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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 220-226
Copyright © 2001 by The Endocrine Society

Original Studies

Early-Onset Type 2 Diabetes: Metabolic and Genetic Characterization in the Mexican Population1

Carlos A. Aguilar-Salinas, Eduardo Reyes-RodrÍguez, Ma. Luisa Ordóñez-Sánchez, Marcelo Arellano Torres, Salvador Ramírez-Jiménez, Aarón Domínguez-López, Juan Ramón MartÍnez-Francois, Ma. Luisa Velasco-Pérez, Melchor Alpizar, Eduardo GarcÍa-GarcÍa, Francisco Gómez-Pérez, Juan Rull and Ma. Teresa Tusié-Luna

Departmento de Medicina y Unidad de Genética de la Nutrición del Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México (M.L.O.-S., S.R.-J., A.D.-L., J.R.M.-F., M.T.T.-L.); Departamento de Endocrinología y Metabolismo de Lípidos del Instituto Nacional de Ciencias Médicas y Nutrición (C.A.A.-S., E.R.-R., M.A.T., M.L.V.-P., E.G.-G., F.G.-P., J.R.); and Instituto Mexicano del Seguro Social (M.A.), Mexico City 14000, Mexico

Address all correspondence and requests for reprints to: Carlos Alberto Aguilar-Salinas, M.D., or Ma. Teresa Tusié-Luna, M.D., Ph.D., Vasco de Quiroga 15, Mexico City 14000, Mexico. E-mail: caas{at}aztlan.innsz.mx


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The objective of this study was to investigate possible defects in the insulin sensitivity and/or the acute insulin response in a group of Mexican patients displaying early-onset type 2 diabetes and to evaluate the contribution of mutations in three of the genes linked to maturity-onset diabetes of the young. We studied 40 Mexican patients with an age of diagnosis between 20 and 40 yr in which the insulin sensitivity as well as the insulin secretory response were measured using the minimal model approach. A partial screening for possible mutations in 3 of the 5 genes linked to maturity-onset diabetes of the young was carried out by PCR-single strand conformation polymorphism analysis. A low insulin secretory capacity (AIRg = 68.5 ± 5 µU/mL·min) and a near-normal insulin sensitivity (3.43 ± 0.2 min/µU·mL x 104) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1{alpha} (HNF-4{alpha}) gene (Asp126->His/Tyr and Arg154->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1{alpha} gene (Gln486->stop codon); 7.5% had positive titers for glutamic acid decarboxylase antibodies. Thirty-five percent of cases had insulin resistance; these subjects had the lipid abnormalities seen in the metabolic syndrome. A defect in insulin secretion is the hallmark in Mexican diabetic patients diagnosed between 20 and 40 yr of age. Mutations in either the HNF-1{alpha} or the HNF-4{alpha} genes are present among the individuals who develop early-onset diabetes in our population. These particular sequence changes have not been previously reported and therefore represent putative new mutations. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE 2 DIABETES mellitus is one of the major health and socio-economic problems worldwide, with a prevalence as high as of 8% in the Mexican population. In Mexico, according to a 1993 National Survey it was calculated that almost 1.9 million subjects were affected by type 2 diabetes; 300,000 of them were diagnosed at age 20–40 yr old (1). The socioeconomic and biological consequences of the early onset of type 2 diabetes are enormous. A large number of temporal or definitive incapacities before age 50 yr results from this characteristic of the disease. Also, these subjects frequently exhibit a more aggressive form of the disease, require insulin treatment at earlier time, and suffer from severe chronic complications (2). This subset of patients, generally refereed as early onset type 2 diabetes, is likely to represent an heterogeneous group. Maturity-onset diabetes of the young (MODY), a monogenic form of diabetes due to deficient insulin secretion (3), is present in a proportion of patients who develop the disease at early age (usually before 25 yr of age). On the other hand, Doria and co-workers described the presence of insulin resistance in a large proportion of early-onset patients from families not linked to any known MODY genes (4). Finally, some cases may correspond to a late-onset autoimmune diabetes.

