Enhanced escape of non-esterified fatty acids from tissue uptake: its role in impaired insulin-induced lowering of total rate of appearance in obesity and Type II diabetes mellitus

Aims/hypothesis. To estimate non-esterified fatty acids kinetics in patients with Type II (non-insulin-dependent) diabetes mellitus and obese subjects in the postabsorptive state and during hyperinsulinaemia using non-equlibrium tracer conditions.¶Methods. We evaluated the effect of hyperinsulinaemia [euglycaemic clamp with insulin infused at 30 mU · kg^–1· h^–1 (3–4 h) and 150 mU · kg^–1· h^–1 (3 h)] on non-esterified fatty acid kinetics, traced with [¹⁴C]-palmitate using non-equlibrium tracer conditions in non-obese and obese healthy subjects and Type II diabetic patients (10 per group). Michaelis-Menten kinetics were applied for total non-esterified fatty acid disposal, which was assumed to be composed of total arterial plasma non-esterified fatty acid rate of appearance (equalling the rate of disappearance) and tissue uptake of non-esterified fatty acids derived from intravascular triglyceride hydrolysis. A model was developed to calculate the rate of escape of non-esterified fatty acids from tissue uptake and the net rate of tissue lipolysis.¶Results. Total arterial plasma non-esterified fatty acid rate of appearance was lower in non-obese healthy subjects than in the other groups at low insulin infusion (p < 0.05) and in obese Type II diabetic patients at high insulin infusion (p < 0.05). Plasma triglycerides were also lowest in non-obese healthy subjects during hyperinsulinaemia (p < 0.05 from other groups). The rate of escape from tissue uptake decreased during hyperinsulinaemia (p < 0.05 for each group) but remained higher in obese Type II diabetic patients (p < 0.05 from non-obese healthy subjects). In contrast, net rate of tissue lipolysis was not different between the groups at baseline and its decline during hyperinsulinaemia (p < 0.05 for each group) was similar in all groups.¶Conclusion/interpretation. This study challenges the view that the antilipolytic effect of insulin is impaired in Type II diabetes and obesity. We suggest that a high plasma triglyceride concentration causes a higher escape of non-esterified fatty acids from tissue uptake, leading to an impaired suppression of total arterial plasma rate of appearance during a low degree of hyperinsulinaemia in obese subjects and Type II diabetic patients and during a high degree of hyperinsulinaemia in obese Type II diabetic patients. [Diabetologia (2000) 43: 416–426]     

Erythromycin improves glycaemic control in patients with Type II diabetes mellitus

Aims/hypothesis. Erythromycin mimics the effect of the gastrointestinal hormone motilin by binding to its receptor and acting as a motilin agonist. We recently found that motilin stimulates insulin secretion at lower doses than doses required to stimulate gastric contractile activity. We studied the effects of erythromycin on insulin secretion and glycaemic control in patients with diabetes mellitus.¶Methods. Inpatients (n = 34) with Type II (non-insulin-dependent) diabetes mellitus were randomly assigned to receive either erythromycin (400 mg orally three times a day, n = 19) or a placebo (n = 15) for 1 week (first study). Another 34 outpatients with Type II diabetes were also treated with erythromycin (200 mg orally three times a day, n = 17) or a placebo (n = 17) for 4 weeks (second study). Finally, nine inpatients with Type II diabetes and eight normal control subjects received intravenous erythromycin (10 mg · kg^–1· h^–1) or saline infusion and insulin secretion was examined (third study).¶Results. Erythromycin lowered fasting blood glucose and fructosamine concentrations (p < 0.01) and increased basal as well as glucose-stimulated insulin secretion (p < 0.05–0.01) (first study). Low doses of erythromycin treatment for 4 weeks also significantly improved glycaemic control in Type II diabetic patients (second study). Erythromycin infusion significantly increased plasma insulin and decreased glucose concentrations in Type II diabetic and control subjects and greatly potentiated glucose-induced insulin secretion in the latter (third study).¶Conclusion/interpretation. These results indicate that erythromycin given orally has an antidiabetogenic effect and therefore erythromycin derivatives that lack the antibacterial activity could have a therapeutic value in Type II diabetic patients. [Diabetologia (2000) 43: 411–415]     

Explaining the sex difference in coronary heart disease mortality among patients with type 2 diabetes mellitus: a meta-analysis

