Journal Club

埼玉医科大学　総合医療センター　内分泌・糖尿病内科Department of Endocrinology and Diabetes,

Saitama Medical Center, Saitama Medical University

松田　昌文Matsuda, Masafumi

2012年 10月 4日　 8:30-8:55８階　医局

Neeland IJ, Turer AT, Ayers CR, Powell-Wiley TM, Vega GL, Farzaneh-Far R, Grundy SM, Khera A, McGuire DK, de Lemos JA.Dysfunctional adiposity and the risk of prediabetes and type 2 diabetes in obese adults.JAMA. 2012 Sep 19;308(11):1150-9.

Pal A, Barber TM, Van de Bunt M, Rudge SA, Zhang Q, Lachlan KL, Cooper NS, Linden H, Levy JC, Wakelam MJ, Walker L, Karpe F, Gloyn AL.PTEN mutations as a cause of constitutive insulin sensitivity and obesity.N Engl J Med. 2012 Sep 13;367(11):1002-11.

JAMA. 2012;308(11):1150-1159

Division of Cardiology (Drs Neeland, Turer, Farzaneh-Far, Khera, McGuire, and de Lemos and Mr Ayers), Department of Clinical Sciences (Mr Ayers and Dr McGuire), and Center for Human Nutrition (Drs Vega and Grundy), University of Texas Southwestern Medical Center, Dallas; and Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland (Dr Powell-Wiley).

Context The risk of type 2 diabetes mellitus is heterogeneous among obese individuals. Factors that discriminate prediabetes or diabetes risk within this population have not been well characterized. A dysfunctional adiposity phenotype, characterized by excess visceral fat and insulin resistance, may contribute to diabetes development in those with obesity.

Objective To investigate associations between adiposity phenotypes and risk for incident prediabetes and diabetes in a multiethnic, population-based cohort of obese adults. Design, Setting, and Participants Among 732 obese participants (body mass index 30) aged 30 to 65 years ≧without diabetes or cardiovascular disease enrolled between 2000 and 2002 in the Dallas Heart Study, we measured body composition by dual energy x-ray absorptiometry and magnetic resonance imaging (MRI); circulating adipokines and biomarkers of insulin resistance, dyslipidemia, and inflammation; and subclinical atherosclerosis and cardiac structure and function by computed tomography and MRI. Main Outcome Measures Incidence of diabetes through a median 7.0 years (interquartile range, 6.6-7.6) of follow-up. In a subgroup of 512 participants with normal fasting glucose values at baseline, incidence of the composite of prediabetes or diabetes was determined.

Abbreviations: BMI, body mass index; BP, blood pressure; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance; hsCRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; METs, metabolic equivalence units; VLDL, very low-density lipoprotein. SI conversion factors: To convert glucose to mmol/L, multiply by 0.0555; HDL-C, LDL-C, and VLDL to mmol/L, multiply by 0.0259; triglycerides to mmol/L, multiply by 0.0113. a Calculated as weight in kilograms divided by height in meters squared. bn=565 and n=74 for the no diabetes and incident diabetes groups, respectively. c Concentration of large particles.

Results Of the 732 participants (mean age, 43 years; 65% women; 71% nonwhite), 84 (11.5%) developed diabetes. In multivariable analysis, higher baseline visceral fat mass (odds ratio [OR] per 1 SD [1.4 kg], 2.4; 95% CI, 1.6-3.7), fructosamine level (OR per 1 SD [1.1 μmol/L], 2.0; 95% CI, 1.4-2.7), fasting glucose level (OR per 1 SD [1.1 μmol/L], 1.9; 95% CI, 1.4-2.6), family history of diabetes (OR, 2.3; 95% CI, 1.3-4.3), systolic blood pressure (OR per 10 mm Hg, 1.3; 95% CI, 1.1-1.5), and weight gain over follow-up (OR per 1 kg, 1.06; 95% CI, 1.02-1.10) were independently associated with diabetes, with no associations observed for body mass index, total body fat, or abdominal subcutaneous fat. Among the 512 participants with normal baseline glucose values, the composite outcome of prediabetes or diabetes occurred in 39.1% and was independently associated with baseline measurements of visceral fat mass; levels of fasting glucose, insulin, and fructosamine; older age; nonwhite race; family history of diabetes; and weight gain over follow-up (P_.05 for each) but not with measurements of general adiposity.

Conclusion Excess visceral fat and insulin resistance, but not general adiposity, were independently　associated　 with　 incident prediabetes　 and　 type　 2　diabetes mellitus in　 obese　adults.

