Familiality of metabolic abnormalities is dependent on age at onset and phenotype of the type 2 diabetic proband

D. Tripathy,1 E. Lindholm,1 B. Isomaa,2 C. Saloranta,3 T. Tuomi,3 and L. Groop1

1Wallenberg Laboratory, Department of Endocrinology, Lund University, S-20502 Malmo, Sweden; 2Jakobstad Hospital, 68601 Jakobstad; and 3Department of Medicine, University Hospital, 00029 Helsinki, Finland

Submitted 18 March 2003 ; accepted in final form 14 July 2003


    ABSTRACT
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
To determine the impact of a family history of the common form of type 2 diabetes and the phenotype of the proband on anthropometric and metabolic variables in normoglycemic first-degree relatives, we studied 2,100 first-degree relatives of patients with the common form of type 2 diabetes (FH+) and 388 subjects without a family history of diabetes (FH–). All subjects participated in an oral glucose tolerance test to allow measurement of insulin secretion [30-min incremental insulin/glucose (I/G 30)] and insulin sensitivity [homeostasis model assessment (HOMA) of insulin resistance (IR)]. A subset participated in a euglycemic clamp (n = 75) and an intravenous glucose tolerance test (n = 300). To study the effect of a particular phenotype of the proband, insulin secretion and sensitivity were also compared between first-degree relatives of diabetic probands with high and low waist-to-hip ratio (WHR) and probands with early and late onset of diabetes. FH+ subjects were more insulin resistant, as seen from a higher HOMA-IR index (P = 0.006) and a lower rate of insulin-stimulated glucose uptake (P = 0.001) and had more features of the metabolic syndrome (P = 0.02, P = 0.0002) compared with FH– subjects. Insulin secretion adjusted for insulin resistance (disposition index, DI) was also lower in the FH+ vs. FH– subjects (P = 0.04). Relatives of diabetic probands with a high WHR had reduced insulin-mediated glucose uptake compared with relatives of probands with a low WHR (P = 0.04). Relatives of diabetic patients with age at onset <44 yr had higher HOMA IR (P < 0.005) and lower DI (P < 0.005) than relatives of patients with age at onset >65 yr (highest quartile). We conclude that early age at onset of type 2 diabetes and abdominal obesity have a significant influence on the metabolic phenotype in the nondiabetic first-degree relative.

insulin secretion; insulin sensitivity; metabolic syndrome; genetics of type 2 diabetes


THERE IS A STRONG GENETIC COMPONENT in the pathogenesis of type 2 diabetes mellitus, with 50–70% lifetime risk in twins (20, 26) and about fourfold increased risk of hyperglycemia in first-degree relatives of patients with type 2 diabetes (30, 35). The inheritance pattern is, however, unclear, and only in a small number of subjects have the underlying genetic defects been documented (7, 33).

Significant heterogeneity is observed in the clinical phenotypes of the different types of diabetes in Scandinavia, where 15% have classical early-onset type 1 diabetes, 10% have latent autoimmune diabetes in adults (LADA), and <5% have maturity onset diabetes of the young (MODY). Also, type 1 and type 2 diabetes occur together in ~10% of all diabetic families (17). The etiology of the remaining 60–65% of the common form of type 2 diabetes remains a topic of controversy (2, 5, 10). To circumvent the problems of secondary defects due to chronic hyperglycemia, several groups have studied normoglycemic relatives of patients with type 2 diabetes (6, 13, 18, 25, 31, 34). Considerable controversy still exists regarding the primacy of insulin resistance or defects in insulin secretion in the pathogenesis of the disease (9, 11, 21, 22, 24). In earlier studies, however, type 2 diabetes in the proband was considered to be homogenous, and the proband was not studied.

Recently, Vauhkonen et al. (32) reported that the metabolic defects in offspring of diabetic parents resemble those in the parents. However, in that study, 50% of the offspring had impaired glucose tolerance at the time of the study. Another problem with the earlier studies is that they did not take into account the dependence of insulin secretion on insulin sensitivity (3, 15, 25) or slight elevations in blood glucose concentrations. This is important, because the presence of insulin resistance could act as a compensatory stimulus for insulin secretion and thereby attenuate putative differences.

