Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome

BACKGROUND Insulin resistance and increased ovarian cytochrome P450c17α activity are both features of the polycystic ovary syndrome. P450c17α, which is involved in androgen biosynthesis, has both 17α-hydroxylase and 17,20-lyase activities. Increased activity of this enzyme results in exaggerated conversion of progesterone to 17α-hydroxyprogesterone in response to stimulation by gonadotropin. We hypothesized that hyperinsulinemia stimulates ovarian P450c17α activity. METHODS We measured serum steroid concentrations during fasting and the response of serum 17α-hydroxyprogesterone to leuprolide, a gonadotropin-releasing hormone agonist, and performed oral glucose-tolerance tests before and after oral administration of either metformin (500 mg three times daily) or placebo for four to eight weeks in 24 obese women with the polycystic ovary syndrome. RESULTS In the 11 women given metformin, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 9303±1603 to 4982±911 μU per milliliter per minute (56±10 to 30±6 nmol per liter per minute) (P = 0.004). This decrease was associated with a reduction in the basal serum 17α-hydroxyprogesterone concentration from 135±21 to 66±7 ng per deciliter (4.1±0.6 to 2.0±0.2 nmol per liter) (P = 0.01) and a reduction in the leuprolide-stimulated peak serum 17α-hydroxyprogesterone concentration from 455±54 to 281±52 ng per deciliter (13.7±1.6 to 8.5±1.6 nmol per liter) (P = 0.01). The serum 17α-hydroxyprogesterone values increased slightly in the placebo group. In the metformin group, the basal serum luteinizing hormone concentration decreased from 8.5±2.2 to 2.8±0.5 mlU per milliliter (P = 0.01), the serum free testosterone concentration decreased from 0.34±0.07 to 0.19±0.05 ng per deciliter (12±3 to 7±2 pmol per liter) (P = 0.009), and the serum sex hormone–binding globulin concentration increased from 0.8±0.2 to 2.3±0.6 μg per deciliter (29±7 to 80±21 nmol per liter) (P CONCLUSIONS In obese women with the polycystic ovary syndrome, decreasing serum insulin concentrations with metformin reduces ovarian cytochrome P450c17α activity and ameliorates hyperandrogenism

Effects of Metformin on Spontaneous and Clomiphene-Induced Ovulation in the Polycystic Ovary Syndrome

ABSTRACT Background Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene. Methods We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days. Results Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (±SE) area under the serum insulin curve after oral glucose administration decreased from 6745±2021 to 3479±455 µU per milliliter per minute (40.5±12.1 to 20.9±2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8±3.4 ng per milliliter [7.6±10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P\u3c0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo. Conclusions The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin. (N Engl J Med 1998;338:1876-80.

Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome

BACKGROUND Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a d-chiro-inositol–containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of d-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. METHODS We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of d-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. RESULTS In the 22 women given d-chiro-inositol, the mean (±SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417±11,572 to 5158±6714 μU per milliliter per minute (81±69 to 31±40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1±0.8 to 0.5±0.5 ng per deciliter (38±28 to 17±17 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women\u27s diastolic and systolic blood pressure decreased by 4 mm Hg (Pchiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P\u3c0.001). CONCLUSIONS d-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations

Role of High Energy Breakfast “Big Breakfast Diet” in Clock Gene Regulation of Postprandial Hyperglycemia and Weight Loss in Type 2 Diabetes

Postprandial hyperglycemia (PPHG) is strongly linked with the future development of cardiovascular complications in type 2 diabetes (T2D). Hence, reducing postprandial glycemic excursions is essential in T2D treatment to slow progressive deficiency of β-cell function and prevent cardiovascular complications. Most of the metabolic processes involved in PPHG, i.e., β-cell secretory function, GLP-1 secretion, insulin sensitivity, muscular glucose uptake, and hepatic glucose production, are controlled by the circadian clock and display daily oscillation. Consequently, postprandial glycemia displays diurnal variation with a higher glycemic response after meals with the same carbohydrate content, consumed at dusk compared to the morning. T2D and meal timing schedule not synchronized with the circadian clock (i.e., skipping breakfast) are associated with disrupted clock gene expression and is linked to PPHG. In contrast, greater intake in the morning (i.e., high energy breakfast) than in the evening has a resetting effect on clock gene oscillations and beneficial effects on weight loss, appetite, and reduction of PPHG, independently of total energy intake. Therefore, resetting clock gene expression through a diet intervention consisting of meal timing aligned to the circadian clock, i.e., shifting most calories and carbohydrates to the early hours of the day, is a promising therapeutic approach to improve PPHG in T2D. This review will focus on recent studies, showing how a high-energy breakfast diet (Bdiet) has resetting and synchronizing actions on circadian clock genes expression, improving glucose metabolism, postprandial glycemic excursions along with weight loss in T2D

Froy O. Effects of caloric intake timing on insulin resistance and hyperandrogenism in lean women with polycystic ovary syndrome. Clin Sci (Lond

