Intrauterine under-nutrition is causal to health outcomes in later life. Under-nutrition, as seen in the developing countries, is of a combined protein-calorie nature and often multigenerational.

We studied Wistar rats at 50 generations of protein-calorie undernutrition (“Thrifty Jerry”).   Thrifty rats demonstrate low birth weight, high visceral adiposity, impaired glucose tolerance and insulin resistance, when compared to age/gender-matched Control (Chow-fed) rats. Serum biochemistry of Thrifty rats revealed higher circulating homocysteine, serum endotoxin and leptin with lower serum adiponectin, B12 and folate. The next logical step to correct for these defects was to place Thrifty rats on a normal diet.  However, following 2 generations of unrestricted access to commercial chow (now called Transition rats), we observe improvement in birth weight but at the cost of increased visceral adiposity, circulating leptin, impaired glucose tolerance and insulin resistance. Our experimental design mimics nutrient transition seen in populations of developing World that have faced under-nutrition for generations. Multiple aspects of metabolic syndrome were analysed using techniques including anthropometry, MRI imaging, DXA analysis, serum biochemistry, hyperinsulinemic-euglycemic clamp studies, gene expression studies and chromatin (histone) methylation analysis. Susceptibility to diabetes was measured by assessing dose response to the diabetogenic agent Streptozotocin (STZ). Following injection of 200mg/Kg of STZ (i.p), 90% of Control rats became diabetic by day 4 while all (n=20) of the Thrifty or Transition rats died within 12 hours of STZ injection. The dosage of STZ had to be reduced down to a single dose of 25mg/Kg to render all of the Thrifty and Transition rats diabetic in 48 hours from injection.

Our studies have significant implications to understanding the role of nutrient transition in development of obesity and diabetes. The 8-fold increase in susceptibility to diabetes in Thrifty and Transition rats suggests that multigenerational under-nutrition “primes” metabolic profile such that the resulting detrimental effects cannot be reversed after 2 generations of (macro-) nutrient availability.