Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4α in Caucasians with maturity onset NIDDM

Summary Mutations in the hepatocyte nuclear factor-4α (HNF-4α) gene cause the type 1 form of maturity onset diabetes of the young (MODY1). To address the question of whether genetic variability of HNF-4α is associated with late onset non-insulin-dependent diabetes mellitus (NIDDM) we have sequenced the coding region and intron/exon boundaries of the gene in 36 randomly recruited Danish NIDDM patients. Two nucleotide substitutions that changed the sequence of HNF-4α were identified: Thr/Ile130, which has been reported previously and a novel Val/Met255. The Val/Met 255 mutation was found in 4 of 477 Danish NIDDM patients and in none of 217 glucose tolerant control subjects; thus it cannot be excluded that this mutation may have an impact on NIDDM susceptibility. Among 509 NIDDM patients the allelic frequency of the Thr/Ile130 variant was 4.7 % (95 % confidence interval: 3.4–6.0 %) compared to 1.9 % (0.7–3.1 %) among 239 control subjects (p = 0.008). However, in a population sample of 942 Swedish men with an average age of 70 years the allelic frequency of the variant was similar in 246 men with either impaired glucose tolerance (5.6 % [2.6–8.6 %]) or NIDDM (5.4 % [2.7–8.1 %]) as compared to 666 glucose tolerant men (5.1 % [3.9–6.3 %]). Also in a population sample of 369 young healthy Danes the prevalence of the codon 130 variant (4.7 % [3.2–6.2 %]) was similar to what was found in Swedish Caucasians. Thus, the allelic frequency of the Thr/Ile130 variant among the control subjects in the Danish case-control study deviates from the prevalence in the two other studies which is why we consider the significant association between the codon 130 variant and NIDDM an incidental finding. In glucose tolerant subjects the codon 130 variant in its heterozygous form had no major effect on glucose-induced insulin and C-peptide release although a tendency to a lower insulin secretion during an oral glucose tolerance test was seen in middle-aged subjects. In conclusion, variability in the coding region of the HNF-4α gene is not a common cause of NIDDM among whites of Danish ancestry. However, a Val/Met255 mutation was found exclusively in NIDDM patients (0.8 % of cases) and functional as well as family segregation studies are needed to determine whether this HNF-4α variant is a NIDDM causing mutation. [Diabetologia (1997) 40: 980–983] Received: 17 April 1997 and in revised form: 28 May 1997     

Incidence of NIDDM and the effects of gender, obesity and hyperinsulinaemia in Taiwan

Summary Our aim is to determine non-insulin-dependent diabetes mellitus (NIDDM) incidence in Taiwan and examine its relation to obesity and hyperinsulinaemia in Chinese men and women. A total of 995 men and 1195 women aged 35–74 years free from diabetes in two townships in Taiwan were followed up with a second examination. At baseline general and metabolic data were recorded, and detailed anthropometric parameters and plasma glucose and insulin were assessed. World Health Organisation (WHO) criteria of fasting glucose 7.8 mmol/l or greater was utilized for defining diabetes. The age-standardized incidence rate based on the United States population in 1970 was 9.3/1000 (CI 5.8–12.8) in men and 9.3/1000 (CI 6.2–12.4) in women and the based on the WHO population in 1976 was 8.9/1000 (CI .5–12.3) in men and 8.9/1000 (CI 5.9–11.9) in women for the Chinese who had a mean BMI slightly greater than 24 (kg/m²). The predictability of the plasma glucose level was greater than that of the insulin level and the obesity indices. NIDDM incidence increased approximately threefold with each 0.67 mmol/l increase in plasma glucose level in men and women. The present study demonstrated the essential relationship of not only BMI but also central obesity indices (such as subscapular and waist circumference) to the incidence of NIDDM among men and women and a stronger relationship between NIDDM incidence and obesity in women than in men. The predictive effects of obesity indices and fasting plasma insulin values on NIDDM risk were independent of each other in men. Obesity and hyperinsulinaemia each without the presence of the other can lead to an increased risk of NIDDM. In women the NIDDM incidence increased more than additively in those with both obesity and hyperinsulinaemia compared to those with single obesity or hyperinsulinaemia. A slightly higher incidence of NIDDM in Taiwan than in western countries was found. The importance of obesity is indicated for predicting NIDDM in the community. Hyperinsulinaemia was found to play a significant role in predicting NIDDM incidence independent of obesity in men and synergistically with obesity in women. [Diabetologia (1997) 40: 1431–1438] Received: 20 January 1997 and in final revised form: 11 June 1997     

