“More than 29 million people in the United States and 420 million globally have diabetes, with a projected global prevalence of 642 million by 2040.1,2 This accelerating pandemic comes with high personal and financial costs to the individual, society, and the economy. The expanding number of antihyperglycemic medication options for type 2 diabetes, often involving different mechanisms of action and safety profiles, can be a challenge for clinicians, and the increasing complexity of diabetes management requires a well-informed strategy for prevention and treatment of this disease.”1
Diabetes continued menacing presence on a global scale has led to the release of a smorgasbord of pharmaceutical options available for the treatment of diabetes. The majority of today’s drugs address a variety of diabetes symptoms. While they do keep blood glucose in check, for the most part, they fail to address the advancement of the illness. Also, many pieces of research have concluded that over time, the body no longer uses the medication as effectively as it once did.
“Type 2 diabetes mellitus (T2DM) as a metabolic disorder has features such as dyslipidemia, insulin resistance, and loss of mass and function of beta-cells. Several reports indicate that insulin resistance as a compensatory response leads to a boost in the number of pancreatic beta-cells via the action of circulating growth factors. Several studies taking advantage of human and mouse models have shown that hepatocyte-derived growth factors stimulate beta-cell division and therefore confirm the involvement of liver and pancreas in the adaptive increased beta-cell division as a compensatory response in insulin resistance.”2
What modern pharmacological progress has been attempting is the concerted effort to halt the advancement of diabetes. This provides the possibility of a better overall outlook for the patient and current medical practitioners’ ability to tackle the many facets of diabetes.
Let’s review some of the drugs that, while still imperfect, have shown incredible promise for future strategies of diabetes treatment.
“Sodium-glucose transporter 2 (SGLT2) inhibitors are a new class of orally active drugs used in the management of type 2 diabetes. The first SGLT2 inhibitor to be authorized was dapagliflozin in Europe in 2012, and nowadays this class, also known as the “gliflozins”, includes other drugs such as canagliflozin, empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, etc.. By inhibiting the SGLT responsible for the reabsorption of glucose from the kidney, their use in patients with type 2 diabetes aims primarily to increase glycosuria and, as a consequence, lower glycemic levels. However, their specific mechanism of action involves other pharmacodynamic consequences; some are beneficial (such as the increased insulin sensitivity or the decrease in systolic blood pressure) but others are potentially harmful adverse reactions.”3
Gliflozins are a class of drugs whose function is to increase the renal absorption of glucose molecules. The kidneys filter blood by absorbing water and cellular waste. The glucose contained within the blood, instead of being filtered and passing through urine, gets returned to our bloodstream where it gets “back in line” to await transportation (insulin) into our cells where they are utilized for energy. This is a normal function. However, in diabetes, blood sugar is already too high and so it would not make sense for the body to keep returning glucose molecules back into the bloodstream. What gliflozins accomplish is that it forces our kidneys to filter circulating glucose from the bloodstream where it becomes part of the urinary waste and they also help to keep cardiac pressure in check. The mechanism in which the drug accomplishes this occurs outside the cell membranes of the nephrons; the functional unit of the kidneys. There is a protein that sits at the outer membrane of the nephron that is responsible for reabsorbing the passing glucose back into the bloodstream called SGLT2 (Sodium-glucose transport protein). Gliflozins are SGLT2 inhibitors and therefore retard glucose reabsorption.
“The mechanism of action of SGLT inhibitors implies binding to the transmembrane SGLT by mimicking a sugar conformation resulting in the blockade of the glucose and sodium transport cycle. However, the way SGLT inhibitors reach their site of action is not clearly determined. Gliflozins only inhibit the reabsorption of the filtered glucose by 30% to 50% (whereas SGLT2 is responsible for 90% of renal glucose reabsorption). In addition, the urinary glucose excretion is maintained during a long time after the plasma levels of the SGLT2 inhibitors have decreased. These two observations indicate that glomerular filtration may not be the only way for SGLT2 inhibitors to reach renal SGLTs and this questions the potential role of other mechanisms: i) renal secretion and/or reabsorption of gliflozins, ii) a site of secretion that could be downstream to where SGLT2 are mainly expressed (S1/S2 segments), iii) potential super potent minor metabolites, iv) augmented capacity of SGLT1 (in S3 segment) secondary to complete SGLT2 inhibition, or other compensatory mechanisms. Furthermore, the action of SGLT inhibitors from inside the cell cannot be excluded.”4
Some side effects of gliflozins are hypoglycemia and ketoacidosis.
We always read about insulin and how it regulates our blood glucose levels but, how many times have you heard incretins come into the picture? Ever wonder how our pancreas knows when to secrete insulin? The communicating hormones responsible for this are produced in certain parts of our digestive system and are called incretins. One of them is GLP-1 (formerly Glucagon-like Peptide 1) and the other is GIP (Gastric Inhibitory Peptide). Both these hormones serve a special function, that is, they “instruct” the pancreas to begin releasing insulin. Conveniently, this occurs after we eat.
