The long history of diabetes diagnosis and treatment is a fascinating study. (See Diabetes Timeline, beginning on p.36.)

For decades, the incidence of Type 2 diabetes steadily increased, but a recently published study evaluating the incidence of Type 2 in adults between 1980 to 2017 shows some degree of reversal in this trend.¹

A similar study evaluating the incidence of Type 1 diabetes is not as encouraging. Mobasseri et al. evaluated the global prevalence and incidence of Type 1 diabetes from Jan. 1980 to Sept. 2019.² They found that the incidence and prevalence of Type 1 are increasing globally, and the researchers postulated that one potential impact would be less accessibility to and an increase in the cost of insulin.²

Regardless, the American Diabetes Association reported in 2018 that 34.2 million Americans, or 10.5% of the population, had diabetes.³ Of that total, approximately 1.6 million were Type 1. Roughly 14.3 million American seniors (26.8%) have some form of diabetes.³ As such, it’s imperative that optometrists, as a primary point of health care, are able to zoom out and look at the patient’s overall health by being aware of the causes and therapies for the disease, as well as the specific eye-related ramifications of diabetes.

 

 

Read more from diabetes edition of Practicing Medical Optometry:

• Diabetes: The Other Pandemic
• Diagnose Diabetic Eye Disease
• Treat Diabetic Eye Disease
• Dive Into Diabetic Eye Care

DIFFERENTIATING TYPE 1 AND TYPE 2

Because the underlying pathologies of Type 1 and Type 2 are very different, research efforts directed at these two conditions are often dissimilar. To better appreciate therapeutic modalities, it would be worthwhile to briefly review the underlying pathophysiology of each.

Type 1 results from autoimmune infiltration and progressive destruction of pancreatic beta cells in the islets of Langerhans.⁴ This process occurs only in genetically susceptible individuals. Beta-cell destruction may be asymptomatic for months to years as insulitis (inflammation of the beta cell).⁴ When 80% to 90% of beta cells have been destroyed, hyperglycemia develops.

Type 2 is characterized by insulin resistance, relative deficiency in insulin secretion and hyperglycemia.⁵ The pathogenesis may result from a combination of factors, including one or more of the following: insulin resistance, relative insulin deficiency and impaired pancreatic beta-cell function.⁴ Environmental factors, such as obesity and inactivity, are among the common causes for Type 2 diabetes, as well as genetic links. It’s worth noting that these environmental factors are also often influenced by genetics.

Type 2 diabetics, with well-controlled disease, may live long, healthy lives, but poorly controlled Type 2 diabetics may develop life-changing complications, such as loss of limbs, renal disease and/or failure, damage to the heart and vessels as well as vision loss or blindness. Up to 75% of Type 2 diabetics eventually die from some form of cardiovascular disease.⁶

Fortunately, researchers and pharmaceutical companies are developing and testing new medications directed at managing and treating the causes of diabetes.

EMERGING THERAPEUTIC OPTIONS

Several new classes of pharmaceutical agents show promise in the management of both Type 1 and Type 2 diabetes. Enteroendocrine cells in the pancreas and intestinal tract produce incretins, which are hormones that significantly impact glucose levels throughout the body.⁷ Incretins hold great promise in the management of Type 2 diabetes. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two particularly important incretins.⁷ They impact glucose levels by regulating insulin secretion from the beta cells in the pancreas. This process occurs in response to blood glucose levels. They also influence glucose levels by inhibiting glucagon secretion from alpha cells.

One issue with incretins is their very short half-life. Within two minutes after natural GLP-1 is secreted, it is degraded by an enzyme, dipeptidyl peptidase-4 (DPP-4).⁷ By adding DPP-4 inhibitors, which suppress the DPP-4 enzyme, the half-life of GLP-1 can be significantly increased.⁷

DIABETES TIMELINE

1500 B.C.

The earliest description of diabetes was recorded by an Egyptian physician, Hesy-Ra, who described a condition characterized by frequent urination and progressive wasting away.¹ As late as the 1100’s, “water tasters” literally sampled the urine of suspected diabetics to determine it was sweet, hence the term diabetes mellitus (meaning honey).²

1806-1886

Apollinaire Bouchardat, widely recognized as the father of modern diabetology, practiced in Paris where he explored the relationship between glycosuria and diabetes.³ He also proposed treating diabetes by altering the patient’s diet, and he explored the role of the pancreas in diabetes.

1869

German medical student Paul Langerhans, a contemporary of Bouchardt, determined two types of cells in the pancreas, acinar cells and small, polygonal cells in the pancreas that had a round nucleus but no nucleolus.⁴ Ultimately, the latter were determined to be the source of insulin and are still known as Langerhans cells, the source of insulin.