Pancreatic beta-cell secretory defect associated with mitochondrial point mutation of the tRNALEU(UUR) gene: a study in seven families with mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes (MELAS)

Summary Recent evidence suggests possible linkage between diabetes mellitus and mitochondrial gene mutation. We surveyed mitochondrial tRNA^LEU(UUR) (3243) mutation in 7 mitochondrial encephalomyopathy, lactic acidosis and stroke-like episode (MELAS) families and identified 24 mutated subjects (7 MELAS probands and 17 non-MELAS relatives) as well as 11 non-mutant family members. An OGTT in the 24 mutant relatives revealed 14 diabetic subjects, 3 with impaired glucose tolerance and 7 with normal glucose tolerance and all non-mutant family members as having normal glucose tolerance. Insulinogenic index was significantly reduced in the mutant diabetic subjects and those with impaired and normal glucose tolerance in comparison with the normal control subjects and the non-mutant members. Urinary 24-h C-peptide immunoreactivity excretion was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance, compared with the control subjects and the non-mutant family members. Plasma C-peptide immunoreactivity 6 min after glucagon injection was markedly reduced in the mutant diabetic subjects and those with normal and impaired glucose tolerance compared with the control subjects and the non-mutant family members. Si, an index of insulin sensitivity of the four mutant subjects was within normal range. Islet cell antibodies were negative in sera of eight mutated diabetic subjects, 2 and 6 with impaired and normal glucose tolerance, respectively. Diabetic retinopathy and nephropathy were demonstrated in 7 (50%) and 12 (85.7%) of 14 mutant diabetic subjects, respectively. Neurosensory deafness was demonstrated in 12 (85.7%) of 14 mutated diabetic subjects, (66.7%) of 3 mutated impaired glucose tolerant subjects, but not detected in 6 mutated normal glucose tolerant subjects and 11 non-mutant family members. These findings suggest that the tRNA^LEU(UUR) mutation is associated with pancreatic beta-cell secretory defect of insulin.Abbreviations MELAS Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes - OGTT oral glucose tolerance test - IGT impaired glucose tolerance - NGT normal glucose tolerance - IRI insulin-like immunoreactivity - CPR C-peptide immunoreactivity - ICA islet cell antibodies - mtDNA mitochondrial DNA - CPEO chronic external ophthalmoplegia - NIDDM non-insulin-dependent diabetes mellitus - AER albumin excretion rate - KSS Kearns-Sayre syndrome - IDDM insulin dependent diabetes mellitus - GAD-Ab glutamic acid decarboxylase antibody - Kb kilobase - bp base pair - BS blood sugar     

Are risk factors for conversion to NIDDM similar in high and low risk populations?

Summary Mexican Americans have an increased risk of non-insulin-dependent diabetes mellitus (NIDDM) relative to non-Hispanic whites which is only partially explained by their excess overall obesity and unfavourable body fat distribution. Non-diabetic Mexican Americans have hyperinsulinaemia and insulin resistance relative to non-Hispanic whites. We therefore hypothesized that the insulin resistance might be a more important predictor of NIDDM in high-risk populations characterized by obesity and insulin resistance, while compromised insulin secretion might be a more important risk factor for NIDDM in low-risk populations. We assessed the ability of ethnicity (Mexican American vs non-Hispanic white), age, overall adiposity (body mass index [BMI]), unfavourable body fat distribution (as assessed by waist-to-hip ratio [WHR]), glucose tolerance (impaired glucose tolerance vs normal glucose tolerance), fasting insulin and compromised insulin secretion (as assessed by increment in insulin to the increment in glucose over the first 30 min of an oral glucose tolerance test (ΔI₃₀/ΔG₃₀)) to predict future NIDDM. In the 8-year follow-up of the San Antonio Heart Study, NIDDM developed in 11.7 % (107/914) of Mexican Americans and in 5.0 % (18/362) of non-Hispanic whites (p < 0.001). Multivariate predictors of NIDDM by multiple logistic regression analysis included increased age, BMI, WHR, fasting insulin and impaired glucose tolerance and decreased insulin secretion. The strongest independent predictors of NIDDM were high fasting insulin and decreased insulin secretion. These risk factors predicted NIDDM equally well in high and low-risk populations. [Diabetologia (1997) 40: 62–66] Received: 16 July 1995 and in revised form: 17 September 1996     

Poor physical fitness,and impaired early insulin response but late hyperinsulinaemia,as predictors of NIDDM in middle-aged Swedish men

