PowerPoint ********* - 埼玉医科大学総合医療センター内分泌・糖尿病

Journal Club
Konstantinos A. Toulis,* Krishnarajah Nirantharakumar,* Ronan Ryan, Tom
Marshall, and Karla Hemming
Bisphosphonates and Glucose Homeostasis: A
Population-Based, Retrospective Cohort Study
J Clin Endocrinol Metab, May 2015, 100(5):1933–1940
doi: 10.1210/jc.2014-3481
2015年８月２０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
Sellami Mnif Houda
Since 2006: Unexpected functions played by the skeleton in whole-organism physiology
the importance of skeleton as an endocrine organ which regulates some metabolic
pathways, in particular, insulin signaling and glucose tolerance
Ocn-deficient mice show few beta cells, great fat mass, and decreased insulin sensitivity 1-2
The decarboxylation of Ocn is dependent
on bone resorption: insulin signaling in
OBs favors the differentiation of OCs and
the formation of resorption lacunae by
inhibiting the expression of OPG .
The low pH present within these lacunae
promotes the decarboxylation of Ocn and
consequently its activation
1- increase GLP-1 secretion
2-, Ocn promotes beta cell
proliferation
passage of Ocn into circulation
3- Ocn increases insulin
sensitivity in liver, muscle, and
adipose tissue by upregulation of
adiponectin gene expression in
adipocytes
1-The osteoblast: an insulin target cell controlling glucose homeostasis. J Bone Miner Res. 2011 Apr;26(4)
2- Skeleton and Glucose Metabolism: A Bone-Pancreas Loop . International Journal of Endocrinology Volume 2015 (2015)
-TOC and uOC : lower in patients with diabetes
- TOC and uOC : insulin resistance indices.
-Bisphosphonates, potent inhibitors of osteoclastic activity:
suppress bone turnover (PH increase) and decrease systemic
uOC levels
T2Diabetes?
On the contrary, incident T2DM was found to be modestly lower in
individuals treated with alendronate in a retrospective cohort study
Objective
- to investigate the effect of exposure to
bisphosphonates on the risk of incident type 2 diabetes
mellitus (T2DM) , Considering the widespread use of
bisphosphonates in the treatment of osteoporosis
Methods
The study is open Cohort
Period : from first January 1995 to December 31, 2010 .
Inclusion Criteria:
1) Age: 60 years at the index date,
2) No diagnosis of diabetes mellitus at the their index date,
3) More than 1 year of treatment with a bisphosphonate
(defined as one or more prescriptions for four consecutive
quarters)
INDEX DATE
4) remained at their practice at least 1 year after their index
date.
Duration of exposure calculated from the index date
1 exposed patient
up to 4 unexposed (control) matched
to cases on gender, age, index date, BMI,
Data synthesis
162 447 individuals included
35 998 subjects
(22.2%) : exposed to
bisphosphonates,
126 459 subjects : unexposed
age/ gender/ BMI-, and GP-matched
controls
-The median follow-up period: approximately 42 month
-The primary outcome : new diagnosis of diabetes mellitus
-Analyses were performed to detect age, gender, BMI, and
medication specific effects .
- Adjustment for patient level covariates (age, gender, BMI,
presence of hypertension, smoking status, deprivation quintile,
steroid treatment)
-Covariates selected for relevancy : the presence of
hypertension, cardiovascular disease (CVD), smoking status,
deprivation quintile, and oral steroid treatment
RESULTS:
Similar effect whatever
BMI/Steroids use
- The risk of incident T2DM was significantly lower in those exposed to
bisphosphonates compared with controls, independent of the specific agent
used
-the greater the duration of exposure, the lower the chance of developing diabetes
mellitus .
- the risk of incident T2DM in the first quartile (1–2.52 y) : significantly higher in
those exposed to bisphosphonates .
CONCLUSIONS
-Patients exposed to bisphosphonates showed a significant 50% lower risk of
developing diabetes mellitus compared with matched controls
- Results may be related to only duration of exposure.
- Hypothesis: This effect may be explained by a favorable change in the uOC /
TOC ratio, induced by long-term exposure to bisphosphonates, and promoting
insulin sensitivity (after a short first stable period) *.