Abstract In women with PCOS (polycystic ovary syndrome), hyperinsulinaemia stimulates ovarian cytochrome P450c17α activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. A total of 60 lean PCOS women [BMI (body mass index), 23.7 + − 0.2 kg/m 2 ] were randomized into two isocaloric (∼ 1800 kcal; where 1 kcal ≈ 4.184 J) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUC glucose (glucose area under the curve) and AUC insulin (insulin area under the curve) by 7 and 54 % respectively. In the BF group, free testosterone decreased by 50 % and SHBG (sex hormone-binding globulin) increased by 105 %. GnRH (gonadotropin-releasing hormone)-stimulated peak serum 17OHP (17α-hydroxyprogesterone) decreased by 39 %. No change in these parameters was observed in the D group. In addition, women in the BF group had an increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17α activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS

Influence of Fasting until Noon (Extended Postabsorptive State) on Clock Gene mRNA Expression and Regulation of Body Weight and Glucose Metabolism

The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an “extended postabsorptive state”, has the potential to cause a deleterious effect on clock gene expression and to disrupt regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, and appetite, and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases and the consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantages of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day

Fasting Until Noon Triggers Increased Postprandial Hyperglycemia and Impaired Insulin Response After Lunch and Dinner in Individuals With Type 2 Diabetes: A Randomized Clinical Trial.

Skipping breakfast has been consistently associated with high HbA1c and postprandial hyperglycemia (PPHG) in patients with type 2 diabetes. Our aim was to explore the effect of skipping breakfast on glycemia after a subsequent isocaloric (700 kcal) lunch and dinner

High-energy breakfast based on whey protein reduces body weight, postprandial glycemia and HbA1C in Type 2 diabetes

Acute studies show that addition of whey protein at breakfast has a glucose-lowering effect through increased incretin and insulin secretion. However, whether this is a long-term effect in Type 2 diabetes is unknown. Fifty-six Type 2 diabetes participants aged 58.9±4.5 years, BMI 32.1±0.9 kg/m2 and HbA1C 7.8±0.1% (61.6±0.79 mmol/mol) were randomized to one of 3 isocaloric diets with similar lunch and dinner, but different breakfast: 1) 42 g total protein, 28 g whey (WBdiet, n=19); 2) 42 g various protein sources (PBdiet, n=19); or 3) high-carbohydrate breakfast, 17 g protein from various sources (CBdiet, n=18). Body weight and HbA1C were examined after 12 weeks. All participants underwent three all-day meal challenges for postprandial glycemia, insulin, C-peptide, intact glucagon-like peptide 1 (iGLP-1), ghrelin and hunger and satiety scores. Overall postprandial AUCglucose was reduced by 12% in PBdiet and by 19% in WBdiet, compared with CBdiet (P<.0001). Compared with PBdiet and CBdiet, WBdiet led to a greater postprandial overall AUC for insulin, C-peptide, iGLP-1 and satiety scores, while postprandial overall AUC for ghrelin and hunger scores were reduced (P<.0001). After 12 weeks, HbA1C was reduced after WBdiet by 0.89±0.05% (11.5±0.6 mmol/mol), after PBdiet by 0.6±0.04% (7.1±0.31 mmol/mol) and after CBdiet by 0.36±0.04% (2.9±0.31 mmol/mol) (P<.0001). Furthermore, the participants on WBdiet lost 7.6±0.3 kg, PBdiet 6.1±0.3 kg and CBdiet 3.5±0.3 kg (P<.0001). Whey protein-based breakfast is an important adjuvant in the management of Type 2 diabetes

High-energy breakfast with low-energy dinner decreases overall daily hyperglycaemia in type 2 diabetic patients: a randomised clinical trial

Aims/hypothesis High-energy breakfast and reduced-energy dinner (Bdiet) significantly reduces postprandial glycaemia in obese non-diabetic individuals. Our objective was to test whether this meal schedule reduces postprandial hyperglycaemia (PPHG) in patients with type 2 diabetes by enhancing incretin and insulin levels when compared with high-energy dinner and reduced-energy breakfast (Ddiet). Methods In a randomised, open label, crossover design performed in a clinic setting, 18 individuals (aged 30-70 years with BMI 22-35 kg/m(2)) with type 2 diabetes (< 10 years duration) treated with metformin and/or diet were given either Bdiet or Ddiet for 7 days. Participants were randomised by a person not involved in the study using a coin flip. Postprandial levels of plasma glucose, insulin, C-peptide and intact and total glucagon-like peptide-1 (iGLP-1 and tGLP-1) were assessed. The Bdiet included 2,946 kJ breakfast, 2,523 kJ lunch and 858 kJ dinner. The Ddiet comprised 858 kJ breakfast, 2,523 kJ lunch and 2,946 kJ dinner. Results Twenty-two individuals were randomised and 18 analysed. The AUC for glucose (AUC(glucose)) throughout the day was 20% lower, whereas AUC(insulin), AUC(C-peptide) and AUC(tGLP-1) were 20% higher for the Bdiet than the Ddiet. Glucose AUC(0-180min) and its peak were both lower by 24%, whereas insulin AUC(0-180min) was 11% higher after the Bdiet than the Ddiet. This was accompanied by 30% higher tGLP-1 and 16% higher iGLP-1 levels. Despite the diets being isoenergetic, lunch resulted in lower glucose (by 21-25%) and higher insulin (by 23%) with the Bdiet vs Ddiet. Conclusions/interpretation High energy intake at breakfast is associated with significant reduction in overall PPHG in diabetic patients over the entire day. This dietary adjustment may have a therapeutic advantage for the achievement of optimal metabolic control and may have the potential for being preventive for cardiovascular and other complications of type 2 diabetes