Summary In a prospective population-based study of middle-aged Caucasian men, performed in Malmö, Sweden, specifically designed to evaluate physical fitness, early and late insulin response as predictors of non-insulin-dependent diabetes mellitus (NIDDM), 4,637 non-diabetic men underwent oral glucose tolerance tests at the ages of 48 and 54 years. At the baseline examination, physical fitness was measured in terms of lung vital capacity and oxygen uptake during ergometry; early insulin response in terms of the 40-min insulin increment during an oral glucose tolerance test (a correlate of acute insulin response to an intravenous glucose tolerance test), and late insulin response were measured in terms of the 2-h insulin value during the oral glucose tolerance test (a correlate of glucose disposal during euglycaemic clamp testing). Of the subjects studied 116 developed NIDDM (0.4% annually), and when compared with non-diabetic men at baseline, they were found to have an 11% higher mean body mass index (p<0.001), a higher frequency of family history of diabetes (31 vs 18%, p<0.001), 16% lower mean physical activity index (p<0.05), 16% lower mean estimated maximal oxygen uptake (p<0.001), 10% lower mean vital capacity (p<0.001), 26% lower 40-min to total insulin response ratio (p<0.001), and a 2.7 times higher mean 2-h insulin value during an oral glucose tolerance test (p<0.001). Regression analysis (using Cox's proportional hazards model) showed both low vital capacity, and impaired early insulin response but late hyperinsulinaemia to be independent predictors of NIDDM, in addition to body mass index and fasting blood glucose level (p=0.05–0.0001). Among subjects with impaired glucose tolerance at baseline (44 of 278 developed NIDDM), fasting glucose level alone predicted diabetes in this model. The findings suggest that in this age group in a Caucasian population, not only does insulin resistance precede glucose intolerance and NIDDM, but also loss of early insulin response indicating impaired beta-cell function to be an early feature of the process culminating in diabetes. As both physical fitness [which correlates inversely with late insulin response (r=–0.42, p<0.0001)], and the level of physical activity were shown to correlate with diabetes development in this large series, measures to correct these adverse features should be included in future strategies for preventing NIDDM.Abbreviations OGTT Oral glucose tolerance test - NGT normal glucose tolerance - IGT impaired glucose tolerance - NIDDM non-insulin-dependent diabetes mellitus - BMI body mass index - IVGTT intravenous glucose tolerance test     

Multiple metabolic abnormalities in normal glucose tolerant relatives of NIDDM families

Summary Non-diabetic first degree relatives of non-insulin-dependent diabetic (NIDDM) families are at increased risk of developing diabetes mellitus, and have been studied to identify early metabolic abnormalities. Hormone concentrations measured by specific enzyme immunoassays were assessed in non-diabetic relatives of North European extraction, and control subjects with no family history of diabetes were matched for age, sex and ethnicity. A 75-g oral glucose tolerance test was conducted and those with newly diagnosed NIDDM were excluded. Basal insulin resistance was determined by homeostasis model assessment (HOMA), and hepatic insulin clearance by C-peptide:insulin molar ratio. Relatives (n = 150) were heavier (BMI: p < 0.0001) than the control subjects (n = 152), and had an increased prevalence of impaired glucose tolerance (15 vs 3 %, p < 0.01). The relatives had increased fasting proinsulin levels and decreased C-peptide levels following the glucose load, while insulin levels were increased at all time points. To examine whether the differences in hormone levels were secondary to the differences in glucose tolerance and adiposity, we studied 100 normal glucose tolerant relatives and control subjects pair-matched for age, sex, waist-hip ratio and BMI. The differences in proinsulin levels were no longer apparent. However, the relatives remained more insulin resistant, and had decreased C-peptide levels and C-peptide:insulin ratios at all time points. In conclusion, we have identified several metabolic abnormalities in the normal glucose tolerant relatives, and propose that the decreased hepatic insulin clearance helps to maintain normoglycaemia in the face of combined insulin resistance and decreased insulin secretion. [Diabetologie (1997) 40: 1185–1190] Received: 11 February 1997 and in revised form: 29 April 1997     

Association of fasting glucose levels with a delayed secretion of insulin after oral glucose in subjects with glucose intolerance