-Ultimately, a relatively higher decrease in TOC (compared with uOC), which
would favor insulin sensitivity, might occur after a longer exposure to alendronate
treatment
- Alternative speculations : the bisphosphonate-induced disruption of prenylation
of small-molecular-mass G proteins / the reduction of the proinflammatory
cytokines (IL-1 and IL-6) / the presence of functional mutations in the receptor of
gastric inhibitory polypeptide
FURTHER INVESTIOGATIONS
* explain the brief increase in the risk of incident T2DM (1–2.5 y
* Schafer AL, Sellmeyer DE, Schwartz AV, et al. Change in undercarboxylated osteocalcin is associated with
changes in body weight, fat mass, and adiponectin: parathyroid hormone (1– 84) or alendronate therapy in
postmenopausal women with osteoporosis (the PaTH study). J Clin Endocrinol Metab. 2011;96:E1982–E1989
Limitations:
1- The theoretical possibility of differentially increased
weight gain in cohort groups
2- Misclassifying patients with type 1 diabetes mellitus as
T2DM
3- The potential effects of concomitant medications
4- Suboptimal persistence with osteoporosis medications
and the intensity of exposure (dose related effects) were
not captured
5- lmportant confounders such as family history of
diabetes were not included
Message
ギリシャの陸軍総合病院の研究グループは、"Journal of clinical endorinology
and metabolism"誌で2015年２月19日に報告した。
２型糖尿病のリスクに対するビスホスホネートの効果を検討した。具体的には、1995
年から2010年までの期間で集団を追跡していく研究で、1年以上ビスホスホネートを
使っていた60歳以上の約3万6000人と、年齢、性別、BMI、その他の条件を合わせ
たビスホスホネートを使っていない12万6000人強を比較するというものだ。
その結果、２型糖尿病のリスクはビスホスホネートを使っていた人では使っていない
人と比べほぼ半減していると分かった。統計学的にも意味のある差と判定できた。男
性では2割強の減少、女性では半減、肥満の人でも半減、ステロイドを使っている人
でも半減と一貫した結果が出てきた。
スタチンなどの投薬による交絡因子を否定しきれない後ろ向き研究ですが、ビスホス
ホネートの服用期間と糖尿病のリスク低下が関連していることや「リスク半減」という
大きな効果を考えると、メカニズムは別として、ビスホスホネート服用で2型糖尿病リ
スクが低下するのは本当かも知れません。
http://ameblo.jp/kunotakayoshi/entry-11996105921.html
Journal Club
Kramer CK, Zinman B, Choi H, Connelly PW, Retnakaran R
The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in
Type 2 Diabetes: Insight from the LIBRA Trial.
J Clin Endocrinol Metab. 2015 Jul 31:jc20152725.
2015年8月20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
63 participants stopped taking all antidiabetic medications and completed an overnight fast before undergoing a 2-h 75-g OGTT the next morning.
After OGTT, they began a 4-week course of multiple daily insulin injection therapy comprising basal insulin detemir and premeal insulin aspart,
with starting total daily doses of 0.2–0.4 units/kg consisting of 60% bolus and 40% basal insulin.
Study medication (liraglutide or placebo) was administered by daily subcutaneous injection in the morning and titrated over a 3-week period from
0.6 mg daily (first week) to 1.2 mg daily (second week) to 1.8 mg daily (third week), with the third-week dose maintained for the 48-week treatment
period.
At 48 weeks, all participants stopped their study medication before undergoing a washout OGTT 2 weeks later to evaluate for persistence of
effects.
Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B.: Liraglutide and the preservation of pancreatic β-cell function
in early type 2 diabetes: the LIBRA trial. Diabetes Care. 2014 Dec;37(12):3270-8. doi: 10.2337/dc14-0893.
Kramer CK, Zinman B, Choi H, Connelly PW, Retnakaran R.: The Impact of Chronic Liraglutide Therapy on Glucagon
Secretion in Type 2 Diabetes: Insight from the LIBRA Trial. J Clin Endocrinol Metab. 2015 Jul 31:jc20152725.
Context:
In patients with type 2 diabetes (T2DM), impaired
suppression of postprandial glucagonemia is a
metabolic defect that contributes to
hyperglycemia. Treatment with a glucagon-like
peptide-1 agonist can reduce hyperglucagonemia
in the acute setting, but little is known about the
durability of this effect with long-term treatment.
Objective:
To evaluate the impact of chronic liraglutide
therapy on glucagon regulation in early T2DM.
