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Department of Pharmacy Practice, Vaageswari College of Pharmacy, Karimnagar, Telangana, India
Introduction The global diabetes epidemic is expanding exponentially, with cases in India alone projected to reach 79.4 million by 2050. While traditional frameworks link diabetes to genetics and overnutrition, the formal recognition of Type 5 Diabetes Mellitus or Malnutrition-Related Diabetes Mellitus (MRDM) highlights a distinct metabolic crisis. It primarily affects young, severely underweight individuals in low-resource settings who do not fit classical Type 1 or Type 2 profiles. Discussion Unlike Type 1 or Type 2 diabetes, Type 5 diabetes is driven by a primary insulin secretory defect caused by compromised pancreatic development linked to early-life starvation. Phenotypically, the disease has an 85% male predilection, presents with a low body mass index (BMI< 19 kg/m2), and exhibits unique resistance to ketosis despite high insulin requirements. Clinical management demands a double-pronged approach combining rigorous nutritional rehabilitation with low-dose oral hypoglycemics or insulin initiated with extreme caution to prevent life-threatening hypoglycemia. Conclusion: Type 5 Diabetes Mellitus represents the long-term metabolic fallout of persistent undernutrition spanning from fetal gestation into early adulthood. Its recognition underscores the necessity of moving beyond standard lifestyle interventions to directly address early-life food insecurity, maternal health, and targeted nutritional support. Combining robust nutritional rehabilitation with carefully tailored, lean-physiology-adjusted pharmacological regimens is vital to reversing metabolic dysfunction and improving quality of life.
The prevalence of diabetes has increased exponentially worldwide, and if current trends continue, cases are predicted to treble by 2050, with an estimated 79.4 million people in India alone. [1] This may be explained by the young population of India today, which obscures the potential effects of genetic, environmental (acquired), and behavioral factors (urban migration, changing lifestyles, and rising living standards). Malnutrition has been linked to the development of insulin-dependent diabetic mellitus, despite obesity being a known risk factor for the disease. In 1985, the World Health Organization recognized malnutrition as a separate condition and included Malnutrition-Related Diabetes Mellitus to the diabetes classification. [2, 3] The International Diabetes Federation (IDF) Diabetes Atlas 2025 provides a sobering yet clarifying view of the diabetes crisis facing the world and India. With over 589 million adults living with diabetes in 2024 and projections rising to 853 million by 2050, it is increasingly evident that this epidemic is shaped not only by lifestyle and genetics but also by systemic nutritional deprivation. [4] The formal recognition of Type 5 Diabetes – Malnutrition-related Diabetes Mellitus (MRDM) – by the IDF is both timely and necessary. It challenges conventional paradigms of diabetes aetiology and refocuses attention on the intersections between chronic undernutrition, poverty and metabolic dysfunction. MRDM primarily affects young, undernourished individuals in low-resource settings, particularly in regions like South Asia and sub-Saharan Africa. [5,6] In India, it is often seen in adolescents and young adults who are underweight, insulin-requiring, and do not fit the classical picture of either Type 1 or Type 2 diabetes. Type 5 diabetes is marked by resistance to ketosis even without insulin, requires high insulin doses to control blood sugar and often involves pancreatic issues like calcifications and exocrine dysfunction. [7] Subtypes such as fibrocalculous pancreatic diabetes and protein-deficient diabetes mellitus further highlight the complex pathophysiology – ranging from pancreatic fibrosis and calcification to functional beta-cell impairment linked with chronic protein-energy malnutrition. While Type 2 diabetes in adults is often associated with overnutrition and sedentary living, MRDM represents the metabolic fallout of persistent undernutrition, starting as early as foetal development. The schematic life course model shows how early gestation and childhood undernutrition – when uncorrected – can lead to beta-cell underdevelopment, pancreatic atrophy, and insulinopenia (a condition where there is a deficiency or abnormally low level of insulin in the body) in adulthood, manifesting as Type 5 diabetes. [8]
CLASSIFICATION
Table 1: Classification of type 5 diabetes mellitus based on underlying Etiology
|
Category |
Specific Cause |
Mechanism of Diabetes Development |
Reference |
|
Pancreatic Disorders |
Chronic Pancreatitis |
Destruction of islet cells and impaired insulin secretion |
Ewald & Bretzel, 2013 [9] |
|
Pancreatic Cancer |
Infiltration of pancreatic tissue affecting endocrine function |
Hart et al., 2016 [10] |
|
|
Cystic Fibrosis |
Fibrosis and cyst formation impair both exocrine and endocrine roles |
Moran et al., 2009 [11] |
|
|
Hemochromatosis |
Iron overload leads to oxidative damage of beta cells |
Niederau et al., 1996 [12] |
|
|
Pancreatectomy |
Loss of insulin-producing tissue |
Rickels et al., 2013 [13] |
|
|
Systemic Endocrine Disorders |
Cushing's Syndrome |
Excess cortisol induces insulin resistance |
Anagnostis et al., 2009 [14] |
|
Acromegaly |
Growth hormone excess reduces insulin sensitivity |
Colao et al., 2004 [15] |
|
|
Hyperthyroidism |
Increases hepatic glucose output and reduces insulin action |
Dimitriadis et al., 2000 [16] |
|
|
Drug-Induced Diabetes |
Glucocorticoids |
Increase gluconeogenesis and insulin resistance |
Clore & Thurby-Hay, 2009 [17] |
|
Thiazide Diuretics |
Hypokalemia impairs insulin secretion |
Zillich et al., 2006 [18] |
|
|
Antipsychotics |
Weight gain and insulin resistance |
Newcomer, 2005 [19] |
|
|
Immunosuppressants (e.g., Tacrolimus) |
Beta-cell toxicity and reduced insulin gene expression |
Hecking et al., 2004 [20] |
Common Symptoms Of Type 5 Diabetes
The symptoms of Type 5 diabetes often develop gradually and may go unnoticed in the early stages. Because it typically affects individuals who are already undernourished, some signs can be mistaken for general weakness or poor health.
