Social inequality in coronary risk: Central obesity and the metabolic syndrome. Evidence from the Whitehall II study

Summary This report describes the social distribution of central obesity and the metabolic syndrome at the Whitehall II study phase 3 examination, and assesses the contribution of health related behaviours to their distribution. Cross-sectional analyses were conducted utilising data collected in 1991–1993 from 4978 men and 2035 women aged 39–63 years who completed an oral glucose tolerance test. There was an inverse social gradient in prevalence of the metabolic syndrome. The odds ratio (95 % confidence interval) for having the metabolic syndrome comparing lowest with highest employment grade was: men 2.2 (1.6–2.9), women 2.8 (1.6–4.8). Odds ratios for occupying the top quintile of the following variables, comparing lowest with highest grade, were, for waist-hip ratio: men 2.2 (1.8–2.8), women 1.6 (1.1–2.4); post-load glucose: men 1.4 (1.1–1.8), women 1.8 (1.2–2.6); triglycerides: men 1.6 (1.2–2.0), women 2.2 (1.5–3.3); fibrinogen: men 1.7 (1.4–2.3), women 1.9 (1.2–2.8). Current smoking status, alcohol consumption and exercise level made a small contribution (men 11 %, women 9 %) to the inverse association between socioeconomic status and metabolic syndrome prevalence. In conclusion, central obesity, components of the metabolic syndrome and plasma fibrinogen are strongly and inversely associated with socioeconomic status. Our findings suggest the metabolic syndrome may contribute to the biological explanation of social inequalities in coronary risk. Health related behaviours appear to account for little of the social patterning of metabolic syndrome prevalence. [Diabetologia (1997) 40: 1341–1349] Received: 5 February 1997 and in revised form: 11 June 1997     

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     

Fasting blood glucose and cancer risk in a cohort of more than 140,000 adults in Austria

Aims/hypothesis We investigated relations between fasting blood glucose and the incidence of cancer.Methods A population-based cohort of more than 140,000 Austrian adults (63,585 men, 77,228 women) was followed over an average of 8.4 years. Incident cancer (other than non-melanoma skin cancers) was ascertained by a population-based cancer registry (n=5,212). Cox proportional-hazards models were used to estimate hazard rate ratios (HR) stratified for age and adjusted for smoking, occupational group and body mass index.Results The highest fasting blood glucose category (≥7.0 mmol/l) was weakly associated with all cancers combined (HR 1.20; 95% CI, 1.03–1.39 in men and 1.28; 95% CI, 1.08–1.53 in women) relative to the reference level (4.2–5.2 mmol/l). The strongest association was found for liver cancer in men (HR 4.58; 95% CI, 1.81–11.62). Positive associations between fasting hyperglycaemia (6.1–6.9 or ≥7.0 mmol/l) and cancer incidence were also observed for non-Hodgkin’s lymphoma in men, and for colorectal and bladder cancer in women. Breast cancer in women diagnosed at or after age 65 was also associated with fasting blood glucose ≥7.0 mmol/l. Positive associations with glucose values >5.3 mmol/l were noted for thyroid cancer, gallbladder/bile duct cancer and multiple myeloma in men and women combined.Conclusions/interpretation These findings provide further evidence that elevated blood glucose is associated with the incidence of several types of cancer in men and women.     

Microalbuminuria is strongly associated with NIDDM and hypertension, but not with the insulin resistance syndrome: the Hoorn Study

