Background and Aims : Energy metabolism is closely related to lipid profiles and sex hormones. Gender affirming hormone therapy (GAHT) can increase adiponectin and leptin levels in transgender females, while resistin levels are unaffected by GAHT. GAHT also increases triglycerides (TG) and total cholesterol (TC) in transgender females and males (Auer, JCEM 2018; Ott; J. Sex. Med. 2011). We examined the relationships among resistin, leptin, adiponectin, testosterone, estradiol, TC, HDL, LDL and TG within 4 gender identity groups.

Pioglitazone is an insulin-sensitizing thiazolidinedione (TZD) whose use is associated with bone loss. We examined the effects of pioglitazone on components of the Wnt signaling pathway (Wnt1, β-catenin) and markers of bone mineralization [osteoprotegerin (OPG), bone sialoprotein (BSP), fibroblast growth factor (FGF)23] as well as mineral content in human osteoblast hFOB 1.19 cells. hFOB 1.19 cells were cultured in K12/DMD medium with or without pioglitazone. PPARγ Wnt1, OPG, BSP, or FGF23 mRNA expression was measured using qRT-PCR; β-catenin, OPG, BSP, or FGF23 using ELISA; and calcium or phosphate content using colorimetry. Treatment with pioglitazone resulted in increased expression of PPARγ mRNA in hFOB 1.19 osteoblasts. Pioglitazone decreased Wnt1 mRNA levels and suppressed components of Wnt signaling pathway as evidenced by a decrease in β-catenin gene expression and secretion as well as β-catenin specific activity. The expression and the activity of OPG, BSP, and FGF23 were also reduced by pioglitazone together with total (but not specific) calcium and phosphate content. Pioglitazone affects Wnt1 signaling pathway and mineral matrix regulation components in human osteoblasts.