Two hundred and nineteen second generation Japanese-American men were classified with a 75-g oral glucose tolerance test: 77 with normal glucose tolerance, 74 with impaired glucose tolerance (IGT), and 68 with noninsulin-dependent diabetes mellitus (NIDDM). The peak insulin response to the oral glucose load was progressively delayed with each of the 3 glucose tolerance categories. A similar finding was observed with the peak C-peptide response to oral glucose, except for the absence of distinction between IGT and NIDDM. Variables measuring the initial rate of insulin or C-peptide secretion (0-30 min) after oral glucose also demonstrated a progressive diminution with increasing glucose intolerance. The relative incremental insulin response at 30 min and the relative incremental C-peptide response at 30 min were highly correlated with the fasting glucose levels (r = -0.61 and r = -0.62; P less than 0.0001, respectively). Variables measuring the 0-30 min secretory response had high variances, whereas the variance for fasting glucose was low. Twelve men who were initially classified as IGT subsequently developed NIDDM. These 12 men had significantly higher fasting glucose levels at baseline than the remaining men who did not develop diabetes, but the 30 min secretory parameters after oral glucose, although lower in those who subsequently developed diabetes, were not significantly different at baseline. However, if fasting glucose is used as a surrogate measure of secretory response, these 12 men appear to have had an impairment of oral glucose-stimulated insulin secretion antedating the development of NIDDM. The inability of the secretory parameters to detect the abnormality may be due to a type II statistical error, which may be resolved by a larger sample size.     

The mitochondrial tRNALeu(UUR) A to G 3243 mutation is associated with insulin-dependent and non-insulin-dependent diabetes in a Chinese population

The mitochondrial DNA tRNA^Leu(UUR) A to G 3243 mutation is associated with maternally inherited diabetes in Caucasians and Japanese. In a Hong Kong Chinese population we have detected the 3243 mutation in 2 of 74 unrelated subjects with well characterized insulin-dependent (Type 1) diabetes mellitus (IDDM) and 2 of 75 unrelated subjects with young onset (<35 years) non-insulin-dependent diabetes (NIDDM). The 3243 mutation has only previously been associated with IDDM in Japanese. Racial differences in association of the mitochondrial 3243 mutation with IDDM suggest the influence of other genes that may increase its diabetogenic pathogenicity in Oriental races. We also found a significant excess of maternal inheritance of diabetes in the young onset NIDDM cohort, with a ratio of diabetic mothers to fathers of 2.4:1, p < 0.005. The 3243 mutation, however, only accounts for a small proportion of the observed excess maternal inheritance, and further study is needed to search for other diabetes associated mitochondrial DNA mutations. © 1997 John Wiley & Sons, Ltd.     

Islet cell autoimmunity and mitochondrial DNA mutation in Korean subjects with typical and atypical Type I diabetes

Aims/hypothesis: The 1997 American Diabetes Association classification of diabetes mellitus included a subset of Type I diabetic patients who do not need insulin for several years but eventually progress to complete insulin deficiency i. e. atypical Type I diabetes mellitus. In Caucasian populations, most Type I diabetic patients have auto-antibodies against islet cells. We examined the frequency of the auto-antibodies against islet cells and mitochondrial DNA 3243 mutation in Koreans with typical and atypical Type I diabetes mellitus. Methods: We measured plasma C-peptide level in 1870 consecutive Korean diabetic patients. Of these, 56 patients had insulin deficiency (fasting and glucagon-stimulated plasma C-peptide concentrations ≤ 0.2 nmol/l and ≤ 0.32 nmol/l, respectively), and they were subdivided into typical (n = 26) and atypical Type I (insulin-dependent) diabetes mellitus (n = 30) according to clinical manifestation. Islet cell antibody was measured by indirect immunofluorescence. Anti-GAD antibody and anti-ICA512 antibody were measured by radioimmunoassay. Mitochondrial DNA 3243 mutation was detected using restriction enzyme Apa-I digestion of the amplified genomic DNA. Results: The overall prevalence of auto-antibodies in the typical and atypical groups was 77 % and 57 %, respectively. Mitochondrial DNA 3243 mutation was found in 3 out of 30 (10 %) of atypical Type I (insulin-dependent) diabetic patients but not in typical Type I (insulin-dependent) diabetic patients. Conclusion/interpretation: Autoimmunity might not be the only cause of progressive insulin deficiency in Koreans. Mitochondrial DNA mutation is another identifiable cause but the cause(s) of insulin deficiency in the remainder of Type I diabetic patients without autoimmunity is not clear. [Diabetologia (2001) 44: 2187–2191] Received: 5 June 2001 and in revised form: 27 July 2001     

Total immunoreactive proinsulin, immunoreactive insulin and specific insulin in relation to conversion to NIDDM: the Mexico City Diabetes Study

