Trends in the mortality of diabetes in Mexico from 1998 to 2022: a joinpoint regression and age-period-cohort effect analysis.

OBJECTIVE: The purpose was to analyze age-standardized trends in diabetes mortality rates (DMR) from 1998 to 2022, stratified by sex and Mexican state, and the effects attributable to age, period, and cohort by sex. STUDY DESIGN: Joinpoint regression and age-period-cohort effect analysis. METHODS: Based on the tenth revision of the International Classification of Diseases, E11, E12, E13, and E14 codes of the death certificate, a daily record of mortality was extracted from the death certificate attributable to diabetes as the main cause. From 1998 to 2022, sexes and ages (≥20 years) were used to calculate the crude mortality rates and standardized at the national and Mexican state levels. Additionally, the age-period-cohort model was used to examine age, period, and cohort effects. RESULTS: From 1998 to 2005, the age-adjusted DMR increased by 3.6% (95% confidence interval [CI]: 2.7, 4.5) for the total population, as shown by the joinpoint regression analysis at a national level; from 2017 to 2020, it increased by 7.4% (95% CI: 0.6, 14.8). The DMR with the highest increase during the study period came mainly from states in the country's southeastern region, 2.3% to 3.7% per year. The net age and period effects showed that mortality increased with advancing age and with going time, respectively; and the net cohort effect revealed that mortality increased in more recent birth cohorts, mainly in men Rate Ratio (RR) = 2.37 (95% CI: 2.29, 2.46) vs RR = 1.13 (95% CI: 1.09, 1.17). CONCLUSION: The DMR increased among older age groups. The period effect showed that mortality increased over time. Furthermore, the cohort effect showed that mortality increased in more recent birth cohorts, especially among men.

The influence of high-density lipoprotein (HDL) and HDL subfractions on insulin secretion and cholesterol efflux in pancreatic derived ß-cells.

BACKGROUND: High-density lipoprotein (HDL) is considered a complex plasma-circulating particle with subfractions that vary in function, size, and chemical composition. We sought to test the effects of HDL, and HDL subfractions on insulin secretion and cholesterol efflux in the ß-cell line MIN-6. METHODS: We used total HDL and HDL subfractions 2a, 2b, 3a, 3b, and 3c, isolated from human plasma, to test insulin secretion under different glucose concentrations as well as insulin content and cholesterol efflux in the insulinoma MIN-6 cell line. RESULTS: Incubation of MIN-6 cells with low glucose and total HDL increased insulin release two-fold. Meanwhile, when high glucose and HDL were used, insulin release increased more than five times. HDL subfractions 2a, 2b, 3a, 3b, and 3c elicited higher insulin secretion and cholesterol efflux than their respective controls, at both low and high glucose concentrations. The insulin content of the MIN-6 cells incubated with low glucose and any of the five HDL subclasses had a modest reduction compared with their controls. However, there were no statistically significant differences between each HDL subfraction on their capacity of eliciting insulin secretion, insulin content, or cholesterol efflux. CONCLUSIONS: HDL can trigger insulin secretion under low, normal, and high glucose conditions. We found that all HDL subfractions exhibit very similar capacity to increase insulin secretion and cholesterol efflux. This is the first report demonstrating that HDL subfractions act both as insulin secretagogues (under low glucose) and insulin secretion enhancers (under high glucose) in the MIN-6 cell line.

The -514C>T polymorphism in the LIPC gene modifies type 2 diabetes risk through modulation of HDL-cholesterol levels in Mexicans.

