Hormones That Change Blood Glucose Levels

While designing our technology, in addition to obesity and insulin-resistance, we considered treating the androgen hormonal excess found in PCOS. However, a fitness tracker cannot incorporate a sensor to measure androgen levels as this requires blood testing. Also, since the adrenal glands and ovaries both produce testosterone, it is difficult to specifically target ovarian hyperandrogenism. Treating three different underlying factors would have also increased the design complexity of our technology unsustainably. We decided that focusing on obesity and insulin resistance would have the attendant effect of correcting androgen excess by stabilizing the hormonal imbalances of the HPO axis. Since even modest weight reduction improves ovulatory function, focusing on comprehensive lifestyle management by regulating weight and blood sugar with natural gut-provided medication would be a healthier overall way to treat PCOS.

For oral administration of gut-hormone medications, we also researched SNAC molecule technology (sodium N8-2hydroxybenzoyl amino-caprylate) which facilitates the transport of compounds with low oral bioavailability. It forms bonds with peptides and helps their absorption across biological membranes. After crossing, the peptide detaches from the SNAC molecule, passes directly into blood circulation, and exercises its intended pharmacological action. We chose the robotic pill over SNAC however, because its drug-delivery method through the intestine directly into the bloodstream, closely resembles the normal physiological release of gut hormones and insulin. Also, its biodegradable capsule is safely eliminated by normal excretion pathways.

We considered basing our project on the genetic basis of PCOS and obesity, since both run in families. The Anti-Müllerian hormone (AMH) which is a regulator of ovarian folliculogenesis is elevated 2-3 times in women with PCOS, and genetic variation contributes to AMH over-secretion. Also, the predisposition to store fat,variations in BMI, and acquisition of obesity-related conditions (like high blood sugar), are familial. But genetics alone cannot account for the worldwide surge of infertility. During millions of years of evolution, humans previously lived in an environment which is totally different from the present day, with its increased pollution, chemicals, processed food, and sedentary lifestyle. Thus obesity and fertility regulatory treatments must be understood in the context of human physiologic and biologic processes. It is unlikely that a treatment modality based solely on gene therapy will be fully effective, so we discarded this idea for our project.

Negative consequences: The food-regulatory homeostatic system is complex. Since gut hormones target the neural circuits affecting appetite regulation and satiety, but also make eating more pleasurable, any drug affecting the brain’s pleasure centers can create side effects related to mood-regulation and depression. They can also cause nausea and vomiting. Also, hormones altering the blood glucose level can cause hypoglycemic sugar drop and dizziness. Satiety, nausea, and glucose balance lie along different points on the continuum to GI stimuli. Slow-dose escalation regimes and maximal tolerated dosages will need to be clearly determined, which can be challenging. Since the hormones are in a peptide molecule form, there is the risk of the body thinking of it as foreign and developing antibodies against the treatment, rendering it ineffective.

Also, the robotic pill delivery system has a limit of 3-5 mg of drug payload. While presently sufficient, this may prove restrictive later. Overall, gut hormonal development can be complicated and expensive for manufacturers. Also, a hormone-based neural treatment does not absolve patients from responsibility for their own lifestyle, or replace a healthy diet and exercise regimen and complexities of PCOS. The greatest benefit will be seen in context of a multidisciplinary approach. Positive consequences: Since endogenous gut hormones regulate glucose levels and weight using the body’s own satiety signals, they mimic the body’s own physiological control system, making it a more natural therapy with fewer side effects than chemical drugs. Drug side effects are also held to higher safety standards, so when fully developed these treatments will be safe and efficacious.

It has been found that gut hormones in combination (PPY and GLP-1, PPY and OXM) with the addition of leptin/insulin give additive anorectic effects and highly promising lowered blood sugar and weight-loss results, with concurrent improvement in ovulatory function and androgenic hormonal assays in PCOS patients. The robotic pill allows for easy oral compliance, painless drug-delivery, exact dose calibration, and an immediate feedback effect by absorption directly into the blood stream. Orally-delivered gut hormone peptides promote a shift in the balance between energy intake and expenditure with minimal interference to other body systems. They represent the next generation of anti-obesity and glucose-lowering drugs, making them the promising wave of the future to tackle the PCOS-linked spike in modern-day infertility rates.