Perinatal Hyperinsulinism as Possible Predisposing Factor for Diabetes Mellitus, Obesity and Enhanced Cardiovascular Risk in Later Life

Abstract

The importance of the intrauterine and neonatal metabolic environment as possible teratogenic determinants of predispositions to diabetes, obesity and cardiovascular diseases is discussed. Epidemiological, clinical and experimental results suggest that gestational diabetes or even slightly impaired glucose tolerance during pregnancy are important risk factors for the development of an increased Type II- and even Type I diabetes susceptibility in the offspring. In addition, early prenatal undernutrition might also predispose to enhanced risk of Type II diabetes, whereas perinatal overnutrition seems to enhance predominantly Type I diabetes susceptibility. In this context, fetal and/or neonatal hyperinsulinism occurring during a critical period of brain development and leading to permanent malorganization of hypothalamic regulation centres for metabolism and hence to malprogramming of the hypothalamo-pancreatic system, is discussed as a possible reason for lifelong enhanced diabetes susceptibility. In view of epidemiological and experimental findings, an epigenetic maternofetal transmission of such acquired persistent modifications can run over several generations, mediated by gestational hyperglycaemia and fetal or neonatal hyperinsulinism. In conclusion, a partial prophylaxis of diabetes mellitus, obesity and cardiovascular diseases appears to be possible by prevention of gestational diabetes--even mild forms of impaired glucose tolerance during pregnancy--as well as early prenatal undernutrition and perinatal overnutrition.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data

“…In vitro and other evidence shows that actively insulin-secreting beta cells are more prone to destruction via various mechanisms such as susceptibility to interleukin 1-beta and increased levels of islet antigens [52]. Further experimental animal data have been reviewed and potential mechanisms previously discussed [53]. A number of studies have found postnatal body size or growth to be associated with risk of type 1 diabetes [54,55].…”

—to: Hales CN, Ozanne SE (2003) For Debate: Fetal and early postnatal growth restriction lead to diabetes, the metabolic syndrome and renal failure. Diabetologia 46:1013–1019

“…It is worth noting that evidence from the literature has confirmed that rapid neonatal weight gain is the "missing" pathophysiological link between low birthweight and later increased risk of adipogenic and metabolic conditions, as we proposed ten years ago [4]. Clearly, there is a supposition that high and rapid neonatal weight gain is caused by neonatal overnutrition.…”

“…In contrast, epidemiological and experimental data exist that suggest that high birthweight as well as rapid neonatal weight gain are independent risk factors for overweight and obesity in later life [3,4,5]. It is worth noting that evidence from the literature has confirmed that rapid neonatal weight gain is the "missing" pathophysiological link between low birthweight and later increased risk of adipogenic and metabolic conditions, as we proposed ten years ago [4].…”

“…Clearly, there is a supposition that high and rapid neonatal weight gain is caused by neonatal overnutrition. Indeed, overfeeding in the neonatal period has been shown to lead to rapid neonatal weight gain, followed by overweight and associated metabolic disturbances later in life [3,4,5,6,7]. Moreover, in animal models of early postnatal overfeeding resulting in rapid early weight gain, all key features of the metabolic syndrome X were observed during life, including early obesity, impaired glucose tolerance and increased blood pressure [7].…”

“…Recognising that problems arise on both ends of the birthweight spectrum, however, will be as crucial in terms of research and clinical implications as investigating which maternal diseases or early postnatal events are of pathophysiological importance for perinatal programming [4].…”