Authors: Uday Saxena, PhD, Subrahmanyam Vangala, PhD and Satishchandran C, PhD
Reagene Innovations Pvt Ltd, ASPIRE-BioNest, University of Hyderabad
Address correspondence to usaxena08@gmail.com
Summary:
Despite the use of several antidiabetic drugs, many patients are unable to reach target glucose levels. There is a need for new safe therapies which can work in combination with existing drugs to help patients reach target glucose levels. We developed a fixed dose composition (FDC) of Vitamin D3, Niacinamide and lipoic acid which targets three critical steps in cellular glucose metabolism. These were: Glucose uptake ( enhanced by Vitamin D3), glucose utilization ( improved by Niacinamide) and resulting mitochondrial redox stress (reduced by lipoic acid). The FDC was active in in vitro L6 muscle cells and improved glucose disposal in mouse OGTT studies. We collected data from 8 patient observation study. All patients were on anti-diabetic drugs either metformin alone, or gliptin, semaglutide in combination with metformin and the FDC was added to the regimen. We found an average drop 24% in fasting plasma glucose from initiation of the FDC with p-value <0.022. The decrease was sustained over several weeks and seen on top of the antidiabetic drugs mentioned above. In 2 patients who were on the FDC for three months, there was a decrease in HbA1C as well. These data provide the impetus for larger clinical studies. This defined FDC of safe nutraceuticals targeting glucose uptake and utilization may allow patients to reach target glucose levels in combination with the prescribed anti-diabetic drugs.
Introduction
Diabetes is a condition that impairs the body’s ability to process blood glucose, otherwise known as blood sugar.High glucose blood levels are responsible for the morbidities and life-style changes associated with diabetes. Type 2 diabetes is a lifelong disease with severe consequences if blood glucose is left uncontrolled. It may lead to irreversible kidney damage (nephropathy), nerve damage (neuropathy), damage to eyes (retinopathy), heart disease and stroke.
Prior to the onset of full-fledged type 2 diabetes, patients undergo a pre-diabetic phase which lasts for years during which there is a year-on-year increase in fasting blood glucose, eventually culminating in full-fledged diabetes if left unchecked.
Normally, muscles take up almost 70% of the glucose from blood which leads to blood glucose lowering. The hormone insulin produced by the islet cells in pancreas is the main trigger for this glucose uptake by muscles. In pre-diabetes and type 2 diabetes, muscles become non-responsive to insulin. Any intervention that can help promote insulin induced muscle glucose uptake will help balance blood glucose levels.
The Figure above shows how glucose levels rise in pre-diabetics and type 2 diabetics when insulin in not effective in promoting glucose uptake by muscle. Supplements that help insulin work better can maintain healthy blood glucose.
Once carbohydrate food is ingested, the dietary carbohydrates get broken down in the gut into glucose, which is then absorbed by the intestinal cells into the blood circulations. Within a short time of glucose absorption, the pancreas releases insulin triggering a cascade of steps that clear glucose for circulation. Essentially the steps are that insulin binds to its receptors in various tissues such as muscle, adipose etc. This then recruits the glucose transporters GLUT4 from cytoplasm to the cell membrane where it binds glucose and transports it inside the cells. Once inside the cell’s glucose can either be utilized to generate energy or be stored as glycogen. The uptake of glucose by the tissues lowers blood glucose levels.
The process of muscle uptake is critical to glucose lowering since muscles account for almost 70% of glucose uptake. During type 2 diabetes, the muscle uptake is defective due to insulin resistance, a process in which muscles do not respond insulin and therefore glucose uptake is limited.
While there are many oral drugs to treat type 2 diabetes by lowering blood glucose, researchers continue to develop novel ways to manage diabetes. Shown below are the drugs that most are frequently used as standard of care today.
As can be seen the drugs target the following tissues
- Metformin targets the liver
- Sulfonylureas target the pancreas to make more insulin
- DPP4 Inhibitors also target increasing insulin production by pancreas by inhibiting the enzyme dipeptidyl peptidase 4 which is responsible for degradation of Glucagon Like Peptide 1 (GLP-1)
- GLP-1 agonists which are mimetics of naturally occurring GLP-1 produced by the intestine
- Sodium Glucose Co-Transporter 1 (SGLT-1) inhibitors, which block the function of SGLT1, by is blocking the reabsorption of glucose from urine
Each of the drugs are either used as monotherapy, usually beginning with metformin and other drugs are added to the treatment regimen as the target glucose control is not reached. While being efficacious, each of the drugs have their own safety/adverse events issues as well.
An import point to reiterate is that none of the drugs targets muscle dysfunction directly. As stated, muscle along with adipose tissue are the major organs which extract glucose from circulation and bring about glucose lowering.
Current drugs used for Type 2 diabetes often still do not lower blood sugar to healthy levels
These are several tablet drugs on the market today for glucose control. Some of these are metformin (acts on liver), Glimepiride and semaglutide (act on pancreas), Gliptins (act on an enzyme in blood) and combinations of these. Despite all of these drugs, in almost half of the patients, reaching healthy levels of blood sugar is still not possible. The doctor tries to increase the dose of the same drugs in the hope of reaching lower glucose levels but along with that comes the danger of hypoglycaemia (blood glucose may become too low and there is risk of coma and damage to brain) and increased side effects if any.
Why are all these drugs alone or in combination not able to reduce glucose further.? The answer lies in the fact 70% of glucose lowering occurs due to uptake of the sugar by the muscle. Yet, none of the present drugs have any affect directly on the muscle.
To maximize glucose lowering a drug or nutraceutical has to impact muscle. In view of this significant gap in current therapy we designed a safe FDC nutraceutical which can be added to your current drug regimen and help you achieve healthy levels safely. Our novel FDC
- Specially targets and Improves muscle glucose uptake
- Helps maintain glucose levels
- Glucose control over and above other type 2 diabetic drugs
- Improves glucose metabolism and energy levels
- Safe combination of 2 vitamins and Lipoic Acid that can be used along with diet, exercise and other medicines
In early clinical studies (8 patients treated with the novel FDC in addition to other antidiabetic drugs) lowered blood glucose over and above the antidiabetics drugs by 24% and in tow patients that were treated for more than three months , HbA1C levels decreased commensurately with glucose levels. We propose that a new era of type 2 treatment is possible with safe and targeted supplemental nutraceuticals such this FDC.