蛋白質變異與第二型糖尿病有關


  【24drs.com】根據義大利研究團隊與美國及法國科學家們合作的研究結果,相較於控制組患者,第二型糖尿病(DM)歐洲白人患者比較容易有HMGA1變異。
  
  這項蛋白質變異稱為IVS5-13insC,會降低HMGA1蛋白質功能,這是調控胰島素受體基因(INSR)表現的基因活化共同因子;這種罕見的HMGA1變異(c.*369del),過去只有2個病例報告,與帶有正常INSR基因的胰島素抗性患者INSR基因表現過低有關。
  
  研究由資深作者義大利卡坦扎羅大學內分泌學教授Antonio Brunetti醫師執行,發表於3月2日的JAMA上,建立在早期的研究結果之上,研究第二型糖尿病患者的功能性HMGA1變異。
  
  研究人員直接定序病患的DNA或分析HMGA1的專一性突變,同時也確認第二型糖尿病與控制組患者的HMGA1訊息RNA、HMGA1表現以及INSR蛋白。
  
  研究人員報告,除了原始的罕見變異c.*369del外,我們在許多受影響的歐洲裔白人身上發現3個新的HMGA1基因功能性變異,這些變異與INSR基因、INSR蛋白表現下降,以及第二型糖尿病有關。
  
  這3個新的功能性變異中,主要是IVS5-13insC,這個變異穩定地表現在7%到8%義大利、美國與法國第二型糖尿病白人患者身上。
  
  當義大利第二型糖尿病患者(共3,278位)與兩個控制組患者(共3328位)相比時,DM患者有IVS5-13insC變異的機率顯著較高:與第一個控制組相比為7.23%與0.43%(勝算比[OR]為15.77;95%信賴區間[CI]為8.57-29.03;P<0.001);與第二控制組相比為7.23%與3.32%(OR為2.03;95% CI為1.51-3.43;P<0.001)。
  
  與美國患者(共970位)及來自北卡羅萊納州的受試者(共958位)相比時,IVS5-23insC變異發生在7.7%第二型糖尿病患者身上,但是控制組受試者僅有4.7%(OR為1.64;95% CI為1.05-2.57;P=0.03)。法國組中,354位第二型糖尿病患者身上有7.6%有此變異,但是50位控制組患者都沒有這種變異(P<0.046)。
  
  HMGA1另外3個變異(包括c.*369del)也在義大利第二型糖尿病患者身上發現;每一種變異發生率都顯著地比控制組受試者高(P=0.01;P<0.001;P<0.001)。整體來說,這四種HMGA1變異發生在9.8%義大利第二型糖尿病患者身上,但是僅發生在0.6%的義大利控制組受試者身上。
  
  特別的是,分析帶有IVS5-13insC患者的訊息RNA與蛋白(HMGA1與INSR)發現,比控制組受試者低了40%到50%。
  
  作者們表示,他們觀察到近10%第二型糖尿病患者有這種解碼MHGA1蛋白基因有害的變異,具有重要的臨床意義。
  
  帶有這些變異有幾個可能的臨床應用:
  * 作為胰島素抵抗性與第二型糖尿病的初期預測標記
  * 預測對治療的反應,例如胰島素致敏劑。
  * 預測第二型糖尿病的臨床病程,例如發生大血管與小血管併發症的可能性。
  * 代表增加HMGA1表現的標的治療對第二型糖尿病患者可能有角色。
  
  在隨後的JAMA主編評論中,達拉斯德州大學西南醫學中心人類營養中心內科醫學部門營養與代謝疾病科主任Abhimanyu Garg醫師總結了HMGA1結構與功能性資訊。
  
  Garg醫師表示,罕見的HMGA1變異與第二型糖尿病之間的關聯性,支持了在第二型糖尿病病理生成中胰島素抵抗性的角色。隨著發現第二型糖尿病全新核心,以及對這些變異如何影響糖尿病感受性的分子機轉進一步了解,可以更清楚地區分第二型糖尿病亞型。這項資訊可能引領發展出第二型糖尿病不同亞型的標的治療。
  
  Garg醫師的結論是,可以預期的,發現全新核心,就像HMGA1一樣可以很快地轉化成治療決策,因而可能改善第二型糖尿病患者的健康。
  
  Brunetti博士接受Telethon-Italy以及MIUR義大利的研究經費贊助;另一位作者接受來自國家衛生研究院的經費贊助。其他作者表示沒有資金上的往來。Garg醫師接受國家衛生研究院、美國食品藥物管理局與Amylin有限公司的經費。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6473&x_classno=0&x_chkdelpoint=Y
  

Variant of Protein Is Associated With Type 2 Diabetes

By Jacquelyn K. Beals, PhD
Medscape Medical News

March 4, 2011 — A variant of HMGA1 occurs significantly more often in patients with type 2 diabetes mellitus (DM) who are of white European heritage than in control patients, according to an Italian research group collaborating with scientists in the United States and France.