PURPOSE: Both type 2 diabetes (T2D) and low levels of high-density lipoprotein cholesterol (HDL-C) are very prevalent conditions among Mexicans. Genetic variants in the LIPC gene have been associated with both conditions. This study aimed to evaluate the association of the -514C < T (rs1800588) LIPC gene polymorphism with different metabolic traits, particularly the effects of this polymorphism on HDL-C plasma levels and T2D risk. METHODS: Mediation analysis was used to assess the direct and indirect effects of the -514C>T LIPC gene variant on HDL-C levels, T2D risk, and body mass index (BMI), in 2105 Mexican mestizo participants. We also assessed the functional effect of the -514C>T LIPC variant on the promoter activity of a reporter gene in the HepG2 cell line. RESULTS: Direct effects show that the -514C>T LIPC polymorphism is significantly associated with increased HDL-C plasma levels (ß = 0.03; p < 0.001). The -514C>T variant resulted in an indirect protective effect on T2D risk through increasing HDL-C levels (ß = - 0.03; p < 0.001). Marginal direct association between -514C>T and T2D was found (ß = 0.08; p = 0.06). Variables directly influencing T2D status were European ethnicity (ß = - 7.20; p < 0.001), age (ß = 0.04; p < 0.001), gender (ß = - 0.15; p = 0.017) and HDL-C (ß = - 1.07; p < 0.001). In addition, we found that the -514C>T variant decreases the activity of LIPC promoter by 90% (p < 0.001). CONCLUSIONS: The -514C>T polymorphism was not directly associated with T2D risk. HDL-C acts as a mediator between -514C>T LIPC gene variant and T2D risk in the Mexican population.

The combination of insulin resistance and visceral adipose tissue estimation improves the performance of metabolic syndrome as a predictor of type 2 diabetes.

AIMS: To assess the performance of metabolic syndrome as a predictor of type 2 diabetes in a model that also includes both a measure of insulin resistance and a metabolic score for visceral fat, and to propose a novel metabolic syndrome definition. METHODS: In a prospective Metabolic Syndrome Cohort (n=6143), we evaluated improvements in type 2 diabetes risk prediction using International Diabetes Federation-defined and Adult Treatment Panel III-defined metabolic syndrome, after inclusion in the model of updated homeostatic model assessment of insulin resistance and a metabolic score for visceral fat. We also developed a modified metabolic syndrome construct, 'MS-METS', which used the metabolic score for visceral fat instead of waist circumference to evaluate improved predictive performance for risk of developing type 2 diabetes. RESULTS: Participants who had metabolic syndrome as defined by both the Adult Treatment Panel III and the International Diabetes Federation criteria had a higher risk of type 2 diabetes compared to participants who did not meet these criteria. Addition of updated homeostatic model assessment of insulin resistance and metabolic score for visceral fat to both metabolic syndrome definitions increased predictive performance for type 2 diabetes risk. Homeostatic model assessment of insulin resistance was the only additional predictor of type 2 diabetes in participants without metabolic syndrome. Conversely, in participants with metabolic syndrome, the use of the metabolic score for visceral fat was the stronger added predictor for type 2 diabetes. When evaluating participants using the MS-METS definition we observed the largest improvement in predictive ability for type 2 diabetes risk and a significant reduction in risk overestimation compared to evaluation using metabolic syndrome defined according to the International Diabetes Federation and Adult Treatment Panel III criteria alone. CONCLUSION: Inclusion of updated homeostatic model assessment of insulin resistance and metabolic score for visceral fat increases performance of metabolic syndrome in prediction of type 2 diabetes. Assessment of insulin resistance could be more useful than conventional metabolic syndrome and assessment of visceral adipose tissue could be more useful in people with metabolic syndrome. Metabolic syndrome as defined using our modified MS-METS construct improved the accuracy of type 2 diabetes prediction.

R230C but not - 565C/T variant of the ABCA1 gene is associated with type 2 diabetes in Mexicans through an effect on lowering HDL-cholesterol levels.

