Metabolic Changes: Linking Cause to Immune Events?

Posted on October 4, 2012


So far, seroconversion to autoantibody positivity is the first detectable sign of an ongoing autoimmune response. But Oresic et al. (320) recently suggested that metabolic dysregulation precedes overt autoimmunity in T1D. Elevated serum concentrations of lysophosphatidylcholine (lysoPC) precede the appearance of each islet autoantibody. In samples from the Finnish DIPP study cohort (235), characteristic changes in serum metabolites were found only in the children who later developed T1D. These changes included reduced serum succinate, PC, phospholipids, and ketoleucine, as well as elevated glutamic acid.

These reactive lipid by-products are capable of activating proinflammatory molecules (286) that function as a natural adjuvant for the immune system (215). It remains unresolved whether these metabolic events trigger the initiation of the autoimmune period, or are just easier to detect. Nevertheless, these findings create an opportunity for earlier diagnosis.


Efects of glucose on glutamate levels in L-cells are a matter

of debate. In the present study, we monitored cellular glutamate

levels in INS-1E L-cells incubated under di¡erent culture

conditions. In particular, we tested glucose concentrations

ranging from sub- to supra-physiological levels (1 to 15 mM

respectively). The results demonstrate that glutamate levels

are highly modulated, either increased by glucose and glutamine,

or decreased by branched-chain amino acids. Similar

glutamate levels can be obtained either in the presence of

5 mM ( 5 mmol/l = 90 mg/dl) glucose without glutamine or by exposure to glutamine

(2 mM) at low glucose (1 mM).

Taken together, these results suggest that glutamate might

have at least two e¡ects in L-cells. At low glucose, GDH

favours the £ux of oxidative deamination of glutamate to

K-ketoglutarate, glutamate being preferentially used as an

anaplerotic fuel for the L-cell due to its position at the crossroad

of amino acid catabolism. This would ensure minimal

requirement for TCA cycle activity and ATP generation. At

elevated glucose, GDH and/or transamination reactions

would favour glutamate generation that could then play a

messenger role outside mitochondria in the amplifcation

pathway of glucose-induced insulin secretion

(FEBS Letters 545 (2003) 167-172 )

Excitotoxic Programmed Cell Death Involves Caspase-Independent Mechanisms. Excitotoxicity is a common pathological process in many neurodegenerative disorders; and this process involves over-stimulation of glutamate receptors and an excessive influx of calcium into cells.Cell death in excitotoxicity is unique in that it does not involve caspase dependent pathways. Overactivation of poly (ADP-ribose) polymerase-1 (PARP-1) is an early pathological event in excitotoxicity that leads to a unique form of cell death called parthanatos. Biochemical events in parthanatos include early accumulation of poly (ADP-ribose) (PAR) and nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria.  (Acute Neuronal Injury, 2010, pp 79-88)

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