鉴别肥胖青少年中1型与2型糖尿病

STEAMBOAT SPRINGS, COLORADO (EGMN) – New-onset type 1 diabetes in an obese youth cannot reliably be distinguished from pediatric type 2 diabetes on clinical grounds in this era of epidemic obesity.

“The only way to distinguish obese type 1 diabetes from type 2 diabetes is to measure diabetes autoantibodies. And those autoantibody panels are commercially available now. Signs and symptoms, diabetic ketoacidosis, family history – they don’t really help you. We get an autoantibody panel routinely in obese kids above age 10 presenting with new-onset diabetes,” said Dr. Charlotte M. Boney, chief of the division of pediatric endocrinology and metabolism at Hasbro Children’s Hospital in Providence, Rhode Island.

Diabetic ketoacidosis is widely thought of as incompatible with type 2 diabetes. Not true. Close to 20% of youth with type 2 diabetes present with DKA. Similarly, while a history of recent weight loss is considered a classic presenting symptom of type 1 diabetes, it’s also present in about one-quarter of young people presenting with type 2 diabetes, Dr. Boney noted.

The presence of pancreatic autoantibodies spells type 1 diabetes metabolically, even if the patient appears phenotypically to have type 2 disease.

“Some pediatric endocrinologists call this ‘type one-and-a-half’ diabetes. No, no, no. Let’s not make things any weirder than they already are. They have autoimmune diabetes, which is clearly type 1 diabetes. It just happens to be a little more complicated in them because they also have the morbidity of obesity,” she explained at the meeting on practical pediatrics sponsored by the American Academy of Pediatrics.

The obesity epidemic has muddied the diagnostic waters, because now 20%-30% of patients with new-onset type 1 diabetes are obese, as is a similar proportion of the general pediatric population. At the same time, the obesity epidemic has led to an increase in type 2 diabetes.

But it’s important to bear in mind that most youths with new-onset diabetes still have type 1 disease, she said.

In the landmark prospective The SEARCH For Diabetes In Youth study, nearly all children who presented under age 10 years had type 1 diabetes. Among 10- to 19-year-olds, the proportion with type 2 disease was 15% among whites, but considerably greater among racial minorities: 58% among African Americans, 46% in Hispanics, 70% in Asian/Pacific Islanders, and 86% among Native Americans (JAMA 2007;297:2716-24).

In the ongoing, multicenter, National Institutes of Health–sponsored Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which enrolled 1,206 subjects with a presumptive diagnosis of type 2 diabetes, 9.8% proved to be positive for GAD-65and/or insulinoma-associated protein 2 autoantibodies. They had to be excluded from participation in the treatment phase (Diabetes Care 2010;33:1970-5).

As a practical approach to the initial therapy of young patients with new-onset diabetes, Dr. Boney urged that those with DKA and ketosis should be started on intravenous fluids and insulin, regardless of their age and body habitus. If they are over age 10 and obese, however, pancreatic autoimmunity should be ruled out before transitioning to long-term therapy. For autoantibody-negative patients whose clinical picture is consistent with type 2 diabetes, the treatment is metformin, the only U.S. Food and Drug Administration (FDA)–approved therapy for children. Extensive experience shows that it’s a very safe drug, she said.

The TODAY trial is designed to determine whether the best treatment for type 2 diabetes in youth is metformin alone, metformin plus rosiglitazone, or metformin and an intensive lifestyle intervention aimed at achieving a 7%-10% weight loss.

The use of metformin to try to prevent diabetes in obese children with insulin resistance and the metabolic syndrome is the subject of large ongoing clinical trials. Until the results come in, Dr. Boney said she sees no role for off-label prescribing of metformin, given that weight loss and exercise are quite effective in improving insulin sensitivity.

Maturity Onset Diabetes of the Young, or MODY, is worth considering in white youth who are pancreatic autoantibody–negative and have a strong history of parental non–type 1 diabetes. MODY is a single-gene disorder that causes diabetes and is inherited from a parent.

“There are a lot of experts in the MODY field that think we’re grossly underdiagnosing monogenic diabetes,” said Dr. Boney.

