Single-Molecule Combinatorial Therapeutics for Treating Obesity and Diabetes

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Single-Molecule Combinatorial Therapeutics for Treating Obesity and Diabetes

It will soon be 100 years since Frederick G. Banting, Charles Best, James Collip, and John J.R. Macleod in 1921 demonstrated that extracts of the pancreas had breathtaking beneficial effects to restore the health of patients with diabetes. While their breakthrough revolutionized the medical management of diabetes, the disease continues today to spread worldwide along with a global increase in obesity. Novel unimolecular gut hormone polyagonists have shown a unique potential to reverse obesity and diabetes in animal models and are currently being assessed in multiple clinical trials for their efficacy and safety.

INSULIN IS NOT THE CURE

Insulin replacement therapy currently remains a central pillar of diabetes management while additional anti-diabetes medicines enhance production, secretion, and action of insulin to improve disease management and enhance patient care. Enormous progress has been made in the precise and continuous quantification of blood glucose, which, together with next-generation insulin pumps, has enabled closed-loop delivery systems, a sizable step forward in the direction of automatized insulin therapy. The cure still remains elusive, and the prevalence of the disease continues to rise across the globe, frighteningly so at an accelerated pace in some of the most populous countries. How can it be that a century after the discovery of insulin, the occurrence of disease is increasing with no cure to stem the epidemic insight?

The vast majority of diabetes worldwide is constituted of what was traditionally characterized as adult-onset, type 2 diabetes (T2D). This form of diabetes is clearly driven by another pandemic—that of obesity—and to an increasing extent is no longer an adult-onset disease. While the specific molecular mechanisms by which obesity is promoting the diabetes epidemic remain unclear, there is no controversy that in the absence of obesity, the magnitude of the diabetes problem would be far less significant and more manageable. However, despite decades of intense, targeted research, we have failed to deliver safe and efficacious antiobesity therapeutics that reverse morbid obesity or even lesser forms of the disease to normal body weight. There is no advanced medicinal development candidate with curative potential, not even one with the promise to manage obesity comparably to the treatment of diabetes with insulin.

A RAPIDLY CLOSING WINDOW?

Has the fight against obesity been lost and with it our chances to reverse the T2D pandemic? Considerable worldwide public health efforts promoting healthier lifestyles via education and public policies have not stemmed from the increase in diabetes prevalence. While this certainly should not lessen our resolve to identify alternatives to pharmaceutical intervention, it does underscore the increased importance and urgency to identify therapeutics with curative potential. At this point, it appears possible that such a discovery remains the only way to save the coming generations from an unimaginable health crisis. The urgency of the situation is magnified by recent insights in epigenetics research. A growing body of data supports a model where daily environmental and behavioral factors can significantly alter stable heritable traits to change protein expression, which cannot be explained by changes in the DNA sequence. Changes in histone code or DNA methylation patterns are frequently considered to be the basis of such epigenetic modifications (5). Such molecular alterations may promote diabetes susceptibility in subsequent generations, rendering them less likely to respond to novel prevention medicines with otherwise curative potential discovered using current models of the disease. Therefore, there is unprecedented urgency in the scientific community to sufficiently address the pandemic until more creative public policy and effective education might deliver a significant epidemiological impact.

INDIRECT BRAIN TARGETING WITH MULTIPLE SIGNALS

Almost a quarter of a century ago, significant hope and enthusiasm were triggered by Friedman’s discovery of the adipocyte-derived hormone leptin (6). It suggested the existence of a hormone with sufficient pharmacological effect to manage severe body weight disorders in a fashion analogous to insulin treatment of severe diabetes. Unfortunately, only a very small number of obese patients directly benefit from leptin therapy; the majority of the obese population did not improve in response to treatment. Still, this unique hormone, which physiologically regulates appetite and energy metabolism, taught us several important points. Most importantly, the seminal role of the central nervous system as the key organ in the regulation of food intake, body weight, energy balance, and system-wide cellular metabolism was embellished. Similar insights were gained from the identification of the gastric-derived peptide ghrelin as an endogenous hunger hormone, which along with leptin serves to control body weight. Today, when accounting for the entirety of data available through genome-wide association studies, it appears quite clear that obesity as the epidemiological driver of the T2D pandemic is predominantly a brain disease. Most of the single nucleotide polymorphisms identified through obesity genetics studies and confirmed in ever-larger human populations pertain to proteins expressed or exerting their most important functions in the brain (7). Therefore, it seems inevitable that the discovery of obesity therapeutics would need to target brain pathways. Recent research advances provide a reason for optimism. While currently approved medicines offer insufficient efficacy to reverse the global epidemic, surgical interventions such as Roux-en-Y gastric bypass or sleeve gastrectomy can successfully reverse most human forms of obesity and diabetes. Of particular interest to metabolism, researchers are that improved glucose homeostasis occurs rapidly, even preceding significant weight loss. This observation suggests that molecular signals emanating from bariatric surgery may directly improve systemic glucose metabolism, independent from weight loss. The essential molecular mechanisms mediating appetite and metabolism improvements following such surgery remain largely unknown but continue to be intensely studied (8). The consensus opinion suggests that several pathways are involved and that central nervous system circuits governing appetite and systemic metabolism are indirectly modulated via gut-derived neuroendocrine signals. Although there are a growing number of proponents calling for broader use of bariatric surgeries to treat both morbid obesity and diabetes (9), these surgical interventions are highly invasive, irreversible, and not risk-free. Possible long-term complications range from a bowel obstruction and dumping syndrome to diarrhea, gallstones, and hypoglycemia. In addition, surgery is not appropriate for all patients with obesity or diabetes, and even if it were, there is insufficient infrastructure (surgeons, surgical space, and financial resources) to address an epidemic of global disease.

Author: Matthias Tschöp and Richard DiMarchi

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