The Botnia study was designed to characterize early metabolic defects in first-degree relatives of diabetic subjects and to identify a genetic basis for these defects (9). Here, we have studied 2,100 glucose-tolerant first-degree relatives of patients with type 2 diabetes (FH+) and 388 spouses with no family history of diabetes (FH–) after exclusion of families with both type 1 and type 2 diabetes, LADA, and MODY. The specific aim was to determine 1) whether a family history of the common form of type 2 diabetes has an impact on insulin sensitivity and/or insulin secretion adjusted for insulin sensitivity and 2) whether the phenotype of the diabetic proband is reflected in the phenotype of the nondiabetic relative.


    METHODS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
The Botnia study was established in 1990 on the Western coast of Finland and later extended to other parts of Finland and Sweden (9). To date, ~9,000 subjects, patients with type 2 diabetes and their family members, have been studied. The subjects belonged to 1,342 nuclear families, with normoglycemic (FH+) individuals in each family averaging 1.5. For the present study, we excluded all subjects with glutamic acid decarboxylase-b (GADAb) >5 relative units and those from families with MODY or both type 1 and type 2 diabetes. All other normoglycemic (plasma glucose concentration <6.1 mmol/l at fasting and <7.8 mmol/l 2 h after an oral glucose tolerance test) relatives (n = 2,100) and control subjects without a family history of diabetes (n = 388) were included in the study.

To study the influence of the specific phenotype of the proband on the metabolic phenotype of the relative, diabetic probands (n = 516) were grouped by their WHR and the age of onset of diabetes.Go



View larger version (14K):
[in this window]
[in a new window]
 
 

We thereby identified 399 first-degree relatives of diabetic subjects with low WHR (1st quartile, males: <0.95 and females: <0.84) and 396 relatives with high WHR (4th quartile, males: >1.02 and females: >0.95). Likewise, the numbers of first-degree relatives of diabetic subjects with early (1st quartile, <44 yr) and late (4th quartile, >65 yr) age of diabetes onset were 310 and 353, respectively.

Body weight and height were measured with subjects in light clothing without shoes. Fat-free mass (FFM) was measured with infrared spectroscopy from the outer layer of the biceps on the dominant arm with a Futrex-5000 device (Futrex, Gaithersburg, MD). The coefficient of variation (CV) of repeated measurements by the same investigator was <1%. Waist circumference was measured with a soft tape on standing subjects midway between the lower rib and iliac crest. Hip circumference was measured over the widest part of the gluteal region, and WHR as a measure of central obesity was accordingly calculated. Three blood pressure recordings were obtained from the right arm of each seated person at 5-min intervals after 30 min of rest, and the mean values were calculated. Fasting blood samples were drawn for the measurement of GADAb, serum total cholesterol, HDL2 and HDL3 cholesterol, triglyceride, and free fatty acid (FFA) concentrations.

All subjects participated in an oral glucose tolerance test (OGTT) by ingesting 75 g of glucose in a volume of 300 ml (Glucodyn; Leiras, Turku, Finland) after a 12-h overnight fast. Samples for the measurement of glucose and insulin were drawn at –10, 0, 30, 60, and 120 min. Several indexes of insulin sensitivity and insulin secretion were calculated from the OGTT. The homeostasis model assessment (HOMA) of insulin resistance (IR) index was calculated by using the fasting plasma glucose and insulin concentrations (19).

As measures of insulin secretion we used the incremental 30-min insulin response (I30), as well as the ratio of 30-min insulin and glucose during the OGTT (I/G30) (12). As a surrogate of the disposition index (DI), we considered the product of insulin sensitivity (1/HOMA) and insulin secretion (I/G30) (14, 27).