Summary Although insulin resistance and decreased insulin secretion are characteristic of established non-insulin-dependent diabetes mellitus (NIDDM), which of these metabolic abnormalities is the primary determinant of NIDDM is still controversial. A disproportionate increase in the proinsulin to insulin ratio has been proposed as a marker of compromised insulin secretion. We examined the association of fasting immunoreactive insulin (which cross-reacts with proinsulin), specific insulin (which does not cross-react with proinsulin), total immunoreactive proinsulin (or insulin precursors), and the fasting proinsulin/specific insulin ratio to the risk of developing NIDDM in the 3.25-year follow-up of the Mexico City Diabetes Study. These measurements were made in 85 subjects who subsequently converted to NIDDM (prediabetic subjects) and in 85 age and gender matched subjects who remained non-diabetic at follow-up (control subjects). Immunoreactive insulin, proinsulin and the proinsulin/specific insulin ratio were significantly higher in prediabetic than in control subjects. However, the relation between specific insulin and the development of NIDDM was weaker than for proinsulin or immunoreactive insulin. After further adjustment for obesity, body fat distribution and glucose tolerance status, proinsulin and the proinsulin/specific insulin ratio, but not specific or immunoreactive insulin, predicted conversion to NIDDM. A high proinsulin/specific insulin ratio predicted conversion to NIDDM both in subjects with normal and those with impaired glucose tolerance at baseline. We conclude that in prediabetic subjects increased proinsulin, a marker of islet cell distress or compromised insulin secretion, is associated with rapid conversion (within 3.25 years) to NIDDM even in obese populations. [Diabetologia (1997) 40: 830–837] Received: 29 November 1996 and in revised form: 12 March 1997     

New variants in the glycogen synthase gene (Gln71His, Met416Val) in patients with NIDDM from eastern Finland

Summary Impaired glycogen synthesis after insulin stimulation accounts for most of the insulin resistance in patients with non-insulin-dependent diabetes mellitus (NIDDM). The glycogen synthase gene (GYS1), which encodes the rate-limiting enzyme for glycogen synthesis, is a promising candidate gene for NIDDM. Therefore, we screened all 16 exons of this gene by single-strand conformation polymorphism analysis in 40 patients with NIDDM (age 67 ± 2 years, body mass index 28.2 ± 0.6 kg/m²) from Taipalsaari, eastern Finland. The Gly464Ser variant (exon 11) and a silent polymorphism TTC342TTT (exon 7) have been reported previously. In addition, we found a new variant Gln71His (exon 2) and a new amino acid polymorphism Met416Val (exon 10). An additional sample of 65 patients with NIDDM and 82 normoglycaemic men (age 54 ± 1 years, body mass index 26.3 ± 1.4 kg/m²) were screened. The allele frequency of the TTC342TTT silent substitution was 0.29 in both NIDDM and normoglycaemic subjects. The Gln71His and Gly464Ser variants were found in 1 (1 %) and 3 (3 %) subjects, respectively, of the 105 NIDDM patients and in none of the 82 normoglycaemic men. The Met416Val polymorphism was found in 16 (15 %) of the 105 NIDDM patients and in 14 (17 %) of the 82 control subjects (all heterozygous). The Met416Val polymorphism was not associated with insulin resistance in two groups of normoglycaemic subjects. In conclusion, the new Gln71His and Met416Val substitutions and other variants of the glycogen synthase gene are unlikely to make a major contribution to insulin resistance and NIDDM in diabetic patients from eastern Finland. [Diabetologia (1997) 40: 1313–1319] Received: 17 April 1997 and in revised form: 30 June 1997     

Polymorphisms of the human hexokinase II gene: lack of association with NIDDM and insulin resistance

Summary Skeletal muscle and adipose tissue hexokinase II is a promising candidate gene for non-insulin-dependent diabetes mellitus (NIDDM) and insulin resistance. Therefore, we investigated the association of alleles at four polymorphic loci in this gene with NIDDM and insulin resistance in 110 Finnish diabetic patients with NIDDM and in 97 Finnish control subjects with normal glucose tolerance and a negative family history of diabetes. The four polymorphic nucleotide substitutions (silent) in the coding region of the hexokinase II gene were: GAC 251 GAT (exon 7), AAC 692 AAT and CCG 736 CCC (exon 15), and CTG 766 CTA (exon 16). Allele frequencies of each of these polymorphisms did not differ between patients with NIDDM and control subjects. In addition, subjects who were homozygous for the less frequent allele of each of the four polymorphisms had a similar degree of insulin resistance, as determined by the euglycaemic clamp technique, as did the subjects who were homozygous for the common allele in both control subjects and in patients with NIDDM. In conclusion, polymorphisms in the hexokinase II gene are not associated with the risk of NIDDM or insulin resistance in the Finnish population.Abbreviations HKII Hexokinase II - NIDDM non-insulin-dependent diabetes mellitus - PCR polymerase chain reaction - SSCP single-strand conformation polymorphism - R_a rate of glucose appearance - R_d rate of glucose disappearance     