The treatment for MODY is not insulin or metformin, but rather oral sulfonylureas, although those agents are not FDA-approved for use in children, she observed.

Dr. Boney reported having no financial conflicts.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

科罗拉多州斯廷博特斯普林斯(EGMN)——在美国儿科学会主办的实用儿科会议上，罗得岛普罗维登斯孩之宝儿童医院的小儿内分泌与代谢科主任Charlotte M. Boney博士指出，在这个肥胖流行的时代，根据临床证据无法确切区分肥胖青少年的新发1型糖尿病和儿童2型糖尿病。

唯一能区分肥胖1型与2型糖尿病的方法是测定糖尿病自身抗体。症状和体征、糖尿病酮症酸中毒(DKA)、家族史无助于医生确诊。对于10岁以上新发糖尿病的肥胖儿童，可常规检查自身抗体指标。人们普遍认为2型糖尿病中DKA很罕见，但实际并非如此，近20%的2型糖尿病青少年会出现DKA。同样，尽管近期体重下降被认为是1型糖尿病的典型发病症状，但这一症状也见于1/4的2型糖尿病青少年。胰腺自身抗体的出现是1型糖尿病的代谢表现，即使患者具有2型糖尿病表型。一些儿科内分泌医生称之为“1型半糖尿病”，不过这显然是1型糖尿病，只是因为患者同时合并肥胖症，所以病情看起来才稍显复杂而已。由于目前的新发1型糖尿病患者中有20%~30%为肥胖者(与一般儿童人群中的肥胖者比例相似)，因此肥胖的流行导致糖尿病的诊断变得愈加困难，也导致2型糖尿病发病率增加。不过，多数新发糖尿病的青少年所患的仍是1型糖尿病，记住这点非常重要。

在名为“在青年人中查找糖尿病”(SEARCH For Diabetes In Youth)的里程碑式前瞻性研究中，几乎所有在10岁以下发病的儿童所患的都是1型糖尿病。在10~19岁年龄段，2型糖尿病患者的比例在白人中为15%，而在少数族裔中的比例明显更大：在美国黑人中为58%，在西班牙裔中为46%，在亚洲人/太平洋岛民中为70%，在美国土著人中为86%(JAMA 2007;297:2716-24)。

一项由美国国立卫生研究院资助的名为“青少年和青年人中2型糖尿病的治疗选择”(Treatment Options for Type 2 Diabetes in Adolescents and Youth)的多中心研究目前正在进行中，该研究入组1,206例疑似2型糖尿病的受试者，结果显示9.8%受试者的GAD-65和(或)胰岛素瘤相关蛋白2自身抗体的检测结果为阳性。处于治疗期的受试者被排除在外(Diabetes Care 2010;33:1970-5)。

对于出现DKA和酮症的新发糖尿病年轻患者，Boney博士建议使用静脉输液和胰岛素进行初始治疗，不管患者的年龄和体型如何。然而，如果患者为10岁以上且肥胖，则应在过渡至长期治疗之前排除胰腺自身免疫的可能性。对于临床上符合2型糖尿病表现的自身抗体阴性患者，可选择唯一被美国食品药品管理局(FDA)批准用于儿童的二甲双胍进行治疗。广泛经验表明该药非常安全。

许多正在进行的大型临床研究的主题是探讨在胰岛素抵抗的肥胖儿童中使用二甲双胍来预防糖尿病和代谢综合征。Boney博士表示，在结果出来之前，二甲双胍不会被广泛超适应证应用，因为减肥和锻炼就已经能够非常有效地改善胰岛素敏感性。

在胰腺自身抗体阴性且父母患非1型糖尿病的白人青少年中，可考虑罹患青少年成年发病型糖尿病(MODY)的可能。MODY领域的许多专家认为，这种单基因糖尿病的诊断严重不足。MODY的治疗药物并非胰岛素和二甲双胍，而是口服磺脲类，不过这类药物未被FDA批准用于儿童。

Boney博士声明无经济利益冲突。

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