Mutations in the genes encoding hepatocyte nuclear factor-4{alpha} (HNF-4{alpha}) (5), glucokinase (6), HNF-1{alpha} (7), insulin promoter factor-1 (8), and HNF-1ß (9) are linked to MODY. Clinical heterogeneity is well established among MODY patients. Those with mutations in the glucokinase gene (MODY 2) present a mild hyperglycemia, good glycemic control without the need for insulin, and rare or null appearance of vascular complications (10). In contrast, patients carrying mutations in the HNF-4{alpha} or the HNF-1{alpha} genes (MODY 1 and MODY 3, respectively) exhibit severe fasting hyperglycemia, a high percentage of insulin requirement, and a frequent occurrence of microvascular complications (11, 12). Different studies suggest that the prevalence of mutations in these genes differs considerably among various ethnic groups (13, 14).

Very few papers had focused their attention on characterization of the metabolic and genetic abnormalities observed in patients with type 2 diabetes diagnosed at age 20–40 yr. We believe that early-onset type 2 diabetes would be a useful model to study the metabolic consequences of the interaction of several degrees of insulin resistance and insulin deficiency in a group of subjects in whom the confounding effect of different ages is not present. The purpose of this study is to describe the metabolic and genetic abnormalities found in a group of type 2 diabetic patients diagnosed at age 20–40 yr.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty diabetic patients diagnosed between 20 and 40 yr of age were included in the study. They were recruited from the out-patient clinic of the Department of Endocrinology and Metabolism of the Instituto Nacional de la Nutrición Salvador Zubirán in Mexico City. Patients with type 1 or 2 diabetes were also included as controls (20 in each group). All cases were found among the patients who attended the clinic during a 3-month period. Diabetes was classified according the National Diabetes Data Group criteria (15). Exclusion criteria included plasma creatinine more than 265 µmol/L, nephrotic syndrome, or the presence of any acute disorder during the 4 weeks previous to the evaluation. Informed consent was obtained from all participants through their attending physicians.

Metabolic studies

The evaluation included the measurement, after a 12-h fasting, of glucose, creatinine, uric acid, blood count, hemoglobin A1c, thyroid and hepatic function tests, C peptide, anti-glutamic acid decarboxylase (GAD) antibody titers, lipid profile, apolipoprotein A1 (apoA1), apoB, apo(a), high density lipoprotein (HDL), and low density lipoprotein (LDL) subclasses and Lp(a) concentrations in every individual. In addition, an insulin-modified iv glucose tolerance test was performed only in the early-onset type 2 group (16). Three blood samples were obtained, at -10, -5, and 0 min, for basal serum glucose and insulin determinations. The mean values for the three samples were taken as basal levels. Thereafter, 0.3 g/kg glucose (50 mL 50% dextrose water) were infused over a 1-min period, followed by iv insulin (0.05 U/kg) dissolved in 30 mL 0.9% normal saline 19 min later, over a 1-min period. Twelve blood samples were obtained at frequent intervals for serum glucose and insulin levels. Samples were centrifuged at 4 C, and the sera were frozen and stored at -20 C until assayed. The insulin sensitivity index (SI; x10-4 min/µU·mL) and the acute insulin response (AIRg; microunits per mL/min) were estimated using the minimal model software program described by Bergman (17).

