Why Lean Individuals Develop Diabetes Type 2?

Type 2 diabetes is frequently considered a condition that only affects overweight persons. However, it can also affect lean and underweight individuals.

There are obese, normal-weight, and lean T2DM patients, with respective BMIs of:

• Underweight: < 19 kg/m².
• Normal BMI: 19–23.9 kg/m².,
• Overweight: BMI of >24 kg/m².,
• Obese: BMI >30 kg/m².
• Morbid Obese: BMI > 40 kg/m².
• Super Obese: BMI >50 kg/m².

The prevalence of various metabolic abnormalities and pathophysiologic processes distinguishes the several diverse T2DM manifestations.

BMI

Age-related reduction in muscle mass and changes in the distribution of fat by sex are not taken into account by the BMI calculation.

Therefore, the BMI values are a misrepresentation of the adiposity that the definition is intended to clarify.

Despite having a normal BMI, a person with central obesity has a high mortality risk.

Although BMI is directly correlated with the level of insulin resistance, diverse populations’ body proportions, or the relationship between body weight and body shape, prevent it from being correlated with a particular level of fatness.

Waist circumference

The waist circumference or waist-hip ratio can be used to assess abdominal obesity (WHR).

Even among these slim patients, it is possible to find aberrant fat pads in numerous body regions, giving them the propensity to be metabolically obese (ectopic fat deposition) [ref].

What causes Diabetes Type 2 in Lean persons?

Lean diabetes may represent a novel pathogenic entity, but the evidence suggests that it is most likely a subtype of T2DM.

A deeper understanding of the genetic and environmental factors that influence insulin action and secretory function will be necessary to fully comprehend the causes of T2DM.

Environmental Elements

Some environmental factors, the majority of which are validated by numerous observational studies, have been related to T2DM in non-obese individuals.

They are broken down into prenatal, early life, and adult social risk factors, such as socioeconomic status, smoking, and alcohol use.

A low-protein diet during infancy is linked to lower beta-cell mass and insulinopenia, according to several animal studies.

Numerous research has revealed a link between lean diabetes, early-life malnutrition, and low socioeconomic position [ref].

Additionally, this kind of diabetes is more common in rural areas than in both obese and non-obese diabetes [ref].

Additionally, pancreatic beta-cell malfunction and apoptosis have been connected to chronic alcohol use. Smoking exposure, both active and passive, is positively and independently associated with diabetes.

Numerous observational studies have shown that the male preponderance of the disease may be related to the prevalence of these societal factors.

By focusing on risk factors that may be changed, like smoking and alcohol consumption, the condition could be stopped before it worsens in slim people [ref].

Genetic influences

The hereditary variables, which differ from region to region of the world, are the biggest indicators of T2DM in non-obese people.

Specific pharmaceutical therapies that can address the pathogenic imbalance causing the disease may be informed by a thorough analysis of the genetic basis of the condition.

In non-obese people with T2DM, several studies support a favorable family history of between 16 and 25 percent. Previous genes have been linked to T2DM risk, but solely through their effects on obesity and lifestyle [ref].

The genetic propensity causes a more fragile beta cell, which causes apoptosis and early cell death. According to other studies, slim people with T2DM are more likely to have the genetic markers for this fragility than obese people.

Additionally detected are polymorphisms in the transcription factor FL2 gene and the ATP-sensitive potassium channel Kir6.2.

Leaner and more susceptible to insulin are those who carry it. The pathogenesis of T2DM in non-obese people may also be genetically influenced by insulin resistance, but this would be better categorized under other distinct forms of diabetes [ref].

Pathophysiology

It is still unclear what exactly is causing hyperglycemia in a patient with lean T2DM. The concept of sarcopenic obesity, in which there is metabolic obesity from excess adiposity with decreasing muscle mass, is becoming increasingly prevalent.

Even the slight increase in insulin resistance that the lean body weight brings about cannot be handled by failing beta cells. In line with this, it makes sense to argue that the ratio of fat to total body weight—rather than the total body weight itself—is more significant.

The crucial point—and one that may be challenging to achieve—is whether we should strive for lower body weight or lower body adiposity to prevent diabetes [ref].

A fast beta-cell loss seems to be the primary pathophysiology as a result of a higher prevalence and earlier onset of insulin use.

Insulin secretion dysfunction

A lack of first-phase insulin secretion in response to intravenous glucose is the earliest and most frequent impairment of insulin secretion.

Reduced insulin secretion is caused in part by decreased beta-cell function mass seen in both lean and obese individuals, as well as additional functional defects of pancreatic insulin secretion, which lead to hyperglycemia, which is more pronounced in the non-obese group.

Reduced secretion of gut incretin hormones is another relatively unknown defect that contributes to impaired insulin secretion in T2DM.

The BMI and the WHR both increase glucagon-like peptide-1 in opposite directions (GLP-1).

According to BMI criteria, only non-obese T2DM patients have preserved GLP-1 secretion in response to an oral glucose load [ref].

Insulin resistance

In comparison to those with normal insulin sensitivity, individuals with insulin resistance have significantly higher TG, LDL, and HDL cholesterol levels.

As with obese people, the fat buildup is still the primary cause of insulin resistance in non-obese individuals. In non-Hispanic whites with T2DM, subcutaneous fat volume is linked to insulin resistance, but not visceral, intraperitoneal, or retroperitoneal fat [ref].

According to certain studies, visceral abdominal fat volume, but not subcutaneous abdominal fat volume, is related to insulin resistance in black people with type 2 diabetes [ref].

Insulin resistance in non-obese individuals is linked to poor insulin signaling in skeletal muscle and activation of the c-Jun N-terminal kinase (JNK) pathway.

The buildup of lipids in skeletal muscles and the higher level of overall adiposity that was noticed in insulin-resistant patients are both responsible for this disruption of cellular insulin action [ref].