Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

Thyroid Hormone Regulation of Metabolism

Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between “substitutive” and “pharmacological” androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of th...

https://www.hormonebalance.org/images/documents/Kauffman%2005%20TDS%20REVIEW%20ER.pdf

The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions The origin of insulin in the brain has been explained from peripheral or central sources, or both Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain The molecular events through which insulin functions in the brain are the same as those operating in the periphery However, certain insulin actions are different in the CNS, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3 In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes (T2DM) and Alzheimer’s disease (AD) A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name “type 3 diabetes” for this association There are links between AD and type 2 diabetes mellitus (T2DM) through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein OGlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of

/pdf/insulin-in-the-brain-its-pathophysiological-implications-for-52adrugpil.pdf

Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer's disease.

Objective: Although clinical hyperthyroidism (HR) is associated with insulin resistance, the information on insulin action in subclinical hyperthyroidism (SHR) is limited. Design and methods: To investigate this, we assessed the sensitivity of glucose metabolism to insulin in vivo (by an oral glucose tolerance test) and in vitro (by measuring insulin-stimulated rates of glucose transport in isolated monocytes) in 12 euthyroid subjects (EU), 16 patients with HR, and 10 patients with SHR. Results: HR and SHR patients displayed higher postprandial glucose levels (area under the curve, AUC0–300 32 190G1067 and 31 497G716 mg/dl min respectively) versus EU (27 119 G1156 mg/dl min, P!0.05). HR but not SHR patients displayed higher postprandial insulin levels (AUC0–300 11 020G985 and 9565G904 mU/l min respectively) compared with EU subjects (AUC0–300 7588G743 mU/l min, P!0.05). Homeostasis model assessment index was increased in HR and SHR patients (2.81G0.3 and 2.43G0.38 respectively) compared with EU subjects (1.27 G0.16, P!0.05), while Matsuda and Belfiore indices were decreased in HR (4.21G0.41 and 0.77G0.05 respectively, P!0.001) and SHR patients (4.47G0.33 and 0.85G0.05 respectively, P!0.05 versus EU (7.76G0.87 and 1 respectively). At 100 mU/ml insulin, i) GLUT3 levels on the monocyte plasma membrane were increased in HR (468.8G7 mean fluorescence intensity (MFI)) and SHR patients (522.2G25 MFI) compared with EU subjects (407G18 MFI, P!0.01 and P!0.05 respectively), ii) glucose transport rates in monocytes (increases from baseline) were decreased in HR patients (37.8G5%) versus EU subjects (61.26G10%, P!0.05). Conclusions: Insulin-stimulated glucose transport in isolated monocytes of patients with HR was decreased compared with EU subjects. Insulin resistance was comparable in patients with both HR and SHR.

/pdf/studies-of-insulin-resistance-in-patients-with-clinical-and-246u1dofqb.pdf

Studies of insulin resistance in patients with clinical and subclinical hypothyroidism.

Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.

Thyroid Dysfunction and Diabetes Mellitus: Two Closely Associated Disorders.

Subclinical hypothyroidism (sH) has been associated with atherosclerotic cardiovascular disease even in the absence of hypercholesterolemia. Objective: Our study was designed to assess the hypothes...

Lipoprotein Alterations, Hepatic Lipase Activity, and Insulin Sensitivity in Subclinical Hypothyroidism: Response to L-T4 Treatment

