Treating Diabetes: Does it Start in the Gut?

Treating Diabetes: Does it Start in the Gut?

Type II Diabetes (T2DM) can be described as a disorder of metabolism and the endocrine system. Put simply, our the signals sent by chemical messengers (hormones) are not functioning properly. This results in poor glucose control, lipid control, appetite control, and body fat regulation.  For the past 30 years insulin therapy and Glucophage (Metformin) has been the gold standard in the treatment of diabetes. Recent medical advances have led to a new wave of pharmacological agents that are being utilized to improve glucose control. These drugs affect the endocrine system and use gut hormones as their vehicle to manipulate insulin production and mediate glucagon levels.  This post will discuss the concepts of two newest classes of drug therapies, their mechanisms of action, efficacy, and safety.

The Incretin Hormones

Incretin hormones are gastrointestinal hormones that interact with the pancreas and other organ tissues in response to nutrient intake. These hormones are secreted predominately by the K-cells and L-cells in the gut.  The two major incretin hormones are glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). This article will focus specifically on GLP-1 as it is the target of the current, most novel pharmacological treatments for diabetes treatment, specifically T2DM.

GLP-1 and GLP-1 Agonists

GLP-1 is secreted by the L-cells in the intestine in response to nutrient ingestion (1) and acts to reduce blood glucose levels. GLP-1 reduces blood glucose via two distinct mechanisms: 1) by stimulating insulin, and 2) by reducing glucagon secretion.  Additionally, GLP-1 effects the hypothalamus and promotes satiety in humans (2). The ability to GLP-1 to reduce blood glucose concentrations and control appetite and energy expenditure has captured the attention of diabetes researchers in the past several decades.  Perhaps the most intriguing aspect of GLP-1 agonists is there ability to cause beta-cell differentiation and neogenesis, suggesting GLP-1 agonists may be beneficial in restoring beta-cell function in “recovering” individuals with T2DM (3). The investigation in GLP-1 has led to the development of pharmacological agents that serve as GLP-1 receptor agonists, mimicking the effect of GLP-1 and at supraphysiological levels.

GLP-1 receptor agonists such exanatide and liraglutide are designed as pharmacological derivatives of GLP-1. They are administered to create supraphysiological levels of GLP-1 signaling and enhance glucose-dependent insulin secretion while reduces hepatic glucose output (HGO) by suppressing the release of glucagon. Individuals with T2DM typically have peripheral insulin resistance, which requires elevated levels of insulin to reduce blood glucose levels. Increased insulin levels along with elevated glucose is the key feature in T2DM. Less well known is they also have increased HGO, most likely due to a discordance between normal glucagon secretion and pathological insulin secretion. In fact, D’Alession recently published an article titled “The role of dysregulated glucagon secretion in type 2 diabetes”. In his paper he states, Excessive production of glucose by the liver contributes to fasting and postprandial hyperglycaemia, hallmarks of type 2 diabetes. A central feature of this pathologic response is insufficient hepatic insulin action, due to a combination of insulin resistance and impaired β-cell function. However, a case can be made that glucagon also plays a role in dysregulated hepatic glucose production and abnormal glucose homeostasis. Plasma glucagon concentrations are inappropriately elevated in diabetic individuals, and α-cell suppression by hyperglycaemia is blunted” (4). While most of the focus for GLP-1 receptor agonists has been on the effect these drugs have on beta-cells and insulin secretion, their role on suppressing HGO may be more important in combating T2DM.

Supraphysiological doses of GLP-1 receptor agonists may have long-term consequences, however, no specific data is present on this issue. Despite the lack of evidence, we can hypothesize in regards to GLP-1 resistance.  There is substantial evidence that resistance develops to other hormones in the hypothalamus including leptin and insulin (5, 6) There is evidence that hyperglycemia and increased GLP-1 results in GLP-1 resistance in endothelial cells, it suggests GLP-1 resistance is possible in the hypothalamus, which may result in further dysregulation of appetite control with prolonged treatment of T2DM with GLP-1 receptor agonists.  Also, interfering with glucagon may also have long-term consequences.  For example, ingestion of dietary protein, specifically amino acids, elicits glucagon secretion to counteract the effect of protein induced insulin secretion. Therefore, suppression glucagon secretion may have consquences. D’Alessio closed his abstract “The α-cell and glucagon receptor remain tempting targets for novel diabetes treatments, but it is important to understand the magnitude of benefit new strategies would provide as preclinical models suggest that chronic interference with glucagon action could entail adverse effects as well.”