PURPOSE: Type 2 diabetes (T2D) and low serum concentration of high-density lipoprotein cholesterol (HDL-c) are common coexisting metabolic disorders. ABCA1 variants have been shown to be associated to these conditions. We sought to test the combined effect of two ABCA1 gene common variants, rs2422493 (- 565C > T) and rs9282541 (R230C) on HDL-c levels and T2D risk. METHODS: Path analysis was conducted in 3,303 Mexican-mestizos to assess the specific contributions of rs2422493 and rs9282541 ABCA1 variants, insulin resistance, waist-to-height ratio (WHtR), and age on HDL-c levels and T2D risk. Participants were classified into four groups according to their ABCA1 variants carrier status: (i) the reference group carried wild type alleles for both ABCA1 variants (-/-), (ii) +/- were carriers of rs2422493 but non-carriers of rs9282541, (iii) -/+ for carriers of rs9282541 but not carriers of rs2422493 and (iv) carriers of minor alleles for both SNPs (+/+). Principal components from two previous genome-wide association studies were used to control for ethnicity. RESULTS: We identified significant indirect effects on T2D risk mediated by HDL-c in groups -/+ and +/+ (ß = 0.04; p = 0.03 and ß = 0.06; p < 0.01, respectively) in comparison to the -/- reference group. Low concentrations of HDL-c were directly and significantly associated with increased T2D risk (ß = -0.70; p < 0.01). WHtR, male gender, age, and insulin resistance were also associated with T2D risk (p < 0.05). There was no significant direct effect for any of the ABCA1 groups on T2D risk: p = 0.99, p = 0.58, and p = 0.91 for groups +/-, -/+, and +/+ respectively. CONCLUSIONS: The ABCA1 rs9282541 (R230C) allele is associated with T2D in Mexicans through its effect on lowering HDL-c levels. This is the first report demonstrating that HDL-c levels act as an intermediate factor between an ABCA1 variant and T2D.

Distribution of triglyceride-rich lipoproteins and their remnants and their contribution to cardiovascular risk in the Mexican population.

BACKGROUND AND AIMS: In recent years, scientific interest in triglyceride-rich lipoproteins (TRL) and remnant cholesterol has increased, focusing on the evidence that these lipoproteins are a causal factor for developing atherosclerotic cardiovascular disease (ASCVD). Furthermore, a high remnant concentration (>38 mg/dL) has been associated with several non-cardiovascular risks. We aimed in this study to describe the percentile distribution of remnant cholesterol. Additionally, we evaluated the association between remnant cholesterol plasma concentration and epidemiologically relevant cardio-metabolic outcomes such as hypertension, type 2 diabetes (T2D), and ASCVD. METHODS: We analyzed data from 9,591 adults from the National Survey of Health and Nutrition (ENSANUT) 2018 with fasting blood samples and complete medical history questionnaires. We built multivariate models to evaluate the association between chronic diseases and blood remnant concentration. To compare our 2018-sub-sample against a population reference, we used the NHANES (2005-2014) publicly available datasets by ethnicity. RESULTS: Remnants were independently associated with cardiovascular risk, diabetes, hypertension, obesity, and metabolic syndrome. For all outcomes, the blood remnant concentration was a stronger predictor than LDL. At all deciles, the blood remnant concentration was higher in ENSANUT-2018. CONCLUSIONS: A remnant blood concentration above 38 mg/dL was highly prevalent among Mexicans. Remnants were significantly associated with a higher risk of diabetes, hypertension, obesity, and cardiovascular risk. This association occurred independently of other lipid markers.

Long-term 4-year safety of saxagliptin in drug-naive and metformin-treated patients with Type 2 diabetes.

