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

2011 年 11 月 10 日　 8:30-8:55８階　医局

Loopstra-Masters RC, Haffner SM, Lorenzo C, Wagenknecht LE, Hanley AJ.Proinsulin-to-C-peptide ratio versus proinsulin-to-insulin ratio in the prediction of incident diabetes: the Insulin Resistance Atherosclerosis Study (IRAS).Diabetologia. 2011 Dec;54(12):3047-54. Epub 2011 Sep 30.

Sumithran P, Prendergast LA, Delbridge E, Purcell K, Shulkes A, Kriketos A, Proietto J.Long-term persistence of hormonal adaptations to weight loss.N Engl J Med. 2011 Oct 27;365(17):1597-604.

1. Preproinsulin (Leader, B chain, C chain, A chain); proinsulin consists of BCA, without L

2. Spontaneous folding3. A and B chains linked by sulphide bonds4. Leader and C chain are cut off5. Insulin molecule remains

http://ja.wikipedia.org/wiki/%E3%82%A4%E3%83%B3%E3%82%B9%E3%83%AA%E3%83%B3

Proinsulin (PI), a polypeptide of 9390 MW (86 amino acids)

C-peptide (MW 3020-3025) (31 amino acids) appears ahead of insulin.(MW 5808) (51 amino acids)

インタクトプロインスリン / インスリン比（ Intact Proinsulin/Insulin Ratio ） プロインスリンは、インスリンの前駆物質であり、 86 個のアミノ酸からなるポリペプチドである。通常、膵 β 細胞内のトランスゴルジネットワークから出たプロインスリンは、そのほとんどが同じく β 細胞内にあるインスリン顆粒に貯蔵され、顆粒内でインスリンと C- ペプチドに分解された後、血中に放出される。しかし、一部はプロインスリン（インタクトプロインスリン）のまま、もしくはインスリンへの分解過程で生じる中間生成物（スプリットプロインスリン）の形で血中に放出される。インタクトプロインスリンはインスリンの 10 ％程度しか血中に存在しておらず、またその生物活性はインスリンの 10 ％程度に過ぎない。しかし、インタクトプロインスリンに特異的な測定系を用いた検討では、空腹時におけるインタクトプロインスリンとインスリンのモル比（ P/I 比）は、耐糖能の悪化に伴って有意に上昇し、インスリン初期分泌能の指標である Insulinogenic Index （ I.I. ）と有意な逆相関を示した。このことから、空腹時 P/I 比は膵 β 細胞の機能障害を反映する指標として注目されている。 現在、膵 β 細胞機能を評価するためには、ブドウ糖やグルカゴン負荷試験により血中インスリンや C- ペプチドを測定する方法が多く利用されている。血中 P/I 比の測定は、空腹時だけで膵 β 細胞機能の評価が可能であることから、負荷試験を補う検査として有用であると思われる。

http://www.medience.co.jp/research/03_04.html

R. C. Loopstra-Masters : A. J. Hanley Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, FitzGerald Building, 150 College St, Toronto, ON, Canada M5S 3E2 e-mail: anthony.hanley@utoronto.ca S. M. Haffner Department of Medicine, Baylor College of Medicine, Houston, TX, USA C. Lorenzo Division of Clinical Epidemiology, University of Texas Health Sciences Center, San Antonio, TX, USA L. E. Wagenknecht Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA

Aims Associations of proinsulin-to-insulin ratios with incident type 2 diabetes have been inconsistent. The use of C-peptide as the denominator in the ratio may allow for better prediction because C-peptide concentration is not affected by hepatic insulin clearance. The objective of this paper was to compare fasting intact and split proinsulin-to-insulin ratios (PI/I, SPI/I) with intact and split proinsulin-to-C-peptide ratios (PI/C-pep, SPI/C-pep) in the prediction of type 2 diabetes.

Methods Prospective data on 818 multi-ethnic adults without diabetes at baseline from the Insulin Resistance Atherosclerosis Study (IRAS) were used. Insulin sensitivity (SI) and acute insulin response (AIR) were determined from frequently sampled intravenous glucose tolerance tests, and fasting intact and split proinsulin were measured using specific two-site monoclonal antibody-based immunoradiometric assays. Associations of proinsulin ratios with type 2 diabetes were determined using logistic regression and differences in prediction were assessed by comparing areas under the receiver operating characteristic curve (AROCs).

