Abstract

The hypothalamus, the master regulator of circadian rhythm, in association with peripheral clocks, plays crucial role in glucose metabolism. Impairment in cerebral sensing, uptake and processing of glucose has been suggested in various animal and human diabetic models. Diabetes mellitus (DM) has been largely superseded by the discovery of insulin and insulin resistance. Expanding horizons of knowledge of the roles of the hypothalamus in glucose metabolism and the overlapping neural pathways of sugar addiction with other classically described substance and behavioral addictions networks have again thrown some light on the cerebral theory of pathogenesis of DM.

Keywords: Diabetes mellitus, hypothalamus, brain, cognitive impairment

Introduction

Evidence in favor of multifaceted afflictions of diabetes mellitus (DM) on the brain has been burgeoning. Contemporary studies exhibited the definitive and deleterious impact of DM on the brain leading to premature brain aging and manifestations ranging from cognitive impairment, and behavioral alteration to focal neurological deficits.¹ Authors, herein, want to decode the inverse relationship. Although, the brain has been regarded as one of the key organs in the classic “ominous octet”,² its exact role in the pathophysiology of DM is yet to be fully decrypted.³ Further elucidation is needed regarding the mechanistic pathways through which psychoneurotic traits, an established risk factor for the development of diabetes mellitus and the maintenance of glycemic balance, operate.^4,5 Is there a possibility of the beta-cell failure to be prospectively orchestrated by altered glucose-sensing machinery residing in the brain? Are there certain pre-existing pre-destined frameworks in the brain responsible for the future development of DM? How can certain brain-behavior relationships lead to the development of DM in later life?

Cerebral Pathogenesis of Diabetes – Role of Hypothalamus, Midbrain and Brainstem

Hypothalamus has long been considered the nodal player in the regulation of satiety, body weight and glycemic status since 1854 when Claude Bernard reported that a lesion in the floor of the fourth ventricle in dogs altered glucose levels, thereby presenting the first evidence of the brain’s role in glycemic regulation.³ Works in Drosophila have found that there are key glucose-sensing neurons, which orchestrate insulin and glucagon secretion downstream.^3,6 A case has been made regarding the common evolutionary origin of beta cells and brain.⁷ The key parameters of glycemic control viz. satiety, obesity, insulin secretion and insulin resistance, which predict the future risk of development of DM have now been proven to be governed by the hypothalamus.^3,8 The hypothalamus, the master regulator of circadian rhythm, in association with peripheral clocks, play crucial roles in glucose metabolism.^9,10 Impairment in cerebral sensing, uptake and processing of glucose has been suggested in various animal and human diabetic models.^11-14 One of the most recent additions to the understanding of cerebral pathogenesis of diabetes is “glucose effectiveness”, the phenomenon through which glucose promotes its own disposal using central K_ATP channels (independent of insulin).¹⁵ Analogous to the leptin resistance in obesity, DM which is also a closely related metabolic disease, can be viewed as a cerebral glucose-resistant state that uplifts the glycemic set-point to set in a new steady-state leading to the generation of a vicious cycle of glucotoxicity and progressive beta-cell failure.^3,16 The role of the brain in glucose metabolism is further strengthened by the evidence that intracerebroventricular administration of leptin ameliorates hyperglycemia by insulin-independent pathways.^17,18 Similarly, intracerebroventricular injection of the fibroblast growth factor (FGF) family of proteins, especially FGF-1, 19 and 21 is capable of reversing hyperglycemia in rodents.^19-21

Addiction Circuitry and Diabetes

Smoking, alcohol and other substance abuse have been causally linked to the pathogenesis of DM based on epidemiological proofs and identifying downstream cascades of deleterious molecular mechanisms. Addictive behavior has a definitive role in the future development of DM, governed by brain networks (addiction and reward circuits) as they share a common genetic susceptibility region afflicting the cerebro-pancreatic network.²² Food addiction has been linked to the development of type 2 DM independent of age, sex, body mass index and other comorbidities including obesity.²³

Contextually, the concept of sugar addiction and its causative role in obesity, DM and other chronic metabolic diseases has already gained popularity in the public health arena.²⁴ Studies already have demonstrated that sugar addiction involves the ventral tegmental area (VTA) and nucleus accumbens (NAc), the same designated brain network involved in substance and behavioral addiction. Dopamine is the key neurotransmitter responsible for food (sugar) addiction with contributions of acetylcholine and opioid neurotransmitters as well.^24,25 Sugar addiction can cause glucotoxicity, rebound insulin release and beta-cell exhaustion in the long-term with an increased risk of developing insulin resistance and eventually DM in the future.²⁶ It has also been observed reciprocally during treatment of DM and subsequent counseling regarding the risk of development of hypoglycemia; patients often take sugar binge without any definitive evidence of hypoglycemia. This is an indirect reflector of addictive behavior (sugar addiction), which significantly interferes with the achievement of proper glycemic control.^27,28 Internet addiction, the most common modern form of behavioral addiction²⁹ has been associated with a sedentary lifestyle,³⁰ which is the harbinger of incident diabetes. In a reverse way, researchers have also untangled the intricate association of increased prevalence of addiction among diabetics compared to nondiabetic individuals further strengthening the role of an in-built “addiction network” in the brain much before the development of DM.³¹

