In the following study the researchers concluded that dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children that later progress to type 1 diabetes. In addition, the researchers found that the individuals who developed diabetes had reduced levels of succinic acid.
J Exp Med. 2008 Dec 22;205(13):2975-84. doi: 10.1084/jem.20081800. Epub 2008 Dec 15.
Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes.
"The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
A lack of DNase1 and protease would lead to dysregulation of lipid and amino acid metabolism, low levels of succinic acid, and also to gut dysbiosis.
In the following study the researchers found that DNase1 (deoxyribonuclease) activity was "markedly lower" in patients with type 1 diabetes.
Exp Clin Endocrinol Diabetes. 2007 Jun;115(6):387-91.
Impaired deoxyribonuclease activity in monoglandular and polyglandular autoimmunity.
Dittmar M, Poppe R, Bischofs C, Fredenhagen G, Kanitz M, Kahaly GJ.
OBJECTIVE: The enzyme desoxyribonuclease (DNase) degrades DNA during early apoptosis. Impaired DNase activity might increase susceptibility to autoimmune diseases. This study examined for the first time DNase activity in endocrine autoimmunity...Compared to healthy controls (median 9.8, range 5.2-16.7 ng/ml), DNase activity was markedly lowered in patients with endocrine autoimmunity (5.8, 2.6-26.2 ng/ml; p<0.0001). Corresponding values in the following MGA, PGA, and relatives groups were 4.8 (2.8-19.0) ng/ml, 7.9 (2.6-26.2) ng/ml, and 8.4 (1.5-19.0) ng/ml, respectively. When MGA patients were splitted up by disease, patients with type 1 diabetes had the lowest DNase activity (3.6, 3.2-3.9 ng/ml) which positively correlated with HbA1c in females (r=0.486, p=0.041). Pathological reduction of DNase activity (below 5 ng/ml) was noted in 54%, 31%, 24%, and 0% of MGA, PGA, relatives, and controls, respectively. Anti-ds-DNA and anti-nucleosome antibodies were negative in the patients with MGA and PGA.
CONCLUSIONS: These findings indicate the potential relevance of DNase activity in patients with monoglandular and polyglandular autoimmunity and their clinically healthy relatives. The impaired DNase activity might reduce removal of circulating self- or pathogen-derived DNA thereby favoring autoimmune mechanisms by Toll-like receptor 9 co-activation.
I am currently making some posts under the thread "Some Interesting Connections" on why a lack of protease and DNase1 would lead to dysregulation of lipid and amino acid metabolism, lack of succinic acid, and gut dysbiosis. We are currently discussing the cytochrome P450 enzyme system. The cytochrome P450 system is involved in the maintenance of lipid homeostasis as the following study confirms.
Curr Drug Metab. 2011 Feb;12(2):173-85.
Regulation of hepatic cytochromes p450 by lipids and cholesterol.
Hafner M, Rezen T, Rozman D.
"Cytochromes P450 of the liver are involved in maintenance of lipid homeostasis (cholesterol, vitamin D, oxysterol and bile acid metabolism) and in detoxification processes of endogenous compounds (i. e. bile acids) and xenochemicals (drugs)..."