AIMS: To evaluate the safety of saxagliptin ± metformin over 4 years in patients with Type 2 diabetes mellitus. METHODS: Drug-naive (n = 401; study 11) or metformin-treated (n = 743; study 14) adults with HbA(1c) of 53-86 mmol/mol (7.0-10%) were enrolled in two randomized, placebo-controlled, double-blind trials of saxagliptin 2.5, 5 or 10 mg/day. Patients rescued during or completing 24 weeks of treatment could continue in a 42-month long-term blinded phase, for which the primary goal was assessment of safety and tolerability. Between-group efficacy was not evaluated in the long-term phase of study 11. Time to rescue or discontinuation because of inadequate glycaemic control, change from baseline in HbA(1c) and percentages of patients achieving HbA(1c) < 53 mmol/mol (< 7.0%) were assessed in study 14. RESULTS: No new safety findings were noted during the long-term phase. Most adverse events were mild or moderate, with slightly greater frequency of upper respiratory infections with saxagliptin. Hypoglycaemic event rates were similar with saxagliptin and placebo. In study 14, time to rescue or discontinuation because of inadequate glycaemic control was longer with saxagliptin plus metformin than for placebo plus metformin. From baseline to week 154, HbA(1c) decreased with saxagliptin but increased with placebo. CONCLUSION: Saxagliptin monotherapy or add-on to metformin is generally safe and well tolerated, with no increased risk of hypoglycaemia, for up to 4 years.

Soy protein isoflavones differentially regulate liver X receptor isoforms to modulate lipid metabolism and cholesterol transport in the liver and intestine in mice.

AIMS/HYPOTHESIS: Liver X receptor (LXR)α regulates the genes involved in cholesterol, fatty acid and glucose metabolism. Soy protein (SP) consumption reduces the hepatic accumulation of cholesterol and triacylglycerol, and improves insulin sensitivity. However, it is not known whether these effects are mediated via LXRα. We therefore investigated whether the consumption of SP regulates metabolic changes in cholesterol metabolism and insulin sensitivity via LXRα. METHODS: Wild-type (WT) and Lxrα(-/-) (Lxrα, also known as Nr1h3) mice were fed an SP diet with or without cholesterol for 28 days. The expression of LXRα target genes was measured in liver and intestine, as were hepatic lipid content and faecal bile acid concentration. Oral glucose and insulin tolerance tests were also performed. Hepatocytes were used to study the effect of isoflavones on LXR activity. RESULTS: The livers of WT and Lxrα(-/-) mice fed an SP high-cholesterol diet showed less steatosis than those fed casein. The SP diet increased the expression of the ATP-binding cassette (ABC) sub-family genes Abca1, Abcg5 and Abcg8 in the liver and intestine, as well as increasing total faecal bile acid excretion and insulin sensitivity in WT mice compared with mice fed a casein diet. However, these effects of SP were not observed in Lxrα(-/-) mice. The SP isoflavone, genistein, repressed the activation of LXRα target genes by T0901317, whereas it stimulated the activation of LXRß target genes. The AMP-activated protein kinase inhibitor, compound C, had the opposite effects to those of genistein. CONCLUSIONS/INTERPRETATION: Our results suggest that SP isoflavones stimulate the phosphorylation of LXRα or LXRß, resulting in different biological effects for each LXR isoform.

Trimethylamine N-oxide levels are associated with NASH in obese subjects with type 2 diabetes.

AIMS: Trimethylamine N-oxide (TMAO), choline and betaine serum levels have been associated with metabolic diseases including type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). These associations could be mediated by insulin resistance. However, the relationships among these metabolites, insulin resistance and NAFLD have not been thoroughly investigated. Moreover, it has recently been suggested that TMAO could play a role in NAFLD by altering bile acid metabolism. We examined the association between circulating TMAO, choline and betaine levels and NAFLD in obese subjects. METHODS: Serum TMAO, choline, betaine and bile acid levels were measured in 357 Mexican obese patients with different grades of NAFLD as determined by liver histology. Associations of NAFLD with TMAO, choline and betaine levels were tested. Moreover, association of TMAO levels with non-alcoholic steatohepatitis (NASH) was tested separately in patients with and without T2D. RESULTS: TMAO and choline levels were significantly associated with NAFLD histologic features and NASH risk. While increased serum TMAO levels were significantly associated with NASH in patients with T2D, in non-T2D subjects this association lost significance after adjusting for sex, BMI and HOMA2-IR. Moreover, circulating secondary bile acids were associated both with increased TMAO levels and NASH. CONCLUSIONS: In obese patients, circulating TMAO levels were associated with NASH mainly in the presence of T2D. Functional studies are required to evaluate the role of insulin resistance and T2D in this association, both highly prevalent in NASH patients.