Message糖尿病（ DM）と心血管疾患のない肥満成人 732人を対象に、肥満と DMの関連をコホート研究で調査。多変量解析では内臓脂肪過多、フルクトサミン高値、空腹時血糖高値などが DMと独立して関連した。ベースライン時の空腹時血糖値正常のサブグループでは、内臓脂肪過多とインスリン抵抗性が独立して前 DM状態および 2型 DM発現と関連した。

N Engl J Med 2012;367:1002-11.

An example of the existence of enzymes and signaling pathways common to both cell cycling and metabolism is the tumor-suppressor phosphatase and tensin homologue (PTEN), a protein and lipid phosphatase, which antagonizes the phosphatidylinositol 3-kinase (PI3K) pathway and also has a role in both the cell-cycle and metabolic pathways. PTEN (located on chromosome 10q23.3) is among the most common somatically mutated genes in tumorigenesis, and germline loss-of-function PTEN mutations cause the Cowden syndrome, a rare cancer-predisposition syndrome. PTEN has also been implicated in type 2 diabetes, since the PI3K-AKT pathway plays a role in insulin signaling.

Background Epidemiologic and genetic evidence links type 2 diabetes, obesity, and cancer. The tumor-suppressor phosphatase and tensin homologue (PTEN) has roles in both cellular growth and metabolic signaling. Germline PTEN mutations cause a cancer　 predisposition syndrome, providing an opportunity to study the effect of PTEN haploinsufficiency in humans.

Methods We measured insulin sensitivity and beta-cell function in 15 PTEN mutation carriers and 15 matched controls. Insulin signaling was measured in muscle and adiposetissue biopsy specimens from 5 mutation carriers and 5 well-matched controls. We also assessed the effect of PTEN haploinsufficiency on obesity by comparing anthropometric indexes between the 15 patients and 2097 controls from a population-based study of healthy adults. Body composition was evaluated by means of dual-emission x-ray absorptiometry and skinfold thickness.

Figure 2. Assessment of Insulin Sensitivity and the Body-Mass Index (BMI) in the 15 Patients and 2097 Population-Based Controls.

Panel A shows the relationship between fasting insulin levels and BMI, with adjustment for age and sex. The 5th and 95th percentiles for the controls are shown as gray dashed lines; the regression slopes between fasting insulin and BMI are shown as solid lines. Panel B shows BMI data for the patients (mean, 32 [range, 23 to 42]) and for the controls (mean, 26 [range, 15 to 48]). In the box-and-whisker plot, the horizontal line inside the box represents the median, the top and bottom of the box represent the interquartile range, and the vertical bars (“whiskers”) represent the range; outliers are shown as individual data points.

Figure 3. AKT Phosphorylation Status in Muscle and Adipose-Tissue Specimens in Five Study Patients and Five Controls. Panel A shows a representative blot of relative AKT and phosphorylated AKT (pAKT) levels in muscle tissue from a patient and a matched control, both in a fasting state. Panel B shows the protein expression levels for AKT and pAKT in muscle tissue in five patients and five controls (between-group P = 0.14 for AKT and P = 0.69 for pAKT, by a two-tailed Wilcoxon signed-rank test). Panel C shows a representative blot of relative pAKT levels in adipose tissue from a patient and a control in the fasting state (at 0 minutes) and the glucose-stimulated state (at 120 minutes after the oral glucose-tolerance test was begun). Panel D shows pAKT expression in adipose tissue from three patients and three controls before and after stimulation with glucose (between-group P = 0.11 and P = 0.28, respectively, by a two-tailed Wilcoxon signed-rank test). (The remaining two samples in each group were not analyzed, owing to insufficient material resulting from technical difficulties.)

Results Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P = 0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P = 0.009). The patients’ insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index [the weight in kilograms divided by the square of the height in meters], 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P<0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.

Conclusions PTEN haploinsufficiency is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic. We demonstrate an apparently divergent effect of PTEN mutations: increased risks of obesity and cancer but a decreased risk of type 2 diabetes owing to enhanced insulin sensitivity.

(Funded by the Wellcome Trust and others.)

Message　腫瘍抑制遺伝子ホスファターゼ・テンシンホモログ（ PTEN）変異保有者 15人を対象に、 PTENハプロ不全の影響を検討。変異保有者はマッチさせた対照 15人に比べインスリン抵抗性が低く、集団ベース研究からの対照に比べ肥満だった。 PTENハプロ不全で肥満と癌リスク増加と、インスリン感受性亢進による糖尿病リスク低下が示唆された。

Matsuda index 活躍していますね！