I HAS BEEN proposed recently that polycystic ovary syndrome (PCOS) develops as a result of increased ovarian sensitivity to insulin (1). Although there is evidence to support the notion of preserved ovarian sensitivity to insulin in the ovaries of patients with PCOS, in my view the evidence for increased ovarian sensitivity in such ovaries is lacking. The three main pieces of evidence advanced in favor of the hypothesis proposing increased ovarian sensitivity to insulin in PCOS patients are as follows: first, ovarian cells from patients with PCOS produce higher amounts of androgens in response to stimulation by insulin than ovarian cells from patients without PCOS; second, not all patients with PCOS are insulin resistant or hyperinsulinemic; and third, treatment with insulin-sensitizing agents reduces ovarian androgen synthesis, even in those patients whose circulating insulin levels change only modestly with administration of these medications (1). In regard to the first observation, it is important to remember that ovarian cells from patients with PCOS produce larger-than-normal amounts of androgens not only in response to insulin but also regardless of the stimulus used (2). Therefore, the larger-than-normal production of androgens in response to insulin in cultured ovarian cells from patients with PCOS is likely to be a consequence of the presence of PCOS, rather than a primary defect that precedes the development of PCOS. Further arguing against the presence of increased sensitivity to insulin in the ovaries of PCOS patients are the studies in obese children (3) and PCOS patients (4 and reviewed in Ref. 5), which demonstrated that serum androgen levels normalize after weight loss. Additionally, studies of granulosa cells from PCOS patients revealed no difference in their steroidogenic response to insulin, compared with the granulosa cells from the normal ovaries, and abnormalities of glucose uptake in the granulosa cells from PCOS patients were demonstrated only in the presence of supraphysiological concentrations of insulin (100 or 1000 ng/ml) (6). Insulin, particularly if present in high concentrations, stimulates not only ovarian androgen production but also synthesis of estrogens and progesterone, affects a variety of steroidogenic enzymes, inhibits production of IGF binding protein (IGFBP)-1, up-regulates ovarian IGF-I binding, promotes ovarian growth and cyst formation, stimulates theca cell proliferation, and enhances ovulation (reviewed in Ref. 7). It seems unlikely that increased sensitivity to insulin in the ovary would affect only one of its multiple effects, namely androgen synthesis. Besides, to describe a state of increased ovarian sensitivity to insulin, one would need to define normal ovarian sensitivity to insulin for each of its effects in the ovary, a task that has not yet been accomplished. In regard to the second point, the lack of insulin resistance in many nonobese PCOS patients (8), who comprise up to 50% of PCOS population (reviewed in Ref. 5), does not necessarily imply increased ovarian sensitivity to insulin in these patients but may be interpreted rather as evidence against significant involvement of insulin in the pathogenesis of PCOS in individuals who are not insulin resistant. Furthermore, insulin hypersecretion may be present even in those PCOS patients who are not insulin resistant (8), once again arguing against increased ovarian sensitivity to insulin. Finally, in regard to the third point, it is important to remember that the insulin-sensitizing agents used for the treatment of PCOS exhibit a variety of direct ovarian effects, both insulin independent and insulin sensitizing (9). Thiazolidinediones, for example, directly inhibit ovarian androgen production in human ovarian cells in the absence of insulin (9). In addition, insulin-sensitizing agents elicit a variety of nonovarian effects. For instance, because SHBG production in the liver is under inhibitory control by insulin (reviewed in Ref. 7), serum SHBG levels rise with thiazolidinedione administration and a fall in circulating free androgen levels follows (10). But as mentioned above, ovarian androgen production is inhibited by thiazolidinediones directly as well (9). Therefore, when one tries to analyze the causes of a reduction in free testosterone levels observed in vivo with thiazolidinedione administration, it is necessary to take into account contributions of both direct (ovarian) and indirect (SHBG-related action in the liver) effects of thiazolidinediones on serum testosterone. Thus, serum androgen responses to insulin-sensitizing agents do not necessarily reflect the state of ovarian insulin sensitivity. For these reasons it may be premature to postulate either global or effect-specific increased sensitivity to insulin in the ovaries of patients with PCOS. On the other hand, there is significant evidence for the hypothesis proposing preserved ovarian insulin sensitivity in patients with PCOS who exhibit systemic insulin resistance (reviewed in Ref. 11). This hyFirst Published Online May 9, 2006 Abbreviations: IGFBP, IGF binding protein; PCOS, polycystic ovary syndrome.

In 1500 B.C., when the author of the Egyptian papyrus Ebers first described an obscure illness that later became known as diabetes mellitus (from Greek diabetes meaning siphon and Latin or Greek mel meaning honey) (1), he could hardly have envisioned the pandemic of metabolic disease that would take place at the end of the 20th century through the beginning of the 21st century. According to the International Diabetes Federation, diabetes affects ∼366 million people worldwide (2). This number is projected to rise to 552 million by 2030 (2). Additionally, there were 280 million people with impaired glucose tolerance in 2011 (2); this number is projected to increase to 398 million in 2030 (2). Thus, by 2030, close to 1 billion people are expected to have abnormal glucose tolerance. The epidemic of diabetes is accompanied by epidemics of obesity and atherosclerotic heart disease and may have at its roots an insulin-resistant state called the metabolic syndrome (3). Why is this epidemic of metabolic disease taking place now? In PNAS, Cai et al. (4) propose one possible explanation.