Common symptoms include:
In children or young adults, additional signs may include delayed growth or puberty. Since the condition often progresses silently, it’s important to pay attention to subtle symptoms—especially in those with a history of poor nutrition. [21]
Risk Factors
Type 5 diabetes is strongly linked to long-term nutritional and environmental challenges. Understanding the key risk factors can help identify those who may be more vulnerable to developing the condition:
Table 2: Comparative Features of Type 1, Type 2, And Type 5 Diabetes. [22]
|
Characteristic |
Type 1 diabetes |
Type 2 diabetes |
Type 5 diabetes |
|
Primary pathophysiology |
Autoimmune destruction of beta cells |
Insulin resistance with progressive beta cell dysfunction |
Insulin secretory defect due to malnutrition |
|
Age of onset |
Usually childhood/adolescence |
Usually over 30 years |
Under 30 years |
|
Body composition |
Usually normal weight |
Often overweight/obese |
Low BMI (<19 kg/m2) |
|
Gender predilection |
Equal gender distribution |
Equal gender distribution |
Predominantly male (85%) |
|
Endogenous insulin |
Absent/very low |
Present (initially) |
Diminished but present |
|
Autoimmune markers |
Positive (GAD-65, IA-2, etc.) |
Negative |
Negative |
|
C-peptide |
Absent/Low |
Normal/High |
Reduced but present |
|
Insulin sensitivity |
Present |
Reduced |
Relatively preserved |
|
Ketosis tendency |
High |
Low |
Resistant despite hyperglycemia |
|
Primary risk factors |
Genetic susceptibility to environmental triggers |
Obesity, sedentary lifestyle, obesity, age |
Malnutrition in early life low birth weight |
|
Primary treatment |
Insulin replacement |
Lifestyle modification, oral medications, insulin |
Insulin or oral medications, nutritional rehabilitation |
GAD-65: Glutamic acid decarboxylase 65, IA-2: Islet antigen-2, BMI: Body mass index
Pathophysiology
The classification known as type 5 diabetes represents a distinct metabolic condition characterized by significant insulin secretory deficiency and suboptimal glycemic regulation. This form differs considerably from type 2 diabetes in that its primary etiology appears linked to sustained nutritional inadequacy, particularly during developmental periods of childhood and adolescence. In contrast, type 1 diabetes develops through autoimmune processes targeting insulin-secreting cells, while type 2 diabetes manifests primarily as ineffective utilization of produced insulin. Type 5 diabetes stands apart with its unique pathogenesis, theorized to involve compromised pancreatic development resulting from extended periods of nutritional insufficiency. [4] Landmark research using state-of-the-art metabolic studies has confirmed its unique metabolic profile.
