High insulin impaired ovarian function in early pregnant mice and the role of autophagy in this process

What effect does diet-induced obesity have on endometrial stromal cell (ESC) decidualization?

There is a persistent perception that oestrogens have an adverse effect on carbohydrate metabolism. It might therefore be expected that their use would result in a corresponding increase in the incidence of diabetes. Recent evidence from clinical trials suggesting that women on postmenopausal oestrogen hormone replacement therapy (HRT) have a reduced incidence of type 2 diabetes therefore appears paradoxical. Short-term supraphysiological oestrogen administration has an adverse effect on glucose tolerance, resulting from suppression of first-phase insulin secretion and increased insulin resistance. Oestrogen-induced increases in glucocorticoid activity could account for these effects. Oestrogen-induced deterioration in glucose tolerance is, however, accompanied by a reduction in fasting glucose, an effect that could be accounted for by glucagon antagonism. These short-term effects contrast with long-term preservation of insulin secretion and glucose homeostasis by oestrogens. In animal studies, ovariectomy is associated with decreased insulin secretion and increased risk of diabetes, whereas oestrogen administration protects against diabetes and increases the insulin response to glucose. The mechanism is uncertain, but direct effects on the pancreas via steroid receptors or indirect effects via oestrogen-induced glucagon antagonism and subclinical increases in glucocorticoids and growth hormone could all contribute. Recent evidence that HRT increases the risk of cardiovascular disease suggests that it should not be used for the prevention of diabetes, but the mechanism responsible for this benefit merits further investigation and might lead to new therapies.

Autophagy functions to degrade and recycle intracellular proteins and damaged organelles, maintaining the normal cellular function. Autophagy has been shown to play an important role in regulating normal function of pancreatic β cells and insulin-target tissues, such as skeletal muscle, liver, and adipose tissue. Enhanced autophagy also acts as a protective mechanism against oxidative stress in these tissues. Altered autophagic activity has been implicated in the progression of obesity to type 2 diabetes through impaired β-cell function and development of insulin resistance. In this review, we outline the normal regulation of autophagy in β cells and insulin target tissues and explore the dysregulation of autophagy in diabetic animal models and human subjects with type 2 diabetes. Furthermore, we highlight the role of impaired autophagy in the pathophysiology of diabetic complications, including nephropathy and cardiomyopathy. Finally, we summarize how autophagy might be targeted as a therapeutic option in type 2 diabetes.