Summary Microalbuminuria is a strong predictor of cardiovascular disease. The aim of this study was to investigate whether microalbuminuria is part of a cluster of risk factors, the insulin resistance syndrome (IRS), or whether it is only associated with, and presumably a complication of, hypertension and non-insulin-dependent diabetes mellitus (NIDDM). An age-, sex- and glucose tolerance-stratified random sample from a 50–75 year old general population (n = 622) was investigated. The urinary albumin-to-creatinine ratio was measured in an early morning spot urine sample. Microalbuminuria was defined as an albumin-to-creatinine ratio greater than 2.0 mg/mmol. We considered, as IRS-related variables, fasting hyperinsulinaemia, insulin resistance (IR; calculated from the formula of the homeostasis model assessment), dyslipidaemia, glucose intolerance, hypertension and waist-to-hip ratio (WHR). Dyslipidaemia was defined as levels of HDL-cholesterol in the lowest and / or levels of triglyceride in the highest tertile. Fasting insulin levels, IR and WHR were divided into tertiles; the highest tertiles were compared to the lowest tertiles. Age-, sex- and glucose tolerance-adjusted analyses showed microalbuminuria to be significantly associated with hypertension, NIDDM and WHR. In multiple logistic regression analyses, microalbuminuria showed independent associations with hypertension, NIDDM and WHR, with odds ratios (ORs [95 % confidence interval]) of 3.33 (1.86–5.96), 2.26 (1.14–4.48) and 2.49 (1.09–5.70), respectively. No associations were found with impaired glucose tolerance, hyperinsulinaemia, IR or dyslipidaemia. Multiple logistic regression analyses in diabetic and non-diabetic subjects separately showed that microalbuminuria was independently associated only with hypertension (ORs 4.31 and 2.69). In this Caucasian population, microalbuminuria was associated with hypertension, NIDDM and WHR and not with other variables of the IRS. It is therefore likely that microalbuminuria is a complication of hypertension and NIDDM, and not an integral part of the IRS. [Diabetologia (1998) 41: 694–700] Received: 7 August 1997 and in revised form: 5 January 1998     

Mutational analysis of the coding region of the uncoupling protein 2 gene in obese NIDDM patients: Impact of a common amino acid polymorphism on juvenile and maturity onset forms of obesity and insulin resistance

Summary Recently, a gene encoding a novel human uncoupling protein, designated UCP2, was discovered. The murine UCP2 was mapped to a region on mouse chromosome 7 which in several models has been shown to be linked to obesity and hyperinsulinaemia. Single strand conformation polymorphism (SSCP) analysis and direct sequencing of the coding region of the UCP2 gene in 35 obese Caucasian NIDDM patients of Danish ancestry revealed one nucleotide substitution, replacing an alanine with a valine at codon 55. The amino acid polymorphism was present in 24 of the 35 (69 %) examined subjects. The allelic frequency of the A/V55 variant was 48.3 % (95 % CI: 42.5–54.1 %) among 144 subjects with juvenile onset obesity, 45.6 % (40.5–50.7 %) among 182 subjects randomly selected at the draft board examination, and 45.5 % (37.1–53.9 %) among lean control subjects selected from the same study cohort. Within these cohorts there were no differences in BMI values at different ages among wild-type carriers and A/V55 carriers. In a population-based sample of 369 young healthy Caucasians the variant showed no association with alterations in BMI, waist-to-hip ratio, fat mass or weight gain during childhood or adolescence. The A/V55 polymorphism was not related to alterations in fasting values of serum insulin and C-peptide or to an impaired insulin sensitivity index. We conclude that genetic variability in the human UCP2 gene is not a common factor contributing to NIDDM in obese Danish Caucasian subjects and the common A/V55 amino acid polymorphism of the gene is not implicated in the pathogenesis of juvenile or maturity onset obesity or insulin resistance in Caucasians. [Diabetologia (1997) 40: 1227–1230] Received: 20 June 1997     

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     

Association of obesity with diabetic retinopathy: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SN-DREAMS Report no. 8)

