Template to improve glycemic control without reducing adiposity or dietary fat

Abstract

Drugs that improve chronic hyperglycemia independently of insulin signaling or reduction of adiposity or dietary fat intake may be highly desirable. Ad36, a human adenovirus, promotes glucose uptake in vitro independently of adiposity or proximal insulin signaling. We tested the ability of Ad36 to improve glycemic control in vivo and determined if the natural Ad36 infection in humans is associated with better glycemic control. C57BL/6J mice fed a chow diet or made diabetic with a high-fat (HF) diet were mock infected or infected with Ad36 or adenovirus Ad2 as a control for infection. Postinfection (pi), systemic glycemic control, hepatic lipid content, and cell signaling in tissues pertinent to glucose metabolism were determined. Next, sera of 1,507 adults and children were screened for Ad36 antibodies as an indicator of past natural infection. In chow-fed mice, Ad36 significantly improved glycemic control for 12 wk pi. In HF-fed mice, Ad36 improved glycemic control and hepatic steatosis up to 20 wk pi. In adipose tissue (AT), skeletal muscle (SM), and liver, Ad36 upregulated distal insulin signaling without recruiting the proximal insulin signaling. Cell signaling suggested that Ad36 increases AT and SM glucose uptake and reduces hepatic glucose release. In humans, Ad36 infection predicted better glycemic control and lower hepatic lipid content independently of age, sex, or adiposity. We conclude that Ad36 offers a novel tool to understand the pathways to improve hyperglycemia and hepatic steatosis independently of proximal insulin signaling, and despite a HF diet. This metabolic engineering by Ad36 appears relevant to humans for developing more practical and effective antidiabetic approaches.

Natural infection of human adenovirus 36 in rhesus monkeys is associated with a reduction in fasting glucose 恒河猴自然感染人36型腺病毒与空腹血糖下降有关

“…Experimental infection of a human adenovirus Ad36, increases adiposity, yet improves glycemic control in rodents 1 . In humans, natural Ad36 infection is cross-sectionally and temporally associated with adiposity and better glycemic control 1–3 .…”

Insulin receptor-independent upregulation of cellular glucose uptake

“…Ad36, a human adenovirus, increases cellular glucose uptake independent of insulin and improves glycemic control, 9– 11 and may offer a novel template to induce these effects without recruiting insulin signaling. In rodent models, experimental infection with Ad36 significantly improves systemic glycemic control in chow fed animals 9,12 and even improves high-fat diet induced hyperglycemia and hepatic steatosis, without requiring a reduction in adiposity.…”

“…In rodent models, experimental infection with Ad36 significantly improves systemic glycemic control in chow fed animals 9,12 and even improves high-fat diet induced hyperglycemia and hepatic steatosis, without requiring a reduction in adiposity. 9 In about 1500 human subjects, natural Ad36 infection predicted better glycemic control and lower hepatic lipid accumulation, independent of age, sex and adiposity. 9 The congruence of animal and human data underscore the potential clinical relevance of these findings.…”

“…9 In about 1500 human subjects, natural Ad36 infection predicted better glycemic control and lower hepatic lipid accumulation, independent of age, sex and adiposity. 9 The congruence of animal and human data underscore the potential clinical relevance of these findings. Overall, Ad36 exhibits ‘insulin sparing action’, 9 and offers a template to exogenously modulate glycemic control and hepatic steatosis, without reducing dietary fat intake or adiposity—a particularly appealing concept, given the challenges of weight loss or maintenance.…”

Innate immunity, insulin resistance and type 2 diabetes

“…Further evidence for a link between the innate immune system and insulin sensitivity comes from recent observations on exposure to infection [17]. Apparently healthy men with exposure to common pathogens (herpes virus 1, herpes virus 2, enteroviruses and Chlamydia) and characterised by persistent and chronic infection, showed increased fat mass and insulin resistance, and the greater the exposure to these pathogens, the higher the serum levels of inflammatory markers and the lower the insulin sensitivity.…”