Perspectives Type 2 Diabetes: Hypoinsulinism, Hyperinsulinism, or Both? Benjamin Glaser ype 2 diabetes is a very common an imprinting disorder on chromosome age, if the insulin secretion defect is metabolic disease and its 6, the precise genetic mechanism evident during fetal life, or normal for Tincidence is increasing rapidly of which has yet to be defi ned [4]. gestational age, if the functional defect worldwide [1]. Despite fi ve to six Common polymorphisms in some of develops after birth. Furthermore, both decades of extensive investigation, the these genes have been associated with HNF1A and HNF4A are thought to basic physiologic defect responsible for increased risk of developing the more interact with each other, affecting each type 2 diabetes mellitus (T2DM) is still common form of polygenic T2DM. Most other’s expression level in the beta-cell not known. It is now well accepted that of the diabetes-related genes thus far [12–14]. Patients with diabetes caused T2DM develops when the beta-cell is identifi ed are expressed in beta-cells by HNF1A and HNF4A mutations are unable to supply the amount of insulin and the diabetes-associated mutations phenotypically similar. It was expected, needed to maintain normal glucose are thought to result in decreased beta- therefore, that defects in either gene levels [2]. But is the primary problem cell function and inadequate insulin would affect fetal growth in the same in the beta-cell itself? Or is the problem secretion. In an article published in way. resistance to insulin action, which puts PLoS Medicine, Pearson et al. report Surprisingly, Pearson et al. found an abnormally high load on the beta- the birth weight of patients carrying that HNF4A mutations were associated cell, causing it to eventually fail? a mutation in either of two closely with increased fetal weight in patients, Epidemiologic studies have shown related genes associated with the whereas HNF1A mutations did not that genetic variation plays a very MODY syndrome, HNF4A and HNF1A, appear to affect fetal weight at all. important part in determining the testing the hypothesis that the primary This increase in fetal growth found in risk of developing diabetes. Currently defect caused by these genes results in HNF4A mutation carriers appears to be available data suggest that for the vast decreased insulin secretion [5]. a direct result of the fetal genotype and majority of patients with T2DM, the is not signifi cantly altered by maternal genetic risk is determined by a variable The New Study genotype. Similar weight gain was seen combination of an unknown number Birth weight is largely determined by in fetuses carrying an HNF4A mutation, of common genetic variants. Any of fetal insulin secretion. Defective insulin regardless of whether the mutation these variants alone is neither suffi cient secretion, such as is found in patients was inherited from the father or the nor necessary for diabetes to occur. with neonatal diabetes, is associated mother. Furthermore, this mutation- Genetic analysis of T2DM has yielded with low birth weight [6]. In contrast, associated increase in birth weight is only a few such genetic variants that beta-cell defects that cause increased, also seen when genetically discordant are consistently associated with risk unregulated insulin secretion siblings are compared, negating of disease. The study of monogenic as is found in hyperinsulinemic the importance of intrauterine disorders of glucose metabolism may hypoglycemia of infancy are associated environment in determining fetal shed light on potential mechanisms for with macrosomia [7]. In addition, weight in this setting. the common form of T2DM. maternal factors infl uence fetal insulin secretion, and thus fetal growth, Gene Mutations in Monogenic Funding: The author is funded by grants from the independently of specifi c genetic Russell Berrie Foundation and D-Cure, Diabetes Care Diabetes defects. Infants of diabetic mothers in Israel. To date, mutations in more than are exposed to increased glucose Competing Interests: The author has declared that ten genes have been associated with levels, which trigger increased fetal no competing interests exist. different forms of monogenic diabetes. insulin secretion and macrosomia. Maternal malnutrition or placental Citation: Glaser B (2007) Type 2 diabetes: Maturity-onset diabetes of the young Hypoinsulinism, hyperinsulinism, or both? PLoS Med (MODY), an autosomal dominant insuffi ciency results in decreased 4(4): e148. doi:10.1371/journal.pmed.0040148 disease with onset of diabetes typically nutrient supply to the fetus, decreased Copyright: © 2007 Benjamin Glaser. This is an before the age of 25 years, can be caused fetal insulin secretion, and poor fetal open-access