The aim of the study was to report the prevalence of obesity indices in individuals with diabetes and find out their association with diabetic retinopathy in the urban Indian population. Subjects (n = 1,414) were recruited from Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular Genetics Study (SN-DREAMS-I), a cross-sectional study between 2003 and 2006. Anthropometric measurements were carried out, and all patients’ fundi were photographed using 45° four-field stereoscopic digital photography. The diagnosis of diabetic retinopathy was based on the modified Klein classification. Generalized obesity and abdominal obesity were defined using WHO Asia Pacific guidelines with the BMI (body mass index) cutoff as ≥23 kg/m², WC (waist circumference) cutoffs as ≥90 cm in men and ≥80 cm in women and WHO guidelines using WHR (waist-to-hip ratio) cutoffs as ≥0.90 for men and ≥0.85 for women. Prevalence of obesity defined by BMI and WC was more in women compared to men, and that defined by WHR was more in men compared to women (P < 0.001). The prevalence of isolated generalized obesity, isolated abdominal obesity and combined obesity were 5.4, 10.1 and 58% in men and 4.5, 10.8 and 74.4% in women, respectively. The prevalence of any diabetic retinopathy and sight-threatening diabetic retinopathy was more in the isolated abdominal obesity group (26.35 and 6.08%, respectively) than in other subgroups. On logistic regression analysis, isolated abdominal obesity (OR 2.02, 95% CI: 1.06–3.86) and increased WHR in women (OR 1.48 95% CI: 1.10–2.38) were associated with diabetic retinopathy; BMI ≥ 23 (OR 0.66, 95% CI: 0.48–0.90) and combined obesity (OR 0.72, 95% CI: 0.53–0.99) had a protective role for any diabetic retinopathy in the overall group. In the urban south Indian population, isolated abdominal obesity and higher WHR in women were associated with diabetic retinopathy, but not with the severity of diabetic retinopathy.     

Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM

Summary Insulin administration to healthy subjects inhibits the production of very low density lipoprotein (VLDL)1 (Svedbergs flotation (Sf) rate 60–400) without affecting that of VLDL2 (Sf 20–60) subclass. This study was designed to test whether this hormonal action is impaired in non-insulin-dependent diabetes mellitus (NIDDM). We studied six men with NIDDM (age 53 ± 3 years, body mass index 27.0 ± 1.0 kg/m², plasma triglycerides 1.89 ± 0.22 mmol/l) during an 8.5 h infusion of saline (control) and then in hyperinsulinaemic (serum insulin ∼ 540 pmol/l) conditions during 8.5 h infusions of glucose and insulin to give either hyper- and normoglycaemic conditions. [3-²H]-leucine was used as tracer and kinetic constants derived using a non-steady-state multicompartmental model. Compared to the control study, patients with NIDDM reduced VLDL1 apo B production by only 3 ± 8 % after 8.5 h of hyperinsulinaemia (701 ± 102 vs 672 ± 94 mg/day respectively, NS) in hyperglycaemic conditions and by 9 ± 21 % under normoglycaemic conditions (603 ± 145 mg/day). In contrast, in normal subjects insulin induced a 50 ± 15 % decrement in VLDL1 apo B production (p < 0.05). Direct synthesis of VLDL2 apo B in patients with NIDDM was not markedly affected by insulin. We conclude that a contributory factor to hypertriglyceridaemia in NIDDM is the inability of insulin to inhibit acutely the release of VLDL1 from the liver, despite efficient suppression of serum non-esterfied fatty acids. [Diabetologia (1997) 40: 454–462] Received: 7 October 1996 and in revised form: 24 December 1996     

The impact of family history of diabetes and lifestyle factors on abnormal glucose regulation in middle-aged Swedish men and women