It is well known that thyroid hormones are important regulators of energy balance and intermediate metabolism. With regard to glucose homeostasis, hyperthyroidism is associated with a state of insulin resistance due to increased hepatic gluconeogenesis (1). In hypothyroidism however, despite the fact that hepatic gluconeogensis has been described as unchanged (2) or decreased (3,4), experiments in animal models have demonstrated a state of insulin resistance both in the adipocyte and in the skeletal muscle (5,6). In humans the literature referring to the connection between thyroid dysfunction and insulin resistance is not consistent; this is in part due to the complex and redundant mechanisms regulating glucose homeostasis, but also to the use of different methods and indexes to assess the insulin sensitivity (indexes derived by the fasting insulin and glucose levels, intravenous [IV] or oral glucose tolerance test, euglycemic hyperinsulinemic clamps, local infusion of insulin and glucose in isolated limbs, examination in vitro of adipocytes, etc.). Specifically, only few studies have evaluated the insulin sensitivity in hypothyroidism and the results are controversial, some (7–12), but not all (13–16) have found that thyroid hormone deficit leads to insulin resistance secondary to decreased glucose disposal. On the other hand, while overt hyperthyroidism has been clearly associated with insulin resistance (1), the data on insulin action in subclinical hyperthyroidism is limited and controversial (17,18). The use of thyroid hormone suppressive therapy for thyroid cancer and its withdrawal before diagnostic or therapeutic intervention offers a unique model to assess the effects of controlled manipulation of circulating thyroid hormones on target pathways, in this case glucose homeostasis. We hypothesized that the lack of thyroid hormones leads to an insulin-resistant state due to a decrease in glucose disposal in skeletal muscle and adipose tissue. Considering the critical impact of insulin resistance on cardiovascular risk (19), we have explored the changes in insulin sensitivity in relation to changes in thyroid hormone homeostasis both under the subclinical hyperthyroid and overt acute hypothyroid status in thyroid cancer patients undergoing thyroid hormone withdrawal. Six women (age 42 11 years, body mass index [BMI] 24 2 kg=m) that underwent total thyroidectomy for differentiated thyroid cancer were included in the study group. Eight healthy subjects (six women and two men, age 37 2 years, BMI 23 2 kg=m) served as controls. The characteristics of the thyroid cancer patients are reported in Table 1. All the volunteers had a normal response to a standard 75 g oral glucose tolerance test. No patient had clinical evidence of metastatic disease as assessed by suppressed thyroglobulin and neck ultrasound. The average dose of levothyroxine taken orally every morning for TSH suppression was 169 34 mg=d. Four patients were studied under TSH suppression with levothyroxine (sub HYPER). Due to the fact that two volunteers dropped out after the initial evaluation, two new volunteers were recruited to replace them in the following phases of the study. This group of four patients were studied 1 week after thyroid hormone withdrawal (EUTHYR) and again, after 6 weeks of levothyroxine withdrawal in a hypothyroid state (HYPO). Eight euthyroid subjects served as controls (CON). None of the subjects was critically ill or taking any medication that might influence glucose metabolism. All study participants provided their informed consent for the study which was approved by the Institutional Review Board and Ethics Committee. Free thyroxine (T4), total triiodothyronine (T3), and thyrotropin (TSH) were measured by chemiluminescence (DPC; Immulite, Los Angeles, CA); normal range for free T4, 0.8–1.9 ng=dL; intraand inter-assay coefficient of variation were 5.8% and 6.7%, respectively; normal range for T3, 0.8– 2 ng=mL; intraand inter-assay coefficient of variation were 5.8% and 6.6%, respectively; normal range for TSH was 0.3– 5.0 mU=mL; intraand inter-assay coefficient of variation were

/pdf/acute-thyroid-hormone-withdrawal-in-athyreotic-patients-4u5s4eq8zl.pdf

Acute thyroid hormone withdrawal in athyreotic patients results in a state of insulin resistance.

With the aim of understanding the variations of the levels of sex hormone-binding globulin (SHBG) in thyroid dysfunction, we studied the influence of factors that also modify SHBG, such as menopausal status, age, and body mass index (BMI) in women with hypothyroidism and hyperthyroidism, both overt and subclinical. Statistical analysis was performed by means of analysis of variance (ANOVA), stepwise multiple regression, and partial correlation. The ANOVA showed a significant statistical difference among the means of SHBG of all groups (p<0.01). The difference was due to the group that included hyperthyroid women. Multiple regression analysis showed that the main factors influencing SHBG were BMI and age, except for the hyperthyroid group, where the most important independent variables were triiodothyronine (T3) and thyroxine (T4). Partial correlation controlling the effect of BMI and age showed no association between SHBG and the other variables in all groups except for the subclinical hyperthyroid and hyperthyroid, where we found a significant association between SHBG and T4 and T3. The premenopausal or postmenopausal status did not modify SHBG levels. When the patients are taken as a whole, BMI, age, T4, and T3 all have an association with SHBG levels according to the multiple regression analysis.

Variations of sex hormone-binding globulin in thyroid dysfunction.

Plasma glucose, insulin and C-peptide responses to a test meal were studied in 7 nonobese patients with type II diabetes mellitus (NIDDM) treated with diet alone and after 6 months of gliclazide therapy, as well as in 6 matched controls. The glycemic levels were significantly higher (p<0.05) in patients under diet alone than in controls and after gliclazide treatment (peak: 12.8±1.0; 7.9±0.4 and 10.0±0.5 mmol/l, respectively;
 
$$\bar x$$

 ±SEM). Diet and gliclazide treated patients showed a reduced B-cell response during the first hour after the meal as indicated by insulin and C-peptide values and areas (insulin areas 0–60 min: controls 57.9 ± 10.9; p<0.01vs diet alone 14.2 ± 2.7 andvs gliclazide 22.1 ± 2.8 µU/ml/min). The hypoinsulinemic phase lasted from 20 to 60 min before gliclazide, and from 20 to 45 min after gliclazide. The first significant C-peptide increase, detected at 10 min in controls and at 30 min under diet alone, was advanced to 15 min after gliclazide treatment. In conclusion: patients with mild, diet-treated NIDDM show a sluggish and attenuated B-cell response to a physiologic challenge (test meal); this secretory impairment is present even after a complete post-prandial glycemic normalization, supporting the idea of a persistent defect. Nevertheless, the slight improvement observed in insulin secretion after gliclazide treatment may be promoting, at least partially, the normalization of prandial hyperglycemia. The benefits of this normalization in diabetic patients previously controlled by diet only await further investigation.

Diet only or diet and sulfonylureas in mild type II diabetes (NIDDM)? Pathophysiologic and therapeutic implications.

Proatherogenic mechanisms in subclinical hypothyroidism: hepatic lipase activity in relation to the VLDL remnant IDL.

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