Genetic studies

For mutation screening, total genomic DNAs were extracted from whole blood as previously described (18). PCR-single strand conformation polymorphism (SSCP) analysis was performed to screen for the presence of possible mutations within the exons and the intron-exon junctions of the glucokinase, HNF-4{alpha}, or HNF-1{alpha} genes. The search was focused on those exons with the highest prevalence of mutations reported for each of these genes (19). The primer sequences and the annealing temperature for each of the analyzed exons are shown in Table 2Go. PCR amplifications were performed in the presence of [{alpha}-32P]CTP. For the SSCP analysis the PCR products were denatured at 95 C in a solution containing 95% formamide and run in 6% acrylamide gels in the presence or absence of 10% glycerol at 2–8 watts for 12–24 h as previously described (20, 21). To determine whether a change in migration corresponded to a possible mutation or represented a sequence polymorphism, a group of 110 healthy individuals was analyzed in parallel. In the SSCP analysis a PCR fragment containing a putative mutation will display a migration pattern not observed among the control individuals. Those fragments with an anomalous migration pattern were further analyzed by direct sequencing by either automatic or manual methods. For manual sequencing the Sequenase version 2.0 kit was used. Automated sequencing was performed using an Applied Biosystem 310 sequencer from Perkin-Elmer Corp. (Foster City, CA), according to the manufacturer’s specifications.


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  		Table 2. Oligonucleotides used for the amplification and sequencing of the corresponding exons for the glucokinase, TCF-14, and the TCF-1 genes

 
Methods

The laboratory of the Department of Endocrinology and Metabolism of the Instituto Nacional de la Nutrición performed all lipid and clinical laboratory measurements using standardized procedures. This laboratory is certified for standardization of the tests by the External Comparative Evaluation of Laboratories Program of the College of American Pathologist. Blood samples were taken after an overnight fast (9–12 h). All laboratory analysis was performed with commercially available standardized methods. Glucose was measured using the glucose oxidase method. Hemoglobin A1c using latex immunoagglutination inhibition (Bayer Corp., Tarrytown, NY). Total serum cholesterol and triglycerides were measured using an enzymatic method [SERA-PAK; coefficient of variation, 3.3%). HDL cholesterol was precipitated with fosfotungstic acid and Mg2+ (coefficient of variation, 2.5%). The LDL cholesterol concentration was estimated using the Friedewald formula. Direct LDL cholesterol was determined by ultracentrifugation (ß quantification) at baseline and at the end of the treatment and in every patient in which triglyceride levels were above 400 mg/dL. The apoB concentration was measured by an immunonephelometric method. Insulin concentrations were estimated using an enzyme-linked immunosorbent assay method. C Peptide levels were measured by a RIA procedure. LDL subclass isolation was performed using a density gradient ultracentrifugation method using a Beckman Coulter, Inc. (Palo Alto, CA), SW40 Ti rotor (22). The cholesterol concentration of the HDL subfractions were measured using a double precipitation assay. The GAD antibody titers were measured using a ELISA method.

Statistical analysis

Results are expressed as the mean ± SD. Differences between groups were evaluated using the Kruskal-Wallis test. Statistical analysis was performed with the Stata, statistics/data analysis version 5.0. All testing was two sided and conducted at a 5% level of significance.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The general characteristics of the studied population are shown in Table 1Go. Eighty percent of the cases had a low income and lived in the Mexico City. Type 1 and 2 diabetic controls were very representative of the vast majority of patients affected by these disorders. In the early-onset type 2 diabetes, the mean age at diagnosis was 28 yr. The majority of the patients were lean at the time of evaluation [body mass index (BMI), 22.9 ± 3.1 kg/m2] and required insulin treatment. Seventy-three percent had a first degree relative who had also type 2 diabetes; only 20% of them had a history of diabetes in both parental lines. Significant differences were found between the early-onset group and the type 2 diabetes cases in BMI, percentage of cases who required insulin treatment, and fasting triglyceride concentrations. The early-onset group required insulin several years later than the type 1 diabetics.


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  		Table 1. Clinical characteristics of the type 1, type 2, and early-onset type 2 diabetic subjects

 
Insulin sensitivity and secretion

Insulin secretion was assessed measuring the fasting C peptide concentrations and the acute insulin response during the minimal model (AIRg). As shown in Table 1Go, the fasting C peptide concentrations of the early-onset type 2 groups were different from the type 1 and 2 patients. Their C peptide levels were intermediate between the other two groups. In the early-onset type 2 group, all cases had either low (72%) or inappropriately normal (28%) concentration (reference range, 0.12–1.2 nmol/L). The insulin secretory defect observed in this group was confirmed during the insulin-modified iv glucose tolerance test. The mean AIRg was 67.5 ± 44.2 µU/mL. An AIRg lower than 100 µU/mL, a cut-off point used for severe insulin deficiency (23), was found in 34 of the 40 cases.