Key pathophysiological features include:
Insulin secretory defect
According to Lontchi-Yimagou et al., people with type 2 diabetes and lean non-diabetics have a much higher total insulin secretory response than people with low body mass index diabetes (LD). A fundamental impairment in insulin secretion rather than insulin resistance is indicated by the significantly reduced first-phase insulin secretion (0–15 min). Because insulin secretion is still higher than in type 1 diabetes, beta-cell activity is partially maintained. [23]
Maintaining insulin sensitivity:
Sophisticated clamp tests showed that people with type 5 diabetes are rather insulin sensitive, despite earlier theories concerning insulin resistance based on high insulin needs [24]. The LD group's endogenous glucose production, a gauge of hepatic insulin resistance, is much lower than that of the type 2 diabetes group. Even after controlling for lean body mass, the LD group's glucose uptake—a measure of peripheral insulin sensitivity—is much higher than that of the type 2 diabetes group. [23]
Distinctive body composition:
Compared to people with type 1 diabetes, type 2 diabetes, and non-diabetic controls, total lean body mass is substantially reduced. These people have a greater visceral-to-subcutaneous adipose tissue ratio despite having low total adiposity. The absence of fatty liver disease is consistent with a much lower hepatocellular lipid concentration than in type 2 diabetes. [23]
Early life nutritional programming:
This condition seems to be associated with maternal malnutrition, low birth weight, or childhood malnutrition.[25] Animal models show that maternal protein malnutrition leads to lower beta-cell mass and decreased beta-cell regeneration capacity in offspring.[26] Small-for-gestational-age newborns had less pancreatic vasculature and smaller fractions of islet cells, according to human research.[25] The distribution of adipose tissue and the pancreas appears to be permanently altered structurally and functionally by early-life starvation.[27]
Figure 1: Developmental programming pathway of type 5 diabetes. Developmental trajectory showing how early life malnutrition leads to metabolic alterations and ultimately type 5 diabetes in young adulthood. BMI: Body mass index.
Dietary Management of Type 5 Diabetes Mellitus
Dietary management is essential in the care of Type 5 Diabetes Mellitus, particularly in patients with pancreatic dysfunction or drug-induced metabolic disturbances [28]. A balanced diet with complex carbohydrates, lean proteins, healthy fats, adequate hydration, and avoidance of simple sugars helps maintain glycemic control and prevent glucose fluctuations [30]. Small frequent meals are recommended to reduce postprandial hyperglycemia and hypoglycemia. Carbohydrates should mainly come from whole grains, legumes, vegetables, and other low-glycemic index foods, while refined sugars and sweetened beverages should be minimized [29]. Moderate protein intake from easily digestible sources such as eggs, lentils, tofu, and cottage cheese helps preserve muscle mass and nutritional status, especially in patients with malabsorption or medication-related weight loss [31]. Healthy unsaturated fats from olive oil, nuts, seeds, and avocados are preferred, whereas saturated and trans fats should be restricted to lower cardiovascular risk [32]. Medium-chain triglycerides may benefit patients with fat malabsorption or pancreatic insufficiency [33]. Micronutrient supplementation is often necessary because pancreatic dysfunction can impair absorption of vitamins A, D, E, and K. Calcium, magnesium, zinc, and B-complex vitamins are also important for maintaining bone health, immune function, and glucose metabolism [34]. Electrolyte depletion caused by certain medications may further worsen insulin sensitivity [36]. In patients with pancreatic exocrine insufficiency, pancreatic enzyme replacement therapy (PERT) containing lipase, amylase, and protease improves digestion and nutrient absorption when taken with meals [35]. Structured dietary patterns such as the Mediterranean diet, rich in fruits, vegetables, legumes, whole grains, olive oil, and fish, have shown benefits in improving insulin sensitivity, lipid profile, and inflammatory status [37]. Overall, combining proper nutrition with pharmacological therapy and lifestyle modification is crucial for improving metabolic control and quality of life in Type 5 diabetes patients.
TREATMENT:
Nutritional rehabilitation forms the base:
Glycemic control is introduced cautiously:
Supportive care includes:
CONCLUSION:
Type 5 Diabetes Mellitus (malnutrition-related diabetes mellitus) is a distinct and emerging form of diabetes primarily associated with chronic undernutrition, impaired pancreatic development, and reduced insulin secretion, particularly among individuals in low-resource settings. Unlike Type 1 and Type 2 diabetes, it is characterized by low body mass index, preserved insulin sensitivity, resistance to ketosis, and nutritional deficiencies resulting from long-term malnutrition and pancreatic dysfunction. This review highlights the important role of early-life nutritional deprivation, poverty, recurrent infections, and inadequate dietary intake in the development of the disease. Effective management requires a comprehensive approach involving nutritional rehabilitation, balanced dietary modifications, micronutrient supplementation, pancreatic enzyme replacement therapy when indicated, careful glycemic control, and lifestyle interventions to improve metabolic outcomes and quality of life. Increasing awareness, early diagnosis, and further research are essential for establishing standardized treatment guidelines and reducing the burden of this often overlooked but clinically significant form of diabetes.
REFERENCES
Thatikonda Sakhitha*, Vaishnavi Shrinivas, Veeragoni Jayadev, Pullela Akarsh, An Overview of Type 5 Diabetes Mellitus: Etiology, Clinical Manifestations, and Nutritional Management, Int. J. Med. Pharm. Sci., 2026, 2 (5), 702-709. https://doi.org/10.5281/zenodo.20416316
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10.5281/zenodo.20416316
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