Dopamine-prolactin pathway potentially contributes to the schizophrenia and type 2 diabetes comorbidity.

C Gragnoli,G M Reeves,J Reazer,T T Postolache

doi:10.1038/tp.2016.50

Abstract

Schizophrenia (SCZ) and type 2 diabetes (T2D) are clinically associated, and common knowledge attributes this association to side effects of antipsychotic treatment. However, even drug-naive patients with SCZ are at increased risk for T2D. Dopamine dysfunction has a central role in SCZ. It is well-known that dopamine constitutively inhibits prolactin (PRL) secretion via the dopamine receptor 2 (DR2D). If dopamine is increased or if dopamine receptors hyperfunction, PRL may be reduced. During the first SCZ episode, low PRL levels are associated with worse symptoms. PRL is essential in human and social bonding, as well as it is implicated in glucose homeostasis. Dopamine dysfunction, beyond contributing to SCZ symptoms, may lead to altered appetite and T2D. To our knowledge, there are no studies of the genetics of the SCZ–T2D comorbidity focusing jointly on the dopamine and PRL pathway in the attempt to capture molecular heterogeneity correlated to possible disease manifestation heterogeneity. In this dopamine–PRL pathway-focused-hypothesis-driven review on the association of SCZ with T2D, we report a specific revision of what it is known about PRL and dopamine in relation to what we theorize is one of the missing links between the two disorders. We suggest that new studies are necessary to establish the genetic role of PRL and dopamine pathway in SCZ–T2D comorbidity.

Highlights

Type 2 diabetes (T2D) is a polygenic complex disorder with a higher incidence of polygenic psychiatric diseases, including schizophrenia (SCZ).[1,2] Genetic factors of mental complex disorders may be common for some diseases.[3,4,5] Even though antidepressants and antipsychotics may cause metabolic dysfunction, some psychiatric disorders increase T2D risk, independently of the therapy.[6,7] Given that T2D is a leading cause of morbidity and mortality among individuals with SCZ, there is a compelling need to identify mechanisms that increase vulnerability for T2D among individuals with psychotic illness.[8]
If our theory is proven valid via genetic studies determining the gene variants in the dopamine–PRL pathway predisposing to SCZ and to T2D, screening for disease biomarkers, such as PRL levels, or for gene risk-variant carriers could be performed in children and teenagers with increased SCZ-familial risk or presenting with cognitive, developmental, emotional and/or behavioral issues, resembling possible predisposition to SCZ
One of many examples of possible interplay between genetics and epigenetics in diabetes is given by the maturity-onset diabetes of the young 4 (MODY4) IPF-1 gene, association, we do not think that oxidative stress is the cause of an essential transcription factor in pancreas development SCZ–T2D comorbidity, but that a Glutathione-S-transferase M1 (GSM1) or Superoxide dismutase 2 (SOD2) variation may and proliferation

Summary

INTRODUCTION

Type 2 diabetes (T2D) is a polygenic complex disorder with a higher incidence of polygenic psychiatric diseases, including schizophrenia (SCZ).[1,2] Genetic factors of mental complex disorders may be common for some diseases.[3,4,5] Even though antidepressants and antipsychotics may cause metabolic dysfunction, some psychiatric disorders increase T2D risk, independently of the therapy.[6,7] Given that T2D is a leading cause of morbidity and mortality among individuals with SCZ, there is a compelling need to identify mechanisms that increase vulnerability for T2D among individuals with psychotic illness.[8]. Drug-naive patients with SCZ/schizoaffective disor- example, hyperthyroidism, acromegaly and Cushing syndrome).[29] der, compared with matched healthy subjects, have hepatic insulin resistance (a T2D trait), not attributable to visceral fat mass differences or factors associated with hepatic insulin resistance, indicating a link between SCZ and hepatic insulin resistance.[21] The study is well conducted as it excludes patients with the following: antipsychotics/any other medication use except for acetaminophen; diabetes; medical/family T2D history; recent history of alcohol abuse or alcohol/cannabis use; alcohol/psychoactive substance abuse dependence disorder; and any somatic illness (for example, metabolic/endocrine diseases, active infection or brain gross structural abnormalities on magnetic resonance imaging). The limitations of this study are the sample size and lack of ethnic diversity.[22]

SCZ subtypes and glucose metabolism

Dopaminergic and PRL pathway in SCZ

Possible impact

BEYOND OUR HYPOTHESIS

Findings

CONCLUSION