Insulin sensitivity was measured using the sensitivity index (SI) obtained during the insulin-modified iv glucose tolerance test. The mean SI of the early-onset type 2 group was 3.73 ± 2 (normal range, 4–6) (24, 25). Thirteen patients (32.5%) had a SI below 4; these cases were classified as insulin resistant.

GAD antibodies

Three cases (7.5%) had positive titers for GAD antibodies in the early-onset type 2 group. All GAD-positive subjects had a C peptide below 0.12 pmol/mL, an AIRg below 100, and a SI above 3. Their BMI was 23.5 ± 4.2 kg/m2; insulin treatment was required in all three cases (as a mean, 3.1 ± 4 yr after the diagnosis).

Search for HNF-1{alpha} and -4{alpha} and glucokinase mutations

In the early-onset type 2 diabetes group, we identified two individuals carrying missense mutations in exon 4 of the HNF-4 {alpha} gene (Asp126->His/Tyr and Arg154->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1 {alpha} gene (Gln486->stop codon). Segregation analysis of possible mutations in HNF-1{alpha} and HNF-4{alpha} could not be performed in any case, because family members were not available.

The biochemical and clinical profiles of patients with detected mutations are shown in Table 3Go. Two of these patients have very low plasma C peptide concentration, all three required insulin within the first 5 yr from diagnosis and have a normal lipid profile. None of them is obese. These patients displayed chronic diabetic complications. Patient 1, carrying the nonsense mutation at the codon 486 of the HNF-1{alpha} gene, presented ketoacidosis at the time of diagnosis and developed nonproliferative retinopathy as has been described for patients carrying mutations in the MODY3 gene (11) (12). It is interesting that patient 3 who has a double substitution in codon 126 Asp->His/Tyr in the HNF-4{alpha} gene developed neuropathy 2 yr after diagnosis, suggesting a more aggressive form of diabetes compared with the other two patients with detected mutations who presented complications 10–15 yr after the onset of the disease. Through clinical questioning, the familial history of diabetes of these three patients was investigated. Two of the individuals belonged to pedigrees compatible with an autosomal dominant inheritance (patients 1 and 2 from Table 3Go; Fig. 1Go), suggesting that they represent MODY patients. In contrast, the pedigree for patient 3 does not present a clear dominant pattern of inheritance, and in addition, this patient carries positive anti-GAD antibodies and presents a clinical history of Graves’ disease. None of the sequence changes we identified have been previously reported in other populations and therefore represent putative new mutations.


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  		Table 3. Clinical and biochemical characteristics of the patients with HNF 1{alpha} or HNF4{alpha} mutations

 


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  		Figure 1. Pedigrees corresponding to the three patients with detected mutations. Familial history of diabetes was investigated through clinical questioning. Patients 1 and 2 showed pedigrees compatible with autosomal dominant inheritance.

 
Lipoprotein abnormalities

The plasma lipid profile of the early-onset type 2 group was different from the type 2 patients. They had significantly lower plasma triglycerides and higher HDL cholesterol levels. No statistical differences were found against the type 1 patients.

Impact of insulin resistance on clinical parameters in the early-onset type 2 group

The presence of insulin resistance had a significant impact on the lipid profile and blood pressure. As shown in Table 4Go, cases with a SI below 4 had significantly higher concentrations of plasma trigylcerides and LDL cholesterol; the predominance among the LDL particles of the smaller and denser LDL subclasses were also more common in these subjects. The insulin-resistant cases also had lower levels of HDL and HDL3 cholesterol and lipoprotein(a). A striking difference was observed in the prevalence of arterial hypertension between the insulin-sensitive (0%) and insulin-resistant (30%) subjects. The mean systolic blood pressure was significantly higher in the insulin-resistant group.


