As diabetes progresses, it wreaks havoc on many of the body's organs, including the brain. The insidious effects include altered mental status, reduced cognitive function, depression and an increased risk of Alzheimer's disease. The molecular mechanisms underlying these deleterious effects are poorly understood. In 2010, a research group led by Dr. Ronald Kahn of the Joslin Diabetes Center pointed a finger at hypoinsulinemia, the insulin shortage associated with diabetes. A series of experiments in mice and cultured cells led Kahn's team to conclude that, in addition to impairing glucose metabolism, hypoinsulinemia globally down-regulates cholesterol synthesis-regulating genes, resulting in a shortage of the cholesterol needed for many of the brain's functions, including the formation of synapses between neuronal cells (Suzuki et al. 2010).
Insulin shortage suppresses hypothalamic cholesterol synthesis
Because the hypothalamus is a major control center of the endocrine system, appetite and energy balance, Kahn and his team wanted to know how diabetes affects hypothalamic gene expression. They used C57BL/6J (B6J, 000664) mice in which diabetes had been induced with streptozotocin (STZ) as their model. They found that the majority of cholesterol synthesis-regulating genes in the hypothalami of these mice are down-regulated and that their expression normalizes if the mice are given insulin.
The most notable of these genes are the sterol regulatory element-binding protein (Srebf2) gene and the genes that it activates. These genes are also down-regulated in the hypothalami of NOD inbred mice (characterized by hypoinsulinemia), BKS.Cg-Dock7m +/+ Leprdb/J (000642) mice (which become hypoinsulinemic with age), brain-specific insulin receptor knockout mice, and mice fasted for 24 hours (fasting lowers insulin and glucose levels). In contrast, the same genes are normally expressed in the hypothalami of diet-induced obese B6J mice and in genetically obese B6.V-Lepob/J (000632) mice (both of which develop insulin resistance without becoming hypoinsulinemic). Kahn and his team also found that treating STZ-induced diabetic mice with phlorizin, which decreases blood glucose levels without restoring insulin secretion, does not normalize the expression of these genes. Additionally, whereas adding insulin to cultured neuron and glial cells from the cortices of B6J mice stimulates the expression of the same genes, incubating these cells with glucose does not.
Taken together, these findings suggest that insulin shortage – not obesity, systemic insulin resistance or hyperglycemia – suppresses hypothalamic Srebf2 expression and cholesterol synthesis.
Cholesterol shortage impairs brain function
The brain is the most cholesterol-rich organ in the body, containing about 25% of the body's cholesterol. Virtually all that cholesterol is produced within the brain itself. It is a crucial component of synaptic structure and function. Kahn and his team suspected that reduced cholesterol synthesis interferes with brain synapses. Indeed, they found that the cholesterol content of synaptosomal membranes in the brains of mice with STZ-induced diabetes is abnormally low. In analyzing the synaptosomal cholesterol content and the expression patterns of cholesterol synthesis-regulating genes in the cerebral cortices of 16 elderly people, they found strong evidence that the factors that control cholesterol synthesis also control synaptosomal cholesterol. Additionally, they found that silencing Srepf2 reduces the number of synaptic markers in cultured mouse hypothalamic neurons.
Taken together, the findings by Kahn and his colleagues indicate that diabetes-associated hypoinsulinemia down-regulates Srepf2, reducing brain cholesterol synthesis and the cholesterol content of synaptosomal cell membranes, and at least partially explaining why diabetes is associated with impaired brain function and some neurological disorders.
Suzuki R, Lee K, Jing E, Biddinger SB, McDonald JG, Montine TJ, Craft S, Kahn CR. 2010. Diabetes and insulin in regulation of brain cholesterol metabolism. Cell Metab 12:567-79.