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Diabetes Mellitus and Natural Product-based Drug Discovery
Novel Directions

David J. Newman

NIH Special Volunteer, Wayne, PA 19087, USA

1.1 Introduction

In terms of saving lives and/or helping people suffering from this disease, I will demonstrate the history of treatments for the diseases known as "diabetes" in which I include both diabetes 1 (autoimmune destruction of insulin-producing ß-cells in the pancreas) and diabetes 2 (inadequate insulin production and/or insulin resistance, though exact mechanisms are not understood). The data presented will exemplify the role(s) of natural products in deriving both the earlier (mainly insulin) and current drugs that ameliorate these diseases. I have included both "versions" of the disease as nowadays there are reports demonstrating adult onset of what would be considered type 1 (T1DM) and a very significant number of type 2 (T2DM), frequently included under the catchall term, "metabolic syndrome" [1] and, later on, some of the current factors that may well lead to such a diagnosis are listed. The chapter will first focus on insulin and its current sources, and will then give details of other agents, some very slightly modified natural products from manifold sources, and then the synthesis of what can be best described as natural product spatial mimics that are in use nowadays, particularly in the treatment of T2DM.

1.2 A Brief History of Insulin

The story surrounding the discovery and utilization of insulin in Canada at the University of Toronto linking the utility of insulin to treat diabetes, was the first clinically reported linkage of this human hormone to the treatment of diabetes. However, reports of this disease went back many centuries, even millennia, with initial reports around 552 BC in the Ebers papyrus (which can be considered the first written description of diseases and potential treatments) by Egyptian scholars. Similar reports from both Chinese and Indian "academics" in a relatively similar time frame also noted the disease, with all reports noting the common link that patients had a constant flow of "sweet urine". In the time frame of roughly 100 years BCE, Demetrius of Apameia was credited with the introduction of the term "diabetes" (from the Greek word for siphon) since he noted the constant flow of urine from patients Then, in the second century CE, the Greek physician Aretaeus of Cappadocia first described the first accurate clinical description of diabetes [2]. Galen, at approximately the same time as Aretaeus, associated diabetes with a disease of the kidneys, and this persisted for the next 1500 years.

Then, following a number of varied experiments using dogs (with or without their pancreas) and other data from diabetic human patients who had damaged islets of Langerhans in their pancreas, led to the suggestion in 1916 by Sharpey-Schafer of a linkage between a secretion from the pancreas and "control" of carbohydrate metabolism by an as yet unidentified hormone that regulated glucose that he named insulin [2]. The complex interactions, both scientific and personal, that led to the purification of insulin and its initial clinical success are well described by Rosenfeld in 2002 [3]. This report also mentions the first production of crystalline insulin in 1926 by Abel at Johns Hopkins and then, in 1951, Sanger sequenced insulin, the first protein hormone to have its formal structure reported [4, 5]. Until the production of human insulin via biotechnological methods, which will be discussed later in this chapter, all supplies of insulin were effectively from utilization of bovine or porcine sources and, at times, chemical modification to aid in stability and/or ease of utilization.

1.3 Biosynthesis of Insulin

The biosynthetic process produces an inactive 110 residue, preproinsulin, which on translation into the endoplasmic reticulum has the signal peptide removed leaving proinsulin, which folds to give three disulfide linkages between the precursors of the A and B chains. This proinsulin then transits through the Golgi apparatus into the secretory granules. Further removal of selected portions by a number of hydrolytic enzymes produces the active insulin composed of A (21 amino acids) and B (30 amino acids) chains connected via two disulfide bonds. It is stored as an "inactive" hexamer and is now available for release of the monomer following the correct metabolic stimulus. It should also be pointed out that this is a very ancient molecule and is found across many eukaryotic genera including fungi, teleost fish and, in a modified form, in the venom of cone snails.

1.3.1 Humulin®, the Second Human Hormone Produced by Biotechnology

In 1977, somatostatin was the first peptide hormone to be produced by the then new and novel recombinant DNA process [6, 7]. This was also effectively the foundation product of the company Genentech, which had been founded the previous year. Since the human genes corresponding to in vivo production of insulin had not been identified/cloned at that stage of rDNA operations, what could be considered "synthetic genes" were made chemically, corresponding to the formal structure of insulin components. The success of this was demonstrated in a 1979 paper by Goeddel et al. [8], which used the "synthetic human genes" published late the previous year by Crea et al. [9]. Proof of the validity of this work was shown by the approval by the US FDA of Humulin. Just to put the timing in perspective, I have used the following quote from Riggs' article [7]. "For example by 2020 the genes for insulin can be made in a few hours by an automated instrument and then cloned and expressed by a single person in about a week."

1.3.2 Further Derivatives of Insulin Using rDNA Techniques

Once the utility of this process was proven, over time since the early 1980s, insulins with improved pharmacology have been approved. In a recent (2019) open access journal, Guney [10] described the number of agents that are currently available and classified them by their pharmacological parameters.

As of the date of that review the following were available (though not perhaps in all countries). I have omitted the premixed and biphasic analogs in Table 1.1.

Table 1.1 Insulin preparations mainly for T1DM treatment.

Thus, there are multiple variations designed to help T1DM patients control their glucose levels before and after meals.

1.4 Current Possible Insulin-based Treatments for T2DM

In a recent paper by Sebastian et al. [11] there is significant discussion of various insulin-based treatments for T2DM with one of the more promising being the Technosphere (TI) inhaled insulin (Afreeza®), which was approved by the FDA in 2014 for both T1DM and T2DM patients, with further details in the 2021 paper by Levin et al. in 2021 [12]. This is in contrast to the current treatments of a glucagon-like peptide (GLP)-1 receptor agonist after metformin, and variations on other mixed oral/injectable treatments.

1.4.1 Metabolic Syndrome (As of June 2022)

In an article in the American Chemical Society's journal Central Science [13], if a patient has any three of the following five criteria as described in Table 1.2 for metabolic syndrome then they have a high risk of T2DM and cardiovascular diseases.

Table 1.2 Symptoms leading to metabolic syndrome diagnosis.

However, there is at least one major caveat in the values listed in Table 1.2 that needs to be taken into account. A significant number of the values listed were taken from the Framingham heart study where less than 5% of the participants were of other than European ancestry. When current data from more diverse populations are...