The variant, designated IVS5-13insC, impairs function of the HMGA1 protein, a cofactor for gene activation that regulates insulin-receptor gene (INSR) expression. The rare HMGA1 variant (c.*369del), previously reported in 2 patients, was associated with low INSR expression in insulin-resistant individuals with normal INSR genes.

The current study was led by senior author Antonio Brunetti, MD, PhD, professor of endocrinology at the University of Catanzaro "Magna Graecia," Catanzaro, Italy. Published March 2 in JAMA, this research built on the earlier report, investigating functional HMGA1 variants in patients with type 2 DM.

Patients' DNA was sequenced directly or analyzed for specific mutations of HMGA1. Levels of messenger RNA and expression of HMGA1 and INSR proteins were also determined in patients with type 2 DM and control patients.

"In addition to the original rare variant, c.*369del..., we found 3 new functional variants of the HMGA1 gene that were associated with decreased INSR gene and INSR protein expression and type 2 DM in a significant proportion of affected individuals of white, European descent," the authors reported.

Chief among these 3 new functional variants was IVS5-13insC. This variant was consistently present in 7% to 8% of patients with type 2 DM in white populations in Italy, the United States, and France.

When Italian patients with type 2 DM (n = 3278) were compared with 2 control groups (n = 3328), the IVS5-13insC variant was significantly more prevalent in patients with DM: 7.23% vs 0.43% for 1 control group (odds ratio [OR], 15.77; 95% confidence interval [CI], 8.57 - 29.03; P < .001); 7.23% vs 3.32% for the second control group (OR, 2.03; 95% CI, 1.51 - 3.43; P < .001).

Among US patients (n = 970) and control participants (n = 958) from Northern California, the IVS5-23insC variant was present in 7.7% of patients with type 2 DM but only 4.7% of control individuals (OR, 1.64; 95% CI, 1.05 - 2.57; P = .03).. In the French group, this variant was identified in 7.6% of the 354 patients with type 2 DM but in 0% of the 50 control patients (P < .046).

Three other variants of HMGA1 (including c.*369del) were also found in Italian patients with type 2 DM; each was significantly more prevalent in patients than in control individuals (P = .01; P < .001; P < .001). Taken together, these 4 HMGA1 variants were found in 9.8% of Italian patients with type 2 DM, but in only 0.6% of Italian control individuals.

Notably, analysis of messenger RNA and protein (HMGA1 and INSR) in patients with the IVS5-13insC variant found that levels were 40% to 50% lower than in control individuals.

"We believe our observation that nearly 10% of individuals with type 2 DM have deleterious variations in the gene encoding HMGA1 has important clinical implications," say the authors.

The presence of these variants suggests several potential clinical uses:

  • as early predictive markers of insulin resistance and type 2 DM;
  • to predict response to therapies such as insulin sensitizers;
  • to predict the clinical course of type 2 DM, such as the likelihood of macro- and microvascular complications; and
  • to indicate patients with type 2 DM for whom targeted therapy could involve agents that upregulate HMGA1 expression.

In a related JAMA editorial, Abhimanyu Garg, MD, chief, Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, summarizes structural and functional information on HMGA1.

"[A]ssociation of rare variants in HMGA1 with type 2 DM supports the role of insulin resistance in the pathogenesis of type 2 DM. With the discovery of novel loci for type 2 DM and development of better understanding of the molecular mechanisms by which these variants affect the susceptibility of diabetes...distinct subtypes of type 2 DM will be recognized more clearly. This information may lead to targeted therapies for various subtypes of type 2 DM," Dr. Garg suggests.

"It is anticipated that the discoveries of novel loci such as HMGA1 will soon be translated into therapeutic decision making," concludes Dr. Garg, "and thereby improve the health of patients with type 2 DM."

Dr. Brunetti received research funding from Telethon-Italy and from MIUR Italy; another author received grant funding from the National Institutes of Health.The other authors have disclosed no relevant financial relationships. Dr. Garg has received grants from the National Institutes of Health, the US Food and Drug Administration, and Amylin Inc.

JAMA. 2011;305(9):903-912, 938-939.

    
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