Intact Proinsulin/Insulin Ratio

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Journal Club
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.
2011年11月10日 8:30-8:55
8階 医局
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
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)
1. Preproinsulin (Leader, B chain, C chain, A chain);
proinsulin consists of BCA, without L
2. Spontaneous folding
3. A and B chains linked by sulphide bonds
4. Leader and C chain are cut off
5. Insulin molecule remains
http://ja.wikipedia.org/wiki/%E3%82%A4%E3%83%B3%E3%82%B9%E3%83%AA%E3%83%B3
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-Cpeptide 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
Abbreviations
AIR Acute insulin response
AROC Area under the receiver operating characteristic curve
FSIGT Frequently sampled intravenous glucose tolerance test
IGT Impaired glucose tolerance
IRAS Insulin Resistance Atherosclerosis Study
NGT Normal glucose tolerance
PI/C-pep Intact proinsulin-to-C-peptide ratio
PI/I Intact proinsulin-to-insulin ratio
SI Insulin sensitivity
SPI/C-pep Split proinsulin-to-C-peptide ratio
SPI/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/Cpep 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Cpeptide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-lowenergy 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
Outcome
Glucose (mmol/L)
week 0
week 10
week 62
Insulin (mU/L)
week 0
week 10
week 62
HOMA-IR (units)
week 0
week 10
week 62
NEFA (mEq/L)
week 0
week 10
week 62
Leptin (ng/ml)
week 0
week 10
week 62
Leptin/Fat mass
(ng/ml/kg)
week 0
week 10
week 62
Fasting
5.9 ± 0.2
5.3 ± 0.2 (p<0.001)
5.9 ± 0.2 (p=0.9)
Fasting % Δ
from week 0
4-h postprandial AUC
AUC % Δ from
week 0
-8.9 (p<0.001)
-1.9 (p=0.9)
6.3 ± 0.2
5.9 ± 0.2 (p=0.03)
6.2 ± 0.2 (p=0.88)
-10.1 (p=0.04)
-0.1 (p=0.91)
17.7 ± 1.7
9.1 ±0.7 (p<0.001)
13.8 ± 1.2 (p=0.02)
-45.6 (p<0.001)
-12.8 (p=0.26)
49.1 ± 5.8
28.4 ± 2.2 (p<0.001)
33.3 ± 3.4 (p<0.001)
-41.0 (p<0.001)
-25.2 (p=0.001)
4.7 ± 0.5
2.2 ± 0.2 (p<0.001)
3.6 ± 0.4 (p=0.04)
-48.7 (p<0.001)
-16.3 (p=0.27)
0.3 ± 0.0
0.4 ± 0.0 (p=0.05)
0.3 ± 0.0 (p=0.14)
16.1 (p=0.03)
-6.5 (p=0.14)
0.52 ± 0.04
0.61 ± 0.04 (p=0.17)
0.50 ± 0.04 (p=0.64)
3.8 (p=0.06)
-5.9 (p=0.66)
32.6 ± 3.0
11.5 ± 1.5 (p<0.001)
20.7 ± 2.0 (p<0.001)
-68.4 (p<0.001)
-31.5 (p<0.001)
0.68 ± 0.06
0.32 ± 0.03 (p<0.001)
0.49 ± 0.04 (p<0.001)
-53.3 (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
Ghrelin (pg/ml)
week 0
week 10
week 62
PYY (pg/ml)
week 0
week 10
week 62
GIP (pg/ml)
week 0
week 10
week 62
GLP-1 (pg/ml)
week 0
week 10
week 62
Amylin (pg/ml)
week 0
week 10
week 62
PP (pg/ml)
week 0
week 10
week 62
CCK (fmol/ml)
week 0
week 10
week 62
Fasting
Fasting % Δ
from week 0
4-h postprandial AUC
AUC % Δ from