1921

Canadian researchers Frederick Banting, M.D., and Charles Best, M.D., instituted a series of experiments that ultimately led to the discovery of insulin. Later that year, they were joined by James Collip, who developed a successful method to extract highly purified insulin that could be used in humans.⁵

1936

Hans Hagedorn and colleagues discovered adding protamine to insulin can prolong its effects in the body. ⁵

1955

First oral medications, sulfonylureas, which stimulate the pancreas to release insulin, became available. ⁵

1966

First pancreas transplant, an effective cure for diabetes, was performed at the University of Minnesota Hospital. ⁵

1976

First wearable infusion pumps, which could administer insulin, were invented. Additionally, laser therapy was introduced for the treatment of diabetic retinopathy. ⁵

1979

National Diabetes Data Group developed classifications for the various forms of diabetes, including Type 1 and Type 2, in addition to Type 3, gestational diabetes, and Type 4, diabetes associated with other medical issues. ⁵

1985

Scientists discover diabetic retinopathy worsens during pregnancy.⁵

1993

Diabetes Control and Complications Trial shows a tight monitoring of blood glucose levels to as close to normal as possible slows the onset and progression of eye, kidney and nerve complications.⁵

2012

Anti-VEGF therapy approved for the treatment of diabetic macular edema.⁵

2015

Anti-VEGF therapy approved for the treatment of diabetic retinopathy in patients who have diabetic macular edema.⁵

TIMELINE SOURCES

1. History of Diabetes. Healthline website. https://www.healthline.com/health/history-type-1-diabetes#1 . Last reviewed Oct. 25, 2017. Accessed Oct. 16, 2020.
2. Green M. A Tale for the Ages: How the Mystery of Diabetes Was Unraveled. Empower 2014, 6(2):14-17.
3. Karamanou M, Koutsilieris M, Laios K, et al. Apollinaire Bouchardat (1806-1886): founder of modern Diabetology. Hormones 2014, 13(2):296-300
4. Ceranowicz P, Cieszkowski J, Zygmunt Warzecha Z, et al. The Beginnings of Pancreatology as a Field of Experimental and Clinical Medicine. Biomed Res Int. 2015;2015:128095. doi: 10.1155/2015/128095. Epub 2015 Jun 9.
5. Timeline. American Diabetes Association website. https://www.diabetes.org/resources/timeline . Accessed Oct. 16, 2020.

Another promising technology for blood glucose management is directed at altering renal physiology.⁸ A group of molecules, known as sodium-glucose cotransporters (SGLT), are found primarily in the proximal convoluted tubules; they mediate glucose reabsorption in the heart, kidneys and gut.⁸ By inhibiting glucose reabsorption, SGLT effectively promotes glucose excretion in the urine and efficiently lowers blood glucose levels.

SGLT has additional benefits to reducing blood glucose levels. SGLT protects the heart and kidney, potentially reducing the risk for cardiovascular events.⁹ This has the potential to delay the onset and progression of renal failure, improve patient quality of life and potentially reduce medical expenses associated with diabetes-related complications.

TREATING THE EYES

Diabetic retinopathy (DR) is an unfortunate but common complication of diabetes, impacting about one-third of the estimated 285 million diabetics worldwide.¹⁰ It is the principal cause of vision loss in individuals 20 to 74 years of age.¹⁰ In one-third of individuals who have DR, (including those who have diabetic macular edema [DME]), their condition is vision-threatening.¹⁰

In regard to DR emerging treatments: Calcium dobesilate is a veno-toxic compound that has been successfully used to treat conditions as diverse as dry eye disease and nonproliferative DR (NPDR).¹¹ A current, ongoing study evaluates the efficacy of dobesilate in the management of mild to moderate DR.¹² The study is being conducted to determine whether calcium dobesilate can prevent DR from advancing in a population of Chinese patients who have mild to moderate NPDR. This compound has been successfully used to treat a variety of conditions, including chronic venous disease and hemorrhoid.¹³

DME is a common finding in patients who have diabetes and other systemic conditions and is a common cause of visual impairment in several metabolic, vascular and inflammatory retinal diseases.¹⁴ DME affects patients and often causes reduced vision with DR, retinal vein occlusion and, in 40% of patients affected, uveitis.¹⁴

Emerging DME therapies include a new generation of anti-VEGF that is undergoing clinical trials. Brolucizumab (Novartis) is a single-chain fragment that binds to VEGF-A and interferes with activation of VEGF receptor 1 and 2 on endothelial cells.¹⁴ Initial studies, directed toward neovascularization associated with wet AMD, show the molecule to be beneficial, but the final results are still years away.