Design/Setting/Participants/Intervention:
In this double-blind, randomized, placebo-controlled trial,
51 patients with T2DM of 2.6 ±1.9 years duration were
randomized to either daily subcutaneous liraglutide or
placebo injection and followed for 48-weeks, with serial
assessment of the glucose, insulin, C-peptide, and
glucagon responses to a 75g oral glucose tolerance test
(OGTT) every 12 weeks.
Main Outcome Measures:
Glucagon response was assessed with the incremental
area-under-the-glucagon-curve (iAUCglucagon) from
measurements at 0-, 30-, 60-, 90- and 120-minutes on
each OGTT.
Each OGTT was performed in the morning after overnight fast, with the study medication
was on the morning of the test, such that the last dose was administered24 hours earlier.
During each OGTT, venous blood samples were drawn for measurement of insulin, Cpeptide, and glucose at fasting and at 10-, 20-, 30-, 60-, 90- and 120-minutes following
ingestion of the 75g glucose load. Specific insulin was measured with Roche Elecsys1010 immunoassay analyzer and electrochemiluminescence immunoassay kit, and Cpeptide was measured with Roche Modular system and electrochemiluminescence
immunoassay kit (Roche Diagnostics, Laval, Canada).
Serum glucagon was measured from samples at fasting and 30-. 60-, 90- and 120minutes on eachOGTT by manual enzyme-linked immunosorbent assay (ELISA) (R&D
Systems, Minneapolis, MN). The samples were collected in chilled tubes with aprotinin
and kept on ice before immediate storage at -80C. All samples from a given participant
were run in the same assay. The assay has no significant cross reactivity with gastric
inhibitory polypeptide, GLP-1, GLP-2, and glicentin-related polypeptide, and < 12%
cross-reactivity with oxyntomodulin. The assay has a detection limit of 14.7 pg/ml and
analytical range 31.3–2000 pg/ml. The interassay coefficient of variation (CV) was
11.22% at low concentration (QC1) and 12.61% at high concentration (QC2). The
intraassay CV was 9.76% for QC1 and 9.72% for QC2.
Whole-body insulin sensitivity was measured by Matsuda index (16) and hepatic insulin
resistance was assessed by Homeostasis Model Assessment (HOMA-IR) (17). β-cell
function was assessed with the Insulin Secretion-Sensitivity Index-2 (ISSI-2), a validated
OGTT-derived measure of β-cell function that is analogous to the disposition index
obtained from the intravenous (IV) glucose tolerance test (18, 19). A secondary measure
of β-cell function was ISR0–120/gluc0–120 × Matsuda index (where ISR is the prehepatic
Little or no cross-reactivity
The Mercodia Glucagon ELISA shows very low or no cross-reactivity to the peptides oxyntomodulin, glicentin,
mini-glucagon, GLP-1, GLP-2 and GRPP.
Know What You Measure – Why measuring glucagon has been a challenge in the past
In pancreatic alpha cells, the processing of pro-glucagon results in expression of GRPP, glucagon and major proglucagon fragment. In endocrine cells in the intestine, pro-glucagon is processed to GLP-1, GLP-2, glicentin and
oxyntomodulin (see figure 1). Since all these peptides are derived from pro-glucagon, constructing specific
antibodies against glucagon is a great challenge. Because of this, the majority of the commercially available
immunoassays for glucagon have cross-reactivity to glicentin. The level of glicentin in plasma is often many times
higher than that of glucagon (see figure 2) and the levels are not correlated, thus causing great problems with
accuracy.
http://www.mercodia.se/uploads/modules/Mercodia/specitivity/Glucagon%20cross-reactivity1.pdf
Mercodia Glucagon ELISA Kitでは glucagonに加えてかなりの量のGlicentin(1-61)が測定されている。
画像のようにglicentin(1-69)が本来のglicentinでMercodiaのキットでも区別できます。しかしglucagonのＣ末端と
Glicentin(1-61)のC末端が同じ構造になることが問題のようで、Glicentin(1-61)がglucagonとして測定されてしまうよう
です。これはMercodiaのキットの抗体の性能が悪い（Dr.北村）。
保険適用のキット
抗グルカゴンウサギ血清（ウサギポリクローナル抗体）
Euro-Diagnostica AB
当科のプロインスリン研究で用いているキット
Guinea Pig anti-Glucagon Serum
Mercodia Glucagon ELISA is a solid phase two-site enzyme
immunoassay based on the sandwich technique, in which two
monoclonal antibodies are directed against separate antigenic
determinants on the glucagon molecule.