Parenting, Personality Development and Risk of Developing Diabetes Mellitus

Personality is the supreme reflection of cognitive and behavioral excursion in a patterned way based on learning and experience in environmentally triggered situations and personal space issues.³² Parental personality and parenting style have dominating effects on the lifestyle and food habits of their children.^33,34 Type A personality of parents and parental stress being transferred to their offspring lead to faulty food habits, altered sleeping patterns decreased play time, competitive attitudes and a sedentary lifestyle from a very early phase of life.³⁵ This prodiabetic personality, behavior and lifestyle of the child and that of the family, implant the seeds of a faulty metabolic milieu deeply inside the evolving nascent networks of the brain of these children, earlier in life much before the development of glycemic dysregulation.³⁶

Conclusion

Although the discovery of neural control of glycemia dates back nearly 200 years, the concept that the brain is the central player in the pathogenesis of DM has been largely superseded by the discovery of insulin and insulin resistance. Expanding horizons of knowledge of the roles of the hypothalamus in glucose metabolism and the overlapping neural pathways of sugar addiction with other classically described substance and behavioral addictions networks have again thrown some light on the cerebral theory of DM pathogenesis. Personality traits of children and their parents, parenting and lifestyles are crucially and intricately related to brain functions and may have the potential to cause DM in later life. Keeping in an analogy of purely neurological and psychiatric illness that occurs in an already compromised brain, the seeds of diabetes mellitus, obesity and metabolic syndrome per se are ingrained in the fertile soil of an already precarious brain.³⁷ Lastly, there has been a long-awaiting dearth of artillery in the therapeutic armamentarium of DM directed at the brain and the authors anticipate that this is an area for an Odysseus voyage in future research.^38,39