Insulin action was also measured in a subset of subjects by a hyperinsulinemic euglycemic clamp. Subjects in different subgroups in which euglycemic clamps were performed numbered 54 for FH+ and 21 for FH–. After a priming dose of insulin, an infusion (infusion rate 45 mU/m2) of short-acting human insulin (Actrapid; Novo Nordisk, Bagsvaerd, Denmark) was started and continued until 120 min. Blood samples for the measurement of blood glucose were obtained at 5-min intervals throughout the clamp. A variable glucose infusion of 20% glucose was started to maintain blood glucose concentration unchanged at 5.5 mmol/l, with a CV of 6%. Insulin sensitivity was calculated from the glucose infusion rates during the last 60 min of the euglycemic clamp (M value) and expressed as glucose uptake per lean body mass.

A subset of subjects underwent an intravenous glucose tolerance test (IVGTT; n = 300: FH+ = 278, FH– = 22). Briefly, 0.3 g/kg body weight of a 50% glucose solution was given at time 0. Blood samples for the measurement of insulin and blood glucose were obtained at –10, 0, 2, 4, 6, 8, 10, 20, 40, 50, and 60 min. The first-phase insulin response (FPIR) was calculated as the incremental insulin response during the first 10 min of the study. To quantify the relation between insulin secretion and insulin sensitivity, we measured the DI (3, 15), the product of insulin sensitivity (M value) and insulin secretion (FPIR).

Assays. Plasma glucose during the clamp was measured with a glucose oxidation method by use of a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Serum insulin concentrations were measured with a specific radioimmunoassay (Pharmacia, Uppsala, Sweden), with an interassay CV of 5%. Serum C-peptide concentrations were measured with radioimmunoassay (Linco Research, St. Charles, MO) with an interassay CV of 9%. FFA were measured by an enzymatic colorimetric method (Wako Chemicals, Neuss, Germany). Serum total cholesterol, HDL subfractions (after precipitation), and triglyceride concentrations were measured on a Cobas Mira analyzer (Hoffman-La Roche, Basel, Switzerland). GAD65 antibodies were determined by a modified radiobinding assay employing 35S-labeled recombinant human GAD65 (10a). Screening for MODY mutations was carried out as described earlier (15a).

Statistical analysis. All data are expressed as means ± SE. The significance of difference between groups was tested with Student's t-test and Mann-Whitney's test when applicable. The average number of individuals from each family was 1.5, with a range from 1 to 6 members in a family. Therefore, the subjects did not completely represent independent observations. To avoid this problem, we reanalyzed the data by using weighted family-specific means from different families for all variables that showed a significant difference in the first analysis. While comparing relatives of diabetic subjects from different phenotypes, we also analyzed the data by limiting individuals to one from each family. Measured variables were log transformed when they were not normally distributed. Computation was performed using the NCSS statistical package (Statistical Solutions, Cork, Ireland). Spearman's correlations were used for univariate correlation between the variables, and least square regression analysis was carried out to test differences in slopes from the regressions.


    RESULTS
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Comparison between subjects with (FH+) and without (FH) a family history of the common form of type 2 diabetes. Despite similar FFM, FH+ subjects had a higher WHR than the FH– subjects (P = 0.0001; Table 1). The difference remained significant even after adjustment for the difference in body mass index (BMI; P = 0.002). Systolic blood pressure (P = 0.009) and triglyceride concentrations were higher (P = 0.02), and HDL (P = 0.02), particularly the HDL2 (P = 0.0002) concentrations, were lower in the FH+ compared with the FH– subjects. There was no difference in age or BMI between FH+ and FH– subjects who had a euglycemic clamp (n = 75) or the IVGTT (n = 300).


View this table:
[in this window]
[in a new window]
 
Table 1. Clinical characteristics of, and insulin secretion and sensitivity in, all subjects with and without a family history of the common form of type 2 diabetes

 

Insulin sensitivity. FH+ subjects were more insulin resistant, as reflected by higher fasting insulin (P = 0.03) and higher HOMA (P = 0.006) values compared with FH– subjects. This was further supported by a reduced rate of glucose uptake (8.11 ± 0.34 vs. 10.3 ± 0.5 mg · FFM kg–1 · min–1, P = 0.001) in FH+ compared with FH– subjects. The insulin area under the OGTT curve adjusted for glucose was also higher in the FH+ than in the FH– subjects (P = 0.04), suggesting impaired insulin action.

