1. 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 2010 年 2 月 18 日 8:30-8:55 ８階 医局 Okamoto K, Iwasaki N, Nishimura C, Doi K, Noiri E, Nakamura S, Takizawa M, Ogata M, Fujimaki R, Grarup N, Pisinger C, Borch-Johnsen K, Lauritzen T, Sandbaek A, Hansen T, Yasuda K, Osawa H, Nanjo K, Kadowaki T, Kasuga M, Pedersen O, Fujita T, Kamatani N, Iwamoto Y, Tokunaga K. Identification of KCNJ15 as a susceptibility gene in Asian patients with type 2 diabetes mellitus. Am J Hum Genet. 2010 Jan;86(1):54-64. Miyake K, Yang W, Hara K, Yasuda K, Horikawa Y, Osawa H, Furuta H, Ng MC, Hirota Y, Mori H, Ido K, Yamagata K, Hinokio Y, Oka Y, Iwasaki N, Iwamoto Y, Yamada Y, Seino Y, Maegawa H, Kashiwagi A, Wang HY, Tanahashi T, Nakamura N, Takeda J, Maeda E, Yamamoto K, Tokunaga K, Ma RC, So WY, Chan JC, Kamatani N, Makino H, Nanjo K, Kadowaki T, Kasuga M. Construction of a prediction model for type 2 diabetes mellitus in the Japanese population based on 11 genes with strong evidence of the association. J Hum Genet. 2009 Apr;54(4):236-41.

2. 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 2010 年 2 月 18 日 8:30-8:55 ８階 医局 Franks PW, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Looker HC. Childhood Obesity, Other Cardiovascular Risk Factors, and Premature Death. N Engl J Med. 2010 Feb 11;362(6):485-493. Currie CJ, Peters JR, Tynan A, Evans M, Heine RJ, Bracco OL, Zagar T, Poole CD. Survival as a function of HbA(1c) in people with type 2 diabetes: a retrospective cohort study. Lancet. 2010 Feb 6;375(9713):481-489. Epub 2010 Jan 26.

3. ARCH PEDIATR ADOLESC MED/VOL 164 (NO. 1), JAN 2010 2010 年 1 月 21 日 8:30-8:55 ８階 医局 One thousand sixty-seven girls starting at age 10 years in the National Growth and Health Study and 822 schoolchildren aged 6 to 18 years at entry from the Princeton Follow-up Study.

4. N Engl J Med 2010;362:485-93. From the Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ (P.W.F., R.L.H., W.C.K., M.L.S., P.H.B., H.C.L.); the Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Section for Medicine, Umeå University Hospital, Umeå, Sweden (P.W.F.); the Medical Research Council Epidemiology Unit, Institute of Metabolic Sciences, University of Cambridge, Cambridge, United Kingdom (P.W.F.); and Mount Sinai School of Medicine, New York (H.C.L.).

5. Background The effect of childhood risk factors for cardiovascular disease on adult mortality is poorly understood.

6. Method In a cohort of 4857 American Indian children without diabetes (mean age, 11.3 years; 12,659 examinations) who were born between 1945 and 1984, we assessed whether body-mass index (BMI), glucose tolerance, and blood pressure and cholesterol levels predicted premature death. Risk factors were standardized according to sex and age. Proportional-hazards models were used to assess whether each risk factor was associated with time to death occurring before 55 years of age. Models were adjusted for baseline age, sex, birth cohort, and Pima or Tohono O’odham Indian heritage. Subects: Residents in a well-defined geographic area of the Gila River Indian Community in Arizona, most of whom were Pima or Tohono O’odham Indians

7. * Plus–minus values are means ±SD. To convert values for glucose to milligrams per deciliter, multiply by 18.01. To convert values for cholesterol to milligrams per deciliter, multiply by 38.67. † The body-mass index is the weight in kilograms divided by the square of the height in meters. ‡ Obesity was defined as a body-mass index in the 95th percentile or higher of the U.S. population according to the 2000 database of the Centers for Disease Control and Prevention. 15 § Hypertension was defined according to the criteria of the National High Blood Pressure Education Program. 16 ¶ Hypercholesterolemia was defined as a cholesterol level higher than the cutoff point designated by the American Heart Association (total cholesterol, 5.18 mmol per liter [200 mg per deciliter]). 17

8. We defined deaths due to endogenous causes as those in which the proximate cause was disease or self-inflicted injury, such as acute alcohol intoxication or drug use, and deaths due to external causes as those that resulted from such causes as accidents or homicide.

