Type 2 Diabetes: Progress Made but Still a Long Road to Travel to Reduce Disease Burden.

Abstract

The basic concept of diabetes mellitus (DM) has undergone dramatic transformations by the application of systematic clinical research since the condition was first described thousands of years ago. The first transformation was from the social meaning of the diagnostic feature of the disease diabetes—the Greek term meaning “to pass through” and considered a disease of the kidneys because of frequent urination that characterized the disease1, 2 to its current understanding as an endocrine disease.2 The second transformation was from the recognition that the feature of the disease has changed from one of predominant insulin deficiency, to one of predominant obesity with a combination of insulin resistance and impaired insulin secretion.3 An ongoing transformation in the disease, observed with the growing incidence of obesity in children, includes an increase in the diagnosis of type 2 diabetes in people <20 years of age. Diabetes mellitus comprises two major forms. Type 1 DM is an autoimmune disease in which the body destroys its pancreatic β cells, resulting in a lack of insulin production, whereas type 2 DM is primarily related to insulin resistance. The term “diabetes” was first coined by Apollonius of Memphis around 230 BC, although the characteristics of the disease had been described in Ebers Papyrus written approximately 1500 BC. The first complete clinical description of diabetes was attributed by many to Aulus Cornelius Celsus (30 BC −50 AD). In 1679, Thomas Willis used the sweet taste of diabetic urine to distinguish between DM and diabetes insipidus, and a century later, in 1776, Mathew Dobson showed that the sweetness of the urine from diabetics was because of the sugar content. He also showed that the presence of sugar in the urine was preceded and accompanied by increased sugar in the blood, the concept of hyperglycemia leading to glycosuria, which later became the hallmark for the detection of DM and also confirmed it as a systemic disease.1, 2 Extensive experimental studies by Claude Bernard demonstrated that degeneration of the pancreas led to the development of DM and that the liver also stored glycogen, which could be released into the circulation. Insulin was finally discovered by Frederick Banting and Charles Best in 1921 as the active extract from the pancreatic islet cells of healthy dogs.1 The early assimilation of insulin into clinical practice represented a significant milestone for the rapid translation of discovery in basic science, to clinical therapeutics and benefit for patients. Drug treatment of DM has mirrored the understanding of the pathophysiology of the disease and its clinical transformation. From the experimental use of pancreatic extracts to the discovery of insulin and its first use in humans,4 earlier treatments aimed to replace insulin, or to meet its biological functions in tissues and organs. For type 1 DM, optimized insulin replacement is the desirable treatment. For type 2 DM, approaches adopted in clinical practice include insulin replacement, drugs that stimulate the pancreas to release insulin, sensitization of tissues to the action of insulin, inhibition of glucose production or the breakdown of glycogen, and increased peripheral utilization of glucose. These drugs have been reviewed extensively in this issue.5 Obesity has been recognized as an important risk factor for type 2 DM.6, 7 Lifestyle changes that reduce body weight are extremely beneficial, providing multiple health benefits and should remain an essential aspect of the treatment of type 2 DM. Despite the availability of a large number of classes of medications, a considerable proportion of patients with type 2 DM do not achieve guideline-based recommendations for HbA1c. Only metformin has been shown to have clinical outcome benefits among drugs currently in use, although the benefit on cardiovascular outcomes was only evident in the 10-year post-trial follow-up of United Kingdom Prospective Diabetes Study. Food elicits the release of two main incretin hormones: glucagon-like peptide-1 and gastric inhibitory polypeptide (glucose-dependent insulinotropic polypeptide that are degraded by the enzyme, dipeptidyl peptidase 4. Consequently, selective dipeptidyl peptidase 4 inhibitors or glucagon-like peptide-1 agonists enhance pancreatic insulin secretion and suppress pancreatic glucagon secretion, resulting in a reduction in blood sugar levels. The long-term cardiovascular effects of these classes of drugs are currently under investigation. Of the different classes of drugs currently used for the treatment of DM, one that is intriguing physiologically is the sodium glucose transporter (SGLT)-2 inhibitor. Their mechanism of action complements the seminal research of Dobson who showed that glycosuria is preceded by hyperglycemia. The majority (∼90%) of glucose filtered in the proximal renal tubules is reabsorbed via SGLT-2 with the remaining reabsorbed via SGLT-1. These transporters are not impacted by any hormones, including insulin. Glycosuria results when the plasma glucose concentration exceeds the renal threshold for glucose (TmG about 200 mg/dL) and was used as a hallmark for the diagnosis and progression of DM, as well as for monitoring response to therapy before the introduction of self-monitored blood glucose monitoring and HbA1c testing. Consequently, except in intrinsic diseases of the kidneys, for example, Fanconi syndrome, or in circumstances in which the renal glucose threshold is impaired, such as in individuals with familial renal glycosuria because of mutations in the SGLT-2 gene, glycosuria has usually been viewed as evidence of DM. Historically, the severity of glycosuria was considered to be a measure of the severity of DM, and the progressive reduction in glycosuria as