Aims/hypothesis We investigated associations between abnormal glucose regulation and family history of diabetes, separately and in combination with lifestyle risk factors.Subjects and methods This cross-sectional study comprised 3,128 men and 4,821 women, aged 35–56 years, half with a family history of diabetes. Oral glucose tolerance testing identified subjects with previously undiagnosed prediabetes (IFG, IGT) and type 2 diabetes. Information on lifestyle factors was obtained by questionnaire. Biological interaction was measured with the synergy index.Results A family history of diabetes conferred a higher odds ratio (OR) for type 2 diabetes in men (OR=3.1, 95% CI 1.7–5.6) than in women (OR=1.7, 95% CI 1.0–3.0), and the synergy index was 2.8 (95% CI 0.9–9.0), suggesting interaction between a family history of diabetes and sex. For prediabetes and diabetes combined, the synergy index was 1.7 (1.0–2.8). Exposure to only one lifestyle risk factor (obesity, physical inactivity, smoking or low sense of coherence [a psychosocial index]) increased the risk to a similar extent in men and women. Combined exposure to a family history of diabetes and lifestyle-related risk factors had a greater effect on type 2 diabetes than any of these factors alone, especially in men. However, analysis of interaction between a family history of diabetes and the lifestyle factors did not indicate any interaction for diabetes, but did indicate interaction for a family history of diabetes and obesity in women with prediabetes.Conclusions/interpretation Our data suggest a more pronounced effect of a family history of diabetes on the risk of type 2 diabetes in men than in women. While both a family history of diabetes and lifestyle risk factors had effects on type 2 diabetes, irrespective of sex, these effects did not appear to interact.     

Increasing incidence of diagnosed type 2 diabetes in Taiwan: analysis of data from a national cohort

Aims/hypothesis Epidemiological evidence shows an increasing prevalence of type 2 diabetes in Taiwan. The aim of this study was to assess the yearly incidence for this country during 1992–1996.Subjects and methods Data obtained by telephone interviews of 93,484 diagnosed diabetic patients enrolled in Taiwan’s National Health Insurance programme formed the basis of this study. A total of 36,153 incident cases of type 2 diabetes (17,097 men and 19,056 women) were identified and incidence rates calculated. The trends of obesity and parental diabetes were also evaluated.Results The overall 5-year incidences for men and women were 187.1 and 218.4 per 100,000 population, respectively. The trends from 1992–1996 were increased for all age groups in men and for most age groups in women. A 2.8-fold increase in incidence was observed for the youngest age group (<35 years), in which the increase in incidence was higher than in the older age groups. Men showed a higher fold increase in incidence than did women (3.5 vs 2.1). Obesity at interview increased from 39.2% in 1992 to 47.6% in 1996 (p<0.001) and was significant for all ages. Parental diabetes showed no yearly change when all patients were analysed together, but there was a trend towards a decrease in the youngest age group (<35 years) and a trend towards an increase in the oldest age groups (≥55 years).Conclusions/interpretation An increasing incidence of diagnosed type 2 diabetes was observed for each sex in most age groups in Taiwan, but was most marked in the youngest age group. A parallel increase in obesity was observed with the increasing incidence of diabetes.     

Abnormal glucose transport and GLUT1 cell-surface content in fibroblasts and skeletal muscle from NIDDM and obese subjects

Summary Glucose transport and GLUT1 expression were studied in fibroblasts from 7 lean and 5 obese non-insulin-dependent diabetic (NIDDM) subjects with at least 2 NIDDM first-degree relatives and from 12 lean and 5 obese non-diabetic subjects with no family history of diabetes. The obese individuals also had a strong family history of obesity. Fibroblasts from all of the subjects exhibited no difference in insulin receptor binding, autophosphorylation, and kinase and hexokinase activity. At variance, basal 2-deoxyglucose (2-DG) uptake and ³H-cytochalasin B binding were 50 % increased in cells from individuals with NIDDM (p < 0.001) and/or obesity (p < 0.01) as compared to the lean non-diabetic subjects. Insulin-dependent (maximally stimulated – basal) 2-DG uptake and cytochalasin B binding were decreased three-fold in cells from the diabetic and/or obese subjects (p < 0.01). GLUT1 mRNA and total protein levels were comparable in fibroblasts from all the groups. However, basal GLUT1 cell-surface content was 50 % greater in fibroblasts from the NIDDM and/or obese subjects as compared to the lean non- diabetic individuals while insulin-dependent GLUT1 recruitment at the cell surface was diminished threefold. Increased basal GLUT1 content in the plasma membrane was also observed in skeletal muscle of 4 NIDDM and 3 non-diabetic obese individuals (p < 0.05 vs the lean non diabetic subjects). Basal 2-DG uptake in fibroblasts from diabetic/obese individuals and lean control subjects strongly correlated with the in vivo fasting plasma insulin concentration of the donor. A negative correlation was demonstrated between the magnitude of insulin-dependent glucose uptake by the fibroblasts and plasma insulin levels in vivo. We conclude that a primary abnormality in glucose transport and GLUT1 cell-surface content is present in fibroblasts from NIDDM and obese individuals. The abnormal GLUT1 content is also present in skeletal muscle plasma membranes from NIDDM and obese individuals. [Diabetologia (1997) 40: 421–429] Received: 9 August 1996 and in final revised form: 11 December 1996     

