Daniela Jakubowicz

Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome

OBJECTIVE Insulin resistance and its compensatory hyperinsulinemia play a key pathogenic role in the infertility of the polycystic ovary syndrome. Numerous studies indicate that insulin-sensitizing drugs can be used to enhance spontaneous ovulation and the induction of ovulation in the syndrome. The aim of this review is to summarize the studies in which insulin-sensitizing drugs were used to increase ovulation rate or improve fertility in women with the PCOS and to translate the information into practical guidelines for the use of these drugs by reproductive endocrinologists. DESIGN Review and critique of studies in which an insulin-sensitizing drug was used to increase ovulation rate or improve infertility in women with the polycystic ovary syndrome. MAIN OUTCOME MEASURE(S) Ovulation rate and pregnancy rate. RESULT(S) Studies have demonstrated that insulin-sensitizing drugs can increase spontaneous ovulation, enhance the induction of ovulation with clomiphene citrate, and increase clinical pregnancy rates. CONCLUSION(S) An algorithmic approach is provided for the use of insulin-sensitizing drugs to treat the anovulation and infertility of women with the polycystic ovary syndrome.

High Caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women

Few studies examined the association between time‐of‐day of nutrient intake and the metabolic syndrome. Our goal was to compare a weight loss diet with high caloric intake during breakfast to an isocaloric diet with high caloric intake at dinner.

Biochemical and metabolic mechanisms by which dietary whey protein may combat obesity and Type 2 diabetes

Consumption of milk and dairy products has been associated with reduced risk of metabolic disorders and cardiovascular disease. Milk contains two primary sources of protein, casein (80%) and whey (20%). Recently, the beneficial physiological effects of whey protein on the control of food intake and glucose metabolism have been reported. Studies have shown an insulinotropic and glucose-lowering properties of whey protein in healthy and Type 2 diabetes subjects. Whey protein seems to induce these effects via bioactive peptides and amino acids generated during its gastrointestinal digestion. These amino acids and peptides stimulate the release of several gut hormones, such as cholecystokinin, peptide YY and the incretins gastric inhibitory peptide and glucagon-like peptide 1 that potentiate insulin secretion from β-cells and are associated with regulation of food intake. The bioactive peptides generated from whey protein may also serve as endogenous inhibitors of dipeptidyl peptidase-4 (DPP-4) in the proximal gut, preventing incretin degradation. Indeed, recently, DPP-4 inhibitors were identified in whey protein hydrolysates. This review will focus on the emerging properties of whey protein and its potential clinical application for obesity and Type 2 diabetes.

EFFECTS OF D-CHIRO-INOSITOL IN LEAN WOMEN WITH THE POLYCYSTIC OVARY SYNDROME

OBJECTIVE To determine whether the administration of D-chiro-inositol, a putative insulin-sensitizing drug, would affect the concentration of circulating insulin, the levels of serum androgens, and the frequency of ovulation in lean women with the polycystic ovary syndrome. METHODS In 20 lean women (body mass index, 20.0 to 24.4 kg/m 2) who had the polycystic ovary syndrome, treatment was initiated with either 600 mg of D-chiro-inositol or placebo orally once daily for 6 to 8 weeks. We performed oral glucose tolerance tests and measured serum sex steroids before and after therapy. To monitor for ovulation, we determined serum progesterone concentrations weekly. RESULTS In the 10 women given D-chiro-inositol, the mean (+/- standard error) area under the plasma insulin curve after oral administration of glucose decreased significantly from 8,343 +/- 1,149 mU/mL per min to 5,335 +/- 1,792 mU/mL per min in comparison with no significant change in the placebo group (P = 0.03 for difference between groups). Concomitantly, the serum free testosterone concentration decreased by 73% from 0.83 +/- 0.11 ng/dL to 0.22 +/- 0.03 ng/dL, a significant change in comparison with essentially no change in the placebo group (P = 0.01). Six of the 10 women (60%) in the D-chiro-inositol group ovulated in comparison with 2 of the 10 women (20%) in the placebo group (P = 0.17). Systolic (P = 0.002) and diastolic (P = 0.001) blood pressures, as well as plasma triglyceride concentrations (P = 0.001), decreased significantly in the D-chiro-inositol group in comparison with the placebo group, in which these variables either increased (blood pressure) or decreased minimally (triglycerides). CONCLUSION We conclude that, in lean women with the polycystic ovary syndrome, D-chiro-inositol reduces circulating insulin, decreases serum androgens, and ameliorates some of the metabolic abnormalities (increased blood pressure and hypertriglyceridemia) of syndrome X.

