Beyond Type 1 & 2: The Rise of Undernutrition-Associated 'Type 5' Diabetes
Dr Nihal Thomas, Head of Stem Cell Research at Christian Medical College, Vellore, shares groundbreaking insights into an atypical form of diabetes.
By Anubha Jain
Published : June 28, 2025 at 5:21 PM IST
|Updated : June 28, 2025 at 8:51 PM IST
Undernutrition, especially in early life, is strongly linked to a higher risk of developing diabetes in adulthood. Recent studies also show that chronic undernutrition during adulthood—even in those previously well-nourished—can lead to metabolic issues, including diabetes.
This form of diabetes often differs from typical type 2 diabetes (T2D), showing features like low BMI (<18.5 kg/m²), low serum C-peptide (indicating poor insulin production), and resistance to ketosis.
It is pertinent to mention that Ketosis is a state where the body burns fat for energy and produces substances called ketones. It usually happens when there isn't enough insulin or carbohydrates. Similarly, Serum C-peptide is a substance made when insulin is produced in the body. Low levels mean the body isn't making enough insulin.
Undernutrition typically results from prolonged deficiencies in protein, calories, and micronutrients, leading to abnormal body composition. Research shows that adults with low BMI have a significantly higher prevalence of diabetes, independent of other risk factors. This suggests that adult undernutrition alone can drive metabolic dysfunction.
These unique clinical features raise the possibility of an undernutrition-related diabetes phenotype, distinct from classic types, but more research is needed to confirm its classification and pathophysiology. Identifying and addressing undernutrition could be key to preventing and managing such atypical diabetes.
Exploring the Complexities of UADM
In an in-depth interview with ETV Bharat, Dr. Nihal Thomas, an endocrinologist and Head of Stem Cell Research at Christian Medical College (CMC), Vellore, shared groundbreaking insights into an atypical form of diabetes known as Undernutrition-Associated Diabetes Mellitus (UADM) — now being proposed for reclassification under the name Type 5 Diabetes.
Global Recognition of a Neglected Diabetes Type
Dr. Thomas highlighted that the International Diabetes Federation (IDF) has recently acknowledged malnutrition-related diabetes as a separate entity under the proposed label Type 5 Diabetes. Although first reported as early as 1955 (and included in the WHO classification in 1985), limited research and clinical focus led to its removal from official classifications in 1998. However, due to rising prevalence in low- and middle-income countries, the scientific community is now revisiting the need for its reclassification.
Epidemiological Footprint and Historical Reports
Dr. Thomas explained that UADM is most commonly observed in low-income countries, including India, Bangladesh, Sub-Saharan Africa, Jamaica, and parts of Latin America. Young adults — typically between 15 to 30 years of age — with low BMI are most affected. While Type 1 Diabetes (T1D) is also seen in individuals with low BMI, UADM patients do not exhibit ketoacidosis or autoimmune markers, key differentiators from T1D. T1D is insulin-dependent, and if insulin is stopped, it can lead to diabetic ketoacidosis (DKA) — a serious and life-threatening condition. In DKA, the lack of insulin prevents the body from using glucose for energy, so it rapidly breaks down fat, producing excess ketones. These ketones accumulate in the blood and urine, making the blood acidic. This can cause breathing difficulties, dehydration, and, if untreated, can lead to coma or death.
He traced the early documentation of this form of diabetes:
- 1955: Referred to as J-type diabetes in Jamaica.
- 1961: Noted in East Pakistan (now Bangladesh) by Dr. Mohammad Ibrahim, a pioneer in South Asian diabetes care.
- From 2010 onwards, emerging reports from Uganda, Ethiopia, Rwanda, and updated investigations in Jamaica reaffirmed its persistence.
What Defines Undernutrition-Associated Diabetes (UADM)?
Dr. Thomas clarified the distinctive features of UADM:
- Occurs in young, lean individuals with low birth weight or a history of chronic undernutrition.
- BMI often falls below 18.5 kg/m², or <19.2 kg/m² in South Asian populations.
- Patients lack autoimmune antibodies (measured by GAD65 antibodies) typically found in T1D.