Prevalence of NIDDM and impaired glucose tolerance in a rural and an urban population in Cameroon

Summary The adoption of Western lifestyles is known to lead to increasing prevalence of non-insulin-dependent diabetes mellitus in Africa, yet epidemiological studies using standardised methods are rare. The prevalence of diabetes and impaired glucose tolerance was determined in a rural and an urban community in Cameroon using the 75-g oral glucose tolerance test and the World Health Organization diagnostic criteria in 719 rural (292 men, 427 women) and 1048 urban (458 men, 590 women) subjects aged 24–74 years. The response rate was 95 and 91 % for the rural and urban population, respectively. The age-standardized prevalence of diabetes in the rural and urban population was respectively 0.9 % (95 % confidence interval (0.2–2.7)) and 0.8 % (0.2–1.8) for men and 0.5 % (0.1–1.6) and 1.6 % (0.7–3.1) for women, and that of impaired glucose tolerance was 5.8 % (3.3–9.4) and 1.8 % (0.9–3.2) for men, and for women, 2.2 % (1.0–4.0) and 2.0 % (0.6–4.5). Although for both men and women the body mass index was higher at all ages in the urban than in the rural area, the 2-h plasma glucose, even after adjustment for age and body mass index, was significantly higher in the rural than in the urban area (p < 0.005, p < 0.002 for men and women, respectively). There was a female excess of diabetes in the urban area and an equal sex distribution in the rural area. In the rural area 67 % (4 of 6) of diabetic subjects were unknown before the survey, compared with 57 % (8 of 14) in the urban area. These data indicate a low prevalence of diabetes in Cameroon; however, the prevalence of impaired glucose tolerance suggests an early stage of a diabetes epidemic. [Diabetologia (1997) 40: 824–829] Received: 19 November 1996 and in revised form: 10 March 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     

Abdominal obesity and inflammation predicts hypertension among prehypertensive men and women: the ATTICA Study

The aim of this work was to assess the 5-year incidence of hypertension and its predictors among prehypertensive adults. Under the context of the ATTICA Study, data from 1188 individuals, free of cardiovascular disease, but with defined high blood pressure levels (prehypertension) at baseline examination (during 2001–2002) were retrieved. In 2006, the 5-year follow-up of the study was performed, and 798 of the prehypertensive participants were allocated. In this work, incidence and determinants of developing hypertension were evaluated. The 5-year ageadjusted incidence of hypertension was 18.7% in men and 24.6% in women (P = 0.05); while almost one half of prehypertensive individuals at the age of 55–65 years developed hypertension, and approximately 6 out of 10 people over 65 years of age developed the disease. Multiple logistic regression analysis revealed that increased age (odds ratio [OR] per 1 year = 1.09, 95% confidence interval [CI] 1.07–1.12), male sex (OR = 0.40, 95% CI 0.21–0.68), high education status (OR per 1 year of school = 0.94, 95% CI 0.88–0.98), waist circumference (OR per 1 cm = 1.04, 95% CI 1.02-1.06) and C-reactive protein (OR per 1 mg/l = 1.12, 95% CI 1.05–1.20), were positively associated with the development of hypertension. Moreover, greater adherence to Mediterranean diet seems to protect only prehypertensive, with abdominal obesity patients prone to develop hypertension (OR = 0.94, 95% CI 0.90–0.98). Annual incidence of hypertension was roughly 4% in men and women. Older people, with low education, abdominal obesity, lower adherence to the Mediterranean diet, and increased inflammation, constitute a model of prehypertensive individuals that are prone to develop hypertension.     