VEGF-A and angiopoietin-2 (Ang-2) are key factors in the pathogenesis of DME. Ang-2 compromises vessel stabilization and promotes neovascularization.¹⁴ Several drugs targeting Ang-2 are in development, such as RO6867461, a bispecific IgG1 antibody that selectively neutralizes VEGF-A and Ang-2.¹⁴

Additionally, there is gene therapy. In May, Adverum Biotechnologies announced a Phase 2, multi-center, randomized, double-masked trial directed at DME. Subjects are to undergo a single intravitreal injection of ADVM-022, a proprietary gene therapy product.¹⁵ This compound was developed to reduce the frequency of injections in patients who have DME or wet AMD, according to the company.

More U.S. clinical trials regarding diabetic eye disease can be found by searching at clinicaltrials.gov .

TARGETING DIABETES

A complete review of new innovative products specifically targeting diabetes, diabetic eye disease and associated complications is beyond the scope of this review. The encouraging news for clinicians is that tremendous amounts of energy, financial investment and intellectual efforts are being targeted toward reducing or eliminating the systemic and ocular complications of diabetes. Hopefully, the information in this article will give you insight into better days ahead for our diabetic patients. OM

REFERENCES

1. Magliano DJ, Islam RM, Barr ELM, et al. Trends in incidence of total or type 2 diabetes: systematic review. BMJ. 2019; 366: l5003 doi: 10.1136/bmj.l5003
2. Mobasseri M, Shirmohammadi M, Amiri T, et al. Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis. Health Promot Perspect. 2020; 10(2): 98–115. doi: 10.34172/hpp.2020.18
3. Statistics about Diabetes. American Diabetes Association website. Accessed Sept. 21, 2020. https://www.diabetes.org/resources/statistics/statistics-about-diabetes
4. The Pancreas. Boundless Anatomy and Physiology course via Lumen Learning. Accessed Sept. 21, 2020. https://courses.lumenlearning.com/boundless-ap/chapter/the-pancreas/
5. McCulloch DK, Robertson RP. Pathogenesis of type 2 diabetes mellitus. UpToDate. Published Oct. 10, 2019. Accessed Sept. 21, 2020. https://www.uptodate.com/contents/pathogenesis-of-type-2-diabetes-mellitus
6. Franks PW, Shungin D. The interplay of lifestyle and genetic susceptibility in Type 2 diabetes risk. Diabetes Manage. (2011) 1(3), 299–307.
7. Yehya, A and Sadhu, AR. New Therapeutic Strategies for Type 2 Diabetes. Methodist Debakey Cardiovasc J. 2018 Oct-Dec; 14(4): 281
8. Mohsen M, Rezaie P, Gao HK, Kengne AP. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized Control Trials With 22 528 Patients. J Am Heart Assoc. 2017 May 25;6(6):e004007. Doi:10.1161/JAHA.116.004007.
9. Ni L, Cheng Y, Chen G, et al. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol. 2020 Jun 26;19(1):98. DOI: 10.1186/s12933-020-01071-y
10. Lee R, Wong TL, and Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015 Sep 30;2:17. doi: 10.1186/s40662-015-0026-2.
11. Cuevas P, Outeiriño LA, Azanza C, Angulo J, Gimenez-Gallego G. Improvement in the signs and symptoms of dry eye disease with dobesilate eye drops. Mil Med Res. 2015 Dec 21;2:35. doi: 10.1186/s40779-015-0068-8. eCollection 2015.
12. Using Calcium Dobesilate to Treat Chinese Patients With Mild to Moderate Non-proliferative Diabetic Retinopathy. ClinicalTrials.gov . Published Feb. 25, 2020. Accessed Sept. 21, 2020. https://clinicaltrials.gov/ct2/show/NCT04283162
13. Herve A, Ramlet AA, Polard E, Bentue-Ferrer D. Safety of calcium dobesilate in chronic venous disease, diabetic retinopathy and haemorrhoids. Drug Saf. 2004;27(9):649-60. doi: 10.2165/00002018-200427090-00003.
14. Sacconi R, Giuffrè C, Corbelli E, et al. Emerging therapies in the management of macular edema: a review. F1000 Research 2019, 8(F1000 Faculty Rev):1413. doi: 10.12688/f1000research.19198.1. eCollection 2019.
15. ADVM-022 Intravitreal Gene Therapy for DME (Infinity). ClinicalTrials.gov . Published June 5, 2020. Accessed Sept. 21, 2020. https://www.clinicaltrials.gov/ct2/show/NCT04418427 .

DR. TOWNSEND practices in Canyon, Texas, and is treasurer of the Ocular Surface Society of Optometry. He is also a consultant or advisor to Alcon, ScienceBased Health and TearLab. Contact him at drbilltownsend@gmail.com.