Meal timing and composition influence ghrelin levels, appetite scores and weight loss maintenance in overweight and obese adults

BACKGROUND Although dietary restriction often results in initial weight loss, the majority of obese dieters fail to maintain their reduced weight. Diet-induced weight loss results in compensatory increase of hunger, craving and decreased ghrelin suppression that encourage weight regain. A high protein and carbohydrate breakfast may overcome these compensatory changes and prevent obesity relapse. METHODS In this study 193 obese (BMI 32.2±1.0kg/m(2)), sedentary non diabetic adult men and women (47±7years) were randomized to a low carbohydrate breakfast (LCb) or an isocaloric diet with high carbohydrate and protein breakfast (HCPb). Anthropometric measures were assessed every 4weeks. Fasting glucose, insulin, ghrelin, lipids, craving scores and breakfast meal challenge assessing hunger, satiety, insulin and ghrelin responses, were performed at baseline, after a Diet Intervention Period (Week 16) and after a Follow-up Period (Week 32). RESULTS At Week 16, groups exhibited similar weight loss: 15.1±1.9kg in LCb group vs. 13.5±2.3kg in HCPb group, p=0.11. From Week 16 to Week 32, LCb group regained 11.6±2.6kg, while the HCPb group lost additional 6.9±1.7kg. Ghrelin levels were reduced after breakfast by 45.2% and 29.5% following the HCPb and LCb, respectively. Satiety was significantly improved and hunger and craving scores significantly reduced in the HCPb group vs. the LCb group. CONCLUSION A high carbohydrate and protein breakfast may prevent weight regain by reducing diet-induced compensatory changes in hunger, cravings and ghrelin suppression. To achieve long-term weight loss, meal timing and macronutrient composition must counteract these compensatory mechanisms which encourage weight regain after weight loss.

Dehydroepiandrosterone Reduces Plasma Plasminogen Activator Inhibitor Type 1 and Tissue Plasminogen Activator Antigen in Men

Dehydroepiandrosterone (DHEA) may help prevent heart disease in men. To test the hypothesis that DHEA might exert its effects by enhancing endogenous fibrinolytic potential, a double-blind, placebo-controlled study was conducted that assessed the effects of DHEA administration on plasma plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator (tPA) antigen. Eighteen men received 50 mg DHEA orally and 16 men received a placebo capsule thrice daily for 12 days. Serum DHEA-sulfate and plasma PAI-1 and tPA antigen were measured before and after treatment. In the DHEA group, serum DHEA-sulfate (from 7.5 +/- 1.2 micromol/L to 20.2 +/- 1.5 micromol/L (P < 0.0001), androstenedione (from 2.6 +/- 0.2 nmol/L to 4.0 +/- 0.4 nmol/L; P < 0.005) and estrone (from 172 +/- 21 pmol/L to 352 +/- 28 pmol/L; P < 0.005) increased, whereas plasma PAI-1 (from 55.4 +/- 3.8 ng/mL to 38.6 +/- 3.3 ng/mL; P < 0.0001) and tPA antigen (from 8.1 +/- 1.9 ng/mL to 5.4 +/- 1.3 ng/mL; P < 0.0005) decreased. In the placebo group, serum DHEA-sulfate declined slightly from 8.0 +/- 3.3 micromol/L to 7.3 +/- 3.4 micromol/L (P < 0.05), but no other measured steroid changed. Plasma PAI-1 and tPA antigen did not change in the placebo group. These findings suggest that DHEA administration reduces plasma PAI-1 and tPA antigen concentrations in men.

