On Saturday, April 27, Charlie Lawrence, JDRF Research Information Volunteer and T1D parent, gave a research update hosted by JDRF and Orange Regional Medical Center. This talk focused on a single area of research: Metabolic Control. This research encompasses Smart Insulin and other hormonal drugs that will work in concert to better treat T1D as we work toward a cure.

The vision of this research is a world in which drugs and drug combinations are commercially available to effectively and conveniently restore overall metabolic balance in people with T1D and our goal is to improve control and metabolic balance without increasing the burden of daily management. Here are some of the highlights from the update.

Next-Generation Insulins:

• Glucose-responsive insulins could be called a drug-based closed-loop system. These insulins will circulate through the bloodstream, turning on when they are needed and turning off when they are not. A rise in blood sugar will act as a biological trigger for the insulin to activate and as that blood sugar drops back into range, the insulin will deactivate. This will prevent highs and lows in blood sugar and significantly reduce the burden of daily management. A once daily shot would provide the necessary insulin and the need for glucose testing would be eliminated.
• Liver-targeted insulins will be drugs mimicking physiology. The liver’s cells can store sugar during a meal to prevent hyperglycemia and release sugar during the rest of the day to prevent hypoglycemia. Those liver cells will only function that way if they receive insulin in the right amount at the right time. A healthy pancreas produces insulin that goes directly to the liver which then delivers it to either muscles for immediate use by the body or to fat cells for storage until the body needs it. With current insulin delivery by pumps or injections, subcutaneous insulin is taken up by muscle and fat cells before it reaches the liver. Liver-targeted insulins will head straight to the liver and bypass fat and muscle. This will reduce the risks of hypoglycemia and improve post-meal blood sugar spikes. Clinical proof of concept comes from implantable insulin pumps, which administer insulin directly to the liver and achieve unparalleled clinical benefits.
• Ultra-Rapid insulins will be “fast-on, fast-off”, lowering blood sugar immediately after administration and not lingering in the body for hours. They will reduce meal-time blood sugar excursions and delayed post-meal hypoglycemia, and allow us to “close the loop” in artificial pancreas devices.

Adjunctive Therapies: drugs that replace other hormones created in the pancreas that are affected by the autoimmune attack which include amylin and glucagon. Also, non-hormonal drugs which include SGLT inhibitors.

• Amylin is a peptide hormone that is co-secreted with insulin from the pancreatic β-cell and is thus deficient in people with diabetes. It inhibits glucagon secretion, delays gastric emptying, and acts as a satiety agent. Taking a synthetic form of amylin in concert with insulin has proven clinical benefits including a reduction in A1c, reduced mealtime blood excursions, and weight loss. To date, it has not been widely adopted because it must be injected separately from insulin; thus increasing the burden of management. JDRF researchers are working on insulin-amylin co-formulations that will increase adoption and allow more people to enjoy the clinical benefits.
• SGLT Inhibitors: Sodium Glucose Co-Transporters 1 and 2. SGLT1 aids in absorbing glucose from the small intestine into blood circulation after meals. SGLT2 aids in re-absorbing glucose from the kidneys back into blood circulation. Both contribute to blood glucose levels. SGLT1 inhibitor will send less glucose from the intestines to the blood and a SGLT2 inhibitor will send less glucose from the kidneys to the blood. Zynquista is an oral dual SGLT1/2 Inhibitor drug that is currently under review at the FDA for use by T1D patients. During clinical trials, Zynquista (with insulin) was found to lower A1c and glycemic variability. Subjects lost weight, experienced a decrease in blood pressure and used less insulin. It did not cause an increase in hypoglycemia. There was a higher risk of DKA in the Zynquista group versus the placebo group.

Pathophysiology and Biomarkers: researching the root cause of the autoimmune attack and studying what triggers that attack. Pathophysiology is the disordered physiological processes associated with disease or injury. Biomarkers are a measurable substance in an organism whose presence is indicative of some phenomenon such as disease. There is much to learn in this area and JDRF supports research in pathophysiology toward the goal of developing improved therapies.

Metabolic Control Summary:

• Next-generation insulins hold exciting potential but research and development is still in early stages
• Therapies adjunctive to insulin (like SGLT inhibitors) will play a crucial role in restoring holistic metabolic balance, and (hopefully) will be emerging for T1D soon
• Understanding T1D pathophysiology better will drive the direction of future therapies

For additional reading:

https://jdrf.org.uk/our-research/about-our-research/treat/smart-insulin/

https://www.jdrf.org/blog/2019/02/26/snail-hold-key-better-blood-sugar-control/

https://www.jdrf.org/blog/2019/04/29/win-t1d-community-zynquista-sotagliflozin-europe-approved-type-1-diabetes/

https://www.jdrf.org/blog/2019/02/08/sglt-inhibition-not-just-type-2-anymore/

https://www.jdrf.org/blog/2018/12/22/jdrf-drives-next-generation-type-1-diabetes-research-with-new-partnerships-breakthrough-science/

Special thanks to Charlie Lawrence for his excellent presentation and to Orange Regional Medical Center for their partnership and dedication to all people living with T1D.