article distributed under the terms by mutations in more than six genes [3]. growth. Interestingly, inappropriately of the Creative Commons Attribution License, Neonatal diabetes, either transient or low birth weight has been shown to be which permits unrestricted use, distribution, and reproduction in any medium, provided the original permanent, can be caused by mutations an important and highly signifi cant author and source are credited. in at least four different genes as well as predictor of late-onset T2DM [8,9]. Since both HNF1A and HNF4A are Abbreviations: MODY, maturity-onset diabetes of the young; T2DM, type 2 diabetes mellitus associated with insulinopenic diabetes The Perspectives section is for experts to discuss the in young adults [10,11], it would Benjamin Glaser is the director of the Endocrinology clinical practice or public health implications of a and Metabolism Service, Internal Medicine published article that is freely available online. be expected that affected newborns Department, Hadassah-Hebrew University Medical would be either small for gestational Center, Jerusalem, Israel. E-mail: [email protected] PLoS Medicine | www.plosmedicine.org 0619 April 2007 | Volume 4 | Issue 4 | e148 To determine if this increase in How then does this relate to the polygenic T2DM. Could the scenario birth weight is indeed caused by pathogenesis of polygenic T2DM? To described by Pearson et al. be a fetal hyperinsulinism, Pearson et defi ne the mechanism by which genetic common pathogenic mechanism for al. reviewed patient records, and variation predisposes to T2DM, two T2DM? Future studies are likely to determined that eight out of 54 of the major scenarios have been proposed. address these important questions. HNF4A patients with mutations had In the fi rst scenario, decreased beta- References transient neonatal hypoglycemia, and cell function, due to a primary beta-cell 1. Zimmet P, Alberti KG, Shaw J (2001) Global in three of these elevated insulin levels defect, predisposes to diabetes. In the and societal implications of the diabetes were documented. In contrast, none presence of increased demand for epidemic. Nature 414: 782–787. 2. Weir GC, Laybutt DR, Kaneto H, Bonner-Weir of the normal siblings or the patients insulin, such as obesity-related insulin S, Sharma A (2001) Beta-cell adaptation and carrying an HNF1A gene mutation resistance or physical inactivity, this decompensation during the progression of diabetes. Diabetes 50 (Suppl 1): S154–S159. had neonatal hypoglycemia. This relative inability to increase insulin 3. Vaxillaire M, Froguel P (2006) Genetic basis unexpected fi nding was confi rmed production becomes more evident of maturity-onset diabetes of the young. in a mouse model of beta-cell- and the incidence of frank diabetes Endocrinol Metab Clin North Am 35: 371–384. HNF4A 4. Diatloff-Zito C, Nicole A, Marcelin G, Labit H, specifi c depletion, which increases. In addition, it has been Marquis E, et al. (2007) Genetic and epigenetic resulted in intrauterine and postnatal hypothesized that fetal nutritional defects at the 6q24 imprinted locus in a cohort hyperinsulinism, with hypoglycemia in deprivation “programs” the beta-cells so of 13 patients with transient neonatal diabetes: New hypothesis raised by the fi nding of a the postnatal period. that they cannot adequately compensate unique case with hemizygotic deletion in the for increased insulin demands later critical region. J Med Genet 44: 31–37. Implications of the Findings in life, providing an environmental 5. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, et al. (2004) Activating Thus, it appears that MODY- mechanism with the same end result. mutations in the gene encoding the ATP- associated HNF4A mutations cause In the second scenario, there is sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med increased insulin secretion in the a primary defect causing insulin 350: 1838–1849. fetal and neonatal period, resulting in resistance. However, only a fraction 6. Pearson ER, Boj SF, Steele AM, Barrett increased birth weight and neonatal of patients with insulin resistance T, Stals K, et al. (2007) Macrosomia and hyperinsulinaemic hypoglycaemia in patients hypoglycemia. Over time, the beta-cell will develop frank diabetes. In the with heterozygous mutations in the HNF4A function decreases, and insulinopenic majority, the pancreas will compensate gene. PLoS Med 4(3): e118. doi:10.1371/ diabetes develops, usually during the with increased insulin secretion, journal.pmed.0040118 7. Glaser B (2000) Hyperinsulinism of the third decade of life. maintaining euglycemia. Thus, a newborn. Semin Perinatol 24: 150–163. This is not the fi rst example of second “defect” limiting the pancreas’s 8. Hales CN, Barker DJ, Clark PM,