Insulin secretion. There was no difference in insulin secretion measured as FPIR between FH+ and FH– groups (250 ± 35 vs. 258 ± 10 mU · l–1 · 10 min–1, P = not significant). However, the insulin secretion adjusted for insulin sensitivity (DI) was lower in FH+ than in FH– subjects (1,805 ± 155 vs. 2,715 ± 422, P = 0.04).

Comparison of clinical and metabolic characteristics between relatives of type 2 diabetic probands with high and low WHR and early and late age of onset of diabetes. The probands were divided into quartiles of WHR and age of onset of diabetes. The relatives of diabetic subjects with high WHR had higher BMI (P < 0.005), and the females had higher WHR compared with relatives of probands with a low WHR (Table 2). The relatives of probands with a high WHR were more insulin resistant, as manifested by a lower rate of insulin-stimulated glucose uptake (8.1 ± 0.6 vs. 10.6 ± 0.7, P = 0.02) and higher lnHOMA IR (0.40 ± 0.02 vs. 0.48 ± 0.02, P = 0.02) compared with relatives of probands from the lowest WHR quartile (Table 2). In addition, they had higher total cholesterol and triglyceride concentrations than relatives of probands with low WHR. The waist circumference in relatives of probands with high (r = 0.526, P < 0.005) and low WHR (r = 0.299, P < 0.005) correlated with the lnHOMA IR. However, the slopes were significantly different (Fig. 1, P = 0.0002); e.g., for the same WHR there was a steeper increase in insulin resistance in those from the high compared with the low WHR. No difference was observed in insulin secretion adjusted for insulin sensitivity between the two groups.


View this table:
[in this window]
[in a new window]
 
Table 2. Clinical characteristics of, and measures of insulin secretion and sensitivity in, normoglycemic first-degree relatives of diabetic probands with low (1st quartile) and high (4th quartile) WHR

 


View larger version (33K):
[in this window]
[in a new window]
 
Fig. 1. Relationship between waist circumference (waist; x-axis) and insulin resistance (IR) described by the homeostasis model assessment (lnHOMA) in relatives of diabetic subjects with a high waist-to-hip ratio (WHR; {triangleup}) and relatives of diabetic subjects with a low WHR. Note difference between the 2 regression lines: unbroken line, relatives of probands with high WHR; broken line, relatives of probands with low WHR. P = 0.0002.

 

Relatives of probands with age at onset before 44 yr (lowest quartile) were, as expected, younger than relatives of probands with onset of diabetes >65 yr (highest quartile; age 42.9 ± 0.9 vs. 48.3 ± 0.7, P < 0.005) (Table 3). Despite this, they were more insulin resistant (HOMA IR 1.85 ± 0.05 vs. 1.59 ± 0.05, P < 0.005) and had significantly reduced {beta}-cell function, lnI/G30 (1.15 ± 0.02 vs. 1.24 ± 0.02, P = 0.001), particularly after adjustment for insulin sensitivity (lnI/G30/HOMA, 0.94 ± 0.001 vs. 1.08 ± 0.01, P < 0.0005) and lower HDL2 and HDL3 concentrations compared with subjects whose relatives had onset of diabetes after 65 yr (Fig. 2).


View this table:
[in this window]
[in a new window]
 
Table 3. Clinical characteristics of, and measures of insulin secretion and sensitivity in, normoglycemic first-degree relatives of probands with early and late onset of diabetes

 


View larger version (17K):
[in this window]
[in a new window]
 
Fig. 2. Insulin sensitivity (lnHOMA IR) and disposition index (I/G30/HOMA IR) in relatives of probands with early (solid bars) and late onset (open bars) of diabetes mellitus.

 


    DISCUSSION
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
The present study adds several pieces of new information regarding familiality of insulin secretion and insulin sensitivity. Insulin resistance was a predominant feature of FH+ subjects, particularly if the proband had abdominal obesity or early onset of diabetes. The presence of insulin resistance was further supported by the occurrence of features of the metabolic syndrome, including high WHR, blood pressure, and triglycerides and low HDL cholesterol concentrations in FH+ subjects.

