Enhancer-Gene Interaction Analyses Identified the Epidermal Growth Factor Receptor as a Susceptibility Gene for Type 2 Diabetes Mellitus

This study showed for the first time the stimulating action of peptides of the insulin family, insulin-like growth factor-1, relaxin, and epidermal growth factor (EGF) on the activity of the adenilate cyclase signal system (ACSS) in lymphocytes from the subjects of the control group. These hormonal effects were enhanced in the presence of guanylimidodiphosphate (GIDP). Moreover, leptin was for the first time shown to increase adenilate cyclase activity in lymphocytes from the control subjects and inhibition of this action by antibodies against leptin receptors. The patients presenting with type 2 diabetes mellitus (DM2) showed the enhanced baseline activity of adenilate cyclase in their lymphocytes whereas its stimulation by the above hormones, both in the presence and absence of GIDP, sharply declined. The influence of leptin on adenilate cyclase activity in patients with DM2 was apparent only at its concentrations above 10–8 M; it was inhibited by antibodies to leptin receptors. The results of this study indicate that disturbances of hormonal stimulation of adenilate cyclase activity in lymphocites of diabetic patients may be due to functional defects located at the receptor level in the case of leptin and at the level of Gs protein and its coupling to adenulate cyclase in case of peptides of the insulin family and GF. These findings confirm the concept being developed by the author according to which molecular defects in the hormone-dependent ACSS system constitute one of the main causes underlying the development of DM2.

Download Full-text

Deficits in hippocampal neurogenesis in obesity-dependent and -independent type-2 diabetes mellitus mouse models

Scientific Reports ◽

10.1038/s41598-020-73401-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jacqueline A. Bonds ◽

Aashutosh Shetti ◽

Terilyn K. L. Stephen ◽

Marcelo G. Bonini ◽

Richard D. Minshall ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Growth Factor ◽

Cognitive Decline ◽

Leptin Receptor ◽

Memory Function ◽

Growth Factor Receptor ◽

Hippocampal Neurogenesis

Abstract Hippocampal neurogenesis plays an important role in learning and memory function throughout life. Declines in this process have been observed in both aging and Alzheimer’s disease (AD). Type 2 Diabetes mellitus (T2DM) is a disorder characterized by insulin resistance and impaired glucose metabolism. T2DM often results in cognitive decline in adults, and significantly increases the risk of AD development. The pathways underlying T2DM-induced cognitive deficits are not known. Some studies suggest that alterations in hippocampal neurogenesis may contribute to cognitive deterioration, however, the fate of neurogenesis in these studies is highly controversial. To address this problem, we utilized two models of T2DM: (1) obesity-independent MKR transgenic mice expressing a mutated form of the human insulin-like growth factor 1 receptor (IGF-1R) in skeletal muscle, and (2) Obesity-dependent db/db mice harboring a mutation in the leptin receptor. Our results show that both models of T2DM display compromised hippocampal neurogenesis. We show that the number of new neurons in the hippocampus of these mice is reduced. Clone formation capacity of neural progenitor cells isolated from the db/db mice is deficient. Expression of insulin receptor and epidermal growth factor receptor was reduced in hippocampal neurospheres isolated from db/db mice. Results from this study warrant further investigation into the mechanisms underlying decreased neurogenesis in T2DM and its link to the cognitive decline observed in this disorder.

Download Full-text