The efficacy of these drugs to treat T2DM has been extensively studied.  A randomized, double-blind, placebo-controlled trial (RPCT) demonstrated that a GLP-1 receptor agonist (lixisenatide) improved HbA1c to a greater extent than placebo, improvements in postprandial glucose levels. However, instances of nausea were 600% greater in the lixisenatide group, a point we will address momentarily (7). Another RPCT utilizing a CLP-1 receptor agonist (albiglutide) demonstrated similar findings in reduced HbA1c and increased reports of nausea, however the nausea decreased overtime (8). Together, these results suggest GLP-1 receptor agonists do indeed improve glycemic control. However, the increased reports of nausea and its dissipation over time suggests there is strong appetite control signaling occurring at the hypothalamus and that this signal is attenuated over time. While this may seem like a small side effect, it is possible that the cause of obesity and T2DM is related to dysregulated appetite control, as posited by Stephan Guyenet and others, and as such, GLP-1 receptor agonists may treat the symptoms, but worsen the underlying cause.  Finally, while there is some retrospective evidence on the ability of GLP-1 receptor agonists to reduce heart disease, prospective, animal model data does not support the hypothesis that GLP-1 receptor agonists reduce CHD in T2DM (9)  In conclusion, GLP-1 receptor agonists do provide benefits in terms of glycemic control and may result in weight loss (as a function of appetite suppression), yet the full extent of their positive and neative effects are unknown.

Figure. GLP-1 and its effects on insulin, glucagon, and appetite control. Image C/O Verspohl, E.J. (2009). Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacology & Therapeutics 124, 113–138.

Figure. GLP-1 and its effects on insulin, glucagon, and appetite control. Image C/O Verspohl, E.J. (2009). Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacology & Therapeutics 124, 113–138.

DPP-4 Inhibitors

            Dipeptidyl peptidase-4 (DPP-4) is an enzyme that plays a major role in metabolism, signal transduction, and has an immunoregulatory role. DPP-4 is responsible for degradation of GLP-1, and therefore plays an indirect role in HGO, insulin secretion, and satiety. DPP-4 inhibitors work to block the DPP-4 depended degradation of GLP-1, thereby maintaining elevated levels of DPP-4 and increasing insulin secretion, decreasing glucagon, and promoting prolonged satiety.  It is for this reason that DPP-4 inhibitors are now being used to treat T2DM.

In contrast to GLP-1 agonists, which simulate supraphysiologic levels of GLP-1 through pharmacologic ligands that stimulate GLP-1 receptors, DPP-4 inhibitors simply slow the degradation process of naturally occurring GLP-1 (Figure 2).  DPP-4 inhibitors are indeed efficacious in increasing GLP-1, decreasing glucagon, improving glucose control in patients with T2DM (10). On the surface, this appears to be a more “natural” approach to using incretin hormone therapy to treat T2DM. Unfortunately, further examination of DPP-4 inhibitors reveals some potentially serious side effects.

In concert with its role in glucose metabolism, DPP-4 is involved in tumor suppression (11, 12). Recent in vitro studies have shown that DPP-4 inhibitors, along with other incretin hormones (GLP-2) increased proliferation, the risk of promoting an already existing intestinal tumor and potential of colon cancer cells to metastasize (13).

Diet and Exercise Instead of GLP-1 Agonists and DPP-4 Inhibitors.

 

GLP-1 agonists and DPP-4 inhibitors do indeed increase GLP-1, lower glucagon mediated HGO, and improve glucose control. Unfortunately, they have potentially serious side effects including central GLP-1 resistance and increased risks of cancer.

There is evidence to suggest that exercise can convey the same benefits of GLP-1 agonists without the side-effects of pharmacologically induced supraphysiological levels. Specifically, exercise results in increased GLP-1 levels in response to a meal in overweight and normal individuals (14). Additionally, the overweight participants showed greater restraint in eating post- exercise. While the study did not provide mechanistic evidence, the data suggests regardless of all the other benefits of exercise on metabolic function (far too many to discuss here), exercise also can positively impact the incretin hormones such that they may improve beta cell function and decrease glucagon induced HGO.

There is also evidence that dietary modification can modulate the activity of incretin hormones. Specifically, a high fat (MUFA or SFA) has been shown to reduces post-prandial area under the curve of glucose and insulin as well as increasing GLP-1 concentrations when compared to an iso-caloric high carbohydrate diet (15).

Conclusion

T2DM is a metabolic disorder resulting from a dysregulated endocrine system. Given that obesity is a major predictor in developing T2DM, is entirely probable that the gut hormones that influence satiety, appetite control, insulin secretion, and HGO, are major players in the pathogenesis of the disease.  Current medical treatments have recognized the need to address these gut hormones (the incretins). The change in focus is commendable; however, while the data surrounding current pharmacological treatments aimed at modulating the incretins suggests they improve glucose control, the full effects of these drugs may have far-reaching consequences. Furthermore, they treat the symptoms and not the cause (lifestyle). From the current state of the evidence, it appears following a healthy, evolutionary-based diet and engaging in physical activity is the best way to treat the symptoms and “cure” the disease.

Appendix 

Untitled

List of Current Pharmacological Treatments for Diabetes

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