Keywords Beta cell function . Insulin sensitivity .Proinsulin . Type 2 diabetes mellitus

AbbreviationsAIR Acute insulin responseAROC Area under the receiver operating characteristic curveFSIGT Frequently sampled intravenous glucose tolerance testIGT Impaired glucose toleranceIRAS Insulin Resistance Atherosclerosis StudyNGT Normal glucose tolerancePI/C-pep Intact proinsulin-to-C-peptide ratioPI/I Intact proinsulin-to-insulin ratioSI Insulin sensitivitySPI/C-pep Split proinsulin-to-C-peptide ratioSPI/I Split proinsulin-to-insulin ratio

Results In logistic regression analyses, PI/C-pep and SPI/Cpep were more strongly associated with incident type 2 diabetes (n=128) than PI/I and SPI/I, and were significantly better predictors of diabetes in AROC analyses (PI/C-pep=0.662 vs PI/I=0.603, p=0.02; SPI/C-pep=0.690 vs SPI/I=0.631, p= 0.01). Both PI/C-pep and SPI/C-pep were associated with type 2 diabetes after adjustment for age, sex, ethnicity, waist circumference, impaired glucose tolerance, lipids and SI. Both PI/C-pep and SPI/C-pep were significantly associated with incident type 2 diabetes in models that included AIR.

Conclusions Proinsulin-to-C-peptide ratios were stronger predictors of diabetes in comparison with proinsulin-to insulin ratios. These findings support the use of C-peptide as the denominator for proinsulin ratios, to more accurately reflect the degree of disproportional hyperproinsulinaemia.

Message/Comments

Proinsulin の測定意義は我々の研究で大きな位置を占めてきたが、 Split タイプや C-peptide の使用意義も見直す必要があるかもしれない。一般的に insulin は肝臓での代謝を受けるので C-peptide がより膵臓からのインスリン分泌を反映する指標という考えは間違えではないであろう。

http://www.phoenixbiotech.net/allobesity/index.html

From the Departments of Medicine (P.S., E.D., K.P., A.K., J.P.), and Surgery (A.S.) (Austin and Northern Health), University of Melbourne; and the Department of Mathematics and Statistics, La Trobe University (L.A.P.)

N Engl J Med 2011;365:1597-604.

Background After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.

Methods We enrolled 50 overweight or obese patients without diabetes in a 10-week weight-loss program for which a very-low-energy diet was prescribed. At baseline (before weight loss), at 10 weeks (after program completion), and at 62 weeks, we examined circulating levels of leptin, ghrelin, peptide YY, gastric inhibitory polypeptide, glucagon-like peptide 1, amylin, pancreatic polypeptide, cholecystokinin, and insulin and subjective ratings of appetite.

Weight-Loss Phase For 8 weeks, participants were instructed to replace all three of their daily meals with a very-low energy dietary formulation (Optifast VLCD, Nestlé) and 2 cups of low-starch vegetables, according to the manufacturer’s guidelines, which provided 2.1 to 2.3 MJ (500 to 550 kcal) per day. During weeks 9 and 10, participants who had lost 10% or more of their initial body weight were gradually reintroduced to ordinary foods, and weight was stabilized to avoid the potential confounding effect of active weight loss on hormone profiles. Meal replacements were stopped at the end of week 10.

Weight-Maintenance Phase At the end of week 10, participants received individual counseling and written advice from a dietician on a dietary intake that would be consistent with their calculated energy expenditure, with the aim of weight maintenance. No specific macronutrient ratios were prescribed, but carbohydrates with a low glycemic index and a reduced intake of fat were recommended. Participants were also encouraged to engage in 30 minutes of moderately intense physical activity on most days of the week. They visited the clinical research unit at Heidelberg Repatriation Hospital every 2 months, and were contacted by telephone between visits for continued dietary counseling.

Leptin, an adipocyte hormone, is an indicator of energy stores20 and acts in the hypothalamus to reduce food intake and increase energy expenditure.

Ghrelin, peptide YY, gastric inhibitory polypeptide, GLP-1, cholecystokinin, pancreatic polypeptide, and amylin are released from the gastrointestinal tract and pancreas in response to nutrient intake; all but two inhibit intake. The exceptions are ghrelin, which stimulates hunger, and gastric inhibitory polypeptide, which may promote energy storage.