“Incretin-based therapies augment glucose-dependent insulin secretion and confer a low risk of hypoglycemia. These agents include injectable glucagon-like peptide 1 receptor agonists (GLP1RA) and dipeptidyl peptidase 4 (DPP4) inhibitors. Glucagon-like peptide 1 is a hormone secreted by the distal small intestine in response to food ingestion. It augments glucose-dependent insulin secretion, decreases islet glucagon secretion, slows gastric emptying, and increases satiety. Glucagon-like peptide 1 is rapidly degraded by the enzyme DPP4. Dipeptidyl peptidase 4 inhibitors maintain endogenous GLP1 concentrations, modestly lower blood glucose, are weight neutral, and do not cause hypoglycemia.
Injectable GLP1RA increases GLP1 to pharmacological levels, robustly lowers blood glucose level, and facilitates weight loss without risk for hypoglycemia (except when used with insulin or sulfonylureas). Glucagon-like peptide 1 can be associated with transient nausea and vomiting (lasting 1–3 months). It is essential to communicate with the patient about the risk of nausea prior to titration with GLP1RA agents and, if needed, treat the gastrointestinal adverse effects to improve adherence. Recently published trials on cardiovascular outcomes demonstrate a cardiovascular benefit of 2 agents in this class: liraglutide and semaglutide.”5
Synthetic GLP-1 drugs have been developed to mimic the function of natural incretins to maximize the amount of insulin released into the bloodstream.
Currently, GLP-1 imitating drugs are only available by injecting subcutaneously.
Betatrophin is a type of peptide that has been under scrutiny over the last few years. According to research, betatrophin are major players in the enhancement of insulin creation because they encourage the enhanced mitotic division of the beta cells responsible for producing insulin. The thinking here is, if we stimulate beta cells to reproduce more, the greater the amount of insulin the pancreas can secrete.
It was discovered some time ago that mice actually carry a gene that produces betatrophin as well. Scientists recently studied the effects of this drug on the metabolism of glucose in mice and it was found to significantly reduce blood glucose levels. However, as we have seen, glucose regulation is a balancing act and betatrophin has also been known to induce hypoglycemia. If trials in human beings prove successful, it would be a major breakthrough in the current advancement of diabetic treatment.
“Betatrophin, also known as TD26/RIFL/lipasin/ANGPTL8/C19orf80, is a novel protein predominantly expressed in human liver. To date, several betatrophin orthologs have been identified in mammals. Increasing evidence has revealed an association between betatrophin expression and serum lipid profiles, particularly in patients with obesity or diabetes. Stimulators of betatrophin, such as insulin, thyroid hormone, irisin, and caloric intake, are usually relevant to energy expenditure or thermogenesis. In murine models, serum triglyceride levels, as well as pancreatic cell proliferation, are potently enhanced by betatrophin. Intriguingly, conflicting phenomena have also been reported that betatrophin suppresses hepatic triglyceride levels, suggesting that betatrophin function is mediated by complex regulatory processes. However, its precise physiological role remains unclear at present.”6
“Besides the pivotal role of betatrophin in beta-cell proliferation, previous studies have shown its correlation with altered lipid metabolism. In accordance with these reports, a lower serum triacylglycerol (TG) level was observed in betatrophin-null mice in response to refeeding, and a significant relationship was found between betatrophin levels and an atherogenic lipid profile. Indeed, betatrophin affects the lipid profile through the regulation of very-low-density lipoprotein (VLDI) secretion from the liver and the inhibition of lipoprotein lipase activity. In addition to the direct role of betatrophin in lipid metabolism, it may also act along with other angiopoietin-like protein (ANGPTL) family members such as ANGPTL33, which regulates cholesterol metabolism in mice and humans.”7
“Serving as a lipase activity regulator, betatrophin could induce postprandial triglyceride utility and storage in adiposity. The name betatrophin was used since it was suggested by Yi and colleagues as a mediator of β-cell proliferation and a potential therapeutic target of diabetes. However, several consequent studies indicated that betatrophin expression could be induced by high-fat diet and insulin, resulting in increased serum triglyceride and insulin resistance instead of improved glucose metabolism. Knockout of betatrophin also failed to alter glucose profiles and β-cell mass in mice. However, current population-based studies indicated that betatrophin could be a biomarker candidate for diabetes and related disorders.”8
(1, 5) Management of Type 2 Diabetes in 2017. Reusch, J.B. & and Manson, J.E. JAMA. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894353/
(2, 7) Circulating Betatrophin Levels Are Associated with the Lipid Profile in Type 2 Diabetes. Ghasemi, H., Tavilani, H., Khodadadi, I., Saidijam, M. & Karimi, J. Chonnan Medical Journal. 2015. https://synapse.koreamed.org/DOIx.php?id=10.4068/cmj.2015.51.3.115
(3, 4) Pharmacological aspects of the safety of gliflozins. Faillie, J.L. Pharmacological Research. 2016. https://www.researchgate.net/publication/304815132_Pharmacological_aspects_of_the_safety_of_gliflozins
(6) Emerging Regulation and Function of Betatrophin. Tseng, Y.H., Yeh, Y.H., Chen, W.J. & Lin, K.H. International Journal of Molecular Science. 2014. https://www.mdpi.com/1422-0067/15/12/23640/htm