Thiazolidinediones (TZDs) are insulin sensitizers used for treatment of diabetes. We have previously reported that TZDs reduce estrogen synthesis by inhibiting aromatase activity in human granulosa cells (HGC). Multiple clinical trials demonstrated that TZDs increase the risk of fractures in postmenopausal women with type 2 diabetes. We studied mouse osteoblasts alone or in a co-culture with HGC to determine whether TZD inhibition of aromatase plays a role in their effects on bone metabolism. Mouse osteoblasts were cultured with and without HGC, and incubated in a medium with or without testosterone, pioglitazone or rosiglitazone. Cell growth, oleic acid uptake, alkaline phosphatase activity, and osteocalcin production were measured. TZDs inhibited estradiol production by up to 84% in HGC/mouse osteoblast co-cultures. TZDs induced mouse osteoblast death and increased oleic acid uptake. TZDs also inhibited alkaline phosphatase activity (58-75%, p<0.046) and osteocalcin production (52-75%, p<0.031). For all the parameters, there were no significant differences between the osteoblast cultures alone and the HCG/osteoblast co-cultures. TZD effects on osteoblast viability, oleic acid uptake, alkaline phosphatase and osteocalcin production are independent of their effects on aromatase.

The effects of rosiglitazone or pioglitazone (thiazolidinediones, TZDs) on estrogen production and aromatase activity in human ovarian cells were examined. Human granulosa cells were incubated in the tissue culture medium supplemented with androstenedione or testosterone, with or without insulin, TZDs, or type 1 17β-hydroxysteroid-dehydrogenase (17β-HSD) inhibitor. Estrogen concentrations in the conditioned medium, aromatase mRNA and protein expression in the cells and androgen substrate binding to aromatase were measured. With androstenedione as substrate, rosiglitazone or pioglitazone inhibited estrone production by up to 22% (p<0.012) while type 1 17β-HSD inhibitor enhanced this effect of rosiglitazone or pioglitazone by 37% (p<0.001) and by 67% (p<0.001), respectively. With testosterone as substrate, rosiglitazone or pioglitazone inhibited estradiol production by 32% (p<0.001). With (3)H-testosterone as substrate, rosiglitazone or pioglitazone inhibited the (3)H-tritiated water release by the cultured cells by 45% and 35%, respectively, thus directly demonstrating inhibition of aromatase. Rosiglitazone or pioglitazone, however, had no significant effect on aromatase mRNA or protein expression. Rosiglitazone or pioglitazone inhibited (125)I-androstenedione and (125)I-testosterone binding to aromatase by 38% (p<0.001). It was concluded that rosiglitazone or pioglitazone inhibit estrogen synthesis in human granulosa cells by interfering with androgen binding to aromatase.

Objective: To establish if glucose management with continuous intravenous insulin infusion (CII) in the early post-operative period after coronary artery bypass graft (CABG) surgery is associated with complication rate and length of hospital stay (LOS) in patients with diabetes mellitus (DM). Research design and methods: We reviewed the records of 587 patients with DM who underwent CABG from January 1999 until January 2008; 316 patients were placed on CII, while 271 patients were treated with subcutaneous insulin. We examined patient age, glycated hemoglobin (HgbA1c), 24- and 72-h post-operative average capillary blood glucose (CBG), length of stay (LOS), and the rate of complications. Results: There was no difference in HgbA1c between the groups. Mean CBG values at both 24 h and 72 h remained the same in the CII group (167 mg/dl), while in the non-CII group they were 194 mg/dl and 189 mg/dl, respectively ( p <0.001 between the groups). Post-surgical median LOS was 6 days in the CII group and 6.5 days in the non-CII group ( p =0.003). Complications occurred at similar rate (in 10% and 11% of patients) in the two groups. Conclusions: CII is associated with a reduced post-surgical LOS in patients with DM who undergo CABG.