Improvement of insulin sensitivity and cardiovascular outcomes in the JCR:LA-cp rat by D-fenfluramine

Summary Obese male rats of the JCR:LA-cp strain are insulin resistant, normoglycaemic, hypertriglyceridaemic, and atherosclerosis-prone. Such rats were treated from 6 to 39 weeks of age with 5 mg · kg^–1· day^–1 of d-fenfluramine. The treatment normalised food intake, after 20 weeks of age, to that of lean control animals. At 39 weeks, treated rats weighed about 650 g compared to 800 g for untreated cp/cp rats and 400 g for + / + controls. Fasting plasma glucose and triglyceride levels were not significantly affected; however, fasting insulin concentrations were lower and the size and volume density of the hyperplastic islets of Langerhans were markedly reduced. The severity of raised atherosclerotic lesions on the aortic arch was decreased by 39 % (p < 0.01). Concomitantly, the occurrence of mature, scarred ischaemic myocardial lesions was virtually abolished (p < 0.01). Severe food restriction of the obese rats to normalise body weights to those of lean controls reduced plasma insulin and triglyceride concentrations at 26 weeks of age, but without a significant reduction in the frequency of myocardial lesions. Rats (with established insulin resistance) were treated from 6 to 12 weeks of age with 2.5 mg · kg^–1· day^–1 of d-fenfluramine. Insulin-mediated glucose turnover during a euglycaemic insulin clamp was strongly increased (p < 0.05). Rats treated from 3 weeks of age (before development of the insulin resistance) showed a significant delay in the development of hyperinsulinaemia and a reduced postprandial increase in plasma insulin. In contrast, restriction of food to that consumed by rats treated with d-fenfluramine did not decrease post-absorptive hyperinsulinaemia. d-fenfluramine treatment markedly improved the maximum relaxant response of aortic rings to acetylcholine, indicating improvement of the defective endothelium-derived relaxation factor system. A matched-food restriction regimen had no effect on vascular relaxation. d-fenfluramine treatment thus improved insulin sensitivity and had anti-atherosclerotic and cardioprotective effects in the presence of continuing obesity and hyperlipidaemia. The results are consistent with the protection of the function and integrity of the vessel wall associated with a decreased hyperinsulinaemia. The results emphasise the importance of focussing treatment of the metabolic syndrome (obesity/insulin resistance/hyperlipidaemia) on improving insulin sensitivity and glycaemic control rather than on the simple normalisation of body weight. [Diabetologia (1998) 41: 380–389] Received: 25 July 1997 and in final revised form: 25 November 1997     

Studies on the mass action effect of glucose in NIDDM and IDDM: evidence for glucose resistance