Diabetes is associated with a higher risk of mortality among women in a middle-income country: Results form the Mexican Teacher's cohort study.

AIMS: In Mexico City, the mortality rate among patients with diabetes appears to be four times that of people without diabetes. Our study aimed to refine analyses of the impact of diabetes on mortality in a large cohort of women from different areas in Mexico with healthcare insurance. METHODS: Our study followed 111,299 women with comprehensive healthcare coverage from the Mexican Teachers' Cohort. After a median follow-up of 7.8years, 5514 (5%) prevalent self-reported diabetes cases and 4023 incident cases were identified, while deaths were identified through employers' databases and next-of-kin reports, with dates and causes of death for 1121 women obtained from mortality databases. Hazard ratios (HRs) for total and cause-specific mortality were estimated by Cox regression models, using follow-up time as the time scale and allowing for time-variable diabetes status after adjusting for age, socioeconomic status, use of health services, and anthropometric and lifestyle variables. RESULTS: In multivariable-adjusted models, the HR for all-cause mortality was 3.28 (95% CI: 2.86-3.75) in women with vs. without diabetes. The impact of diabetes on mortality was higher in rural vs. urban areas (HR: 4.72 vs. 2.98, respectively). HRs were 1.57 and 23.44 for cancer and renal disease mortality, respectively. CONCLUSION: In women with healthcare coverage in Mexico, the magnitude of the association between diabetes and all-cause mortality was higher than that observed in high-income countries, but less than what has previously been reported for Mexico. Such elevated mortality suggests a lack of adequate access to quality diabetes care in the population despite comprehensive healthcare coverage.

Strong association of socioeconomic status with genetic ancestry in Latinos: implications for admixture studies of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of this epidemiological difference that can be ascribed to genetic or environmental factors is unknown. To determine whether genetic ancestry is correlated with diabetes risk in Latinos, we estimated the proportion of European ancestry in case-control samples from Mexico and Colombia in whom socioeconomic status had been carefully ascertained. METHODS: We genotyped 67 ancestry-informative markers in 499 participants with type 2 diabetes and 197 controls from Medellín (Colombia), as well as in 163 participants with type 2 diabetes and 72 controls from central Mexico. Each participant was assigned a socioeconomic status scale via various measures. RESULTS: Although European ancestry was associated with lower diabetes risk in Mexicans (OR [95% CI] 0.06 [0.02-0.21], p = 2.0 x 10(-5)) and Colombians (OR 0.26 [0.08-0.78], p = 0.02), adjustment for socioeconomic status eliminated the association in the Colombian sample (OR 0.64 [0.19-2.12], p = 0.46) and significantly attenuated it in the Mexican sample (OR 0.17 [0.04-0.71], p = 0.02). Adjustment for BMI did not change the results. CONCLUSIONS/INTERPRETATION: The proportion of non-European ancestry is associated with both type 2 diabetes and lower socioeconomic status in admixed Latino populations from North and South America. We conclude that ancestry-directed search for genetic markers associated with type 2 diabetes in Latinos may benefit from information involving social factors, as these factors have a quantitatively important effect on type 2 diabetes risk relative to ancestry effects.

Single-pill amlodipine/atorvastatin helps patients of diverse ethnicity attain recommended goals for blood pressure and lipids (the Gemini-AALA study).