Impairment in insulin action has been reported in nondiabetic relatives of patients with diabetes (6, 11, 13, 34). On the other hand, there have been conflicting reports regarding the impact of a family history of diabetes on insulin secretion (1, 18, 21, 24). Compared with these earlier studies, the present study is unique in several aspects. First, we have a truly homogeneous population of a large number of individuals without confounding factors affecting pancreatic {beta}-cell function, like the presence of GAD antibodies or known MODY mutations. Second, we have included only subjects with normal glucose tolerance. Third, insulin secretion has been adjusted for the degree of glycemia and insulin sensitivity. Fourth, we have also taken into account the possible heterogeneity in the phenotype of the diabetic probands.

Insulin sensitivity was clearly impaired in FH+ subjects, reflected by lower insulin-stimulated glucose uptake and higher HOMA IR. Also, insulin secretion (FPIR) adjusted for insulin sensitivity (M value) was reduced, suggesting that the FH+ subjects were not able to compensate for their degree of insulin resistance. This measure (DI) is an important test of the degree of metabolic derangement, because subjects with low DI have been shown to have an increased risk of developing future diabetes (36).

A key finding was also that relatives of diabetic probands with abdominal obesity were more insulin resistant and showed more features of the metabolic syndrome than relatives of nonobese probands. Interestingly, in siblings of probands with high WHR, a small increase in abdominal obesity had a greater impact on insulin resistance than in siblings of probands with low WHR. Several studies have shown that measures of abdominal obesity show strong heritability (16, 29). It has been suggested that genetic factors account for ~40% of total body fat but that genetic factors contribute more to abdominal than to subcutaneous fat (4, 23, 28). Familiality does not a priori mean that a trait is inherited; twin studies have shown that both genetic and environmental factors contribute to insulin resistance, whereas genetic factors are more likely to determine insulin secretion (16). These findings may seem at variance with studies suggesting greater recurrence risk of diabetes in first-degree relatives of nonobese than obese type 2 diabetic patients (35). It should, however, be kept in mind that we did not estimate risk of diabetes in the relatives, only the presence of metabolic abnormalities.

Relatives of diabetic probands with early-onset disease were more insulin resistant and had lower insulin secretion compared with relatives of subjects with late-onset diabetes. Our results agree with similar observations in the Pima Indians, where the offspring of mothers with early-onset diabetes (<35 yr) had a reduced {beta}-cell function but unchanged insulin sensitivity (8). These data suggest not only that the probands with early-onset diabetes had a more severe form of diabetes but also that the metabolic abnormalities showed a greater degree of familiality than in relatives of type 2 diabetic patients with late-onset disease. Of importance, this is not due to admixture of patients with MODY and LADA, who were excluded by genetic and antibody testing.

In conclusion, this study clearly reinforces the importance of age at diabetes onset when patients are selected for genetic studies, because the metabolic phenotype of the proband is shared by relatives of probands with early- but not of late-onset diabetes. The study further emphasizes the value of stratifying for a phenotype characterized by abdominal obesity, as this characteristic also shows a high degree of familiality.


    DISCLOSURES
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
The study was financially supported by grants from the Sigrid Juselius Foundation, J. D. F. Wallenberg, the Academy of Finland, Swedish Medical Research Council, Finnish Diabetic Research Foundation, Swedish Diabetic Research Foundation, European Economic Council Paradigm (BMU4-CT96–0662), and the Novo Nordisk Foundation.


    ACKNOWLEDGMENTS
 
We express our sincere gratitude to the participating subjects and to the Botnia Research Group for excellent technical assistance and for recruiting and clinically studying the patients.