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

OBJECTIVE 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. RESEARCH DESIGN AND METHODS In a crossover design, 22 patients with diabetes with a mean diabetes duration of 8.4 ± 0.7 years, age 56.9 ± 1.0 years, BMI 28.2 ± 0.6 kg/m2, and HbA1c 7.7 ± 0.1% (61 ± 0.8 mmol/mol) were randomly assigned to two test days: one day with breakfast, lunch, and dinner (YesB) and another with lunch and dinner but no breakfast (NoB). Postprandial plasma glucose, insulin, C-peptide, free fatty acids (FFA), glucagon, and intact glucagon-like peptide-1 (iGLP-1) were assessed. RESULTS Compared with YesB, lunch area under the curves for 0–180 min (AUC0–180) for plasma glucose, FFA, and glucagon were 36.8, 41.1, and 14.8% higher, respectively, whereas the AUC0-180 for insulin and iGLP-1 were 17% and 19% lower, respectively, on the NoB day (P < 0.0001). Similarly, dinner AUC0-180 for glucose, FFA, and glucagon were 26.6, 29.6, and 11.5% higher, respectively, and AUC0-180 for insulin and iGLP-1 were 7.9% and 16.5% lower on the NoB day compared with the YesB day (P < 0.0001). Furthermore, insulin peak was delayed 30 min after lunch and dinner on the NoB day compared with the YesB day. CONCLUSIONS Skipping breakfast increases PPHG after lunch and dinner in association with lower iGLP-1 and impaired insulin response. This study shows a long-term influence of breakfast on glucose regulation that persists throughout the day. Breakfast consumption could be a successful strategy for reduction of PPHG in type 2 diabetes.

Big breakfast rich in protein and fat improves glycemic control in type 2 diabetics

Our goal was to evaluate the effect of breakfast size and composition on body weight, glycemic control, and metabolic markers in adults with type 2 diabetes mellitus (T2DM).

Effects of caloric intake timing on insulin resistance and hyperandrogenism in lean women with polycystic ovary syndrome

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/m²] 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.

Influences of Breakfast on Clock Gene Expression and Postprandial Glycemia in Healthy Individuals and Individuals With Diabetes: A Randomized Clinical Trial

OBJECTIVE The circadian clock regulates glucose metabolism by mediating the activity of metabolic enzymes, hormones, and transport systems. Breakfast skipping and night eating have been associated with high HbA1c and postprandial hyperglycemia after lunch and dinner. Our aim was to explore the acute effect of breakfast consumption or omission on glucose homeostasis and clock gene expression in healthy individuals and individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS In a crossover design, 18 healthy volunteers and 18 volunteers with 14.5 ± 1.5 years diabetes, BMI 30.7 ± 1.1 kg/m2, and HbA1c 7.6 ± 0.1% (59.6 ± 0.8 mmol/mol) were randomly assigned to a test day with breakfast and lunch (YesB) and a test day with only lunch (NoB). Postprandial clock and clock-controlled gene expression, plasma glucose, insulin, intact glucagon-like peptide 1 (iGLP-1), and dipeptidyl peptidase IV (DPP-IV) plasma activity were assessed after breakfast and lunch. RESULTS In healthy individuals, the expression level of Per1, Cry1, Rorα, and Sirt1 was lower (P < 0.05) but Clock was higher (P < 0.05) after breakfast. In contrast, in individuals with type 2 diabetes, Per1, Per2, and Sirt1 only slightly, but significantly, decreased and Rorα increased (P < 0.05) after breakfast. In healthy individuals, the expression level of Bmal1, Rorα, and Sirt1 was higher (P < 0.05) after lunch on YesB day, whereas the other clock genes remained unchanged. In individuals with type 2 diabetes, Bmal1, Per1, Per2, Rev-erbα, and Ampk increased (P < 0.05) after lunch on the YesB day. Omission of breakfast altered clock and metabolic gene expression in both healthy and individuals with type 2 diabetes. CONCLUSIONS Breakfast consumption acutely affects clock and clock-controlled gene expression leading to normal oscillation. Breakfast skipping adversely affects clock and clock-controlled gene expression and is correlated with increased postprandial glycemic response in both healthy individuals and individuals with diabetes.