This chapter will review the role of vitamin D in the pathogenesis and treatment of type 1 diabetes mellitus.We will discuss the mechanisms through which vitamin D might affect pancreatic function.We will summarize the results of in-vitro and animal studies and will conclude with a review of the relevant clinical trials. DefinitionType 1 diabetes mellitus is an autoimmune disease in which the pancreas is unable to respond to secretagogue stimulation with appropriate insulin secretion.Hyperglycemia develops when more than 70-90% of the insulin-producing beta cells are destroyed.An autoimmune destructive process, which plays a central role in the development of type 1 diabetes mellitus, is facilitated by the subject's own genetic susceptibility and by non-genetic factors.Non-genetic factors include viral infections, toxic chemicals, and others.Vitamin D deficiency is a non-genetic factor that appears to be associated with an increased risk of developing type 1 diabetes mellitus.Type 1 diabetes mellitus complications are classified into acute and chronic.The acute complications include life-threatening conditions like severe hypoglycemia or diabetic ketoacidosis (DKA).Chronic diabetic complications can be divided into microvascular complications (retinopathy, neuropathy and nephropathy) and macrovascular complications (cardiovascular, cerebrovascular and peripheral vascular disease).Severe microvascular and macrovascular complications can lead to renal failure (the most common cause of hemodialysis in the US), blindness or lower extremity amputations.Overall, uncontrolled diabetes mellitus in patients over 50 years of age reduces life expectancy in males and females by 7.5 and 8.2 years respectively (Franco et al.,2007). EpidemiologyIn 2010, about 215,000 people younger than 20 years of age had diabetes (type 1 or type 2) in the United States.A 2011 Centers for Disease Control and Prevention (CDC) report estimates that nearly 26 million Americans have diabetes.Diabetes affects 8.3% of www.intechopen.comType 1 Diabetes -Complications, Pathogenesis, and Alternative Treatments 404 Americans of all ages and 11.3% of adults aged 20 years and older, according to the National Diabetes Fact Sheet for 2011.About 27% of those with diabetes (approximately 7 million Americans) do not know they have the disease. 1 in every 400 children and adolescents has type 1 diabetes.Type 1 diabetes mellitus continues to be highly prevalent in many countries, with an overall annual increase estimated at 3% (International Diabetes Federation [IDF] 2010).Worldwide, it is more common in males than in females, with a ratio of 1.5.The 4 th edition of the IDF Diabetes Atlas, released in 2009 at the 20 th World Diabetes Congress, estimated that in 2010, 285 million people would have diabetes (6.4% of world's adult population).The same forum predicts that by 2030, 438 million people will have diabetes world-wide.Type 1 diabetes in children is estimated at 480,000 patients worldwide in 2010, and the number of newly diagnosed cases per year is 75,800 (IDF 2010). Natural historyThe natural history of type 1 diabetes is characterized by an autoimmune destruction of the beta cells in the islands of Langerhans in the pancreas.The autoimmune process has cellular and humoral components, leading to the destruction of the beta cells and a decreased insulin secretion.As beta-cell mass declines, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels.After 70-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed.The natural history of type 1 diabetes has 4 stages: genetic susceptibility, autoimmune process, pre-diabetes and diabetes.The rate of beta cell destruction is variable.In some patients years will go by before the onset of diabetes, while other patients may never develop beta cell insufficiency, perhaps due to the regaining of tolerance.Most patients with type 1 diabetes mellitus have one or more susceptible human leukocyte antigen (HLA) class II, and over 90% have beta cell autoantibodies present.The appearance of circulating islet cell autoantibodies is the first detectable sign of this immune process. Pathogenesis of type 1 diabetes mellitus Genetic componentGenetics has an important role in the etiology of type 1 diabetes.However, extra-genetic components influence the penetrance of diabetes susceptibility genes.If data are obtained at a single point in time, the risk of type 1 diabetes mellitus between monozygotic twins can be as low as 30%, but if the monozygotic twins are followed long-term, the cumulative incidence of diabetes reaches 65% (Redondo et al., 2008).In the same cohort of monozygotic twins, the rate of persistent autoantibody positivity, type 1 diabetes mellitus, or both, reached 78% (Redondo et al., 2008).To better understand the genetic susceptibility to diabetes, candidate gene studies were conducted in order to identify genes that are associated with autoimmune type 1 diabetes.Human leukocyte antigen (HLA) associations have been long recognized in many autoimmune diseases.In type 1 diabetes mellitus, the HLA on chromosome 6p21 is well described and is considered to play an important role in more than 50% of the familial cases in Caucasians (Noble et al., 1996).HLA DR4-DQ8 or DR3-DQ2 haplotypes are detected in up to 90% of patients with type 1 diabetes mellitus (Devendra & Eisenbarth, 2003).The combination www.intechopen.com How to referenceIn order to correctly reference this scholarly work, feel free to copy and paste the following:

Insulin and insulin like-growth factor-I (IGF-I) participate in the regulation of ovarian steroidogenesis. In insulin resistant states ovaries remain sensitive to insulin because insulin can activate alternative signaling pathways, such as phosphatidylinositol-3-kinase (PI-3 kinase) and mitogen-activated protein-kinase (MAPK) pathways, as well as insulin receptors and type 1 IGF receptors. We investigated the roles of MAPK-Erk1/2 and MAPK-p38 in insulin and IGF-I signaling pathways for progesterone production in human ovarian cells. Human ovarian cells were cultured in tissue culture medium in the presence of varying concentrations of insulin or IGF-I, with or without PD98059, a specific MAPK-Erk1/2 inhibitor, with or without SB203580, a specific MAPK-p38 inhibitor or with or without a specific PI-3-kinase inhibitor LY294002. Progesterone concentrations were measured using radioimmunoassay. PD98059 alone stimulated progesterone production in a dose-dependent manner by up to 65% (p<0.001). Similarly, LY294002 alone stimulated progesterone production by 13-18% (p<0.005). However, when used together, PD98059 and LY294002 inhibited progesterone production by 17-20% (p<0.001). SB203580 alone inhibited progesterone production by 20-30% (p<0.001). Insulin or IGF-I alone stimulated progesterone production by 40-60% (p<0.001). In insulin studies, PD98059 had no significant effect on progesterone synthesis while SB203580 abolished insulin-induced progesterone production. Either PD98059 or SB203580 abolished IGF-I-induced progesterone production. Both MAPK-Erk1/2 and MAPK-p38 participate in IGF-I-induced signaling pathways for progesterone production, while insulin-induced progesterone production requires MAPK-p38, but not MAPK-Erk1/2. These studies provide further evidence for divergence of insulin and IGF-I signaling pathways for human ovarian cell steroidogenesis.

Vitamin D Receptor (VDR) is expressed in both animal and human ovarian tissue, however, the role of vitamin D in human ovarian steroidogenesis is unknown. Cultured human ovarian cells were incubated in tissue culture medium supplemented with appropriate substrates, with or without 50 pM-150 pM or 50 nM-150 nM of 1,25-(OH)2D3, and in the presence or absence of insulin. Progesterone, testosterone, estrone, estradiol, and IGFBP-1 concentrations in conditioned tissue culture medium were measured. Vitamin D receptor was present in human ovarian cells. 1,25-(OH)2D3 stimulated progesterone production by 13% (p<0.001), estradiol production by 9% (p<0.02), and estrone production by 21% (p<0.002). Insulin and 1,25-(OH)2D3 acted synergistically to increase estradiol production by 60% (p<0.005). 1,25-(OH)2D3 alone stimulated IGFBP-1 production by 24% (p<0.001), however, in the presence of insulin, 1,25-(OH)2D3 enhanced insulin-induced inhibition of IGFBP-1 production by 13% (p<0.009). Vitamin D stimulates ovarian steroidogenesis and IGFBP-1 production in human ovarian cells likely acting via vitamin D receptor. Insulin and vitamin D synergistically stimulate estradiol production. Vitamin D also enhances inhibitory effect of insulin on IGFBP-1 production.

This commentary reviews the current state of knowledge regarding the role of vitamin D in the pathogenesis of diabetes mellitus. In type 1 diabetes mellitus or in adult onset latent autoimmune diabetes (LADA), vitamin D exhibits immunomodulatory actions, influencing the activity of lymphocytes and interleukins. In type 2 diabetes mellitus vitamin D appears to act through different mechanisms, affecting insulin secretion and insulin sensitivity through its effects on the beta cells, mediators of inflammation and parathyroid hormone. Much work remains to be done in this new field of knowledge before the role of vitamin D in the pathogenesis of diabetes mellitus is completely understood. Copyright (c) 2009 John Wiley & Sons, Ltd.

