The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Results Baseline levels of IL-6 (P,001) and CRP (P,001) were significantly higher among cases than among controls The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 75 for IL-6 (95% confidence interval [CI], 37-154) and 157 for CRP (95% CI, 65-379) Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol, and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 23 for IL-6 (95% CI, 09-56; P for trend=07) and 42 for CRP (95% CI, 15-120; P for trend=001) Similar results were observed in analyses limited to women with a baseline hemoglobin A1c of 60% or less and after adjustment for fasting insulin level

https://jamanetwork.com/journals/jama/articlepdf/1150732/JOC10096.pdf

C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus

Adipose tissue as an endocrine organ.

Obesity is becoming a global epidemic in both children and adults. It is associated with numerous comorbidities such as cardiovascular diseases (CVD), type 2 diabetes, hypertension, certain cancers, and sleep apnea/sleep-disordered breathing. In fact, obesity is an independent risk factor for CVD, and CVD risks have also been documented in obese children. Obesity is associated with an increased risk of morbidity and mortality as well as reduced life expectancy. Health service use and medical costs associated with obesity and related diseases have risen dramatically and are expected to continue to rise. Besides an altered metabolic profile, a variety of adaptations/alterations in cardiac structure and function occur in the individual as adipose tissue accumulates in excess amounts, even in the absence of comorbidities. Hence, obesity may affect the heart through its influence on known risk factors such as dyslipidemia, hypertension, glucose intolerance, inflammatory markers, obstructive sleep apnea/hypoventilation, and the prothrombotic state, in addition to as-yet-unrecognized mechanisms. On the whole, overweight and obesity predispose to or are associated with numerous cardiac complications such as coronary heart disease, heart failure, and sudden death because of their impact on the cardiovascular system. The pathophysiology of these entities that are linked to obesity will be discussed. However, the cardiovascular clinical evaluation of obese patients may be limited because of the morphology of the individual. In this statement, we review the available evidence of the impact of obesity on CVD with emphasis on the evaluation of cardiac structure and function in obese patients and the effect of weight loss on the cardiovascular system.

/pdf/obesity-and-cardiovascular-disease-pathophysiology-3oufiofv6y.pdf

Obesity and Cardiovascular Disease: Pathophysiology, Evaluation, and Effect of Weight Loss

Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.

The anti-inflammatory effect of exercise

We measured arterio-venous differences in concentrations of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) across a sc adipose tissue bed in the postabsorptive state in 39 subjects [22 women and 17 men; median age, 36 yr (interquartile range, 26-48 yr); body mass index, 31.8 kg/m2 (range, 22.3- 38.7 kg/m2); percent body fat, 28.7% (range, 17.6-50.7%)]. A subgroup of 8 subjects had arteriovenous differences measured across forearm muscle. Thirty subjects were studied from late morning to early evening; 19 ate a high carbohydrate meal around 1300 h, and 11 continued to fast. We found a greater than 2-fold increase in IL-6 concentrations across the adipose tissue bed [arterial, 2.27 pg/mL (range, 1.42-3.53 pg/mL); venous, 6.71 pg/mL (range, 3.36-9.62 pg/mL); P < 0.001], but not across forearm muscle. Arterial plasma concentrations of IL-6 correlated significantly with body mass index (Spearman's r = 0.48; P < 0.01) and percent body fat (Spearman's r = 0.49; P < 0.01). Subcutaneous adipose tissue IL-6 production increased by the early evening (1800-1900 h) in both subjects who had extended their fasting and those who had eaten. Neither deep forearm nor sc adipose tissue consistently released TNF alpha [across adipose tissue: arterial, 1.83 pg/mL (range, 1.36-2.34 pg/mL); venous, 1.85 pg/mL (range, 1.44-2.53 pg/mL); P = NS: across forearm muscle: arterial, 1.22 pg/mL (range, 0.74-2.76 pg/mL); venous, 0.99 pg/mL (range, 0.69-1.70 pg/mL); P = NS]. Although both IL-6 and TNF alpha are expressed by adipose tissue, our results show that there are important differences in their systemic release. TNF alpha is not released by this sc depot. In contrast, IL-6 is released from the depot and is thereby able to signal systemically.

/pdf/subcutaneous-adipose-tissue-releases-interleukin-6-but-not-4k9lq0ryf4.pdf

Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.