11. First, childhood cholesterol and blood-pressure levels were not predictive of death, perhaps indicating that they do not track into adulthood as persistently as obesity and impaired glucose tolerance do. Alternatively, these risks may follow patients into adulthood, but primary care clinicians can then detect and manage elevated blood pressure and lipid levels with drugs, whereas they are ill equipped to manage obesity and impaired glucose tolerance (“prediabetes”). Second, associations related to impaired glucose tolerance should not necessarily be generalized to impaired fasting glucose, as it is defined by the American Diabetes Association. Impaired fasting glucose in adults is associated with the development of diabetes and with death, but whether this association holds true in the case of youths is not clear. In addition, a recent study showed that among adolescents, elevated glucose levels were no more predictive of later diabetes than either body-mass index or systolic blood pressure — reminding us that the best predictors of imminent diabetes among adults may be different from the best predictors of long-term risk of diabetes among youths. Third, since most of the deaths from endogenous causes among the population studied in the article occurred before the participants were 45 years of age, this study examined only premature death. The mortality rates were more than twice those of the general U.S. population and were inordinately affected by deaths from liver disease, a finding that merits further study. We should not assume that follow-up into the seventh and eighth decades of life, when most people die of more typical causes, would yield similar associations between impaired glucose tolerance and death. Finally, these and other authors suggest that the life spans of future generations may be affected by the epidemics of obesity and diabetes; this might not be so, given the improvements in care and in the treatment of risk factors — improvements that continue to push life spans to record highs and that have ironically contributed to the growing prevalence of type 2 diabetes. Note on interpretation of the results (editorial)

12. Results There were 166 deaths from endogenous causes (3.4% of the cohort) during a median follow-up period of 23.9 years. Rates of death from endogenous causes among children in the highest quartile of BMI were more than double those among children in the lowest BMI quartile (incidence-rate ratio, 2.30; 95% confidence interval [CI], 1.46 to 3.62). Rates of death from endogenous causes among children in the highest quartile of glucose intolerance were 73% higher than those among children in the lowest quartile (incidence-rate ratio, 1.73; 95% CI, 1.09 to 2.74). No significant associations were seen between rates of death from endogenous or external causes and childhood cholesterol levels or systolic or diastolic blood-pressure levels on a continuous scale, although childhood hypertension was significantly associated with premature death from endogenous causes (incidence-rate ratio, 1.57; 95% CI, 1.10 to 2.24).

13. Conclusion Obesity, glucose intolerance, and hypertension in childhood were strongly associated with increased rates of premature death from endogenous causes in this population. In contrast, childhood hypercholesterolemia was not a major predictor of premature death from endogenous causes.

14. Rather than focusing on adults who may be set in their ways, we should perhaps target our youth. Among Pima Indian youths 5 to 19 years of age, obesity and 2-hour glucose levels (below the threshold for impaired glucose tolerance, but above normal levels), were associated with a rate of death in young adulthood and middle age that was about twice that of peers without diabetes. It will be important to convert these results into effective prevention policies. Our search for ways to alter the common source must continue.