The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study

Summary Although an increased plasma non-esterified fatty acid (NEFA) concentration has been shown to increase insulin resistance (Randle cycle), decrease insulin secretion and increase hepatic gluconeogenesis, the effect of NEFA on the deterioration of glucose tolerance has not been studied prospectively in Caucasian subjects. Therefore, we investigated whether plasma NEFA may be regarded as predictors of deterioration of glucose tolerance in subjects with normal (NGT, n = 3671) or impaired (IGT, n = 418) glucose tolerance who were participants in the Paris Prospective study. The subjects were first examined between 1967 and 1972 and underwent two 75-g oral glucose tolerance tests 2 years apart with measurements of plasma glucose, insulin and NEFA concentrations. Glucose tolerance deteriorated from NGT to IGT or non-insulin-dependent diabetes (NIDDM) in 177 subjects and from IGT to NIDDM in 32 subjects. In multivariate analysis, high fasting plasma NEFA in NGT subjects and high 2-h plasma NEFA and low 2-h plasma insulin concentrations in IGT subjects were significant independent predictors of deterioration along with older age, high fasting and 2-h plasma glucose concentrations and high iliac to thigh ratio. When subjects were divided by tertiles of plasma NEFA concentration at baseline, there was an increase in 2-h glucose concentration with increasing NEFA in the subjects who did not deteriorate, but no effect of plasma NEFA in those who deteriorated. In subjects with IGT who deteriorated compared with those who did not 2-h plasma insulin concentration was lower but there was no evidence that this resulted from an effect of plasma NEFA. Our data suggest that a high plasma NEFA concentration is a risk marker for deterioration of glucose tolerance independent of the insulin resistance or the insulin secretion defect that characterize subjects at risk for NIDDM. [Diabetologia (1997) 40: 1101–1106] Received: 11 March 1997 and in revised form: 20 May 1997     

Relatively more atherogenic coronary heart disease risk factors in prediabetic women than in prediabetic men

Summary Men with non-insulin-dependent diabetes mellitus (NIDDM) have a twofold increased risk of coronary heart disease and women with NIDDM have a fourfold increased risk. The reasons for this higher relative risk in NIDDM women than in NIDDM men is not completely understood. Since some studies suggest that duration of clinical diabetes and degree of hyperglycaemia have only a modest effect on coronary heart disease risk, we hypothesized that women who eventually convert to NIDDM might have a more atherogenic pattern of lipids and blood pressure relative to subjects who do not convert than male converters, even in the prediabetic period. We examined this issue in Mexican-American subjects in the 8-year follow-up of the San Antonio Heart Study. Seventy-nine out of 801 men converted to NIDDM compared to 133 out of 1131 women. In both men and women, conversion to NIDDM was significantly associated with increased body mass index, fasting insulin and glucose, higher triglyceride and blood pressure and lower high density lipoprotein (HDL) cholesterol. The relative differences between converters and non-converters was significantly greater for women than for men; this interaction term for gender by conversion status was statistically significant for fasting insulin, triglyceride, HDL cholesterol and diastolic blood pressure. Thus, the higher relative risk for coronary heart disease in women with NIDDM relative to men with NIDDM may be partially due to their greater burden of cardiovascular risk factors even prior to the onset of diabetes. [Diabetologia (1997) 40: 711–717] Received: 7 November 1996 and in revised form: 11 March 1997     

The prevalence of the mitochondrial DNA 16189 variant in non-diabetic Korean adults and its association with higher fasting glucose and body mass index.

AIMS: To evaluate the prevalence of the 16189 variant of mitochondrial DNA in Korean adults and its association with insulin resistance. METHODS: We investigated 160 non-diabetic subjects from a community-based diabetes survey conducted in Yonchon County, Korea in 1993. We extracted the DNA from peripheral blood and examined the 16189 variant by polymerase chain reaction and restrictive enzyme digestion. We compared body mass index (BMI), blood pressure, fasting plasma glucose, 2-h plasma glucose after 75 g glucose load, fasting insulin, cholesterol, and homeostasis model assessment of insulin resistance and beta-cell function between the subjects with 16189 variant and wild type. RESULTS: The prevalence of the 16189 variant in Korean adults was 28.8% (46 of 160). Subjects with the 16189 variant had higher fasting glucose and BMI than those with wild type, but fasting insulin, homeostasis model assessment of insulin resistance and beta-cell function, cholesterol, and blood pressure were not different between two groups. CONCLUSION: Our results provide evidence for an association of a frequent mitochondrial polymorphism with higher fasting glucose and the risk factors of diabetes mellitus.     