evidence of improvement or drug response. Similarly, the renal threshold for glucose was used to predict glycosuria in experimental settings and to distinguish pre-diabetics from healthy subjects. Thanks to translational science, currently, drugs that induce glycosuria as their main mechanism of action are now used to treat DM, a disease that causes glycosuria. What a paradox! The SGLT-2 inhibitors in clinical use have the advantage of lowering not only HbA1c, but also reducing body weight and blood pressure. Because the SGLT-2 inhibitors work independently of pancreatic β cells, they offer the potential of providing durable glycemic control. However, because this class of medications has only been recently approved, the long-term benefit/risk awaits results of further study to provide data on the long-term safety of the class. Recently, the US Food and Drug Administration issued a drug safety communication about reports of ketoacidosis in patients receiving SGLT-2 inhibitors. Factors identified in some reports as having potentially triggered ketoacidosis included major illnesses, reduced food and fluid intake, and reduced insulin dose. Inflammatory response is regarded as a legacy of prolonged hyperglycemia and DM elicits increases in systemic inflammatory biomarkers, such as interleukin-6 and C-reactive protein, which predicts adverse cardiovascular events. In their commentary, Jialal and Devaraj8 reviewed evolving evidence in this field and conclude that ameliorating inflammation is a novel therapeutic strategy that may provide the potential for reducing cardiovascular adverse events. Whether there is a future for combined anti-inflammatory and antidiabetic drugs is still to be determined. Pioglitazone reduces HbA1c and C-reactive protein and also decreased major adverse cardiovascular events in the PROACTIVE trial. Although importantly, the effect on cardiovascular events was on a hypothesis-generating, secondary endpoint and is by no means definitive. In his review of the current drug treatment landscape for DM and prospects for the future, Bailey5 provides a most comprehensive review of current drugs used for the treatment of DM worldwide. He discusses the mechanisms underlying both the therapeutic and adverse effects of these drugs and offers insights about future developments based on an array of ongoing assessments of investigational programs. The predominant cause of death in diabetics is a cardiovascular complication.9-13 Cardiovascular complications may result from the microvascular and macrovascular toxicogenic effects of hyperglycemia. However, some antidiabetic drugs also have adverse cardiovascular effects, a fact that underlies the need for these drugs to be assessed in cardiovascular outcomes trials during development. Alvarez et al.14 reviewed the entire field of the management of DM. Antidiabetic drugs may have direct adverse effects on the cardiovascular system, or indirect effects through their metabolic actions, especially by modulating changes in serum lipids. Antidiabetic drugs may also exert an effect on advanced glycation end products, modified proteins, or lipids that have been nonenzymatically glycated and oxidized after contact with aldose sugars. Interestingly, HbA1c, the commonly accepted surrogate endpoint for diabetes, is a glycation product. Advanced glycation end products form in vivo in hyperglycemic environments and during aging, and contribute to the pathophysiology of vascular disease in DM.15 In their article, Litwinoff et al.16 describe targeting the receptor for advanced glycation end products as a therapeutic option for treating or preventing adverse cardiovascular outcomes in DM. Whether this pathway will prove to be critical for drugs that improve cardiovascular outcomes and other consequences of microvascular damage, such as the retina and the kidneys, remain to be determined. Can DM be prevented? This is certainly an important question, especially for a chronic disease that affects such a large portion of the world's population with tremendous consequences on health economics and patient morbidity and mortality. Although the goals in the treatment of DM are long-term control of glycemia and ultimately a cure, prevention would be the ideal focus of Public Health. Srinivasan and Florez17 discuss the therapeutic challenges in preventing DM. Although some drugs and bariatric surgery show promise, the authors conclude “We have not found the exercise pill” that prevents this disease. DM is certainly a challenging disease to treat. Although there is no known cure, it is gratifying to note that the epidemic of type 2 DM can be prevented primarily by lifestyle changes that reduce obesity. It is intriguing that statins, which have proven benefits in reducing cardiovascular events, increase the incidence of DM somewhat, although the benefit from the prevention of adverse cardiovascular outcomes confers a positive benefit-risk ratio.18 Similarly, thiazide diuretics and β-blockers, two other classes of medications that have been shown to reduce cardiovascular events, can also worsen glycemia. This apparent contradiction highlights that, for the future, therapies that reduce cardiovascular burden of type 2 DM will likely need to produce broad salutary pharmacological effects, above and beyond simply lowering glucose. Several treatment algorithms that ensure adequate and stable control of hyperglycemia are currently available, but whether these also prevent long-term cardiovascular complications, which are the usual cause of death, have not been clearly determined. With the advances in drug treatment and patient care, DM has ceased to be regarded as a death sentence. Whether it will convert to a life sentence for patients will depend on the ongoing and future progress in the prevention of adverse cardiovascular outcomes that accompany long-term hyperglycemia.