week 0
127.0 ± 16.0
184.1 ± 20.3 (p<0.001) 56.5 (p<0.001)
152.9 ± 19.7 (p=0.07) 7.8 (p=0.02)
101.3 ± 12.4
148.4 ± 15.9 (p<0.001) 47.3 (p<0.001)
120.0 ± 12.9 (p=0.006) 21.4 (p=0.002)
71.7 ± 5.4
54.0 ± 4.9 (p<0.001)
54.5 ± 4.2 (p=0.001)
-25.4 (p<0.001)
-27.1 (p=0.004)
75.7 ± 4.8
66.5 ± 4.4 (p=0.001)
60.7 ± 3.5 (p<0.001)
-12.4 (p=0.001)
-20.6 (p=0.001)
-27.3 (p=0.51)
20.5 (p=0.17)
70.0 ± 5.5
93.2 ± 9.6 (p=0.02)
94.5 ± 7.3 (p<0.001)
29.0 (p=0.005)
24.9 (p<0.001)
-14.2 (p=0.002)
-5.6 (p=0.93)
48.2 ± 3.0
47.8 ± 3.5 (p=0.26)
44.4 ± 2.3 (p=0.31)
-6.9 (p=0.28)
-3.9 (p=0.69)
-43.8 (p=0.007)
-40.4 (p=0.25)
149.2 ± 15.3
93.9 ± 6.9 (p<0.001)
112.5 ± 7.7 (p=0.03)
-32.4 (p=0.001)
-24.1 (p=0.15)
8.4 (p=0.17)
0.8 (p=0.41)
164.8 ± 17.5
205.3 ± 27.6 (p=0.08)
209.5 ± 24.2 (p=0.05)
12.0 (p=0.05)
18.8 (p=0.007)
-34.2 (p=0.008)
-9.1 (p=0.24)
2.9 ± 0.2
2.4 ± 0.2 (p=0.003)
2.6 ± 0.2 (p=0.20)
-15.0 (p=0.012)
-5.4 (p=0.70)
19.8 ± 1.8
15.8 ± 1.5 (p=0.09)
23.9 ± 2.5 (p=0.28)
40.8 ± 3.2
34.8 ± 2.7 (p=0.002)
37.5 ± 1.9 (p=0.44)
89.9 ± 9.4
49.0 ± 3.5 (p<0.001)
59.7 ± 5.4 (p=0.007)
71.5 ± 12.6
74.1 ± 11.9 (p=0.48)
68.1 ± 11.9 (p=0.89)
1.7 ± 0.2
1.2 ± 0.1 (p=0.003)
1.6 ± 0.2 (p=0.08)
Supplementary Table 1: Mean fasting and post-prandial biochemical values, and
median percentage changes from baseline
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.
Outcome
Fasting (mm)
Hungry
week 0
32.2 ±
week 10
43.4 ±
week 62
42.8 ±
Full
week 0
46.3 ±
week 10
38.7 ±
week 62
37.2 ±
Desire to eat
week 0
41.5 ±
week 10
47.7 ±
week 62
47.5 ±
Prospective consumption
week 0
42.3 ±
week 10
50.2 ±
week 62
48.8 ±
Urge to eat
week 0
32.4 ±
week 10
45.7 ±
week 62
40.8 ±
Preoccupied with food
week 0
38.8 ±
week 10
33.2 ±
week 62
36.4 ±
4.6
3.8 (p=0.03)
4.5 (p=0.09)
4.6
3.9 (p=0.14)
3.7 (p=0.05)
4.5
4.4 (p=0.22)
4.6 (p=0.21)
3.5
3.0 (p=0.02)
3.5 (p=0.06)
Fasting % Δ
from week 0
4-h postprandial
AUC
AUC % Δ from
week 0
40.0 (p=0.003)
28.9 (p=0.02)
23.5 ± 2.1
31.6 ± 3.4 (p=0.01)
20.5 (p=0.02)
33.7 ± 3.0 (p<0.001) 37.4 (p<0.001)
-12.9 (p=0.41)
-12.5 (p=0.11)
53.6 ± 3.8
56.7 ± 3.3 (p=0.45)
50.8 ± 3.1 (p=0.55)
19.5 (p=0.09)
10.3 (p=0.12)
26.7 ± 2.4
34.6 ± 3.9 (p=0.03)
10.5 (p=0.03)
37.0 ± 3.3 (p=0.001) 26.4 (p=0.001)
13.6 (p=0.006)
18.2 (p=0.02)
31.6 ± 2.3
36.9 ± 3.5 (p=0.14)
8.8 (p=0.10)
38.6 ± 2.9 (p=0.009) 16.1 (p=0.009)
1.6 (p=0.26)
-5.4 (p=1.00)
4.1
3.7 (p=0.007) 25.0 (p=0.01)
3.4 (p=0.16)
1.6 (p=0.33)
24.6 ± 2.3
32.1 ± 3.7 (p=0.02)
28.7 (p=0.02)
33.5 ± 2.9 (p=0.003) 20.6 (p=0.001)
4.0
3.6 (p=0.54)
3.3 (p=0.66)
24.3 ± 2.6
28.8 ± 3.7 (p=0.18)
30.1 ± 2.8 (p=0.02)
3.6 (p=0.99)
-5.0 (p=0.99)
12.0 (p=0.18)
10.2 (p=0.01)
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.
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。
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