Cancer and comorbidity: The role of leptin in breast cancer and associated pathologies

Table 1 Selected recent reports on diabetes and epidemiological/clinical characteristics of breast cancer

Authors and report time	Study types, geographical areas and patients	Findings in brief
Bronsveld et al[44] 2017	Population-based cohort study among British population, 2371 breast cancer cases during approximately 1.6 million person-years	Approximately 2880 women with T2D are diagnosed with breast cancer per year in the United Kingdom
Charlot et al[45] 2017	1621 African-American women with invasive breast cancer (232 had T2D) were followed	A positive association of T2D with breast cancer mortality
Dankner et al[46] 2016	Israel, 2186196 individuals (prevalent diabetes: 159104 and incident diabetes: 408243) were followed for various cancers	Diabetes posed an increased risk of breast cancer in postmenopausal women
Gini et al[47] 2016	Retrospective population-based cohort study, Italy, 32247 T2D patients	T2D patients are at increased risk of several cancers, and of premature death in women with breast cancer
Lipscombe et al[48] 2015	Retrospective cohort study, Ontario, Canada, 38407 women with breast cancer (6115 had diabetes)	Diabetes was associated with more advanced-stage breast cancer
Luo et al[49] 2014	Women’s Health Initiative, United States, 8108 women with breast cancer	T2D increased risk of total mortality among women with breast cancer
Ma et al[50] 2014	China, 865 early stage triple-negative breast cancer cases	T2D exhibited a significantly lower disease-free survival; increased likelihood of recurrence and metastasis
Maskarinec et al[51] 2017	Multiethnic cohort, Among 103721 women with 14558 T2D cases, 6692 women developed breast cancer	T2D status was primarily associated with higher breast cancer risk in Latinas
Palmer et al[52] 2017	Prospective cohort of African-American women, 1851 breast cancer cases during 847934 person-years of follow-up	Women with T2D were at increased risk of developing ER(-) breast cancer
Pan et al[53] 2018	Prospective study in China, 17463 incident cases (various cancers) among 508892 participants	Participants with T2D had increased risks of breast cancer
Samson et al[54] 2016	Retrospective cohort study, South Carolina, 7310 participants (3835 European-origin and 3475 African-American women)	Negative association between T2D and breast cancer was stronger in African-American women
Wu et al[55] 2015	Multiethnic cohort, California, 8952 breast cancer cases	Risk of mortality increased among cases with diabetes
Xu et al[56] 2015	Population-based retrospective cohort study, China, 36379 T2D patients	Elevated risk of breast cancer

T2D: Type-2 diabetes; ER(-): Estrogen receptor negative; Person-years: Amount of total time in years contributed by all participants.