The Gemini-AALA (Australia, Asia, Latin America, Africa/Middle East) study evaluated the efficacy and safety of single-pill amlodipine/atorvastatin (Caduet) for the treatment of patients of diverse ethnicity with concomitant hypertension and dyslipidaemia. This was a 14-week, open-label study including patients from 27 countries across the Middle East, Asia-Pacific, Africa and Latin America. Eight dosage strengths of single-pill amlodipine/atorvastatin (5/10, 10/10, 5/20, 10/20, 5/40, 10/40, 5/80 and 10/80 mg) were titrated to improve blood pressure and lipid control. Blood pressure and lipid goals were determined according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP ATP III) guidelines, respectively (blood pressure, <140/90 or <130/80 mm Hg; low-density lipoprotein cholesterol (LDL-C), <4.1 to <2.6 mmol l(-1) (<160 to <100 mgdl(-1))). Overall, 1649 patients received study medication. Most patients (91.4%) had >or=1 cardiovascular risk factor (as defined by NCEP ATP III guidelines) in addition to hypertension/dyslipidaemia, and 61.7% had coronary heart disease/risk equivalent. At baseline, mean blood pressure was 146.6/88.3 mm Hg and LDL-C was 3.4 mmol l(-1) (130.2 mgdl(-1)). At week 14, 55.2% of patients reached both blood pressure and lipid goals, 61.3% reached blood pressure goal and 87.1% reached lipid goal (34.0% were at lipid goal at baseline). Mean blood pressure reduction was 20.2/11.4 mm Hg. For patients who were lipid-lowering drug naive at baseline, mean reduction in LDL-C was 41.0%. Treatment-related adverse events led to the discontinuation of 3.6% of patients. Single-pill amlodipine/atorvastatin therapy was well tolerated and effective for the reduction of blood pressure and lipids to recommended goals in patients from diverse ethnic backgrounds.

The Mexican consensus on nonalcoholic fatty liver disease. / Consenso mexicano de la enfermedad por hígado graso no alcohólico.

Nonalcoholic fatty liver disease (NAFLD) affects nearly one third of the population worldwide. Mexico is one of the countries whose population has several risk factors for the disease and its prevalence could surpass 50%. If immediate action is not taken to counteract what is now considered a national health problem, the medium-term panorama will be very bleak. This serious situation prompted the Asociación Mexicana de Gastroenterología and the Asociación Mexicana de Hepatología to produce the Mexican Consensus on Fatty Liver Disease. It is an up-to-date and detailed review of the epidemiology, pathophysiology, clinical forms, diagnosis, and treatment of the disease, whose aim is to provide the Mexican physician with a useful tool for the prevention and management of nonalcoholic fatty liver disease.

Composition of gut microbiota in obese and normal-weight Mexican school-age children and its association with metabolic traits.

BACKGROUND: Childhood obesity is a serious public health problem in Mexico. Adult gut microbiota composition has been linked to obesity, but few studies have addressed the role of gut microbiota in childhood obesity. OBJECTIVES: The aim of this study is to compare gut microbiota composition in obese and normal-weight children and to associate gut microbiota profiles with amino acid serum levels and obesity-related metabolic traits. METHODS: Microbial taxa relative abundance was determined by 16S rRNA sequencing in 67 normal-weight and 71 obese children aged 6-12 years. Serum amino acid levels were measured by mass spectrometry. Associations between microbiota composition, metabolic parameters and amino acid serum levels were tested. RESULTS: No significant differences in phyla abundances or Firmicutes/Bacteroidetes ratios were observed between normal-weight and obese children. However, Bacteroides eggerthii abundance was significantly higher in obese children and correlated positively with body fat percentage and negatively with insoluble fibre intake. Additionally, Bacteroides plebeius and unclassified Christensenellaceae abundances were significantly higher in normal-weight children. Abundance of both these species correlated negatively with phenylalanine serum levels, a metabolite also found to be associated with obesity in Mexican children. CONCLUSIONS: The study identified bacterial species associated with obesity, metabolic complications and amino acid serum levels in Mexican children.

Lack of agreement between the World Health Organization Category of impaired glucose tolerance and the American Diabetes Association category of impaired fasting glucose.

