prevention of clinical onset of type 1 diabetes in high risk first degree relatives

Conditions: Diabetes, Type I

Summary: prophylactic administration of metabolically active insulin can prevent or delay clinical onset of diabetes in a high risk group of nondiabetic siblings as defined by positivity for autoantibodies against ia-2 (ia-2-a).

hypotheses: primary: prophylactic administration of metabolically active insulin can prevent or delay clinical onset of diabetes in a high risk group of nondiabetic siblings as defined by positivity for autoantibodies against ia-2 (ia-2-a). secondary: 1) untreated siblings with positivity for ia-2-a develop clinical diabetes significantly faster than untreated offspring with the same marker positivity. 2) plasma proinsulin levels increase disproportionately before clinical onset of type 1 diabetes both in siblings and offspring. 3) prophylactic administration of metabolically active insulin reduces the plasma proinsulin/c-peptide ratio in non-diabetic antibody positive siblings and offspring. 4) prophylactic administration of metabolically active insulin reduces the presence and/or levels of diabetes-associated autoantibodies directed against islet cell components. endpoints: fasting glycemia; fasting and stimulated plasma c-peptide and proinsulin values; islet cell autoantibodies; incidence of hypoglycemia; body weight gain.

Eligibility criteria:
inclusion criteria: * sibling/offspring of a type 1 diabetic patient * in good general condition * age 5-39 years * fasting plasma glucose \<126 mg/dl and an ogtt that is non-diabetic by 1997 ada criteria (33): 1. normal glycemia: * fasting plasma glucose \< 110 mg/dl and * 2 hour plasma glucose \< 140 mg/dl 2. impaired fasting glucose (ifg): * fasting plasma glucose 110-125 mg/dl and * 2 hour plasma glucose \< 140 mg/dl 3. impaired glucose tolerance (igt): * fasting plasma glucose \<110 mg/dl and * 2 hour plasma glucose 140-199 mg/dl * at least positive for ia-2-a * absence of a protective dq genotype: a4-b2/x or x/y or x/x where x = a2-b3.3, a1-b1.9, a1-b1.2, a4-b3.1, a2-b2 or a4.23-b3.1 y = a1-b1.1, a1-b2, a1-b1.azh, a3-b2, a3-b3.1, a3-b3.3, a3-b4, a4-b4, a4.23-b4, a4-b3.2, a3-b1.1, a4-b3.3, a4-b1.1 or a4.23-b2 (32) * cooperative and reliable subject (age ≥ 14 yrs) / parents (age \< 14 yrs) giving informed consent by signature; the patient/parents should be informed in sufficient detail on the content and procedure of the protocol, indicating potential risks of insulin therapy; early intervention with metabolically active insulin treatment should be identified as a clinical trial. both parents should sign and agree with the protocol procedure. exclusion criteria: * diabetes by 1997 ada criteria (33): * fasting plasma glucose ≥ 126 mg/dl, or * 2 hour plasma glucose ≥ 200 mg/dl * donation of blood during the study or within one month prior to screening * pregnancy or lactation in women * use of inadequate anticonception by female patients of childbearing potential * use of illicit drugs or overconsumption of alcohol (\> 3 beers/day) or history of drug or alcohol abuse * being legally incapacitated, having significant emotional problems at the time of the study, or having a history of psychiatric disorders * having received antidepressant medications during the last 6 months * treatment with immune modulating or diabetogenic medication (such as corticosteroids) * presently participating in another clinical study or having done so during the last 12 months * history of any illness that, in the opinion of the investigator, might confound the results of the study or pose additional risks to the patient

Keywords: prevention