BACKGROUND: Most studies suggest that diabetes is a stronger coronary heart disease (CHD) risk factor for women than men, but few have adjusted their results for classic CHD risk factors: age, hypertension, total cholesterol level, and smoking. OBJECTIVE: To establish an accurate estimate of the odds ratio for fatal and nonfatal CHD due to diabetes in both men and women. METHODS: We compared the summary odds ratio for CHD mortality and the absolute rates of CHD mortality in men and women with diabetes. We searched the MEDLINE and Cochrane Collaboration databases and bibliographies of relevant articles and consulted experts. Studies that included a nondiabetic control group and provided sex-specific adjusted results for CHD mortality, nonfatal myocardial infarction, and cardiovascular or all-cause mortality were included. Of 4578 articles identified, 232 contained primary data, and 182 were excluded. Two reviewers recorded data on study characteristics, quality, and outcomes from 50 studies. RESULTS: Sixteen studies met all inclusion criteria. In unadjusted and age-adjusted analyses, odds of CHD death were higher in women than men with diabetes. From 8 prospective studies, the multivariate-adjusted summary odds ratio for CHD mortality due to diabetes was 2.3 (95% confidence interval, 1.9-2.8) for men and 2.9 (95% confidence interval, 2.2-3.8) for women. There were no significant sex differences in the adjusted risk associated with diabetes for CHD mortality, nonfatal myocardial infarction, and cardiovascular or all-cause mortality. Absolute CHD death rates were higher for diabetic men than women in every age strata except the very oldest. CONCLUSIONS: The excess relative risk of CHD mortality in women vs men with diabetes was absent after adjusting for classic CHD risk factors, but men had more CHD deaths attributable to diabetes than women.     

Relation between glycaemic control,hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes

Aims/hypothesis: Increased plasma concentrations of circulating adhesion molecules in patients with Type II (non-insulin-dependent) diabetes mellitus could be associated with the increased cardiovascular risk in these patients. However, it is controversial whether increased adhesion molecule plasma concentrations are primarily related to hyperglycaemia or to hyperinsulinaemia. Methods: We evaluated the plasma concentrations of soluble E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) at baseline and during euglycaemic hyperinsulinaemic clamp in three different groups without additional cardiovascular risk factors: group A (control group), 28 healthy volunteers with normal glucose tolerance; group B, 24 subjects with fasting hyperinsulinaemia, normal fasting glucose but impaired glucose tolerance; group C, 32 patients with Type II diabetes, fasting hyperinsulinaemia and chronic hyperglycaemia. Results: Plasma soluble E-selectin, ICAM-1, and VCAM-1 concentrations were higher (p < 0.05) in patients with Type II diabetes (group C) compared with the other groups. The adhesion molecule concentrations correlate with the fasting plasma glucose (r = 0.59, p < 0.001), the 2-h OGTT plasma glucose (r = 0.70, p < 0.01), and the HbA_{1 c} value (r = 0.61, p < 0.05). The E-selectin but not the ICAM-1 and VCAM-1 plasma concentrations correlated with the fasting insulin concentrations (r = 0.62, p < 0.05) or the whole body glucose uptake (r = 0.59, p < 0.05) in the clamp. The hyperinsulinaemia during the euglycaemic hyperinsulinaemic clamp had no significant effect on the plasma concentrations of E-selectin, ICAM-1, and VCAM-1 in all three groups. Conclusion/interpretation: Our results suggest that increased E-selectin concentrations are related to hyperglycaemia, hyperinsulinaemia and insulin resistance, whereas increased ICAM-1 and VCAM-1 plasma concentrations in patients with Type II diabetes are rather related to hyperglycaemia than to hyperinsulinaemia or insulin resistance. [Diabetologia (2002) 45: 210–216] Received: 13 August 2001 and in revised form: 1 October 2001     

Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in Type 2 (non-insulin-dependent) diabetic and non-diabetic subjects

