTIVE: Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists thiazolidinediones (TZDs) are thought to ameliorate hyperandrogenism in polycystic ovary syndrome by reducing hyperinsulinemia. However, TZDs also exhibit direct effects in the human ovary. We examined interactions among PPAR-gamma, insulin signaling pathways, and steroidogenic acute regulatory (StAR) protein in human ovarian cells. MATERIALS AND METHODS: Mixed human ovarian tissue culture that contained granulosa, theca, and stromal cells, and a culture of purified granulosa cells obtained during in vitro fertilization, were established as previously described. Cells were cultured in the presence or absence of insulin, with or without 25 or 50 microm rosiglitazone or pioglitazone. Expression of PPAR-gamma, insulin receptor, or insulin receptor substrate (IRS)-1 in both cell systems and of the StAR protein in granulosa cells was measured using immunoprecipitation and immunoblotting. RESULTS: Rosiglitazone stimulated expression of PPAR-gamma, insulin receptor alpha- and beta-subunits, and IRS-1 up to 168% (P < 0.05), 679% (P < 0.006), 290% (P < 0.037), and 323% (P < 0.01) of baseline, respectively. Pioglitazone stimulated expression of PPAR-gamma, insulin receptor alpha- and beta-subunits, and IRS-1 up to 222% (P < 0.01), 362% (P < 0.001), 402% (P < 0.029), and 492% (P < 0.03), respectively. Insulin alone stimulated expression of PPAR-gamma, alpha-subunit and beta-subunit of insulin receptor, and IRS-1 up to 174% (P < 0.001), 692% (P < 0.014), 275% (P < 0.024), and 431% (P < 0.01), respectively. In purified granulosa cell culture, rosiglitazone stimulated expression of StAR protein up to 540% (P < 0.007), and pioglitazone stimulated expression of StAR protein up to 670% (P < 0.007). Insulin alone stimulated expression of StAR protein up to 600% (P < 0.012). CONCLUSIONS: Insulin and TZDs independently stimulate expression of PPAR-gamma, insulin receptor, IRS-1, and StAR protein in human ovarian cells. Thus, PPAR-gamma, insulin receptor with its signaling pathways, and StAR protein constitute a novel human ovarian regulatory system with complex interactions among its components.

Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production.

CONTEXT AND OBJECTIVE: Hyperinsulinemia contributes to the pathogenesis of ovarian dysfunction in insulin-resistant states, including polycystic ovary syndrome (PCOS). Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonists [thiazolidinediones (TZDs)] ameliorate hyperandrogenism in polycystic ovary syndrome presumably because they reduce systemic hyperinsulinemia. Direct effects of TZDs in the ovary, however, cannot be excluded. We explored direct effects of TZDs in cultured human ovarian cells. METHODS: Human ovarian cells, obtained from oophorectomy specimens, were cultured in the presence or absence of rosiglitazone or pioglitazone, insulin, and gonadotropins. Steroid hormone and IGF-binding protein-1 (IGFBP-1) concentrations were measured in conditioned tissue culture medium. RESULTS: Rosiglitazone or pioglitazone stimulated progesterone production up to 156% (P < 0.001) and 131% (P < 0.001) of baseline, respectively. Pioglitazone but not rosiglitazone, inhibited baseline and FSH-stimulated estradiol production by 20% (P < 0.001) and 50% (P < 0.001), respectively. Both rosiglitazone and pioglitazone abolished insulin-dependent stimulation of estradiol production in the presence of FSH. Rosiglitazone and pioglitazone inhibited testosterone production by 10% (P < 0.012) and 15% (P < 0.023), respectively, and abolished insulin-induced stimulation of testosterone production. In the absence of insulin, pioglitazone or rosiglitazone stimulated IGFBP-1 production up to 160% (P < 0.001) and 125% (P < 0.036) of baseline, respectively. Pioglitazone and rosiglitazone enhanced insulin-induced inhibition of IGFBP-1 production by 13% and 20%, respectively (P < 0.001). CONCLUSIONS: PPAR-gamma agonists directly stimulate progesterone and IGFBP-1 production, inhibit estradiol and testosterone production, abolish insulin-induced stimulation of testosterone production and insulin-dependent stimulation of estradiol production in the presence of FSH, and enhance insulin-induced inhibition of IGFBP-1 production in human ovarian cells. PPAR-gamma represents a novel system of ovarian regulation.