Summary The ability of hyperglycaemia to enhance glucose uptake was evaluated in 9 non-insulin-dependent (NIDDM), 7 insulin-dependent (IDDM) diabetic subjects, and in 6 young and 9 older normal volunteers. Following overnight insulin-induced euglycaemia, a sequential three-step hyperglycaemic clamp (+ 2.8 + 5.6, and + 11.2 mmol/l above baseline) was performed with somatostatin plus replacing doses of basal insulin and glucagon, 3-³H-glucose infusion and indirect calorimetry. In the control subjects as a whole, glucose disposal increased at each hyperglycaemic step (13.1 ± 0.6, 15.7 ± 0.7, and 26.3 ± 1.1 μmol/kg · min). In NIDDM (10.5 ± 0.2, 12.1 ± 1.0, and 17.5 ± 1.1 μmol/kg · min), and IDDM (11.2 ± 0.8, 12.9 ± 1.0, and 15.6 ± 1.1 μmol/kg · min) glucose disposal was lower during all three steps (p < 0.05–0.005). Hepatic glucose production declined proportionally to plasma glucose concentration to a similar extent in all four groups of patients. In control subjects, hyperglycaemia stimulated glucose oxidation (+ 4.4 ± 0.7 μmol/kg · min) only at + 11.2 mmol/l (p < 0.05), while non-oxidative glucose metabolism increased at each hyperglycaemic step (+ 3.1 ± 0.7; + 3.5 ± 0.9, and + 10.8 ± 1.7 μmol/kg · min; all p < 0.05). In diabetic patients, no increment in glucose oxidation was elicited even at the highest hyperglycaemic plateau (IDDM = + 0.5 ± 1.5; NIDDM = + 0.2 ± 0.6 μmol/kg · min) and non-oxidative glucose metabolism was hampered (IDDM = + 1.8 ± 1.5, + 3.1 ± 1.7, and + 4.3 ± 1.8; NIDDM = + 0.7 ± 0.6, 2.1 ± 0.9, and + 7.0 ± 0.8 μmol/kg · min; p < 0.05–0.005). Blood lactate concentration increased and plasma non-esterified fatty acid (NEFA) fell in control (p < 0.05) but not in diabetic subjects. The increments in blood lactate were correlated with the increase in non-oxidative glucose disposal and with the decrease in plasma NEFA. In conclusion: 1) the ability of hyperglycaemia to promote glucose disposal is impaired in NIDDM and IDDM; 2) stimulation of glucose oxidation and non-oxidative glucose metabolism accounts for glucose disposal; 3) both pathways of glucose metabolism are impaired in diabetic patients; 4) impaired ability of hyperglycaemia to suppress plasma NEFA is present in these patients. These results suggest that glucose resistance, that is the ability of glucose itself to promote glucose utilization, is impaired in both IDDM and NIDDM patients. [Diabetologia (1997) 40: 687–697] Received: 20 August 1996 and in revised form: 5 March 1997     

The role of diabetes mellitus in the aetiology of renal cell cancer

Summary To investigate the relation between diabetes mellitus and the risk of renal cell cancer we carried out a population-based retrospective cohort study. Patients identified in the Swedish Inpatient Register who were discharged from hospitals with a diagnosis of diabetes mellitus between 1965 and 1983 formed a cohort of 153 852 patients (80 005 women and 73 847 men). The cohort members were followed up to 1989 by record linkage to three nation-wide registries. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using age-specific sex-specific and period-specific incidence and mortality rates derived from the entire Swedish population. After exclusion of the first year of observation, a total of 267 incidences of renal cell cancer (ICD-7 : 180.0) occurred in diabetic patients compared with the 182.4 that had been expected. Increased risks were observed in both women (SIR = 1.7, 95 % confidence interval, CI = 1.4–2.0) and men (SIR = 1.3; 95 % CI = 1.1–1.6) throughout the duration of follow-up (1–25 years). A higher risk was seen for kidney cancer (ICD-7 : 180) mortality (SMR = 1.9; 95 % CI = 1.7–2.2, women; SMR 1.7, 95 % CI = 1.4–1.9, men). In comparison with the general population, patients with diabetes mellitus have an increased risk of renal cell cancer. [Diabetologia (1999) 42: 107–112] Received: 12 December 1997 and in final revised form: 25 August 1998     

UDP-N-acetylglucosamine transferase and glutamine: fructose 6-phosphate amidotransferase activities in insulin-sensitive tissues