Supplementary Figure 1: Mean fasting and post-prandial measurements for GIP, GLP-1, PP and insulin at weeks 0, 10 and 62

Supplementary Table 1: Mean fasting and post-prandial biochemical values, and median percentage changes from baseline

Outcome Fasting Fasting % Δ 4- h postprandial AUC AUC % Δ fromfrom week 0 week 0

Glucose (mmol/ L)week 0 5.9 ± 0.2 6.3 ± 0.2week 10 5.3 ± 0.2 (p<0.001) - 8.9 (p<0.001) 5.9 ± 0.2 (p=0.03) - 10.1 (p=0.04)week 62 5.9 ± 0.2 (p=0.9) - 1.9 (p=0.9) 6.2 ± 0.2 (p=0.88) - 0.1 (p=0.91)Insulin (mU/ L)week 0 17.7 ± 1.7 49.1 ± 5.8week 10 9.1 ± 0.7 (p<0.001) - 45.6 (p<0.001) 28.4 ± 2.2 (p<0.001) - 41.0 (p<0.001)week 62 13.8 ± 1.2 (p=0.02) - 12.8 (p=0.26) 33.3 ± 3.4 (p<0.001) - 25.2 (p=0.001)HOMA- IR (units)week 0 4.7 ± 0.5week 10 2.2 ± 0.2 (p<0.001) - 48.7 (p<0.001)week 62 3.6 ± 0.4 (p=0.04) - 16.3 (p=0.27)NEFA (mEq/ L)week 0 0.52 ± 0.04 0.3 ± 0.0week 10 0.61 ± 0.04 (p=0.17) 3.8 (p=0.06) 0.4 ± 0.0 (p=0.05) 16.1 (p=0.03)week 62 0.50 ± 0.04 (p=0.64) - 5.9 (p=0.66) 0.3 ± 0.0 (p=0.14) - 6.5 (p=0.14)Leptin (ng/ ml)week 0 32.6 ± 3.0week 10 11.5 ± 1.5 (p<0.001) - 68.4 (p<0.001)week 62 20.7 ± 2.0 (p<0.001) - 31.5 (p<0.001)Leptin/ Fat mass(ng/ ml/ kg)week 0 0.68 ± 0.06week 10 0.32 ± 0.03 (p<0.001) - 53.3 (p<0.001)week 62 0.49 ± 0.04 (p<0.001) - 36.5 (p<0.001)

Supplementary Table 1: Mean fasting and post-prandial biochemical values, and median percentage changes from baseline

Outcome Fasting Fasting % Δ 4- h postprandial AUC AUC % Δ fromfrom week 0 week 0

Ghrelin (pg/ ml)week 0 127.0 ± 16.0 101.3 ± 12.4week 10 184.1 ± 20.3 (p<0.001) 56.5 (p<0.001) 148.4 ± 15.9 (p<0.001) 47.3 (p<0.001)week 62 152.9 ± 19.7 (p=0.07) 7.8 (p=0.02) 120.0 ± 12.9 (p=0.006) 21.4 (p=0.002)PYY (pg/ ml)week 0 71.7 ± 5.4 75.7 ± 4.8week 10 54.0 ± 4.9 (p<0.001) - 25.4 (p<0.001) 66.5 ± 4.4 (p=0.001) - 12.4 (p=0.001)week 62 54.5 ± 4.2 (p=0.001) - 27.1 (p=0.004) 60.7 ± 3.5 (p<0.001) - 20.6 (p=0.001)GIP (pg/ ml)week 0 19.8 ± 1.8 70.0 ± 5.5week 10 15.8 ± 1.5 (p=0.09) - 27.3 (p=0.51) 93.2 ± 9.6 (p=0.02) 29.0 (p=0.005)week 62 23.9 ± 2.5 (p=0.28) 20.5 (p=0.17) 94.5 ± 7.3 (p<0.001) 24.9 (p<0.001)GLP- 1 (pg/ ml)week 0 40.8 ± 3.2 48.2 ± 3.0week 10 34.8 ± 2.7 (p=0.002) - 14.2 (p=0.002) 47.8 ± 3.5 (p=0.26) - 6.9 (p=0.28)week 62 37.5 ± 1.9 (p=0.44) - 5.6 (p=0.93) 44.4 ± 2.3 (p=0.31) - 3.9 (p=0.69)Amylin (pg/ ml)week 0 89.9 ± 9.4 149.2 ± 15.3week 10 49.0 ± 3.5 (p<0.001) - 43.8 (p=0.007) 93.9 ± 6.9 (p<0.001) - 32.4 (p=0.001)week 62 59.7 ± 5.4 (p=0.007) - 40.4 (p=0.25) 112.5 ± 7.7 (p=0.03) - 24.1 (p=0.15)PP (pg/ ml)week 0 71.5 ± 12.6 164.8 ± 17.5week 10 74.1 ± 11.9 (p=0.48) 8.4 (p=0.17) 205.3 ± 27.6 (p=0.08) 12.0 (p=0.05)week 62 68.1 ± 11.9 (p=0.89) 0.8 (p=0.41) 209.5 ± 24.2 (p=0.05) 18.8 (p=0.007)CCK (fmol/ ml)week 0 1.7 ± 0.2 2.9 ± 0.2week 10 1.2 ± 0.1 (p=0.003) - 34.2 (p=0.008) 2.4 ± 0.2 (p=0.003) - 15.0 (p=0.012)week 62 1.6 ± 0.2 (p=0.08) - 9.1 (p=0.24) 2.6 ± 0.2 (p=0.20) - 5.4 (p=0.70)

Self-reported ratings of appetite were also recorded at these times with the use of a validated 100-mm visual-analogue scale.