15. Message 糖尿病の予防は小児期から？

17. ピオグリタオンは メトホルミンと比べ 総死亡のリスクが低い 性別、年齢、糖尿病の罹病期間、心血管疾患の既往、心不全の既往、末梢動 脈疾患の既往、他の薬剤の有無、糖尿病合併症の既往で補正を行っている。 Tzoulaki et al.;BMJ,339,b4731,2009 1990 年 -2005 年の英国実地診療データベースより 35 歳から 90 歳の糖尿病患者 91,521 人を抽出し、 心筋梗塞、うっ血性心不全、総死亡の発生リスクを経口糖尿病薬別に比較検討した。 （ 95% 信頼区 間） 総死亡のハザード比 第 2 世代 SU 剤 vs メトホ ルミン ロシグリタゾン vs メトホ ルミン ピオグリタゾン vs メトホ ルミン その他併用療法 vs メトホ ルミン 第１世代 SU 剤 vs メトホル ミン 2.01.51.00.5 1.43 1.40 1.01 0.92 0.62 * *** * * ** p ＜ 0.001 p=0.078 ** *** p=0.0004 グリベンクラミ ド UK general practice research database

18. Lancet 2010; 375: 481–89 Department of Medicine, School of Medicine, Cardiff University, Cardiff, UK (C J Currie PhD); Department of Medicine, University Hospital of Wales, Cardiff, UK (J R Peters FRCP, M Evans MD); Eli Lilly and Company, Indianapolis, IN, USA (A Tynan MSc, Prof R J Heine FRCP, O L Bracco MD, T Zagar PhD); and Department of Epidemiology, Pharmatelligence, Cardiff, UK (C D Poole PhD) UK general practice research database

19. Objective Results of intervention studies in patients with type 2 diabetes have led to concerns about the safety of aiming for normal blood glucose concentrations. We assessed survival as a function of HbA1c in people with type 2 diabetes.

20. Method Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the UK General Practice Research Database from November 1986 to November 2008. We identified 27965 patients whose treatment had been intensified from oral monotherapy to combination therapy with oral blood-glucose lowering agents, and 20005 who had changed to regimens that included insulin. Those with diabetes secondary to other causes were excluded. All-cause mortality was the primary outcome. Age, sex, smoking status, cholesterol, cardiovascular risk, and general morbidity were identified as important confounding factors, and Cox survival models were adjusted for these factors accordingly.

21. T-chol 5.4 mmol/L = 209 mg/dl (/0.0259 Creatinine 130 micromol/L= 1.47 mg/dl (/88.4)

22. T-chol 5.4 mmol/L = 209 mg/dl (/0.0259 Creatinine 130 micromol/L= 1.47 mg/dl (/88.4)

23. The Charlson comorbidity index predicts the relative likelihood of 1-year mortality for a patient who might have any of 22 comorbid disorders, such as heart disease or cancer.

28. Results For combined cohorts, compared with the glycated haemoglobin (HbA1c) decile with the lowest hazard (median HbA1c 7 ・ 5%, IQR 7 ・ 5–7 ・ 6%), the adjusted hazard ratio (HR) of all-cause mortality in the lowest HbA1c decile (6 ・ 4%, 6 ・ 1–6 ・ 6) was 1 ・ 52 (95% CI 1 ・ 32–1 ・ 76), and in the highest HbA1c decile (median 10 ・ 5%, IQR 10 ・ 1–11 ・ 2%) was 1 ・ 79 (95% CI 1 ・ 56–2 ・ 06). Results showed a general U-shaped association, with the lowest HR at an HbA1c of about 7 ・ 5%. HR for all-cause mortality in people given insulin-based regimens (2834 deaths) versus those given combination oral agents (2035) was 1 ・ 49 (95% CI 1 ・ 39–1 ・ 59).

29. Conclusion Low and high mean HbA1c values were associated with increased all- cause mortality and cardiac events. If confirmed, diabetes guidelines might need revision to include a minimum HbA1c value.

30. Message 血糖管理基準の変更があるかもしれない。 しかし，観察データは原因と結果がはっきりし ないのでどうかと感じる。 ( また英国の HbA 1C の 7.5% は 日本では 7.1%) SU 薬とメトホルミンの併用はもともとリスクが 高く，インスリン治療では低血糖リスク回避が うまくされていない可能性が強い。 インスリン治療者で HbA 1C を 7.1% にするには 結構大変かもしれない。