Insulin Effect During Embryogenesis Determines Fetal Growth A Possible Molecular Link Between Birth Weight and Susceptibility to Type 2 Diabetes Yasuo Terauchi, Naoto Kubota, Hiroyuki Tamemoto, Hiroshi Sakura, Ryozo Nagai, Yasuo Akanuma, Satoshi Kimura, and Takashi Kadowaki
Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic -cell type glucokinase knockout (Gck+/–) mice and female wild-type (WT) or Gck+/– mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck–/– neonates had significantly smaller birth weights than WT or Gck+/– neonates (means ± SE 1.49 ± 0.03 [n = 30] vs. 1.63 ± 0.03 [n = 30] or 1.63 ± 0.02 [n = 50] g, respectively; P < 0.01). Thus, Gck mutations in -cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes. Diabetes 49:82–86, 2000
From the Department of Internal Medicine (Y.T., N.K., R.N., S.K., T.K.), Graduate School of Medicine, University of Tokyo; the Department of Molecular Medicine (H.T.), Institute for Molecular and Cellular Regulation, Gunma University; the Diabetes Center (H.S.), Tokyo Women’s Medical University; and Institute for Diabetes Care and Research (Y.A.), Asahi Life Foundation, Tokyo, Japan. Address correspondence and reprint requests to Takashi Kadowaki, MD, PhD, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail:
[email protected]. Received for publication 22 June 1999 and accepted in revised form 5 October 1999. Gck, glucokinase; IRI, immunoreactive insulin; Irs, insulin receptor substrate; PCR, polymerase chain reaction. 82
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ype 2 diabetes is characterized by insulin secretory dysfunction and peripheral insulin resistance (1,2). These abnormalities are either genetically defined or augmented by hyperglycemia itself and may interact in a complex manner to cause and sustain hyperglycemia. Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance (3,4). These observations have led to the hypothesis that growth retardation affecting the development of particular organs at the fetal stage will predispose the individual to impaired organ function with consequent disease in later life (5). Hales et al. (6) have hypothesized that low birth weight, which is a reflection of nutritional deprivation in utero, predisposes individuals to diabetes in later life. The researchers have suggested that type 2 diabetes is mainly the result of intrauterine environmental factors and that genetic factors play little or no role in its development, and they refer to this phenomenon as the “thrifty phenotype hypothesis” (6). On the other hand, many diabetes geneticists have assumed that individual susceptibility to type 2 diabetes is in large part genetically determined. In the early formulation of the thrifty genotype hypothesis, Neel (7) proposed that the exploding prevalence of diabetes in societies undergoing rapid Westernization resulted from selection for metabolically thrifty genes. These genes may have enhanced survival during prehistory but predispose individuals to diabetes given dietary abundance and a sedentary lifestyle. Thus, both environmental and genetic factors are considered to be involved in the pathogenesis of human type 2 diabetes. The same genetic factors that cause impaired insulin secretion and/or insulin resistance may alter both intrauterine growth and glucose tolerance in adulthood, thereby providing a link between them. Thus, we investigated whether birth weight can be modified in genetically engineered mice and cause impaired insulin secretion or insulin resistance. Glucose is the primary regulator of insulin secretion, and glucose-induced insulin secretion serves as a basic mechanism whereby mammals maintain their blood glucose levels within narrow limits. Glucokinase (Gck), which is mainly expressed in pancreatic -cells and in the liver, constitutes a rate-limiting step in glucose metabolism in these tissues (8,9). Thus, Gck has been proposed to act as a glucose senDIABETES, VOL. 49, JANUARY 2000
Y. TERAUCHI AND ASSOCIATES
TABLE 1 Birth weight variation, blood glucose levels, and serum insulin levels according to the presence of a fetal Gck gene mutation in offspring derived from crosses between Gck+/– father and WT mother or crosses between Gck+/– father and Gck+/– mother
WT Gck+/– father and WT mother§ Birth weight (g) Blood glucose (mg/dl) Serum IRI (ng/ml) IRI/blood glucose (ng/mg) Insulin content per total pancreas (µg of insulin/mg of protein) Gck+/+ father and Gck+/– mother Birth weight (g) Blood glucose (mg/dl) IRI (ng/ml)
Genotype of fetus Gck+/–
1.62 ± 0.02 (29) 52 ± 4 (29) 1.81 ± 0.25 (13) 3.27 ± 0.54 (13) 13.0 ± 2.0 (13)
1.54 ± 0.02 (26) 61 ± 6 (26) 1.28 ± 0.20 (16) 1.91 ± 0.30 (16) 13.7 ± 1.3 (16)
1.63 ± 0.03 (30) 41 ± 5 (21) 3.06 ± 0.51 (16)
1.63 ± 0.02 (50) 51 ± 6 (29) 2.15 ± 0.28 (18)
Gck–/– — — — — —
1.49 ± 0.03 (30) 61 ± 8 (11) 1.51 ± 0.20 (15)
P value*
P value†
P value‡