Hypertension and overweight associated with hyperinsulinaemia and glucose tolerance: a longitudinal study of the finnish and dutch cohorts of the seven countries study

Summary To elucidate the role of hypertension as part of the insulin resistance syndrome, the longitudinal relationships of hypertension and overweight with hyperinsulinaemia and glucose tolerance were examined in the Dutch and Finnish cohorts of the Seven Countries Study (Zutphen, and east and west Finland). Three cohorts of men, born between 1900 and 1919, were first examined in 1959/1960. At the 30-year follow-up survey a 2-h glucose tolerance test was carried out on 619 of the surviving men, and fasting insulin was also measured. Blood pressure and body mass index (BMI) were measured several times during the entire 30-year follow-up period. In cross-sectional analyses, men with diabetes and impaired glucose tolerance at the 30-year follow-up examination had a significantly higher systolic blood pressure and a higher prevalence of hypertension than men with normal glucose tolerance, independent of age, cohort and BMI (p < 0.01). These differences had already been seen 5, 20 and 30 years earlier. Subjects with hyperinsulinaemia (fasting insulin ≥ 9.2 mU/l) had a higher BMI and a higher prevalence of hypertension. This cross-sectional association with hypertension was independent of age, cohort and BMI. BMI levels of men with hyperinsulinaemia had been shown to be higher 5, 20 and 30 years earlier, but blood pressure levels had not. These results indicate that hypertension is independently associated with glucose tolerance and insulin resistance in three Caucasian cohorts. Changes in blood pressure precede abnormal glucose tolerance but not hyperinsulinaemia; therefore, glucose tolerance appears to be a stronger correlate of hypertension than hyperinsulinaemia. [Diabetologia (1995) 38: 839–847] Received: 20 July 1994 and in revised form: 17 January 1995     

Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetic subjects

Summary We have investigated the association of a family history of diabetes with glucose tolerance in a population of Swedish men. All men 35–54 years of age in 1992 and living in four different local municipalities of the outer Stockholm area were screened by questionnaire. From 10 236 completed questionnaires 1622 men, selected for presence of such a history but without known diabetes, as well as 1507 men without a family history underwent an oral glucose tolerance test. Diabetes (2 h-plasma glucose levels > 11.0 mmol/l) was detected in 55 and impaired glucose tolerance (plasma glucose levels 7.8–11.0 mmol/l) in 172 subjects. The odds ratio of diabetes, associated with a family history, was 4.1, confidence interval 2.1–8.3 and for impaired glucose tolerance 1.6, confidence interval 1.2–2.3. Influence of a family history was measurable also within the range of normal 2-h glucose concentrations: compared to 2-h glucose levels < 3.8 mmol/l; the odds ratio associated with a family history was 1.4, confidence interval 1.1–1.7 and 1.3, confidence interval 1.1–1.6 for concentrations 4.8–5.7 mmol/l and 5.8–7.7 mmol/l respectively. The odds ratio of diabetes and impaired glucose tolerance among men with a family history increased with number and closeness of relatives with diabetes but was not affected by the gender of the family member. Overweight (BMI > 25.0 kg/m²) increased the odds ratio of diabetes in subjects with a family history, the odds ratio being 24, confidence interval 3–177, when both conditions were present. In subjects with Type II (non-insulin-dependent) diabetes mellitus discovered during the investigation, the presence of a family history of diabetes was associated with decreased insulin secretion rather than insulin resistance as assessed by fasting insulin, homeostasis model assessment, and the 2-h insulin response to the oral glucose tolerance test. We conclude that a family history of diabetes strongly but independently of gender associates with decreased glucose tolerance. Furthermore, the results are compatible with a major role for low insulin secretion in the diabetogenic influence of a family history of diabetes in middle-aged Swedish men. Lastly, the very high risk for diabetes in middle-aged men with both a family history of diabetes and obesity indicates that such people should, for the purpose of therapeutic intervention, be identified in the general population. [Diabetologia (1999) 42: 15–23] Received: 9 March 1998 and in revised form: 1 July 1998     

Glucose tolerance and insulin response in parents of patients with insulin-dependent and juvenile-onset non-insulin-dependent diabetes mellitus.