Glucagon Quantikine ELISA Kit
monoclonal antibody against Glucagon. Glucagon Microplate
a monoclonal antibody against Glucagon conjugated to
horseradish
peroxidase with preservatives. Glucagon Conjugate
SPECIFICITY
This assay recognizes natural Glucagon. The factors listed below were prepared at 50 ng/mL in Calibrator
Diluent and assayed for cross-reactivity. Preparations of the following factors at 50 ng/mL in a mid-range
Glucagon control were assayed for interference. No significant cross-reactivity or interference was observed.
Natural proteins:
Gastric Inhibitory Polypeptide
Glucagon-like Peptide 1
Glucagon-like Peptide 2
Glicentin-related Polypeptide
Oxyntomodulin cross-reacts < 12% in this assay.
Figure 1. Changes over time in (Panel A) insulin response and (Panel B) C-peptide response
to 75g OGTT at randomization, 12-weeks, 24-weeks, 36-weeks and 48-weeks in the
liraglutide (black square) and placebo (open circle) arms. Means ± SEM are shown.
Figure 1. Changes over time in (Panel A) insulin response and (Panel B) C-peptide response
to 75g OGTT at randomization, 12-weeks, 24-weeks, 36-weeks and 48-weeks in the
liraglutide (black square) and placebo (open circle) arms. Means ± SEM are shown.
Figure 2. Changes over time in (Panel A) glucose response and (Panel B) glucagon response
to 75g OGTT at randomization, 12-weeks, 24-weeks, 36-weeks and 48-weeks in the
liraglutide (black square) and placebo (open circle) arms. Means ± SEM are shown.
Figure 2. Changes over time in (Panel A) glucose response and (Panel B) glucagon response
to 75g OGTT at randomization, 12-weeks, 24-weeks, 36-weeks and 48-weeks in the
liraglutide (black square) and placebo (open circle) arms. Means ± SEM are shown.
Figure 3. Changes over time in
glucagon response to glycemia as
measured by the incremental
increase in glucagon per
incremental increase in blood
glucose in response to 75g OGTT at
randomization, 12-weeks, 24-weeks,
36-weeks and 48-weeks in the
liraglutide (black square) and
placebo (open circle) arms.
Means ± SEM are shown.
P for linear trend
RESULTS:
As expected, compared to placebo, liraglutide induced a
robust enhancement of the post-challenge insulin and Cpeptide response at each of 12-, 24-, 36- and 48-weeks, with
a concomitant reduction in glycemic excursion. However,
liraglutide also induced a paradoxical increase in postchallenge glucagonemia that first emerged at 12-weeks and
persisted over the 48-week treatment period. Indeed,
baseline-adjusted iAUCglucagon was significantly higher in
the liraglutide group as compared to placebo at 12-weeks
(170.2±34.9 vs 65.4±36.4 pg/ml*2h, P=0.04), 36-weeks
(162.2±27.9 vs 55.7±30.4 pg/ml*2h, P=0.01), and 48weeks (155.5±26.5 vs. 45.7±27.0 pg/ml*2h, P=0.006).
Conclusion:
In contrast to its acute glucagon-lowering effect,
chronic treatment with liraglutide is associated
with increased post-challenge
hyperglucagonemia in patients with early T2DM.
Message
リラグルチドかプラセボの投与後、48週間のフォローアップ、糖負荷試験後のグルカ
ゴン値はリラグルチド群でプラセボより高値となる。
・空腹時のグルカゴン値はブラセボと同等か低値
・糖負荷後のグルカゴン値はプラセボより増強される。
・グルカゴンのピークはプラセボより遅れる
ヒトのグルカゴン受容体不活化変異は、α細胞のhyperplasia と高グルカゴン血症を
もたらす。
リラグルチドによる長期のグルカゴン低下効果が、α細胞のcompensation と糖負荷試
験のグルカゴン過剰反応を起こしているかもしれない。
空腹時のグルカゴン抑制は維持されるが、糖負荷後のグルカゴン抑制はリラグルチド
投与12週より失われている。
空腹時と糖負荷後のグルカゴン分泌の決定要素は異なるようだ。食事負荷 (mixed
meal) での評価が必要。
長期のGLP-1受容体作動薬に対するα細胞と膵島の反応をさらに明らかにする必要があ
る。
http://diabetologistnote.blog119.fc2.com/blog-entry-595.html

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