Table 2 Levels of circulating leptin in various pathophysiological conditions

Investigators	Subjects and salient findings
Al-Daghri et al[105] 2007 (Saudi Arabia)	308 adults participated [type-2 diabetes = 142 (female- 45), prediabetes = 86 (female- 37), normal controls = 80 (female- 35)]. Serum leptin levels among male subjects with type-2 diabetes (BMI- 27.3 ± 4.1 kg/m2) were 12.4 (3.2-72) ng/mL; among pre-diabetes (BMI- 28.5 ± 4.3 kg/m2) - 7.6 (1.2-72) ng/mL; and in controls (BMI- 29.2 ± 7.3 kg/m2) - 3.9 (0.8-20) ng/mL. Leptin levels among female subjects with type-2 diabetes (BMI- 32.5 ± 10.3 kg/m2) were 13.3 (3.6-49.1) ng/mL; among pre-diabetes (BMI- 32.5 ± 8.4 kg/m2) - 14.09 (2.8-44.4) ng/mL; and in controls (BMI- 30.4 ± 6.4 kg/m2) - 10.2 (0.25-34.8) ng/mL
Al-Harithy[106] 2004 (Saudi Arabia)	Females (n = 57) had higher serum leptin concentration (6.04 ± 4.71 ng/mL vs 1.72 ± 0.95 ng/mL) than males (n = 65). BMI values showed a strong association with leptin levels in both genders
Al Maskari and Alnaqdy[107] 2006 (Oman)	Overall, there was a significant difference in serum leptin between the obese group (n = 35, 34.78 ± 13.96 ng/mL) and the control non-obese subjects (n = 20, 10.6 ± 4.2 ng/mL). Obese females (n = 25): age- 29.2 ± 1.6 yr, BMI- 39.6 ± 1.5 kg/m2, leptin- 38.2 ± 2.5 ng/mL; Obese males (n = 10): age- 30.0 ± 3.1 yr, BMI- 39.0 ± 2.9 kg/m2, leptin- 27.0 ± 4.9 ng/mL
Kazmi et al[108] 2013 (Pakistan)	Obese and overweight group: n = 40, female- 33, age- 34.8 ± 4.6 yr, BMI- 31.7 ± 3.1 kg/m2; and non-obese group: n = 50, female- 32, age- 32.7 ± 6.1 yr, BMI- 21.2 ± 1.5 kg/m2. Serum leptin concentrations were higher in obese subjects (52.8 ± 24.6 ng/mL) than in non-obese subjects (6.3 ± 3.1 ng/mL)
Laimer et al[109] 2002 (Austria)	18 morbidly obese women were studied before and one year after SAGB. In addition, eight lean women were examined as a control group. Serum leptin levels decreased from 44.6 ± 18.0 ng/mL in pre-SAGB subjects (age- 40.3 ± 9.8 yr, BMI- 42.9 ± 5.6 kg/m2) to 20.0 ± 13.1 ng/mL in post-SAGB state (BMI- 32.9 ± 6.0 kg/m2). Control subjects: age- 38.3 ± 9.8 yr, BMI- 22.9 ± 2.2 kg/m2, leptin- 6.3 ± 3.3 ng/mL
Miyawaki et al[110] 2002 (Japan)	During four weeks, ten obese subjects (five men and five premenopausal women: age- 33 ± 13 yr, BMI- 35.4 ± 2.4 kg/m2, plasma leptin level- 46.2 ± 14.6 ng/mL) underwent 800 kcal/day LCD. In addition, ten obese subjects (five men and five premenopausal women: age- 31 ± 11 yr, BMI- 32.3 ± 2.1 kg/m2, leptin- 14.9 ± 3.5 ng/mL) consumed a 1400 kcal/day BDD for the same period. Plasma leptin levels in the LCD group markedly decreased (13.2 ± 3.6 ng/mL) with the decrement in BMI (33.1 ± 2.2 kg/m2); while in the BDD group, BMI and leptin concentrations were 31.0 ± 2.5 kg/m2 and 13.4 ± 2.8 ng/mL, respectively
Osegbe et al[111] 2016 (Nigeria)	80 obese females (BMI- 39.1 ± 7.2 kg/m2) were examined. Prevalence of hyperleptinemia was 92.5% and serum leptin levels- 48.4 ± 24.4 ng/mL
Sinorita et al[112] 2010 (Indonesia)	57 obese persons (female- 33) were divided into obese class I (BMI > 25 kg/m2 to < 30 kg/m2) and obese class II (BMI > 30 kg/m2). Leptin concentration in obese class I was 13.998 ± 13.486 ng/mL, and in obese class II was 31.074 ± 26.158 ng/mL
Tasaka et al[113] 1997 (Japan)	In BMI < 25 kg/m2, plasma leptin was 2.24 ± 0.25 ng/mL in males (n = 29) and 3.01 ± 0.39 ng/mL in females (n = 13); in BMI 25-30 kg/m2, levels were 3.14 ± 0.31 ng/mL in males (n = 10) and 10.66 ± 2.86 ng/mL in females (n = 7) and in BMI > 30 kg/m2, levels were 8.98 ± 1.5 ng/mL in males (n = 11) and 11.74 ± 2.2 ng/mL in females (n = 6)
Tong et al[114] 2005 (United States)	The subjects consisted of nondiabetic Japanese-American population (n = 518, male- 51%) enrolled in the Japanese-American Community Diabetes Study. The mean plasma leptin level for men (BMI- 25.2 ± 3.0 kg/m2) was 4.0 ± 2.7 pmol/L and 11.6 ± 7.3 pmol/L for women (BMI- 22.9 ± 3.1 kg/m2) (1 pmol/L = 0.445 ng/mL)
van Rossum et al[115] 2000 (United States)	54 postmenopausal obese women before and after a 6-mo hypocaloric diet - the women lost an average of 7.1% of body weight and 14.5% serum leptin levels during the 6-mo weight loss intervention (initial BMI- 32.0 ± 4.5 kg/m2, leptin- 30.9 ± 20.2 ng/mL; and after weight loss BMI- 29.8 ± 4.7 kg/m2, leptin- 24.3 ± 14.8 ng/mL)

BMI: Body mass index; SAGB: Swedish adjustable gastric banding; LCD: Low-calorie diet; BDD: Balanced deficit diet.