Summary The purpose of the present study was to examine 10-year cardiovascular morbidity and mortality in patients with newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus and non-diabetic control subjects and to evaluate the effects of general risk factors, plasma insulin, urinary albumin excretion, lipoprotein abnormalities characteristic of Type 2 diabetes and the degree of hyperglycaemia in diabetic patients on cardiovascular mortality. Furthermore, the extent to which the above-mentioned factors could contribute to the excessive cardiovascular mortality observed in diabetic patients was examined. In the years 1979–1981, altogether 133 (70 men, 63 women) newly-diagnosed patients with Type 2 diabetes and 144 (62 men, 82 women) non-diabetic control subjects aged 45–64 years were studied. Both groups were re-examined in the years 1985–1986 and 1991–1992. The impact of different factors on cardiovascular mortality was examined by univariate analyses after adjustment for age and sex and by multiple logistic regression analyses. The age-standardized total and cardiovascular mortality rates were substantially higher in diabetic men (17.8 and 15.0%, total and cardiovascular mortality, respectively p = 0.06 and NS) and women (18.5 and 16.6%, p<0.01 for both) than in non-diabetic control men (5.2 % both total and cardiovascular mortality) and women (4.2 and 2.2 %). Cardiovascular mortality was not related to the treatment modality (diet, oral drugs, insulin) at 5 years from diagnosis. Use of diuretics, beta-blocking agents or their combination at baseline did not make a significant contribution to cardiovascular mortality either. In multiple logistic regression analysis on diabetic patients, age, LDL triglycerides, smoking, blood glucose and ischaemic ECG at baseline had independent associations with cardiovascular mortality. Interestingly, urinary albumin excretion rate measured at 5-year examination also predicted 10-year cardiovascular mortality after adjustment for the effects of major risk factors including lipoprotein abnormalities, but its predictive power reduced to a nonsignificant level when the effect of plasma glucose was taken into account. The relative risk of cardiovascular mortality associated with diabetes was 8.2 after allowing for age alone, but it declined to 3.7 when all contributing factors from the baseline examination (except blood glucose) were taken into account. In conclusion, the present results indicate that LDL triglycerides and/or other changes in lipoprotein composition characteristic of Type 2 diabetes and manifesting as elevated serum triglycerides are atherogenic and they strongly predict increased cardiovascular mortality. Furthermore, it is hypothesized that the consequences of long-term hyperglycaemia could explain a large proportion of the remaining excessive cardiovascular mortality risk among Type 2 diabetic patients.     

Paraoxonase2 polymorphisms are associated with nephropathy in Type II diabetes

Aims/hypothesis. Paraoxonase is a member of a multigene family of three genes. Paraoxonase2 gene polymorphisms have been associated with coronary heart disease in non-diabetic patients and with an increased fasting glycaemia in patients with Type II (non-insulin-dependent) diabetes mellitus. We tested the hypothesis of whether paraoxonase1 and paraoxonase2 polymorphisms were associated with diabetic nephropathy.¶Methods. Our case-control study of 299 Swiss patients with Type II diabetes included 147 patients with confirmed diabetic nephropathy.¶Results. In univariate analyses the two paraoxonase2 polymorphisms were associated with diabetic nephropathy. When subjected to multivariate analyses, both paraoxonase2 polymorphisms remained statistically associated with diabetic nephropathy independent of traditional risk factors (paraoxonase2–148: OR = 2.53, p = 0.003; paraoxonase2–311: OR = 2.67, p = 0.002). In addition, BMI interacted with paraoxonase2 polymorphisms as a risk factor of nephropathy.¶Conclusions/interpretation. The paraoxonase2 gene polymorphisms were significantly associated with diabetic nephropathy independent of traditional risk factors in Type II diabetic patients. The susceptibility to diabetic nephropathy was intensified by the degree of obesity. Pathophysiological pathways should be investigated and could be involved in insulin resistance or lipids metabolism or both. [Diabetologia (2001) 44: 104–107]     

Diabetes, mortality and coronary heart disease in the prospective Dubbo study of Australian elderly

Background: A prospective study of Australian elderly living in Dubbo has shown that diabetes is a significant predictor of all-causes mortality and coronary heart disease (CHD). Aim: To examine and contrast clinical and socio-demographic predictors of these outcomes in those with and without diabetes. Methods: The data are derived from a community-based sample of subjects 60 years and older followed over 62 months since 1988. Of 1155 men and 1472 women, 9.2% and 6.9% respectively manifested diabetes at baseline, based on history or fasting hyper-glycaemia. Results: In the presence of diabetes, all-causes mortality was increased twofold in both sexes, CHD incidence was increased twofold in men and threefold in women, stroke incidence was increased twofold in women but little changed in men. Proportional hazards models were derived separately for persons with and without diabetes and risk factors differentially predictive in diabetes were sought. Significant predictors of death in diabetes were old age and current smoking. Those factors differentially predictive were ‘being married’ (Relative Risk [RR] 1.60 with diabetes and 0.69 without diabetes) and higher body mass index (BMI) (RR 1.03 with diabetes and 0.79 without diabetes). Significant predictors of CHD in diabetes were old age, prior CHD, severe hypertension, low HDL cholesterol and self-rated health. Those factors differentially predictive were higher body mass index (RR 1.14 vs 0.83) and physical disability (RR 0.69 vs 1.55). Differential predictions with regard to BMI may relate in part to excess CHD and mortality at low BMI in non-diabetic subjects. Conclusion: The vascular disease burden of diabetes in the elderly has been confirmed, especially in women. A number of conventional risk factors are contributing to this burden and may be amenable to treatment.     