Supplementary Figure 2: Mean fasting and post-prandial ratings of fullness, prospective consumption, urge to eat and preoccupation with thoughts of food at weeks 0, 10 and 62. Rating scores are in millimeters, with minimum possible score 0 and maximum 100mm.

Supplementary Table 2: Mean fasting and post-prandial visual analogue scale ratings of appetite, and median percentage changes from baseline AUC values have been normalized, so that mean AUC at week 0 is equal to the mean of the fasting and post-prandial VAS ratings at week 0. For fasting and AUC values, mean ± SEM are given. For % changes, medians are shown. Missing data has been replaced using linear interpolation. P-values are from exact Wilcoxon Signed Rank tests for paired comparisons between each of weeks 10 and 62 with week 0, and are therefore not directly comparable with those from the more thorough LME analyses.

Outcome Fasting (mm) Fasting % Δ 4- h postprandial AUC % Δ fromfrom week 0 AUC week 0

Hungryweek 0 32.2 ± 4.6 23.5 ± 2.1week 10 43.4 ± 3.8 (p=0.03) 40.0 (p=0.003) 31.6 ± 3.4 (p=0.01) 20.5 (p=0.02)week 62 42.8 ± 4.5 (p=0.09) 28.9 (p=0.02) 33.7 ± 3.0 (p<0.001) 37.4 (p<0.001)Fullweek 0 46.3 ± 4.6 53.6 ± 3.8week 10 38.7 ± 3.9 (p=0.14) - 12.9 (p=0.41) 56.7 ± 3.3 (p=0.45) 1.6 (p=0.26)week 62 37.2 ± 3.7 (p=0.05) - 12.5 (p=0.11) 50.8 ± 3.1 (p=0.55) - 5.4 (p=1.00)Desire to eatweek 0 41.5 ± 4.5 26.7 ± 2.4week 10 47.7 ± 4.4 (p=0.22) 19.5 (p=0.09) 34.6 ± 3.9 (p=0.03) 10.5 (p=0.03)week 62 47.5 ± 4.6 (p=0.21) 10.3 (p=0.12) 37.0 ± 3.3 (p=0.001) 26.4 (p=0.001)Prospective consumptionweek 0 42.3 ± 3.5 31.6 ± 2.3week 10 50.2 ± 3.0 (p=0.02) 13.6 (p=0.006) 36.9 ± 3.5 (p=0.14) 8.8 (p=0.10)week 62 48.8 ± 3.5 (p=0.06) 18.2 (p=0.02) 38.6 ± 2.9 (p=0.009) 16.1 (p=0.009)Urge to eatweek 0 32.4 ± 4.1 24.6 ± 2.3week 10 45.7 ± 3.7 (p=0.007) 25.0 (p=0.01) 32.1 ± 3.7 (p=0.02) 28.7 (p=0.02)week 62 40.8 ± 3.4 (p=0.16) 1.6 (p=0.33) 33.5 ± 2.9 (p=0.003) 20.6 (p=0.001)Preoccupied with foodweek 0 38.8 ± 4.0 24.3 ± 2.6week 10 33.2 ± 3.6 (p=0.54) 3.6 (p=0.99) 28.8 ± 3.7 (p=0.18) 12.0 (p=0.18)week 62 36.4 ± 3.3 (p=0.66) - 5.0 (p=0.99) 30.1 ± 2.8 (p=0.02) 10.2 (p=0.01)

Results Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P = 0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P = 0.004), and pancreatic polypeptide (P = 0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P = 0.04), insulin (P = 0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P = 0.002), as well as hunger (P<0.001).

Conclusions One year after initial weight reduction, levels of the circulating mediators of appetite that encourage weight regain after diet-induced weight loss do not revert to the levels recorded before weight loss. Long-term strategies to counteract this change may be needed to prevent obesity relapse.

(Funded by the National Health and Medical Research Council and others; ClinicalTrials.gov number, NCT00870259.)

Message/Comments

食事制限による減量プログラムの参加者 50人を対象に、体重制御にかかわる血中末梢ホルモン濃度、空腹感を調査。減量によりレプチン、ペプチド YY などの血中濃度が有意に低下、胃抑制ポリペプチド、膵ポリペプチドが有意に増加した。減量 1 年後も体重再増加を促す末梢ホルモンの濃度、空腹感は、減量プログラム開始時には戻らなかった。