To investigate in vivo adipose tissue production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we determined arteriovenous differences in their levels across abdominal subcutaneous adipose tissue in obese subjects. Subjects had a median (interquartile range) age of 44.5 (27–51.3) yr, body mass index (BMI) of 32.9 (26.0–46.6) kg/m2, and %body fat of 42.5 (28.5–51.2) %. Although there was not a significant difference in the arteriovenous concentrations of TNF-α (P = 0.073) or sTNFR-II (P = 0.18), the levels of sTNFR-I (P = 0.002) were higher in the vein compared with artery, suggesting adipose tissue production of this soluble receptor. There was a significant arteriovenous difference in IL-6 (P < 0.001) but not in its soluble receptor (P = 0.18). There was no relationship between TNF-α levels and adiposity indexes (r s = 0.12–0.22, P = not significant); however, levels of bot...

https://www.physiology.org/doi/pdf/10.1152/ajpendo.1999.277.6.E971

Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo.

OBJECTIVE
To study interactions between leptin and the pituitary–thyroid axis, both in euthyroid and dysthyroid states.

SUBJECTS AND MEASUREMENTS
We investigated the relationships of plasma leptin to levels of free thyroid hormones and TSH in 18 patients with newly diagnosed hyperthyroidism, 22 with newly diagnosed primary hypothyroidism, and 32 lean (body mass index [BMI]   30 kg/m2) euthyroid subjects. Hypothyroid patients were restudied during thyroxine replacement treatment.

RESULTS
Median [interquartile range] plasma leptin concentrations were highest in obese euthyroid subjects (31.5 [19.0–48.0] and in untreated hypothyroid patients (19.2 [11.5–31.5]), and lowest levels in untreated hyperthyroid patients (8.9 [5.5–11.1]) and lean euthyroid control subjects (6.6 [3.9–14.4] μg/l (Kruskall–Wallis one-way analysis of variance; P < 0.0001). In euthyroid subjects, plasma leptin levels were higher in obese than in lean subjects (P < 0.00001). In obese subjects plasma levels of TSH correlated with percentage body fat (r = 0.67; P < 0.001) and plasma leptin (r = 0.61; P < 0.001). In untreated hyperthyroid subjects plasma leptin was unrelated to free T3, and in untreated hypothyroidism plasma leptin was unrelated to either free T3 or TSH concentrations (all P = NS). In untreated hyperthyroid, but not hypothyroid, patients plasma leptin concentrations correlated with BMI (r = 0.57; P = 0.02). Treatment of hypothyroidism with thyroxine resulted in a significant reduction in plasma leptin concentrations from 20.8 (11.8 to 31.6) to 12.9 (4.6–21.2) μg/l (P = 0.005), but BMI did not change significantly in the hypothyroid subjects being studied prospectively.

CONCLUSIONS
(i) In euthyroid subjects, plasma leptin and TSH levels correlate, and both are positively correlated with adiposity. (ii) Plasma leptin was significantly elevated in hypothyroid subjects, to levels similar to those seen in obese euthyroid subjects. (iii) Treatment of hypothyroidism resulted in a reduction in the raised plasma leptin levels. The data are consistent with the hypothesis that leptin and the pituitary–thyroid axis interact in the euthyroid state, and that hypothyroidism reversibly increases leptin concentrations.

Leptin and the pituitary–thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects

In non-diabetic subjects, insulin concentrations and insulin resistance are clearly connected, and both correlate with leptin levels, making interpretations about mechanisms difficult. In non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), however, insulin concentrations and insulin resistance are less closely associated. Therefore, we examined the relationship of plasma leptin concentrations within insulin resistance and insulin levels in 32 subjects with NIDDM, who underwent measurement of insulin resistance with an insulin sensitivity test. Plasma leptin was measured with an in-house monoclonal immunoradiometric assay. Fasting leptin level correlated with BMI (r = 0.78; p < 0.001), metabolic clearance rate of glucose (= -0.44; p = 0.015), and fasting specific insulin (r = 0.58; p = 0.001), but not with age, cholesterol, triglycerides or blood pressure (r = -0.26 to 0.21; p = NS). In linear regression analysis, after adjustment for BMI and gender, leptin concentrations correlated with those of insulin (partial r = 0.42; p = 0.025), but not insulin resistance (partial r = -0.10; p = NS). We conclude that in NIDDM, concentrations of plasma leptin are closely related to those of insulin per se and to obesity, but not to insulin resistance. Insulin may be an important regulator of leptin concentration in NIDDM.

Relationships between plasma leptin and insulin concentrations, but not insulin resistance, in non-insulin-dependent (Type 2) diabetes mellitus

Central obesity, depression and the hypothalamo–pituitary–adrenal axis in men and postmenopausal women

S Goodrick

Papers

Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo.

Production of soluble tumor necrosis factor receptors by human subcutaneous adipose tissue in vivo.

Leptin and the pituitary–thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects

Relationships between plasma leptin and insulin concentrations, but not insulin resistance, in non-insulin-dependent (Type 2) diabetes mellitus

Central obesity, depression and the hypothalamo-pituitary-adrenal axis in men and postmenopausal women.