Metabolism

Purines and Glucose Regulation

Insulin resistance and metabolic syndrome are tied to increased uric acid, PMID 26395162, 23588856, connecting glucose metabolism to purines. Among the purines, hypoxanthine and XOR activity (the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid) are correlated with adiposity and insulin resistance PMID 31916414, while inosine is correlated with decreased adiposity/ white fat and increased metabolism/ brown fat PMID 35790189.

Introduction of hypoxanthine and xanthine-similar medications can cause insulin resistance and chronic metabolic syndrome.

Does a distortion in purine metabolism cause metabolic syndrome?

Hypoxanthine Signaling

Hypoxanthine is associated with increased adiposity PMID 31916414.

Hypoxanthine or xanthine-similar thiazide diuretics can cause (sometimes reversible PMID 3243177, sometimes irreversible PMID 18326972) insulin resistance PMID 2671740. This drug class lowers BP more, but cardiac risk less, when compared to other BP medicines PMID 12479763 (analysis).

Xanthine Signaling

Caffeine, a xanthine derivative, reliably causes insulin resistance PMID 11815511 which can be clinically significant PMID 28935543.

The antipsychotic medications correlated most profoundly with insulin resistance are also xanthine-similar, as is mirtazapine, the antidepressant most strongly tied to weight gain.

Xanthine was used as a basis for designing a class of insulin resistance treatments called DPP-4 inhibitors PMID 24900744, 27560285: linagliptin includes the entire xanthine structure. It is easy to imagine xanthine similarities identifying receptors of interest while appendages prevent activation.

Common Structure Across Classes

PNP products are xanthine, hypoxanthine, and guanine. PNP inhibitors include 8-aminoguanine PMID 36071153, 11201210 and 8-amino hypoxanthine PMID XXXX: it seems likely that 8-amino xanthine acts similarly. If so, 8-amino xanthine compounds could be expected to have an antihyperglycemic effect by decreasing the amount of (insulin-resistance-inducing) xanthine produced.

Oral antihyperglycemics from different classes often approximate an 8-aminoxanthine structure. Drugs that share this structure have been repurposed to treat insulin resistance, including bromocriptine PMID 20977575 and acetazolamide PMID 30192255. Perhaps PNP inhibition is an unrecognized contributing mechanism of action among these agents?

SLGT2 Inhibitors Also Suggest Purines

SGLT2 inhibitors seem to mimic xanthosine, possibly using it's similarity to the PNP precursor to reduce PNP activity?

Connection to Schizophrenia

If schizophrenia is caused by guanine excess, this excess is expected to correlate with excess xanthine (via guanase) or excess xanthine and hypoxanthine (via PNP, with secondarily increased xanthine and uric acid). This is consistent with the observed correlation between treatment-naive schizophrenia and insulin resistance PMID 19407273.

While some antipsychotics are associated with worsening metabolism, allopurinol shows antipsychotic efficacy and prevents metabolic syndrome PMID 16234313, possibly by acting as a PNP inhibitor.

Connection to Parkinsonian Symptoms

If Parkinsonism is caused by guanine deficit, while insulin resistance is caused by hypoxanthine/ xanthine excess, inhibition of GMP reductase should have the effect of exchanging an excess IMP (hypoxanthine precursor) for a needed GMP (guanine precursor), resolving both symptom sets simultaneously.

This chart reflects a clinical case in which Parkinsonian symptom resolution was concurrent and commensurate with resolution of insulin resistance/ need for treatment. The patient was discharged without Parkinsonian symptoms, and without insulin resistance symptoms or treatment.

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