Mortality in African-Americans with Type 1 diabetes: The New Jersey 725.

AIM: To determine rates and risk factors for all-cause mortality in African-Americans with Type 1 diabetes from a 3-year observational follow-up study of 725 African-Americans with Type 1 diabetes conducted between 1 January 1999 and 31 December 2001. METHODS: Date of death was ascertained either from telephone contact with the patient's family or from relatives or on line review of the US Social Security death index. RESULTS: Since the initial examination, 131 (18.1%) patients, 60 (20%) men and 71 (17%) women, have died. At the time of death, the mean age of the men was 40.7 +/- 10.6 years and that of the women 39.4 +/- 10.5 years. The median duration of diabetes at the baseline examination was 8.04 years, interquartile range (IQR) 3.76-15.22 years for men and median 10.54, IQR 4.49-18.36 years for women. Three-year mortality rates were 7.1% for women and 10.6% for men. Age-adjusted mortality rates were not significantly different between men and women. Relative to the general US and the New Jersey African-American population, standardized mortality ratios of African-Americans with Type 1 diabetes were 12 and six times greater for women and men, respectively. Older age, low socio-economic status, low body mass index, high diastolic blood pressure, macroangiopathy, proteinuria, severe diabetic retinopathy and heavy alcohol consumption were independent risk factors for all-cause mortality. In patients with microproteinuria at initial examination, the mortality rate for men was twice that of women. CONCLUSION: Microproteinuria and other potentially modifiable factors, including hypertension, macroangiopathy and heavy alcohol consumption, are independent risk factors for mortality in this ethnic group.     

Regulation of gene expression during severe caloric restriction: lack of induction of p85alpha phosphatidylinositol 3-kinase mRNA in skeletal muscle of patients with Type II (non-insulin-dependent) diabetes mellitus

Aims/hypothesis. Alterations in the regulation of gene expression could be involved in the development of Type II (non-insulin-dependent) diabetes mellitus.¶Methods. We compared the mRNA concentrations of eight genes encoding proteins involved in insulin action and intermediary metabolism in skeletal muscle of healthy volunteers and Type II diabetic patients. The in vivo regulation of the expression of these genes was investigated after 5 days of hypocaloric diet (1045 kJ/day).¶Results. In the basal state, diabetic muscle showed reduced insulin receptor (–38 %), hexokinase II (–73 %), glycogen synthase (–45 %) and lipoprotein lipase (–70 %) mRNA expression. There was no difference in the mRNA abundances of IRS-1, GLUT 4, p85α phosphatidylinositol-3-kinase (p85αPI3K) or Rad. In both groups, caloric restriction induced weight loss, reduced glycaemia and increased plasma ketone body concentrations. The diet also increased plasma concentrations of fatty acids and decreased whole-body insulin sensitivity in control subjects. In control subjects, the diet increased p85αPI3K ( + 146 %), insulin receptor ( + 100 %) and Rad ( + 40 %) mRNA concentrations in muscle. In Type II diabetic patients, the diet increased insulin receptor ( + 41 %) and Rad ( + 31 %) mRNAs but the expression of p85αPI3K was not modified.¶Conclusion/interpretation. The regulation of the expression of p85αPI3K is altered during caloric restriction in skeletal muscle of Type II diabetic patients. Because we have shown in an earlier study that there is also a defective regulation of p85αPI3K gene expression in response to insulin, these data support the hypothesis that alterations in the regulation of gene expression could be involved in the pathogenesis of Type II diabetes. [Diabetologia (2000) 43: 356–363]     

Insulin resistance,haemostatic and inflammatory markers and coronary heart disease risk factors in Type 2 diabetic men with and without coronary heart disease

Aims/hypothesis We have examined markers of haemostasis and inflammation in men with diabetes, coronary heart disease (CHD) or both, and assessed their associations with insulin resistance in men with Type 2 diabetes.Methods The study was carried out in 4066 British men aged 60 to 79 years who were not on warfarin or insulin, of whom there were 426 men with prevalent Type 2 diabetes and 842 with prevalent CHD.Results Men with Type 2 diabetes were more likely to have multiple risk factors and higher levels of haemostatic and inflammatory markers than men without, irrespective of CHD status. Compared with men with CHD only, men with diabetes only showed increased levels of tissue plasminogen activator antigen, increased plasma and blood viscosity, and increased levels of coagulation factors VII, VIII and IX. They also had dyslipidaemia. In men with diabetes, increased insulin resistance (homeostasis model assessment, HOMA) was associated with increased levels of haemostatic markers and dyslipidaemia. The prevalence of CHD increased significantly with increasing tertiles of HOMA (adjusted odds ratio 1.32 [95% CI: 0.72–2.42] in the second, and 1.70 [95% CI: 0.92–3.44] in the third tertile; p=0.04 for trend).Conclusions/interpretation Increased insulin resistance among men with Type 2 diabetes is associated with increased prevalence of CHD and of activated haemostasis and dyslipidaemia. Reducing insulin resistance in men with diabetes may reduce their tendency to develop thrombosis and hence CHD risk.     

