Low birth weight associated with a distinct type 2 diabetes phenotype

Low birth weight (LBW) is associated with an increased risk of type 2 diabetes. At the recent EASD meeting in Stockholm, researchers at the Steno Diabetes Center in Copenhagen revealed that people with LBW are diagnosed at lower BMI and younger age than those of normal birthweight. They also reported that a high-carbohydrate diet has an adverse metabolic impact on those with LBW. Dr Susan Aldridge reports.

The risk for type 2 diabetes starts in the womb and, although obesity is a risk factor for type 2 diabetes for children and adults, the opposite is the case for babies. Low birth weight (LBW), linked to foetal malnutrition, is associated with a higher risk of type 2 diabetes, hypertension, cardiovascular disease and cancer. Dr Alexsander Lühr Hansen’s research on the Danish DD2 cohort explores what they believe to be a distinct type 2 diabetes phenotype associated with LBW.

“To do this, you need good birth data,” he said. “With older individuals, data don’t go that far back so we partnered with the Danish National Archives to digitise the original midwife records for the entire DD2 cohort.”

The study population was 6886 individuals newly diagnosed with type 2 diabetes either by the GP or at an outpatient clinic, divided into three birth weight categories – low (LBW – less than 3000g), normal (NBW – 3000g to 3700g) and high (HBW – more than 3700g).

The researchers looked at LBW versus NBW with respect to BMI and age at diagnosis. “We saw that low birth weight is associated with a higher prevalence of being under 45 or between 45 and 55 at diagnosis and lower prevalence of being diagnosed at age over 75 compared with those who had normal or high birth weight,” said Dr Lühr Hansen. “People with lower birth weight are also more likely to have a lower BMI of under 25 or between 25 and 30, and less likely to have a BMI over 40 at diagnosis.”

Other differences noted were that people with LBW had a lower waist circumference, a lower waist-hip and waist-height ratio and were less likely to have a family history of type 2 diabetes than those with higher birth weight. Finally, LBW was also associated with the presence of three or more comorbidities at diagnosis of type 2 diabetes. One of these was hypertension, with those with LBW being more likely to be on multiple hypertension medications than those of higher birth weight.

The researchers also explored the linearity of these associations. “For every kilogram of difference in birth weight, we see a 3.3 year difference in age of diagnosis,” said Dr Lühr Hansen. “And for BMI, the change per kilogram is 1.46 and for waist circumference it’s 3.9 cm.”

Finally, they looked at the possible role of genetic confounding. A polygenic risk score, including all the known genetic variants for type 2 diabetes, was worked out for a subgroup of participants. This was used as an exposure and LBW as the outcome. No specific associations were found, suggesting that genetic factors are not involved in the LBW phenotype. Studies are ongoing to shed light on the pathophysiology of the LBW phenotype – looking at, for instance, whether it is driven by beta cell deficiency.

Carb overfeeding study

“Low birth weight is a known risk factor for type 2 diabetes, especially when someone is exposed to affluent conditions and there is a mismatch between the foetal and the postnatal environment,” said senior researcher Charlotte Brøns. Accordingly, she and her team have been investigating the metabolic and physiological impact of various diets on people with LBW.

For instance, in one study, they showed that five days of high-fat overfeeding led to peripheral insulin resistance in lean young men. “In our most recent study, we showed that early middle-aged, non-obese, low birth weight men have significantly increased hepatic fat content compared with normal birth weight men,” Charlotte said. “And 20% of the low-birthweight men already had NAFLD.”  The reason is probably that diets high in simple carbohydrates, especially fructose, stimulate hepatic fat deposition and increase the risk of NAFLD through de novo lipogenesis.

To investigate the impact of carbohydrates in LBW individuals, they put together a new study. This involves four weeks overfeeding with simple carbohydrates to see if this is associated with differential changes in hepatic fat content, insulin resistance, whole-body energy metabolism, key metabolic hormones and metabolomic and lipidomic profiles in healthy, early middle-aged, LBW, non-obese men compared with NBW controls.

Data on 22 LBW and 21 NBW men with a mean age of 38 and no history of type 2 diabetes was drawn from the Danish Medical Birth Registry. The carbohydrate overfeeding consisted of giving the men packages containing 25% in excess of their daily calorie requirement in the form of fruit juice, sugar-sweetened soda and candy. As expected, they all increased their BMI as a result of overfeeding.

The LBW men had more hepatic fat than the NBW men at baseline and, in response to overfeeding, both groups had a similar increase in hepatic fat, but this did not affect the hepatic glucose production or hepatic insulin resistance. Both groups had an increase in fasting glucose and C-peptide, and an increase in energy expenditure.

With fasting plasma hormones, LBW individuals had lower levels of adiponectin, both at baseline and with overfeeding, while leptin levels were increased significantly in response to overfeeding, but it decreased in the NBW group. In the metabolomics part of the study, eight out of 65 metabolites responded differently to overfeeding in LBW men compared with NBW men. Further analysis revealed that these changes could increase reactive oxygen species and affect mitochondrial function in LBW individuals. And, in the lipidomics part of the study, the LBW group had a significantly higher number of lipids, including triglycerides and others known to be associated with the risk of NAFLD, insulin resistance and type 2 diabetes.

“We can speculate that with time and continued overfeeding, an increase in reactive oxygen species generation may lead to insulin resistance, mitochondrial damage and overt type 2 diabetes,” Charlotte concluded. “And the lipidomic signature is associated with insulin resistance, NAFLD and type 2 diabetes.” Further research into the impact of a high-carb diet on LBW individuals is needed, but the take-home message is that they need to take extra care to adhere to a healthy balanced diet if they want to mitigate their risk of type 2 diabetes.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.