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Lean Patients with Type 2 Diabetes?

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Author: Jerrine Fletcher, Doctor of Pharmacy Candidate, Florida A&M University College of Pharmacy and Pharmaceutical Sciences

Patients with lean body types/normal BMI’s and the indication of type 2 diabetes.

Type 2 diabetes is classified into insulin-resistant or insulin-deficient phenotype groups. There is a strong correlation between type 2 diabetes and the primary characteristic of obesity or overweight. However, a significant fraction of lean individuals, with a mean body mass index of 29 kg/m2, is developing type 2 diabetes.

The Journal of Clinical Endocrinology and Metabolism published a study looking at women with gestational diabetes who developed prediabetes or manifest diabetes ten months after delivery, and women who had normal glucose tolerance after gestational diabetes. The study reported that almost half the patients with prediabetes or type 2 diabetes had a low and definitively normal BMI around 22 kg/m2, low waist circumference, normal triglyceride levels, and a liver fat content below 1%. In addition, these patients’ condition could not be explained by insulin deficiency or beta-cell dysfunction, because they displayed a mixed phenotype of deficient insulin secretion along with insulin resistance.

In patients living with prediabetes, insulin secretion characterized by acute insulin response is usually lost in many cases. Lean women with prediabetes, however, have a normal critical insulin response. This response suggests a preserved beta-cell function. The oral glucose tolerance test also supported this finding because there were intact C-peptide responses in the first 30 minutes, which indicates a rapid insulin response. However, there was some beta-cell dysfunction because of documented increases in fasting glucose or impaired glucose tolerance.

The study also looked at the origins of insulin resistance and showed both hepatic and muscular insulin resistance components compared with the controls. The oral glucose tolerance test helped to calculate hepatic insulin resistance using the Abdul-Ghani and co-workers algorithm.  Increased liver fat is typically linked to hepatic insulin resistance. However, many post-gestational diabetes patients with prediabetes or T2DM with less than 1% of liver fat content showed hepatic insulin resistance. Hepatic insulin resistance is rapidly lost in patients with obesity and fatty livers if their calories are restricted. In lean patients, however, this type of energy overload would not be expected. To establish actual hepatic insulin resistance in lean subjects, insulin sensitivity, including hepatic glucose production and lipogenesis measurements, will have to be more directly addressed. In a study about type 2 diabetes, hepatic lipogenesis was linked to diabetes remission and relapse. An exciting aspect might be to use the fraction of palmitate in the liver-derived-very-low-density lipoprotein as a marker of hepatic lipogenesis.

Free fatty acids were noticeably increased in lean post-gestational diabetes women with glycemic disturbances. These patients had normal triglycerides and high-density lipoproteins-cholesterol and liver fat content below 1%. Thus, the presence of free fatty acids in lean patients can indicate peripheral adipose tissue lipolysis. Peripheral adipose tissue lipolysis may be linked to some degree of adipose tissue insulin resistance, which can impair the whole body and hepatic insulin sensitivity.

In the Whitehall II Study, a significant subgroup of participants with type 2 diabetes had a similar lean phenotype without metabolic syndrome. This study established a more comprehensive representation of this phenotype.  Studies conducted with lean patients are not in agreement with each other. Some studies report that normal-weight patients are at low risk for type 2 diabetes progression and cardiovascular disease. Others report a higher risk for the rapid decline of beta-cell function and cardiovascular disease.

Patients with diabetes who have impaired fasting glucose and impaired glucose tolerance are more likely to avoid T2DM onset than patients with impaired glucose tolerance. In the Diabetes Prevention Program, metformin was more effective in preventing the onset of diabetes in women with gestational diabetes mellitus than in any other group. This effect, however, was significant in participants who had obesity.

A lower VO2 max has been linked to less physical activity. In this report, prediabetic lean women had a lower VO2 maximum, and it is recommended that these patients increase physical activity and lower their free fatty acids. Exercise seems most effective in patients with impaired fasting glucose only or impaired glucose tolerance, and not a combination of the two. Further studies need to be conducted with lean patients and young patients without metabolic syndrome. There isn’t a definitive answer on how specific treatments may impact patients’ different prediabetes subtypes.

Practice Pearls:

  • Type 2 diabetes is strongly associated with obesity; however, many lean patients develop type 2 diabetes.
  • Metformin was the most effective at preventing the development of type 2 diabetes in women with gestational diabetes.
  • Acute insulin response was expected in lean women with prediabetes. However, the critical insulin response is typically lost in many cases of prediabetes.

 

Pfeiffer, Andreas F H, and Stefan Kabisch. “Lean (Pre)Diabetes – Underestimated and Underexplored.” The Journal of clinical endocrinology and metabolism vol. 106,8 (2021): e3278-e3280. doi:10.1210/clinem/dgab198

 

Jerrine Fletcher, Fourth Year Doctor of Pharmacy Candidate, Florida A&M University College of Pharmacy

 

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