Proinsulin c peptide is produced in placental tissue even in mothers with diabetes type 1 (T1D). This may mask the lack of c peptide production for the fetus in the body of the mothers. [i] Although the brain is also producing insulin and c peptide independently of the pancreas, the lack of c-peptide secreted by pancreatic cells may have developmental consequences for the children born to mothers with insulin-dependent diabetes mellitus.[ii]

The risk of autism spectrum disorder (ASD) in offspring born to mothers with T1D is significantly elevated even compared to mothers with diabetes type 2 (T2D) and mothers with gestational diabetes (GDM). “Relative to no diabetes exposure, the adjusted HRs for exposure to maternal diabetes were 2.36 (95% CI, 1.36-4.12) for T1D, 1.45 (95% CI, 1.24-1.70) for T2D, 1.30 (95% CI, 1.12-1.51) for GDM by 26 weeks’ gestation, and 0.99 (95% CI, 0.88-1.12) for GDM after 26 weeks. “ [iii]

Remarkably, autonomic dysfunction and reduced heart rate variability (HRV) is observed in individuals with ASD and with T1D as well. [iv] [v] [vi] The supplementation of proinsulin c peptide for patients with T1D improves autonomic function and increases HRV.[vii] This effect may be also achieved even more efficiently by the central/intranasal administration of c-peptide.[viii] [ix] It may be also relevant that higher HRV is related to better expressive and receptive language in ASD children. [x]

Proinsulin c peptide may inactivate cofilin, the actin severing protein that is important for early brain development. [xi] The lack of proinsulin c-peptide may predispose cofilin to be excessively activated that may cause early growth cessation of the hippocampus. [xii]

Indeed, one of the most promising methods of improving the symptoms of ASD suggested by investigators is the inactivation of cofilin in neurons. [xiii] Neuroinflammation is associated with ASD. [xiv] In this respect it is of relevance that cofilin knockdown reduces the inflammatory processes associated with microglia, the brain resident immune cells.[xv]

[i] Kwand-San Liu et al.: Insulin-related genes expressed in human placenta from normal and diabetic pregnancies In: Proc. Nati. Acad. Sci. USA Vol. 82, pp. 3868-3870, June 1985

[ii] Csajbok E.A. et al.: Expression of GLP-1 receptors in insulin-containing interneurons of rat cerebral cortex In: Diabetologia. 2019 Apr;62(4):717-725.

[iii] Anny H.X. et al.: Maternal Type 1 Diabetes and Risk of Autism in Offspring In: JAMA. 2018 Jul 3; 320(1): 89–91.

[iv] Thapa R. et al.: Reduced heart rate variability in adults with autism spectrum disorder In: Autism Res 2019 Jun;12(6):922-930.

[v] Brent Goodman:  Autonomic Dysfunction in Autism Spectrum Disorders (ASD) (P5.117) In: Neurology Apr 2016, 86 (16 Supplement) P5.117;

[vi] Moshenets K. et al.: Heart Rate Variability in Patients with Type 1 Diabetes and Hypoglycemia with Different Control of Diabetes Mellitus In: Diabetes 2018 Jul; 67(Supplement 1)

[vii] Johansson BL, et al.:  C-peptide improves autonomic nerve function in IDDM patients. Diabetologia. 1996;39(6):687-695.

[viii] Okamoto S, ez al.: Proinsulin C peptide obviates sympathetically mediated suppression of splenic lymphocyte activity in rats. Diabetologia. 2000;43(12):1512-1517.

[ix] Derkach KV, et al.: Intranasal Administration of Proinsulin C-Peptide Enhances the Stimulating Effect of Insulin on Insulin System Activity in the Hypothalamus of Diabetic Rats. Bull Exp Biol Med. 2019;167(3):351-355.

[x] Bazelmans T, et al. Heart rate mean and variability as a biomarker for phenotypic variation in preschoolers with autism spectrum disorder. Autism Res. 2019;12(1):39-52.

[xi] Aleksic M, et al. Signalling processes involved in C-peptide-induced chemotaxis of CD4-positive lymphocytes. Cell Mol Life Sci. 2009;66(11-12):1974-1984.

[xii] Lauterborn J.C. et al.: Cofilin Activation Is Temporally Associated with the Cessation of Growth in the Developing Hippocampus In: Cereb Cortex. 2017 Apr; 27(4): 2640–2651.

[xiii] Duffney LJ, et al. Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators. Cell Rep. 2015;11(9):1400-1413.

[xiv]  Siniscalco D,et al.: Inflammation and Neuro-Immune Dysregulations in Autism Spectrum Disorders. Pharmaceuticals (Basel). 2018;11(2):56.

[xv] Alhadidi Q, Shah ZA. Cofilin Mediates LPS-Induced Microglial Cell Activation and Associated Neurotoxicity Through Activation of NF-κB and JAK-STAT Pathway. Mol Neurobiol. 2018;55(2):1676-1691.