Indian Write- Ups

Diagnosis

Lean Type 2 Diabetes

What is "lean type 2 diabetes"?

Type 2 diabetes mellitus or non-insulin diabetes mellitus (NIDDM) is generally associated with obesity especially in western populations. Indian patients with Type 2 diabetes are of normal body weight, or obese and in some cases are positively lean i.e. have a body mass index (BMI) (ratio of body weight in kg to the square of the height in meters) less than 20. Diabetes in the presence of low BMI is extremely rare in western populations and has mostly been described in patients from India and other developing countries. Several Indian investigators have characterized “lean Type 2 diabetes” patients seen in their practice and have advised more research to fully characterize this state which is rarely reported in western literature. In India the prevalence of Type 2 diabetes is very high, the prevalence of obesity is low, the onset of diabetes is at a younger age and the prevalence of ischemic heart disease is high. There has been considerable interest in the entity called “lean NIDDM” because such a subgroup of Type 2 diabetes is rarely seen among Europeans.

What are the peculiarities reported in “lean type 2 diabetes”?

Several Indian investigators have reported their findings in the state of Orissa, up to 22% of patients with Types 2 diabetes have been reported to be lean (BMI<19). Another report on patients seen at Hyderabad found 17.9% of them to be lean (BMI <20).

Mohan et al in a study that defined lean as BMI<18.5 reported that 3.5% of the patients seen at their center were lean. They had more severe diabetes and an increased prevalence of retinopathy, nephropathy and neuropathy. Lean Type 2 diabetes needed insulin more often than obese or normal weight Type 2 diabetes.

Shah et al found that lean (BMI<21) diabetes tended to have a less frequent family history of diabetes and hypertension, a lower systolic and diastolic blood pressure, and lower fasting triglyceride, cholesterol and insulin. Interestingly they found that when the patients were stratified according to the waist hip ratio (WHR). There was a systematic increase in fasting triglyceride at higher WHR. They thus opined that the use of BMI alone for defining ‘lean Type 2 diabetes’ misses a significant role played by regional fat distribution in relation to the risk for developing large vessel disease.

What is the pathophysiology in “lean Type 2 diabetes”?

Type 2 diabetes is a heterogeneous disorder unified under the term essential hyperglycemia. While several molecular mechanisms, which lead to secretion of abnormal insulin, abnormal insulin gene expression, abnormal insulin receptor expression, insulin receptor defects, have been described. These are rare and the exact cause of the great majority of common Type 2 diabetes is unknown. Defects in insulin secretion as well as insulin have been described. These include:

Loss of normal pulsatility of insulin secretion
Loss of first phase of insulin secretion
Insulin insensitivity at the insulin receptor level in liver, skeletal muscle and fat cells
Post receptor signaling defects
Prolonged second stage of insulin secretion and hyperinsulinaemia
Hyperproinsulinaemia and inadequate processing of proinsulin to insulin
Excessive amyloid deposition in between islet Beta cells
Beta cells exhaustion

Based on an analysis of data from their elegantly designed studies Kannan concluded that “lean Type 2 diabetes” is a distinct phase in the natural history of Type 2 diabetes mellitus as the patients march through a phase of deteriorating Beta-cell function with lean Type 2 patients and obese Type 2 patients at the opposite ends of the spectrum. After maximally recommended doses of OHAs, at least one-third of these patients require insulin for adequate control.

In addition to this some patients with presumed Type 2 diabetes are found to have antibodies to islet cell proteins and glutamic acid decarboxylase. These have now been labelled as ‘Latent Auto-immune Diabetes in Adults’ (LADA), but as the test is not done routinely, several of them are treated as Type 2 diabetes; and many respond to OHAs for a few years as the rate of islet Beta-cell destruction is low. Ultimately however these patients need insulin earlier than other Type 2 diabetes patients for optimal glycaemic control and to prevent ketosis.

In the lean patient with presumed Type 2 diabetes the possibility of LADA should be kept in mind. However Mohan et al have opined that there is a difference between LADA and “lean NIDDM” based on serum insulin as

What is the clinical implication of this knowledge?

Both Type 1 and Type 2 diabetes can occur at any age. The occurrence of Type 2 diabetes is not limited to the obese patient and Type 1 is not limited to the younger patient. The “lean” person with Type 2 diabetes may have an slowly developing Type 1 diabetes, have a maturity onset diabetes of the young (MODY) in which case a history of vertical transmission in the family for at least 3 generation can be found, or may have the secondary pancreatic, or may have what is called “lean Type 2 diabetes”.

The lean Type 2 diabetic is prone to develop more severe diabetes, and requires insulin earlier than normal weight or obese patients for adequate glycaemic control. Further research is ongoing to determine the exact nature of the defect and differences if any in complication rates.