    FOOTNOTES
 

Address for reprint requests and other correspondence: L. Groop, Dept. of Endocrinology, Malmü Univ. Hospital, Lund Univ., S-20502 Malmo, Sweden (E-mail: leif.groop{at}endo.mas.lu.se).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


    REFERENCES
 TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 

  1. Alford FP, Henriksen JE, Rantzau C, Vaag A, Hew LF, Ward GM, and Beck-Nielsen H. Impact of family history of diabetes on the assessment of beta-cell function. Metabolism 47: 522–528, 1998.[ISI][Medline]
  2. Arner P, Pollare T, and Lithell H. Different aetiologies of type 2 (non-insulin-dependent) diabetes mellitus in obese and nonobese subjects. Diabetologia 34: 483–487, 1991.[ISI][Medline]
  3. Bergman RN, Phillips LS, and Cobelli C. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68: 1456–1467, 1981.[ISI][Medline]
  4. Carey DG, Nguyen TV, Campbell LV, Chisholm DJ, and Kelly P. Genetic influences on central abdominal fat: a twin study. Int J Obes Relat Metab Disord 20: 722–726, 1996.[Medline]
  5. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37: 667–687, 1988.[ISI][Medline]
  6. Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E, Schalin C, and Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med 321: 337–343, 1989.[Abstract]
  7. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P, Permutt M, Beckmann J, Bell G, and Cohen D. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328: 697–702, 1993.[Abstract/Free Full Text]
  8. Gautier JF, Wilson C, Weyer C, Mott D, Knowler WC, Cavaghan M, Polonsky KS, Bogardus C, and Pratley RE. Low acute insulin secretory responses in adult offspring of people with early onset type 2 diabetes. Diabetes 50: 1828–1833, 2001.[Abstract/Free Full Text]
  9. Groop L, Forsblom C, Lehtovirta M, Tuomi T, Karanko S, Nissen M, Ehrnstrom BO, Forsen B, Isomaa B, Snickars B, and Taskinen MR. Metabolic consequences of a family history of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 45: 1585–1593, 1996.[Abstract]
  10. Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, and DeFronzo RA. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84: 205–213, 1989.[ISI][Medline]
  11. Grubin CE, Daniels T, Toivola B, Landin-Olsson M, Hagopian WA, Li L, Karlsen AE, Boel E, Michelsen B, and Lernmark A. A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37: 344–350, 1994.[ISI][Medline]
  12. Gulli G, Ferrannini E, Stern M, Haffner S, and DeFronzo RA. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 41: 1575–1586, 1992.[Abstract]
  13. Haffner SM, Miettinen H, Gaskill SP, and Stern MP. Decreased insulin action and insulin secretion predict the development of impaired glucose tolerance. Diabetologia 39: 1201–1207, 1996.[ISI][Medline]
  14. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, and Patterson JK. Increased insulin concentrations in nondiabetic offspring of diabetic parents. N Engl J Med 319: 1297–1301, 1988.[Abstract]
  15. Jensen CC, Cnop M, Hull RL, Fujimoto WY, and Kahn SE. Beta-cell function is a major contributor to oral glucose tolerance in high-risk relatives of four ethnic groups in the U.S. Diabetes 51: 2170–2178, 2002.[Abstract/Free Full Text]
  16. Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP, and Ponte D. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42: 1663–1672, 1993.[Abstract]
  17. Lehto M, Wipemo C, Ivarsson SA, Lindgren C, Lipsanen-Nyman M, Weng J, Wibell L, Widen E, Tuomi T, and Groop L. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia 42: 1131–1137, 1999.[ISI][Medline]
  18. Lehtovirta M, Kaprio J, Forsblom C, Eriksson J, Tuomilehto J, and Groop L. Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins. Diabetologia 43: 285–293, 2000.[ISI][Medline]
  19. Li H, Isomaa B, Taskinen MR, Groop L, and Tuomi T. Consequences of a family history of type 1 and type 2 diabetes on the phenotype of patients with type 2 diabetes. Diabetes Care 23: 589–594, 2000.[Abstract]
  20. Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-Jarvinen H, Freymond D, Nyomba BL, Zurlo F, Swinburn B, and Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318: 1217–1225, 1988.[Abstract]
