new research on diabetes drugs

New cause of diabetes discovered, offering potential target for new classes of drugs to treat the disease

Researchers at Case Western Reserve University and University Hospitals have identified an enzyme that blocks insulin produced in the body -- a discovery that could provide a new target to treat diabetes.

Their study, published Dec. 5 in the journal Cell, focuses on nitric oxide, a compound that dilates blood vessels, improves memory, fights infection and stimulates the release of hormones, among other functions. How nitric oxide performs these activities had long been a mystery.

The researchers discovered a novel "carrier" enzyme (called SNO-CoA-assisted nitrosylase, or SCAN) that attaches nitric oxide to proteins, including the receptor for insulin action.

They found that the SCAN enzyme was essential for normal insulin action, but also discovered heightened SCAN activity in diabetic patients and mice with diabetes. Mouse models without the SCAN enzyme appeared to be shielded from diabetes, suggesting that too much nitric oxide on proteins may be a cause of such diseases.

"We show that blocking this enzyme protects from diabetes, but the implications extend to many diseases likely caused by novel enzymes that add nitric oxide," said the study's lead researcher Jonathan Stamler, the Robert S. and Sylvia K. Reitman Family Foundation Distinguished Professor of Cardiovascular Innovation at the Case Western Reserve School of Medicine and president of Harrington Discovery Institute at University Hospitals. "Blocking this enzyme may offer a new treatment."

Given the discovery, next steps could be to develop medications against the enzyme, he said.

The research team included Hualin Zhou and Richard Premont, both from Case Western Reserve School of Medicine and University Hospitals, and students Zack Grimmett and Nicholas Venetos from the university's Medical Science Training Program.

Many human diseases, including Alzheimer's, cancer, heart failure and diabetes, are thought to be caused or accelerated by nitric oxide binding excessively to key proteins. With this discovery, Stamler said, enzymes that attach the nitric oxide become a focus.

With diabetes, the body often stops responding normally to insulin. The resulting increased blood sugar stays in the bloodstream and, over time, can cause serious health problems. Individuals with diabetes, the Centers for Disease Control reports, are more likely to suffer such conditions as heart disease, vision loss and kidney disease.

But the reason that insulin stops working isn't well understood.

Excessive nitric oxide has been implicated in many diseases, but the ability to treat has been limited because the molecule is reactive and can't be targeted specifically, Stamler said.

"This paper shows that dedicated enzymes mediate the many effects of nitric oxide," he said. "Here, we discover an enzyme that puts nitric oxide on the insulin receptor to control insulin. Too much enzyme activity causes diabetes. But a case is made for many enzymes putting nitric oxide on many proteins, and, thus, new treatments for many diseases."

• Diseases and Conditions
• Hormone Disorders
• Chronic Illness
• Alzheimer's
• Huntington's Disease
• Disorders and Syndromes
• Nitrous oxide
• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Drug discovery
• Nitrogen oxide

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Materials provided by Case Western Reserve University . Note: Content may be edited for style and length.

Journal Reference :

• Hua-Lin Zhou, Zachary W. Grimmett, Nicholas M. Venetos, Colin T. Stomberski, Zhaoxia Qian, Precious J. McLaughlin, Puneet K. Bansal, Rongli Zhang, James D. Reynolds, Richard T. Premont, Jonathan S. Stamler. An enzyme that selectively S-nitrosylates proteins to regulate insulin signaling . Cell , 2023; DOI: 10.1016/j.cell.2023.11.009

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• Review Article
• Published: 11 September 2023

Physiology and Biochemistry

Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions

• Mohammad Azam Ansari   ORCID: orcid.org/0000-0002-6122-5479 1 ,
• Waseem Chauhan 2 ,
• Shoaib Shoaib 3 ,
• Sami A. Alyahya 4 ,
• Mubashshir Ali 5 ,
• Hamid Ashraf 6 ,
• Mohammad N. Alomary 7 &
• Ebtesam A. Al-Suhaimi 8  

International Journal of Obesity volume  47 ,  pages 1179–1199 ( 2023 ) Cite this article

