What is Type 5 Diabetes: Is It A New Disease ?

 

A doctor friend Prof Dr Vythi sent me this piece  of information about Type 5 Diabetes asking me for comment: 

Prof JB, any comment on this Type 5 Diabetes? Thanks Prof. 

Type 5 Diabetes: A Newly Recognized Form of Malnutrition-Related Diabetes

Malnutrition-related diabetes—seen primarily in lean, undernourished adolescents and young adults in low- and middle-income countries—has now been officially classified as Type 5 Diabetes by the International Diabetes Federation (IDF).

This landmark recognition follows decades of clinical observation and advocacy, led by Dr. Meredith Hawkins, Professor of Medicine and Founding Director of the Global Diabetes Institute at Albert Einstein College of Medicine. “This form of diabetes has been historically under-diagnosed and poorly understood,” said Dr. Hawkins. “IDF’s designation is a crucial step in raising awareness and improving outcomes.”

While type 2 diabetes, driven by obesity, remains the dominant form in developing nations, type 5 diabetes reflects the opposite nutritional extreme—emerging from chronic undernutrition. It is estimated to affect 20–25 million people globally, particularly in Asia and Africa. Tragically, many affected individuals die within a year of diagnosis, and clinicians remain uncertain about how best to treat them.

Although first described nearly 70 years ago, and briefly recognized by the World Health Organization (WHO) in 1985, malnutrition-related diabetes was removed from WHO classification in 1999 due to insufficient data. Interest was reignited in the 2000s as physicians worldwide reported puzzling cases of young, thin patients with diabetes who were not responding to insulin and did not fit the profiles of type 1 or type 2 diabetes.

Dr. Hawkins founded the Global Diabetes Institute in 2010 to investigate this neglected condition. In a landmark 2022 study published in Diabetes Care, in collaboration with Christian Medical College, Vellore, her team demonstrated that affected individuals do not exhibit classic insulin resistance, but rather have a severe insulin secretory defect—a fundamental and previously unrecognized distinction.

This discovery challenges long-held assumptions and underscores the urgent need for novel diagnostic and therapeutic strategies tailored to type 5 diabetes. The IDF’s recognition is expected to catalyze global research and healthcare policy reforms, focusing on this underappreciated form of diabetes rooted in nutritional poverty.

Here is my reply for Prof Vythi

Thank you so much for sharing this incredibly important development. The recognition of Type 5 Diabetes, or Malnutrition-Related Diabetes (MRD), by the International Diabetes Federation marks a pivotal moment in global endocrinology and public health. I am honoured to explore the pathophysiology of this form of diabetes with you Prof Dr Vythi.

Pathophysiology of Type 5 Diabetes (Malnutrition-Related Diabetes)

1. Core Mechanism: Severe Insulin Secretory Defect

Unlike Type 1 diabetes, which is autoimmune beta-cell destruction; and Type 2 diabetes, which involves insulin resistance and eventual beta-cell exhaustion;

Type 5 diabetes is driven by a profound failure of insulin secretion, but without the autoimmune component.

Affected individuals have no insulin resistance (in fact, they are highly insulin-sensitive due to their lean body mass). There is also no evidence of islet autoimmunity, and there is minimal to no C-peptide levels, reflecting exhausted or developmentally impaired beta cells.

Type 5 diabetes is a nutritional deficiency disease that nutritionists can understand and diagnose better. 

It is a disease that impairs the pancreatic beta cells during chronic undernutrition, especially during fetal development and early childhood, leads to inadequate micronutrients (zinc, magnesium, B-vitamins, etc.) crucial for pancreatic development. It also impaired islet cell growth and differentiation.

This disorder is triggered by possible epigenetic alterations affecting insulin gene expression. Furthermore, long-term energy deficiency causes the body to prioritize essential organs (brain, heart) at the expense of pancreas, resulting in underdeveloped or metabolically fragile beta cells.