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  		Table 4. Clinical characteristics of insulin-sensitive and insulin-resistant early-onset type 2 diabetic subjects

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
About 15% of type 2 diabetic patients in Mexico are diagnosed between 20 and 40 yr of age. We have here described a group of Mexican diabetic patients who presented as diabetics at age 20–40 yr, but subsequently displayed atypical metabolic features of type 2 diabetes. The genetic pattern, the early insulin requirement, the lack of insulin dependence for some few years, and the type of onset are clinical patterns difficult to include in a single type of diabetes. Similar cases have been described in other ethnic groups, including African-American, Chinese, and Native American (26, 27) subjects. Several degrees of insulin deficiency or insulin resistance have been described in these cases (28). Also, mutations affecting the glucokinase and the HNF-1{alpha} genes have been reported (29, 30). Our main purpose was to describe some of the genetic and metabolic characteristics observed in Mexican patients with type 2 diabetes diagnosed between ages 20 and 40 yr.

Insulin resistance has been implicated as one of the main determinants of type 2 diabetes, especially in Mexican Americans. However, several groups have previously reported that even in subjects older than 40 yr, some patients with type 2 diabetes are not insulin resistant (31, 32, 33, 34, 35, 36). The proportion was lower than 10% in every ethnic group (including Mexican Americans) analyzed in the Insulin Resistance Atherosclerosis Study project (31). Even in nonobese subjects (BMI, <30 kg/m2) the proportion of insulin-sensitive cases was low (3.6–9.7%). A greater proportion (~40%) of insulin-sensitive cases was reported by Banerji (32) and Chaiken (33). Those who were insulin sensitive had lower BMI, less intraabdominal fat (34), and fewer cardiovascular risk factors. In the early-onset cases here reported, a striking feature was a deficient insulin secretion and a near-normal insulin sensitivity. Eighty-five percent of them had severe insulin deficiency during the insulin-modified iv glucose tolerance test. This finding is in accordance with other reports in young type 2 diabetics (28). The absence of insulin resistance in a large proportion of the cases and the demonstration of insulin deficiency in almost every case suggest that insulin deficiency is the main abnormality responsible for the premature presentation of diabetes in this group. There seems to be multiple causes of the insulin deficiency. The presence of markers of autoimmune destruction of the ß-cells was observed in 7.5% of the cases. Also, mutations in the HNF-1{alpha} and HNF-4{alpha} genes were identified among our group of patients. Two of the subjects with detected mutations are likely to represent MODY individuals, suggesting that this monogenic type of diabetes is present in at least 3% of the early-onset cases in our population. However, in the vast majority of the cases, the reason for the severe insulin deficiency was not identified. It is possible that mutations exist within the exons and/or introns of the HNF-1{alpha}, HNF-4{alpha}, or glucokinase genes, which were not analyzed in the present study. Also, it might be possible that the other known MODY genes (insulin promoter factor-1 and HNF-1ß) as well as other as yet unidentified genes contribute to the expression of early-onset diabetes in our population. The absence of mutations within the exons analyzed for the glucokinase gene is consistent with a previous study in which glucokinase mutations were not found among 22 Mexican families displaying early-onset type 2 diabetes, including MODY families in which the analysis included the entire gene (37). HNF-1{alpha} mutations have been identified in subjects with early-onset type 2 diabetes in different populations. However, the frequency of such mutations varies widely among ethnic groups. They were found in 9 of 25 unrelated early-onset diabetics from Germany (13). In contrast, mutations were present in less than 5% of the early-onset type 2 patients in Northern Europe, and none was found in the Japanese population (13, 38, 39). In the report by Lehto and co-workers (13), they studied a population of 155 unrelated individuals with early-onset diabetes. Among this group, they found 12 different MODY mutations (2 in the HNF4, 4 in glucokinase, and 6 in the HNF-1 genes), corresponding to a prevalence of around 13.8% of MODY cases. Additionally, in about 40% of their families with a transmission pattern compatible with autosomal dominant, none of the MODY genes seemed to be responsible, implying the involvement of different genes in a high proportion of the families. It is interesting that in our study every patient displayed insulin deficiency regardless of the low proportion of them with positive anti-GAD antibodies or HNF-1 and HNF-4 mutations, supporting the participation of additional MODY genes in this and other populations.