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• Gastrointestinal hormones

Diabetes is a serious health issue that causes a progressive dysregulation of carbohydrate metabolism due to insufficient insulin hormone, leading to consistently high blood glucose levels. According to the epidemiological data, the prevalence of diabetes has been increasing globally, affecting millions of individuals. It is a long-term condition that increases the risk of various diseases caused by damage to small and large blood vessels. There are two main subtypes of diabetes: type 1 and type 2, with type 2 being the most prevalent. Genetic and molecular studies have identified several genetic variants and metabolic pathways that contribute to the development and progression of diabetes. Current treatments include gene therapy, stem cell therapy, statin therapy, and other drugs. Moreover, recent advancements in therapeutics have also focused on developing novel drugs targeting these pathways, including incretin mimetics, SGLT2 inhibitors, and GLP-1 receptor agonists, which have shown promising results in improving glycemic control and reducing the risk of complications. However, these treatments are often expensive, inaccessible to patients in underdeveloped countries, and can have severe side effects. Peptides, such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are being explored as a potential therapy for diabetes. These peptides are postprandial glucose-dependent pancreatic beta-cell insulin secretagogues and have received much attention as a possible treatment option. Despite these advances, diabetes remains a major health challenge, and further research is needed to develop effective treatments and prevent its complications. This review covers various aspects of diabetes, including epidemiology, genetic and molecular basis, and recent advancements in therapeutics including herbal and synthetic peptides.

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Acknowledgements

WC and SS are thankful to Indian Council of Medical Research (ICMR), New Delhi and Council of Scientific and Industrial Research (CSIR), New Delhi for providing senior research fellowship, respectively.

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Mohammad Azam Ansari

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Waseem Chauhan

Department of Biochemistry, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Shoaib Shoaib

Wellness and Preventive Medicine Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia

Sami A. Alyahya

USF Health Byrd Alzheimer’s Center and Neuroscience Institute, Department of Molecular Medicine, Tampa, FL, USA

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Rajiv Gandhi Center for Diabetes and Endocrinology, Faculty of Medicine, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

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Advanced Diagnostic and Therapeutic Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, 11442, Saudi Arabia

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Ansari, M.A., Chauhan, W., Shoaib, S. et al. Emerging therapeutic options in the management of diabetes: recent trends, challenges and future directions. Int J Obes 47 , 1179–1199 (2023). https://doi.org/10.1038/s41366-023-01369-3

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DOI : https://doi.org/10.1038/s41366-023-01369-3

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Affiliations.

• 1 Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.) [email protected]; [email protected]; [email protected].
• 2 Department of Pharmacology (L.S.S.), Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine (L.S.S., S.A.S., E.M.W.), and Brehm Diabetes Center (L.S.S., S.A.S., E.M.W.), University of Michigan Medical School, Ann Arbor, Michigan; and VA Ann Arbor Healthcare System, Ann Arbor, Michigan (S.A.S.).
• PMID: 34193595
• PMCID: PMC8274312
• DOI: 10.1124/pharmrev.120.000160

Both type 1 and type 2 diabetes mellitus are advancing at exponential rates, placing significant burdens on health care networks worldwide. Although traditional pharmacologic therapies such as insulin and oral antidiabetic stalwarts like metformin and the sulfonylureas continue to be used, newer drugs are now on the market targeting novel blood glucose-lowering pathways. Furthermore, exciting new developments in the understanding of beta cell and islet biology are driving the potential for treatments targeting incretin action, islet transplantation with new methods for immunologic protection, and the generation of functional beta cells from stem cells. Here we discuss the mechanistic details underlying past, present, and future diabetes therapies and evaluate their potential to treat and possibly reverse type 1 and 2 diabetes in humans. SIGNIFICANCE STATEMENT: Diabetes mellitus has reached epidemic proportions in the developed and developing world alike. As the last several years have seen many new developments in the field, a new and up to date review of these advances and their careful evaluation will help both clinical and research diabetologists to better understand where the field is currently heading.

Trial registration: ClinicalTrials.gov NCT02239354 .

U.S. Government work not protected by U.S. copyright.

Publication types

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Research Support, U.S. Gov't, Non-P.H.S.
• Diabetes Mellitus, Type 1*
• Diabetes Mellitus, Type 2* / drug therapy
• Hypoglycemic Agents / therapeutic use
• Hypoglycemic Agents

Associated data

• ClinicalTrials.gov/NCT02239354

Grants and funding

• R01 DK108921/DK/NIDDK NIH HHS/United States
• P30 DK020572/DK/NIDDK NIH HHS/United States
• U01 DK127747/DK/NIDDK NIH HHS/United States
• I01 BX004444/BX/BLRD VA/United States
• R01 DK046409/DK/NIDDK NIH HHS/United States