This diabetes is characterized by low muscle mass and low hepatic glycogen stores. These patients have low muscle mass, hence low glucose disposal capacity, and are prone to hypoglycemia in the absence of robust insulin-glucagon regulation,

Patients may display paradoxical glucose swings (somewhat like brittle diabetes) due to poor metabolic buffering.

 Here are Additional Features of Type 5 Diabetes

Feature	Type 1	Type 2	Type 5 (MRD)
Autoimmunity	Yes	No	No
Insulin resistance	No	Yes	No
C-peptide	Very low	Normal/High early	Very low
Nutritional status	Normal/overfed	Overfed	Chronically undernourished
Ketosis-prone	Yes	Sometimes	Sometimes (but atypical pattern)
Response to insulin	Good (Type 1)	Variable (Type 2)	Poor or paradoxical in some cases

Type 5 Diabetes Is It Hard to Manage for the following reasons: 

1. Unpredictable insulin requirements – Because insulin sensitivity is high but secretion is minimal.
2. Lack of standard diagnostic criteria – Until recently, they were misclassified as atypical Type 1 or 2.
3. Poor access to healthcare – Many live in low-resource settings without proper monitoring tools.
4. High mortality – Many succumb to untreated hyperglycemia or ketoacidosis within a year.

 Hypotheses for Pathogenesis

1. Developmental Origins of Health and Disease (DOHaD): Suggests that malnutrition during fetal and early postnatal life "programs" the endocrine pancreas in a way that compromises later insulin secretion.

2. Protein-Calorie Malnutrition (PCM): Chronic PCM reduces the availability of amino acids and cofactors needed for insulin biosynthesis.
3. Pancreatic Atrophy or Fibrosis: Chronic undernutrition and infection may cause subclinical pancreatitis or pancreatic fibrosis, leading to reduced insulin output.

Micronutrient Deficiency Hypothesis:

1. Zinc deficiency impairs insulin crystallization and secretion,

2. Magnesium affects insulin receptor signaling (less relevant here, but still systemic),
3. Vitamin A is crucial for islet cell integrity.

Global Health Significance

The recognition of this entity allows focused clinical trials, biomarker development, and targeted therapy, such as:

1. Nutritional rehabilitation with micronutrient-enriched formulas,

2. Possibly pancreas-supportive agents (like GLP-1 analogs) where feasible,
3. Carefully titrated insulin therapy (lower doses than in T1DM),
4. Longitudinal screening of undernourished children for early pancreatic dysfunction.

Summary: 

Type 5 Diabetes is not merely a metabolic disorder, but a disease of early life deprivation, echoing Barker’s hypothesis about fetal programming. It is an urgent call to integrate nutrition, developmental biology, and endocrine care in underserved populations.

My simple short theory behind this pathology is because the body ties to compensate for low blood sugar in energy-deficiency malnutrition such as in marasmus by increasing the blood sugar levels. 

The body compensates for chronic low energy availability by attempting to elevate blood sugar level. This adaptive response may indeed stress the pancreatic beta cells over time, especially when they are already developmentally compromised by malnutrition. What starts as a survival mechanism may eventually contribute to metabolic failure.

In fact, in muramic or severely underfed individuals, the body is in a catabolic state where:

• Gluconeogenesis is upregulated (from amino acids, glycerol),

• Insulin levels are suppressed to preserve glucose for the brain,

• Counter-regulatory hormones like cortisol and glucagon are elevated,

• And over time, the pancreas becomes metabolically inactive or atrophied—a kind of "use it or lose it" phenomenon.

My short explanation above is not only simple, but I believe is  foundational. In science, such core insights often blossom into deeper understanding when placed under the microscope of physiology. 

It is my joy and honour to explore these frontiers with you Professor Dr Vythi.  You are a true seeker of truth and wisdom to share this piece  of "new" disease of malnutrition with me, and I consider it a privilege to accompany you on this path of learning new discoveries in medicine

lim ju boo