D. Diabetes


March 8, 2023

Accomplishments of scientific research in diabetes are recognized from two aspects. First, a variety of commercial drugs are available to meet the broad needs of patients and some of them are quite effective and affordable for people with low income, such as metformin. Secondly, all the drugs for the treatment of either type 2 or type I diabetes are linked to one or more categories of known mechanisms disclosed in the public domain. For some drugs, either new or old, more pathological contributors may be included for their therapeutic functions but little novel revelation is defined by their biochemical natures.

Like many other fields, there are quite a few missing pieces in the whole pattern of drug R&D for diabetes. One of them stems from misinterpretations of drug therapeutic mechanisms, and this undesirable shortcoming has become a stumbling block against in-depth advancement for a long time. From the point of glycogenolysis or gluconeogenesis or both, for instance, many opportunities exist to pick up drug candidates of small molecules, either repurposed commercial or investigational ones, for type 1 diabetes. Still, the accessibility appears to be mostly unseen to date. Here metformin is chosen as an illustrative example.

Metformin for type 2 diabetes is a typical compound that plays an ideal role in glucose homeostasis by properly coordinating the gluconeogenesis pathway. Carrying partial functions of five sulfatide molecules, it delicately acts to neutralize three groups of well-known biomolecules:

  Six free amino acids, such as proline, valine, and Argine. Note that elevated proline levels
      are also associated with obesity in addition to type 2 diabetes.

  Three glycerol-related molecules, such as glycerol monolactate. Few commercial drugs
      directly interact with glycerol.

  One of the three keto bodies and two alpha-ketoacids.

A new phenomenon that metformin consumes fucose and deoxyribose deserves further exploration. At present, four other commercial drugs for type 2 diabetes on the market are family members of metformin.

In the human body, metformin actually takes action on many other types of biomolecules, meaning that it is a multifunctional molecule, as a modest antiviral and a neuroprotectant, for example.

Excluding the difference in solubilities, when the functional properties of a special sulfatide molecule are fully and solely represented by a small molecule, the drug candidate reveals its efficacies for the treatment of type 1 diabetes, such as verapamil. When the representation decreases by two-thirds, the functionality of a drug for type 1 diabetes weakens but the indication still remains, such as vildagliptin which adds additional functions of the other four sulfatides as a type-2-diabetes drug. Evidently, many opportunities are available to find optimized drug molecules to fill the blank. In addition, abundant small molecules are also available for competing with insulin drugs in this area.

Efficiently helping weight loss is a remarkable function of several drugs for diabetes. The therapeutic mechanism behind it is not mysteriously complicated at all because they are just family members of endogenous molecules that reduce food intake, especially, fat intake through various approaches.

In addition to sulfatides, numerous other endogenous molecules in the brain can be classified into the category that insulin belongs to. Is diabetes mellitus a neurodegenerative disease? Substantial R&D work is needed for the answer to this question.