OBJECTIVE: To study the concordance between the 1997 American Diabetes Association (ADA) impaired fasting glucose (IFG) category with the World Health Organization (WHO) impaired glucose tolerance (IGT) status in a population with a high prevalence of diabetes. RESEARCH DESIGN AND METHODS: We analyzed the oral glucose tolerance tests (OGTTs) carried out at the Instituto Nacional de la Nutrición Salvador Zubiran (INNSZ) central laboratory from June to December 1997. We included patients with fasting plasma glucose (FPG) between 60 and 160 mg/dl. The results from the glucose tolerance test were selected as the gold standard. RESULTS: Among the 1,802 glucose tolerance test results available for analysis, 1,706 fulfilled the requirements to be included. Diabetes and IGT were remarkably more frequently diagnosed when the WHO criteria were applied. The new ADA criteria failed to diagnose 69% of WHO diabetic patients and the vast majority of WHO glucose-intolerant subjects. Using the new criteria, 82% were considered normal. Of the IFG subjects, 39% were classified as diabetic and 23% were normal according to the 2-h postchallenge glucose values. Only 37% of the IFG patients were, in fact, glucose intolerant according to the WHO criteria. CONCLUSIONS: Our results clearly show that the 1997 ADA criteria are less sensitive for diagnosing diabetes than OGTT-based WHO criteria. Even more important, there is poor agreement between the WHO category of IGT and the ADA category of IFG.

Early-onset type 2 diabetes: metabolic and genetic characterization in the mexican population.

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 muU/mL.min) and a near-normal insulin sensitivity (3.43 +/- 0.2 min/muU.mL x 10(4)) were found in these patients. Among this group we found two individuals carrying missense mutations in exon 4 of the hepatocyte nuclear factor-1alpha (HNF-4alpha) gene (Asp(126)-->His/Tyr and Arg(154)-->Gln, respectively) and one carrying a nonsense mutation in exon 7 of the HNF-1alpha gene (Gln(486)-->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-1alpha or the HNF-4alpha 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.

Metabolic modes of action of the statins in the hyperlipoproteinemias.

Conflicting results have been published during the past few years regarding the physiologic modes of action of the hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors, generally referred to as statins, using standard doses. Three mechanisms have been described: increased LDL catabolic rate, increased removal of LDL precursors resulting in decreased LDL production and decreased VLDL production. The physiologic effects of statins seem to depend on the underlying pathology of the disorders under therapy. More recent data using either the more potent atorvastatin or larger doses of previously available statins (e.g. simvastatin 80-160 mg/day), suggest that both the potency of the statins and the underlying pathopHysiology are important in determining the predominant physiologic responses of patients. To understand physiologic responses more completely, drug-dose-physiologic response curves of apo B kinetics in various groups of patients are needed. Simultaneous studies of apo B, triglycerides and cholesterol metabolism are also needed and are currently feasible.

Efficacy and safety of atorvastatin in hyperlipidemic, type 2 diabetic patients. A 34-week, multicenter, open-label study.

Hyperlipidemia is common in type 2 diabetic patients and is an independent risk factor for cardiovascular disease. The aim of this trial was to evaluate the efficacy and safety of once-daily atorvastatin 10-80 mg for the treatment of hyperlipidemia in type 2 diabetics with plasma low-density lipoprotein cholesterol (LDL-C) levels exceeding 3.4 mmol/l (130 mg/dl). One hundred and two patients met the study criteria and received 10 mg/day atorvastatin. Patients who reached the target LDL-C level of

The prevalence of diabetes and associated coronary risk factors in urban and rural older Mexican populations.