  21. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, and Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: 412–419, 1985.[ISI][Medline]
  22. Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, and Friedman GD. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30: 763–768, 1987.[ISI][Medline]
  23. O'Rahilly S, Turner RC, and Matthews DR. Impaired pulsatile secretion of insulin in relatives of patients with non-insulin-dependent diabetes. N Engl J Med 318: 1225–1230, 1988.[Abstract]
  24. Perseghin G, Ghosh S, Gerow K, and Shulman GI. Metabolic defects in lean nondiabetic offspring of NIDDM parents: a cross-sectional study. Diabetes 46: 1001–1009, 1997.[Abstract]
  25. Perusse L, Rice T, Chagnon YC, Despres JP, Lemieux S, Roy S, Lacaille M, Ho-Kim MA, Chagnon M, Province MA, Rao DC, and Bouchard C. A genome-wide scan for abdominal fat assessed by computed tomography in the Quebec Family Study. Diabetes 50: 614–621, 2001.[Abstract/Free Full Text]
  26. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, and Gerich J. Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 273: 1855–1861, 1995.[Abstract]
  27. Pontiroli AE, Monti LD, Costa S, Sandoli PE, Pizzini A, Solerte SB, Mantovani E, and Piatti PM. In middle-aged siblings of patients with type 2 diabetes mellitus normal glucose tolerance is associated with insulin resistance and with increased insulin secretion. The SPIDER study. Eur J Endocrinol 143: 681–686, 2000.[ISI][Medline]
  28. Poulsen P, Kyvik KO, Vaag A, and Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study. Diabetologia 42: 139–145, 1999.[ISI][Medline]
  29. Radziuk J. Insulin sensitivity and its measurement: structural commonalities among the methods. J Clin Endocrinol Metab 85: 4426–4433, 2000.[Abstract/Free Full Text]
  30. Samaras K, Spector TD, Nguyen TV, Baan K, Campbell LV, and Kelly PJ. Independent genetic factors determine the amount and distribution of fat in women after the menopause. J Clin Endocrinol Metab 82: 781–785, 1997.[Abstract/Free Full Text]
  31. Selby JV, Newman B, Quesenberry CP Jr, Fabsitz RR, Carmelli D, Meaney FJ, and Slemenda C. Genetic and behavioral influences on body fat distribution. Int J Obes 14: 593–602, 1990.[ISI][Medline]
  32. Shaw JT, Purdie DM, Neil HA, Levy JC, and Turner RC. The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with Type II diabetes mellitus. Diabetologia 42: 24–27, 1999.[ISI][Medline]
  33. Stewart MW, Humphriss DB, Berrish TS, Barriocanal LA, Trajano LR, Alberti KG, and Walker M. Features of syndrome X in first-degree relatives of NIDDM patients. Diabetes Care 18: 1020–1022, 1995.[Abstract]
  34. Vauhkonen I, Niskanen L, Vanninen E, Kainulainen S, Uusitupa M, and Laakso M. Defects in insulin secretion and insulin action in non-insulin-dependent diabetes mellitus are inherited. Metabolic studies on offspring of diabetic probands. J Clin Invest 101: 86–96, 1998.[Abstract/Free Full Text]
  35. Velho G, Byrne MM, Clement K, Sturis J, Pueyo ME, Blanche H, Vionnet N, Fiet J, Passa P, Robert JJ, Polonsky KS, and Froguel P. Clinical phenotypes, insulin secretion, and insulin sensitivity in kindreds with maternally inherited diabetes and deafness due to mitochondrial tRNALeu(UUR) gene mutation. Diabetes 45: 478–487, 1996.[Abstract]
  36. Warram JH, Martin BC, Krolewski AS, Soeldner JS, and Kahn CR. Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113: 909–915, 1990.[ISI][Medline]
  37. Weijnen CF, Rich SS, Meigs JB, Krolewski AS, and Warram JH. Risk of diabetes in siblings of index cases with Type 2 diabetes: implications for genetic studies. Diabet Med 19: 41–50, 2002.[ISI][Medline]
  38. Weyer C, Bogardus C, Mott DM, and Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 104: 787–794, 1999.[Abstract/Free Full Text]




This Article
Abstract
Full Text (PDF)
All Versions of this Article:
285/6/E1297    most recent
00113.2003v1
Alert me when this article is cited
Alert me if a correction is posted
Citation Map
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Google Scholar
Articles by Tripathy, D.
Articles by Groop, L.
Articles citing this Article
PubMed
PubMed Citation
Articles by Tripathy, D.
Articles by Groop, L.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2003 by the American Physiological Society.