References

1. Biessels GJ, Nobili F, Teunissen CE, Simó R, Scheltens P. Understanding multifactorial brain changes in type 2 diabetes: a biomarker perspective. Lancet Neurol. 2020;19(8):699-710.
2. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773-95.
3. Alonge KM, D’Alessio DA, Schwartz MW. Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes. Diabetologia. 2021;64(1):5-14.
4. Deleskog A, Ljung R, Forsell Y, Nevriana A, Almas A, Möller J. Severity of depression, anxious distress and the risk of type 2 diabetes - a population-based cohort study in Sweden. BMC Public Health. 2019;19(1):1174.
5. Ghosh S, Chatterjee S. Should depressive patients undergo a regular diabetes screening test? Indian J Endocrinol Metab. 2013;17(3):537-8.
6. Oh Y, Lai JS, Mills HJ, Erdjument-Bromage H, Giammarinaro B, Saadipour K, et al. A glucose-sensing neuron pair regulates insulin and glucagon in Drosophila. Nature. 2019;574(7779):559-64.
7. Arntfield ME, van der Kooy D. β-Cell evolution: How the pancreas borrowed from the brain: The shared toolbox of genes expressed by neural and pancreatic endocrine cells may reflect their evolutionary relationship. Bioessays. 2011;33(8):582-7.
8. Roh E, Song DK, Kim MS. Emerging role of the brain in the homeostatic regulation of energy and glucose metabolism. Exp Mol Med. 2016;48(3):e216.
9. Parameswaran G, Ray DW. Sleep, circadian rhythms, and type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2022;96(1):12-20.
10. Barca-Mayo O, López M. Astrocyte clocks and glucose homeostasis. Front Endocrinol (Lausanne). 2021;12:662017.
11. Hwang JJ, Jiang L, Hamza M, Sanchez Rangel E, Dai F, Belfort-DeAguiar R, et al. Blunted rise in brain glucose levels during hyperglycemia in adults with obesity and T2DM. JCI Insight. 2017;2(20):e95913.
12. Ma Y, Ratnasabapathy R, Izzi-Engbeaya C, Nguyen-Tu MS, Richardson E, Hussain S, et al. Hypothalamic arcuate nucleus glucokinase regulates insulin secretion and glucose homeostasis. Diabetes Obes Metab. 2018;20(9):2246-54.
13. Thorens B. GLUT2, glucose sensing and glucose homeostasis. Diabetologia. 2015;58(2):221-32.
14. Flak JN, Goforth PB, Dell’Orco J, Sabatini PV, Li C, Bozadjieva N, et al. Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin. J Clin Invest. 2020;130(6):2943-52.
15. Carey M, Lontchi-Yimagou E, Mitchell W, Reda S, Zhang K, Kehlenbrink S, et al. Central K_ATP channels modulate glucose effectiveness in humans and rodents. Diabetes. 2020;69(6):1140-8.
16. Brown JM, Scarlett JM, Schwartz MW. Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis. J Clin Invest. 2019;129(8):3035-7.
17. German JP, Thaler JP, Wisse BE, Oh-I S, Sarruf DA, Matsen ME, et al. Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia. Endocrinology. 2011;152(2):394-404.
18. Meek TH, Matsen ME, Dorfman MD, Guyenet SJ, Damian V, Nguyen HT, et al. Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia. Endocrinology. 2013;154(9):3067-76.
19. Bentsen MA, Rausch DM, Mirzadeh Z, Muta K, Scarlett JM, Brown JM, et al. Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission. Nat Commun. 2020;11:4458.
20. Morton GJ, Matsen ME, Bracy DP, Meek TH, Nguyen HT, Stefanovski D, et al. FGF19 action in the brain induces insulin-independent glucose lowering. J Clin Invest. 2013;123(11):4799-808.
21. Brown JM, Scarlett JM, Matsen ME, Nguyen HT, Secher A, Jorgensen R, et al. The hypothalamic arcuate nucleus-median eminence is a target for sustained diabetes remission induced by fibroblast growth factor 1. Diabetes. 2019;68(5):1054-61.
22. Duncan A, Heyer MP, Ishikawa M, Caligiuri SPB, Liu XA, Chen Z, et al. Habenular TCF7L2 links nicotine addiction to diabetes. Nature. 2019;574(7778):372-7.
23. Horsager C, Bruun JM, Færk E, Hagstrøm S, Lauritsen MB, Østergaard SD. Food addiction is strongly associated with type 2 diabetes. Clin Nutr. 2023;42(5):717-21.
24. DiNicolantonio JJ, O’Keefe JH, Wilson WL. Sugar addiction: is it real? A narrative review. Br J Sports Med. 2018;52(14):910-3.
25. Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39.
26. DiNicolantonio JJ, O’Keefe JH, Lucan SC. Added fructose: a principal driver of type 2 diabetes mellitus and its consequences. Mayo Clin Proc. 2015;90(3):372-81.
27. Chevinsky JD, Wadden TA, Chao AM. Binge eating disorder in patients with type 2 diabetes: diagnostic and management challenges. Diabetes Metab Syndr Obes. 2020;13:1117-31.
28. Salles J, Ponté C, Rougier C, Hakimi Y, Schmitt L, Hanaire H, et al. Sugar addictive behavior resulting from hypoglycemia provoked by insulin misuse. Prim Care Companion CNS Disord. 2021;23(2):20l02788.
29. Jorgenson AG, Hsiao RC, Yen CF. Internet addiction and other behavioral addictions. Child Adolesc Psychiatr Clin N Am. 2016;25(3):509-20.
30. Han G, Zhang J, Ma S, Lu R, Duan J, Song Y, et al. Prevalence of internet addiction and its relationship with combinations of physical activity and screen-based sedentary behavior among adolescents in China. J Phys Act Health. 2021;18(10):1245-52.
31. Lindekilde N, Scheuer SH, Diaz LJ, Rubin KH, Plana-Ripoll O, Henriksen JE, et al. Risk of developing type 2 diabetes in individuals with a psychiatric disorder: a nationwide register-based cohort study. Diabetes Care. 2022;45(3):724-33.
32. Dubey S, Sengupta S, Ghosh R, Dubey MJ, Chatterjee S, Das G, et al. COVID-19 pandemic, personality and geriatric population: proposed pragmatism. J Patient Exp. 2021;8:23743735211059051.
33. Precenzano F, Smirni D, Vetri L, Marzuillo P, Lanzara V, Bitetti I, et al. Childhood obesity and maternal personality traits: a new point of view on obesity behavioural aspects. Pediatr Rep. 2021;13(3):538-45.
34. Pazzagli C, Germani A, Buratta L, Luyten P, Mazzeschi C. Childhood obesity and parental reflective functioning: Is there a relation? Int J Clin Health Psychol. 2019;19(3):209-17.
35. Rouland A, Chauvet-Gelinier JC, Sberna AL, Crevisy E, Buffier P, Mouillot T, et al. Personality types in individuals with type 1 and type 2 diabetes. Endocr Connect. 2020;9(3):254-60.
36. Jiang D, Huang TY, Chen J, Xiao WC, Liu Z. The association of personality traits with childhood obesity: a systematic review and meta-analysis. Available from: https://www.medrxiv.org/content/10.1101/2022.06.22.22276748v1
37. Dubey S, Ghosh R, Dubey MJ, Das S, Chakraborty AP, Santra A, et al. Psychosocial basis of human sufferings and poverty in patients with neurological and psychiatric disorders. Med Res Arch. 2023;11(6). Available from: https://esmed.org/MRA/index.php/mra/article/view/3919
38. Donato J Jr. The central nervous system as a promising target to treat diabetes mellitus. Curr Top Med Chem. 2012;12(19):2070-81.
39. Thorens B. Targeting the brain to cure type 2 diabetes. Diabetes. 2019;68(3):476-8.