Glucose tolerance and insulin response were examined using a 100 g oral glucose tolerance test (OGTT) in 108 parents of 23 patients with insulin-dependent (IDDM) and 31 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose age of onset of diabetes was less than 35 years. Thirty-two age-matched healthy volunteers without a family history of diabetes were also examined as a control group. Diabetes and impaired glucose tolerance (IGT) were significantly more frequent in parents of NIDDM (diabetes 34%, IGT 27%) than in parents of IDDM (diabetes 7%, IGT 13%) (P less than 0.001). At least one parent had diabetes or IGT in 30% of IDDM and 84% of NIDDM patients (P less than 0.001), and both parents had diabetes or IGT in 9% of IDDM and 39% of NIDDM patients (P less than 0.02). Even in cases with 'normal' glucose tolerance, the mean plasma glucose was higher in parents of NIDDM than in control subjects, suggesting a high prevalence of abnormal glucose tolerance including the marginal degree of abnormality in the families of NIDDM. The early phase insulin response was decreased more among parents of NIDDM with the greater impairment of glucose tolerance. However, among those with 'normal' glucose tolerance, early phase insulin response did not differ between parents of IDDM and NIDDM, and control subjects. The results confirmed a stronger familial background in NIDDM patients of younger onset than in IDDM. The different patterns of glucose tolerance among two parents of young-onset NIDDM patients suggest heterogeneity of the mode of inheritance of NIDDM among families.     

Rising prevalence of NIDDM in an urban population in India

Summary A survey conducted in 1988–1989, in the city of Madras, South India, showed that the prevalence of diabetes mellitus in adults was 8.2 % and prevalence of impaired glucose tolerance (IGT) was 8.7 %. The present survey was another cross-sectional study conducted 5 years later in the same urban area to study the temporal changes in the prevalence of diabetes and IGT. The two sample populations surveyed were similar in age structure and socioeconomic factors. In the second survey in 1994–1995, a total of 2183 subjects, 1081 men and 1102 women, with a mean age of 40 ± 12 years were tested by an oral glucose tolerance test; fasting and 2-h post-glucose plasma glucose were measured. Anthropometric measurements, details of physical activity and clinical history of diabetes were recorded. Age-standardised prevalence of diabetes had increased to 11.6 % from 8.2 % in 1989 and IGT was 9.1 %, similar to 8.7 % in 1989. Multiple regression analysis showed age, waist : hip ratio, body mass index (BMI) and female sex were correlated to diabetes. Family history of diabetes showed interaction with age and BMI. Prevalence of IGT correlated to age, BMI and waist : hip ratio. This study highlights the rising trend in the prevalence of non-insulin-dependent diabetes (NIDDM) in urban Indians. The persistent high prevalence of IGT may also be a predictor of a further increase in NIDDM in the future. No significant differences in the anthropometric data were noted in this compared to the previous study. [Diabetologia (1997) 40: 232–237] Received: 24 April 1996 and in final revised form: 31 October 1996     

The effects of coenzyme Q10 treatment on maternally inherited diabetes mellitus and deafness, and mitochondrial DNA 3243 (A to G) mutation

Summary The characteristic clinical features of diabetes mellitus with mitochondrial DNA (mtDNA) 3243(A-G) mutation are progressive insulin secretory defect, neurosensory deafness and maternal inheritance, referred to as maternally inherited diabetes mellitus and deafness (MIDD). A treatment for MIDD to improve insulin secretory defects and reduce deafness has not been established. The effects of coenzyme Q₁₀ (CoQ₁₀) treatment on insulin secretory response, hearing capacity and clinical symptoms of MIDD were investigated. 28 MIDD patients (CoQ₁₀-DM), 7 mutant subjects with impaired glucose tolerance (IGT), and 15 mutant subjects with normal glucose tolerance (NGT) were treated daily with oral administration of 150 mg of CoQ₁₀ for 3 years. Insulin secretory response, blood lactate after exercise, hearing capacity and other laboratory examinations were investigated every year. In the same way we evaluated 16 MIDD patients (control-DM), 5 mutant IGT and 5 mutant NGT subjects in yearly examinations. The insulin secretory response assessed by glucagon-induced C-peptide secretion and 24 h urinary C-peptide excretion after 3 years in the CoQ₁₀-DM group was significantly higher than that in the control-DM group. CoQ₁₀ therapy prevented progressive hearing loss and improved blood lactate after exercise in the MIDD patients. CoQ₁₀ treatment did not affect the diabetic complications or other clinical symptoms of MIDD patients. CoQ₁₀ treatment did not affect the insulin secretory capacity of the mutant IGT and NGT subjects. There were no side effects during therapy. This is the first report demonstrating the therapeutic usefulness of CoQ₁₀ on MIDD. [Diabetologia (1998) 41: 584–588] Received: 16 October 1997 and in revised form: 21 January 1998