The presence of insulin resistance was observed in 35% of the early-onset type 2 group. This finding is in accordance with the results obtained by Doria et al. (4), who reported the presence of insulin resistance in early-onset patients type 2 patients. No differences were found between insulin-sensitive and insulin-resistant cases regarding glycemic control, BMI, or insulin dosage. The presence of insulin resistance had a significant impact on the lipid profile and the blood pressure. The insulin-resistant cases showed many of the lipid abnormalities described in the metabolic syndrome (40). They had significantly higher concentrations of plasma trigylcerides and LDL cholesterol; the predominance among the LDL particles of the smaller and denser LDL subclasses were also more common in these subjects. The insulin-resistant cases also had lower levels of HDL and HDL3 cholesterol and lipoprotein(a). These observations are similar to those reported by Haffner and co-workers (41, 42). They demonstrated that insulin-resistant prediabetic and type 2 diabetic patients had more cardiovascular risk factors than their insulin-sensitive control peers. Controversy exists regarding the role of hyperinsulinemia in the pathophysiology of the lipid abnormalities of the metabolic syndrome (43). These observations demonstrate that even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile. Our data also confirm that a low level of lipoprotein(a) is a feature of the insulin-resistant syndrome, as previously reported by Rainwater and co-workers (44). This effect is independent of the apo(a) genotype. We believe that early-onset type 2 diabetes could be an adequate model for the study of the diabetes-related lipoprotein abnormalities. The presence or absence of insulin resistance in a group of lean insulinopenic subjects and a narrow range of age are characteristics desirable for isolating the effects of insulin resistance on different metabolic parameters.

We identified a patient with an apparent type 1 diabetes carrying a double substitution in codon 126 of the HNF-4 {alpha} gene (Asp126->His/Tyr). Although mutations in the HNF-1{alpha} gene have been described for type 1 diabetics in the Japanese and Caucasian populations and in one Mexican-American patient (45, 46, 47), this is the first report of putative mutations in the HNF-4{alpha} gene in a patient carrying ß-cell autoimmunity markers. The double substitution found in this patient deserves further analysis, as neither the mother of the proband nor any of her siblings are diabetic, suggesting that one of the substitutions may not be diabetogenic. Functional studies of independent mutants (Asp126->His and Asp126->Tyr) will be necessary to determine the roles of these changes in the expression of diabetes in this patient. Previously reported mutations and the new putative mutations identified in exon 4 are shown in Fig. 2Go.



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  		Figure 2. Schematic representation of the HNF-4{alpha} gene, showing the sites for known and new mutations. Previously reported mutations are shown below each of the corresponding exons in bold. The new putative mutations identified in exon 4 appear close to the previously reported mutation.

 
In conclusion, patients with type 2 diabetes diagnosed between ages 20 and 40 yr is a clinically and genetically heterogeneous group. Insulin deficiency seems to be a common feature in this group. The coexistence of insulin resistance was found in 35% of cases. Even in the absence of endogenous hyperinsulinemia, insulin resistance is associated with an adverse lipid profile


   Acknowledgments
 
We thank Laura Riba for the critical reading of the manuscript.


   Footnotes
 
1 This work was supported by Grant IN207493 from the Dirección General de Asuntos del Personal Académico, UNAM. Back

Received April 25, 2000.

Revised August 10, 2000.

Accepted October 2, 2000.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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