Women with HIV infection use dehydroepiandrosterone (DHEA) because of its potential effects on mood and energy. We examined the effects of DHEA on the hypothalamic-pituitary-adrenal and gonadal axes and on insulin sensitivity. Fifteen HIV-positive women were randomized to receive placebo (6 subjects) or oral DHEA (9 subjects). ACTH-, CRF-, and GnRH-stimulation tests were performed before and after 8 weeks of treatment. DHEA, DHEA-S, dihydrotestosterone, total testosterone, free testosterone, sex hormone-binding globulin, estrone, estradiol, cortisol, insulin, IGF-1, IGFBP-1, IGFBP-3, and adiponectin in plasma or serum were measured. There was a significant increase in DHEA (p<0.004), DHEA-S (p<0.008), total testosterone (p<0.008), dihydrotestosterone (p<0.004), androstenedione (p<0.04), and estrone (p<0.03) from baseline within the DHEA group but not within the placebo group. There was a significant increase in DHEA (p<0.0006), DHEA-S (p<0.032), total testosterone (p<0.01), and dihydrotestosterone (p<0.005) in the DHEA group compared with the placebo group. Oral DHEA produces significant increases in circulating DHEA, DHEA-S, testosterone, DHT, and, possibly, androstenedione and estrone levels in premenopausal women with HIV infection. In the current pilot study these hormone changes did not affect the pituitary or adrenal axis or insulin/IGF indices. Long-term studies with larger groups of patients are needed to confirm these data and to determine their clinical significance.

OBJECTIVE:To evaluate the inter-patient and intra-patient reproducibility of the glycemic response to a mixed meal in individuals with type 2 diabetes mellitus (DM).SUBJECTS/SETTING:Six individuals with DM were admitted to the General Clinical Research Center for 6 days.INTERVENTION:Subjects consumed 3 different meal plans consisting of 4 meals daily (breakfast, lunch, dinner and snack) on 2 separate occasions. Serum insulin and glucose levels were sampled at 19 time points every day. The glycemic response (GR) to a meal was calculated as the area under the glucose response curve after consumption of a given meal. In addition, the incremental area under the curve (IGR) was calculated assuming a pre-prandial (baseline) glucose value before each meal as zero.RESULTS:Intra-patient correlation coefficients (R) of GR for meals in subjects with DM were quite good, ranging 0.69-0.94. The range of the inter-patient coefficients of variation (CV) for the same meals was 21.5-30.4%. For IGR, the R values ranged from 0.64 to 0.91 for 8 out of 12 meals, confirming good intra-patient reproducibility for these meals. CV for IGR ranged from 31% to 113%.CONCLUSIONS:For patients with DM, the GR of individual meals exhibits excellent intra-patient reproducibility, allowing prediction of the glycemic response to a given meal in an individual subject. However, significant inter-patient variability of the GR precludes its use for the prediction of post-prandial glucose concentrations in groups of patients with diabetes.

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.

Both obesity and the polycystic ovary syndrome (PCOS) are commonly seen in women of reproductive age. Fifty percent of all patients with PCOS are obese, and the presence of obesity affects the clinical manifestations of PCOS. The underlying pathogenetic mechanisms appear to involve insulin resistance and hyperinsulinemia, the magnitude of which is greater in obese than in non-obese women with PCOS. Specific effects of obesity on the manifestations of PCOS, underlying mechanisms of the interactions between obesity and PCOS, and therapeutic implications of these interactions are discussed in this article.

"Principles of Diabetes Mellitus, Second Edition" is an important update to the comprehensive textbook first published in 2002 and reissued in 2004. It is written for physicians of all specialties who