Summary Glutamine:fructose 6-phosphate amidotransferase (GFA) is rate-limiting for hexosamine biosynthesis, while a UDP-GlcNAc β-N-acetylglucosaminyltransferase (O-GlcNAc transferase) catalyses final O-linked attachment of GlcNAc to serine and threonine residues on intracellular proteins. Increased activity of the hexosamine pathway is a putative mediator of glucose-induced insulin resistance but the mechanisms are unclear. We determined whether O-GlcNAc transferase is found in insulin-sensitive tissues and compared its activity to that of GFA in rat tissues. We also determined whether non-insulin-dependent diabetes mellitus (NIDDM) or acute hyperinsulinaemia alters O-GlcNAc transferase activity in human skeletal muscle. O-GlcNAc transferase was measured using ³H-UDP-GlcNAc and a synthetic cationic peptide substrate containing serine and threonine residues, and GFA was determined by measuring a fluorescent derivative of GlcN6P by HPLC. O-GlcNAc transferase activities were 2–4 fold higher in skeletal muscles and the heart than in the liver, which had the lowest activity, while GFA activity was 14–36-fold higher in submandibular gland and 5–18 fold higher in the liver than in skeletal muscles or the heart. In patients with NIDDM (n = 11), basal O-GlcNAc transferase in skeletal muscle averaged 3.8 ± 0.3 nmol/mg · min, which was not different from that in normal subjects (3.3 ± 0.4 nmol/mg · min). A 180-min intravenous insulin infusion (40 mU/m²· min) did not change muscle O-GlcNAc transferase activity in either group. We conclude that O-GlcNAc transferase is widely distributed in insulin-sensitive tissues in the rat and is also found in human skeletal muscle. These findings suggest the possibility that O-linked glycosylation of intracellular proteins is involved in mediating glucose toxicity. O-GlcNAc transferase does not, however, appear to be regulated by either NIDDM or acute hyperinsulinaemia, suggesting that mass action effects determine the extent of O-linked glycosylation under hyperglycaemic conditions. [Diabetologia (1997) 40: 76–81]     

Short-term oestrogen replacement therapy improves insulin resistance, lipids and fibrinolysis in postmenopausal women with NIDDM

Summary Oestrogen replacement therapy is associated with a decreased risk of cardiovascular disease in postmenopausal women. Patients with non-insulin-dependent diabetes mellitus (NIDDM) have an increased cardiovascular risk. However, oestrogen replacement therapy is only reluctantly prescribed for patients with NIDDM. In a double blind randomized placebo controlled trial we assessed the effect of oral 17 β -estradiol during 6 weeks in 40 postmenopausal women with NIDDM. Glycated haemoglobin (HbA_1c), insulin sensitivity, suppressibility of hepatic glucose production, lipoprotein profile and parameters of fibrinolysis were determined. The oestrogen treated group demonstrated a significant decrease of HbA_1c and in the normotriglyceridaemic group a significantly increased suppression of hepatic glucose production by insulin. Whole body glucose uptake and concentrations of non-esterified fatty acids did not change. LDL-cholesterol- and apolipoprotein B levels decreased, and HDL-cholesterol, its subfraction HDL₂-cholesterol and apolipotrotein A1 increased. The plasma triglyceride level remained similar in both groups. Both the concentration of plasminogen activator inhibitor-1 antigen and its active subfraction decreased. Tissue type plasminogen activator activity increased significantly only in the normotriglyceridaemic group. Oestrogen replacement therapy improves insulin sensitivity in liver, glycaemic control, lipoprotein profile and fibrinolysis in postmenopausal women with NIDDM. For a definite answer as to whether oestrogens can be more liberally used in NIDDM patients, long term studies including the effect of progestogens are necessary. [Diabetologia (1997) 40: 843–849] Received: 12 November 1996 and in revised form: 21 March 1997