Beyh YS, Narayan KMV, Jagannathan R. Severe insulin-deficient diabetes: Updated review of epidemiology, biology, and clinical implications. World J Diabetes 2026; 17(8): 119203 [DOI: 10.4239/wjd.119203]
Corresponding Author of This Article
Yara S Beyh, PhD, Post Doctoral Researcher, Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA 30322, United States. ybeyh@emory.edu
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Endocrinology & Metabolism
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review-article
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Beyh YS, Narayan KMV, Jagannathan R. Severe insulin-deficient diabetes: Updated review of epidemiology, biology, and clinical implications. World J Diabetes 2026; 17(8): 119203 [DOI: 10.4239/wjd.119203]
World J Diabetes. Aug 15, 2026; 17(8): 119203 Published online Aug 15, 2026. doi: 10.4239/wjd.119203
Severe insulin-deficient diabetes: Updated review of epidemiology, biology, and clinical implications
Yara S Beyh, K M Venkat Narayan, Ram Jagannathan
Yara S Beyh, K M Venkat Narayan, Ram Jagannathan, Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, United States
K M Venkat Narayan, Department of Endocrinology, Emory School of Medicine, Emory University, Atlanta, GA 30322, United States
Author contributions: Narayan KMV conceptualized the idea of the review; Beyh YS conducted the research and wrote the initial manuscript; Beyh YS and Jagannathan R edited the manuscript; all authors have read and approved the final manuscript.
AI contribution statement: AI tools were not used in the production of this manuscript.
Supported by National Heart, Lung, and Blood Institute, No. P01HL154996; and National Institute of Diabetes and Digestive and Kidney Diseases, No. R01-DK139632.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding author: Yara S Beyh, PhD, Post Doctoral Researcher, Emory Global Diabetes Research Center, Hubert Department of Global Health, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Atlanta, GA 30322, United States. ybeyh@emory.edu
Received: January 21, 2026 Revised: May 22, 2026 Accepted: July 14, 2026 Published online: August 15, 2026 Processing time: 196 Days and 8.8 Hours
Abstract
Type 2 diabetes mellitus is increasingly recognized as heterogeneous in pathophysiology, clinical course, and treatment needs. Data-driven clustering across diverse cohorts has identified severe insulin-deficient diabetes (SIDD), whose frequency varies by race/ethnicity and geography, with a higher relative burden reported in South Asian populations. SIDD is characterized by marked hyperglycemia, profound β-cell dysfunction, relatively lower or intermediate body mass index, and absence of autoimmune markers. Genetic and multi-omic evidence increasingly implicates insulin secretion pathways and β-cell stress programs rather than autoimmunity, supporting biological distinctiveness. Clinically, SIDD is consistently associated with adverse microvascular outcomes particularly diabetic retinopathy near diagnosis and during follow-up. Associations with macrovascular disease are more heterogeneous and may reflect differences in ascertainment, glycemic exposure, and treatment. Emerging evidence also suggests heterogeneity in all-cause mortality and excess life-years lost across diabetes and prediabetes subtypes, with insulin-deficient phenotypes showing an adverse mortality profile. Therapeutically, SIDD often requires early escalation and frequent insulin and may respond poorly to metformin alone. Key gaps include subtype stability over time and lack of cluster-guided trials; priorities include electronic health record-implementable classification and trials testing subtype-tailored strategies using hard outcomes.
Core Tip: Severe insulin-deficient diabetes (SIDD) is a reproducible, non-autoimmune subtype of type 2 diabetes defined by profound β-cell dysfunction, marked hyperglycemia, and relatively lower body mass index. This review synthesizes global evidence showing that SIDD carries disproportionate microvascular risk particularly retinopathy and often requires early treatment intensification with frequent insulin use. A key innovation is highlighting population-specific subtype distributions, with insulin-deficient phenotypes more common in South Asians and linked to emerging signals for higher mortality and excess life-years lost. We integrate genetic and multi-omic insights implicating β-cell stress pathways and outline priorities for electronic health record-ready classification and subtype-guided trials.