- There is no history of diabetic ketoacidosis (DKA).
- Pancreatic scans usually rule out structural abnormalities.
Pathophysiology: What Drives the Disease
Dr. Nihal Thomas explained that insulin deficiency is the key factor in Undernutrition-Associated Diabetes Mellitus (UADM). The condition often originates in utero, when the fetus is exposed to maternal undernutrition, particularly protein deficiency, due to extreme poverty in parts of rural Sub-Saharan Africa, Asia, and South America, or during war or famine. This poor nutritional environment affects the epigenetic regulation of genes essential for fetal development, particularly pancreatic beta cells, which produce insulin. As a result, beta cell function is compromised, leading to an insulin-deficient form of diabetes.
Dr. Thomas emphasised that normal DNA is required for correct protein synthesis. When disrupted, it may lead to abnormal or inadequate protein production, affecting multiple organs. Additionally, muscle cells may develop with reduced capacity to absorb glucose, worsening insulin resistance. This complex interplay between early-life malnutrition, impaired beta-cell function, and altered muscle metabolism defines the unique pathology of UADM.
Dr. Thomas cautioned that even in developed countries, infants born with low birth weight due to poor maternal nutrition may later develop hypertension, cardiovascular diseases, and type 2 diabetes, indicating the global relevance of this condition.
Landmark Collaborative Study with Albert Einstein College, New York
A seven-year study conducted jointly by CMC Vellore and Albert Einstein College of Medicine (New York) under Dr. Meredith Hawkins and Dr. Nihal Thomas brought unprecedented clarity on UADM.
In 2022, the findings were published in the American Diabetes Association's journal, Diabetes Care, titled “An Atypical Form of Diabetes Among Individuals With Low BMI.” The study utilised advanced euglycemic-hyperinsulinemic clamp techniques to analyse insulin dynamics in lean Indian individuals.
Study’s key results: Tests revealed that individuals with this atypical form of diabetes showed insulin resistance, but not complete insulin deficiency, unlike Type 1 diabetes. However, the insulin deficiency was milder. When given isotope-labelled glucose, their livers did not overproduce glucose as typically seen in Type 2 diabetes. Body composition scans showed that their total body fat was significantly lower (well below the normal ~20% body fat) compared to individuals with Type 1 or Type 2 diabetes. MRI scans further confirmed extremely low fat levels in the liver and muscles, distinguishing them metabolically from both T1D and T2D patients.
Five-Group Comparative Study
The team compared patients with Type 1 and Type 2 diabetes, Lean healthy individuals, and Obese healthy individuals. This comparison established UADM as a metabolically and clinically distinct entity. These findings have subsequently been described in detail and reaffirmed in the journal Physiology in 2025.
UADM Not A Subtype Of T1D or T2D
Dr. Nihal Thomas emphasised that Type 5 Diabetes (UADM) differs significantly from both Type 1 and Type 2 diabetes in its cause, presentation, and treatment. Unlike Type 1 Diabetes, which is autoimmune, associated with GAD65 antibodies, and prone to ketoacidosis, UADM patients do not exhibit these features. Unlike Type 2 Diabetes, which typically affects overweight or older individuals with preserved beta-cell function and insulin resistance, UADM occurs in young, lean individuals, often with a history of low birth weight and early-life undernutrition.
Treatment of UADM patients
In terms of treatment, T1D requires lifelong insulin, while patients with UADM often respond well to oral medications or require only low doses of insulin. Diagnosis is based on clinical features: rural background, absence of family history, no ketoacidosis, and negative antibody tests. CT scans are needed to rule out structural pancreatic disease, but no single biomarker exists yet for Type 5 diabetes.
Concluding note: Dr. Thomas advocates for its inclusion as a distinct classification in the diabetes taxonomy, not as a subtype of T1D or T2D. Recent research, including the 2018 Swedish and Indian studies that identified Severe Insulin-Deficient Diabetes (SIDD) as a subtype of Type 2 Diabetes (T2D), but these patients have a higher BMI than Type 5 diabetes. UADM clearly warrants recognition based on its unique pathophysiology and clinical profile.
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