Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60

Abstract

We studied the genetic and clinical features of diabetic subjects in a 5-generation Michigan-Kentucky pedigree ascertained through a proband with pancreatic agenesis and homozygous for the IPF1 mutation Pro63fsx60. Diabetic and nondiabetic family members were genotyped and phenotyped. We also carried out genetic studies to determine the history of the IPF1 mutation in the Michigan-Kentucky family and a Virginia family with the same mutation. We identified 110 individuals; 34 are currently being treated for diabetes and 10 of these are Pro63fsX60 carriers (ie, MODY4). Subjects with MODY as well as those with type 2 diabetes are characterized by obesity and hyperinsulinemia. Genetic studies suggest that the IPF1 mutation was inherited from an ancestor common to both the Michigan-Kentucky and Virginia families. MODY4 and type 2 diabetes in the Michigan-Kentucky pedigree are associated with obesity and hyperinsulinemia. Obesity and hyperinsulinemia have been observed occasionally in other subtypes of MODY, which suggests that hyperinsulinemia may be a general phenomenon when obesity occurs in MODY subjects. Hypoinsulinemia in nonobese MODY subjects seems to be caused by a functional defect in the beta cell. Genetic testing should be considered in multigenerational obese diabetic subjects, particularly when such families contain young diabetic members.

Figure 1

Michigan-Kentucky family with IPF1 mutation Pro63fsX60 and permanent neonatal diabetes, MODY4, type 2 diabetes, obesity and hyperinsulinemia. Because of its large size we show the pedigree in two panels, Figure 1A and 1B. Note that III-9 is shown in both Fig. 1A and B. Subject III-9, the grandfather of proband V-5, had three wives, two of whom with their offspring IV-16–20 are omitted from the figures. II-8 and II-9 were said to be third cousins. Squares indicate male and circles female subjects. The proband is shown in blue. Dark red denotes diabetic IPF-1 carrier (NM) or diabetic presumptive IPF1 carriers (I-4, II-2, II-12, III-7). Dark green denotes type 2 diabetes (NN) or presumptive type 2 diabetes (III-12, III-15). Black denotes non-genotyped diabetic subjects. Light red denotes untested (for carbohydrate intolerance) IPF1 carriers (NM) and light green untested IPF1 non-carriers (NN). A diagonal line through the symbol indicates normal glucose tolerance (IV-14 and -22). An open symbol indicates untested for carbohydrate intolerance and non-genotyped. White vertical stripe (V-4) indicates intermittent diabetes. A circle with slashes denotes gestational diabetes (IV-7). A slash extending beyond symbol indicates that the subject is deceased. Generation number is given on the left. The number to the upper left of individual subject gives individual numbers within each generation. Number immediately below subject is present age, followed by genotype (N = normal sequence allele, M – allele with Pro63fsX60 mutation). Number below genotype is age at diagnosis of diabetes. OHA = oral hypoglycemic agent; insulin = insulin therapy. Body weight: Obese, Normal = normal weight or thin.

Figure 1

Michigan-Kentucky family with IPF1 mutation Pro63fsX60 and permanent neonatal diabetes, MODY4, type 2 diabetes, obesity and hyperinsulinemia. Because of its large size we show the pedigree in two panels, Figure 1A and 1B. Note that III-9 is shown in both Fig. 1A and B. Subject III-9, the grandfather of proband V-5, had three wives, two of whom with their offspring IV-16–20 are omitted from the figures. II-8 and II-9 were said to be third cousins. Squares indicate male and circles female subjects. The proband is shown in blue. Dark red denotes diabetic IPF-1 carrier (NM) or diabetic presumptive IPF1 carriers (I-4, II-2, II-12, III-7). Dark green denotes type 2 diabetes (NN) or presumptive type 2 diabetes (III-12, III-15). Black denotes non-genotyped diabetic subjects. Light red denotes untested (for carbohydrate intolerance) IPF1 carriers (NM) and light green untested IPF1 non-carriers (NN). A diagonal line through the symbol indicates normal glucose tolerance (IV-14 and -22). An open symbol indicates untested for carbohydrate intolerance and non-genotyped. White vertical stripe (V-4) indicates intermittent diabetes. A circle with slashes denotes gestational diabetes (IV-7). A slash extending beyond symbol indicates that the subject is deceased. Generation number is given on the left. The number to the upper left of individual subject gives individual numbers within each generation. Number immediately below subject is present age, followed by genotype (N = normal sequence allele, M – allele with Pro63fsX60 mutation). Number below genotype is age at diagnosis of diabetes. OHA = oral hypoglycemic agent; insulin = insulin therapy. Body weight: Obese, Normal = normal weight or thin.

Figure 2

Offspring of II-8 (panel A), II-9 (panel B) and III-16 (panel C). The symbols and abbreviations are described in the legend to Figure 1.