OBJECTIVE: To determine the prevalence of diabetes and examine its association with food intake, anthropometric and metabolic variables, and other coronary risk factors in urban and rural older Mexican populations. DESIGN: A cross-sectional study. SETTING: Three Mexican communities (urban areas of medium and low income and a rural area). PARTICIPANTS: A total of 121 men and 223 women aged 60 years and older and 93 men and 180 women aged 35 to 59 years were selected randomly for inclusion in the survey, which was derived from the CRONOS study (Cross-Cultural Research on Nutrition in the Older Adult Study Group) promoted by the European Economic Community. MEASUREMENTS: A personal interview assessed demographic information, personal medical history, and functional status, and a 24-hour diet recall was obtained. A physical examination included anthropometric and blood pressure measurements. A fasting blood sample was obtained for measurements of lipids, insulin, and glucose. RESULTS: Diabetes prevalence was higher in men than in women for all age groups: 16.7% versus 9.5% in younger adults and 30.8% versus 22.8% in older adults. For all age groups, diabetes was more highly prevalent in urban communities. Using a multivariate stepwise logistic regression, variables associated independently with diabetes in older individuals were: gender (male sex: OR = 2.1; P < .009); diminished carbohydrate intake in the diet (OR = 0.77; P < .03); central distribution of adiposity (OR = 1.9; P < .03); and functional disability (OR = 2.3; P < .01). This relationship was not observed with living area, income, education, fiber and alcohol intake, body mass index, or age. Individuals 80 years and older had a diminished atherogenic risk profile. Diabetes in older people was associated significantly with hypertriglyceridemia, impaired functional status, and an increased prevalence of ischemic heart disease; in younger adults diabetes was associated with low density lipoprotein (LDL) hypercholesterolemia, hypertriglyceridemia, and a proportionally higher fat intake. CONCLUSION: This survey confirms the high prevalence of diabetes in the older Mexican population - particularly in men and in individuals living in urban areas - associated with an increased prevalence of other coronary risk factors. Diabetes was associated with higher fat, low carbohydrate, low fiber diets and increased prevalence of central distribution of adiposity. In the older subjects, diabetes was associated significantly with hypertriglyceridemia, impaired functional status, and increased prevalence of ischemic heart disease. A bias produced by early mortality and a survivorship effect must be considered in studies of older individuals. The health situation in the older Mexican population presents a complex problem that needs correct diagnosis and better strategies to benefit those segments of the population at increased risk.

Effect of malnutrition during the first year of life on adult plasma insulin and glucose tolerance.

There is evidence linking intrauterine growth retardation with increased cardiovascular risk and diabetes mellitus (DM) later in life. However, little is known about the association between malnutrition during the first year of life and metabolic abnormalities in adulthood. The objective of this study was to assess the effect of documented malnutrition during the first year of life on glucose tolerance, plasma insulin, lipid profile, and blood pressure in early adulthood, as well as to assess the interaction between body mass index (BMI) and malnutrition on these variables. A study group of young men with a documented history of malnutrition during their first year of life was recruited from 4 pediatric hospitals in Mexico City and compared with a control group. Subjects included were 52 men, aged 20.2 +/- 3.6 years, with a mean birth weight of 3.0 +/- 0.7 kg and documented malnutrition in their first year of life; controls were 50 men, aged 23.3 +/- 1.8 years, with a mean birth weight of 3.2 +/- 0.5 kg. Insulin and glucose concentrations, fasting and in response to an oral glucose load, plasma lipids, blood pressure, and an insulin sensitivity index (ISI) were measured. The areas under the curves of glucose (AUCG) and insulin (AUCI) were significantly higher in cases (P =.012 and <.002, respectively), independent of birth weight, BMI, or age. BMI was significantly associated with fasting plasma insulin (FPI), AUCI, ISI, triglyceride, and high-density lipoprotein (HDL)-cholesterol concentrations in cases, but not in controls. These data suggest that early malnutrition in extrauterine life, independently of birth weight, has an adverse effect on insulin metabolism and glucose tolerance in young men, and it worsens as body mass increases even within the normal range of BMI. Therefore, it is advisable to prevent obesity in individuals exposed to early malnutrition.