Do women exhibit greater differences in established and novel risk factors between diabetes and non-diabetes than men? The British Regional Heart Study and British Women’s Heart Health Study

Aims/hypothesis  

Type 2 diabetes is associated with greater relative risk of CHD in women than in men, which is not fully explained by conventional cardiovascular risk factors. We assessed whether cardiovascular risk factors including more novel factors such as markers of insulin resistance, inflammation, activated coagulation and endothelial dysfunction differ more between diabetic and non-diabetic women than between diabetic and non-diabetic men, and the role of insulin resistance.     

Hyperinsulinaemia as long-term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project

Abstract. Nilsson P, Nilsson J‐Å, Hedblad B, Eriksson K‐F, Berglund G. (University Hospital, Malmö, Sweden) Hyperinsulinaemia as long‐term predictor of death and ischaemic heart disease in nondiabetic men: The Malmö Preventive Project. J Intern Med 2003; 253: 136–145. Objectives. Prospective studies have indicated that hyperinsulinaemia/insulin resistance is a risk factor for ischaemic heart disease (IHD), the risk decreasing with time of follow‐up. Few studies have so far investigated the role of hyperinsulinaemia in the prediction of long‐term total mortality. Setting. Section of Preventive Medicine, Department of Medicine, University Hospital, Malmö, Sweden. Subjects. A total of 6074 nondiabetic, middle‐aged, healthy Swedish males. Screening examination. We determined IHD risk factors including blood glucose and plasma insulin before and 2 h after an oral glucose tolerance test (OGTT). Total follow‐up time was 19 years. Hyperinsulinaemia was defined as values above the 10th decentile of fasting or 2 h insulin concentration. Main outcome measures. Total mortality and cardiac event (CE) rate for IHD. Results. Unadjusted relative risks (RRs) for both death and CE were J‐shaped with the highest relative risk (RR: 1.4–1.6) in the hyperinsulinaemic group compared with all other men. The RRs for death and CE were significant for fasting insulin but became nonsignificant after adjustment for other risk factors and also with a longer follow‐up. The risk of death in hyperinsulinaemic men, defined on the basis of 2‐h insulin level, increased with time of follow‐up and was still significantly increased after 19 years [RR: 1.32 (95% CI: 1.05–1.65], even after adjustment for other risk factors. Conclusions. Fasting hyperinsulinaemia was a predictor of total mortality and IHD in nondiabetic men, although not more significantly after adjustment for other risk factors and with lengthening of follow‐up time. The 2‐h postglucose hyperinsulinaemia appeared to be a stronger and independent predictor of mortality over long‐term follow‐up. These findings support the view that insulin resistance with associated cluster of risk factors predicts increased long‐term risk of mortality and IHD.     

Albuminuria in Australian Aboriginal people: prevalence and associations with components of the metabolic syndrome

Aims/hypothesis. To examine the prevalence and associations with the metabolic syndrome of albuminuria among Australian Aboriginal people.¶Methods. Early-morning urine specimens were collected as part of community-based risk factor surveys assessing the prevalence of diabetes and cardiovascular disease in eight remote communities, with a sample size of 1,075 people. Microalbuminuria was defined as urinary albumin : creatinine ratio 3.4–33.9 mg/mmol, macroalbuminuria as albumin : creatinine ratio equal to or greater than 34 mg/mmol.¶Results. There were high prevalences of microalbuminuria (men 22.2 %, women 26.9 %) and of macroalbuminuria (men 10.4 %, women 13.5 %). There were highly statistically significant linear associations of microalbuminuria and macroalbuminuria with increasing number of coexisting components of the metabolic syndrome (hypertension, glucose intolerance, dyslipidaemia, insulin resistance, abdominal obesity): among people with zero, one, two and three to five of these conditions, respectively, prevalence of microalbuminuria was 16 %, 20 %, 36 % and 32 % (p < 0.001); prevalence of macroalbuminuria was 2 %, 6 %, 12 % and 32 % (p < 0.001). There were independent associations of microalbuminuria with hypertension (odds ratio, 95 % confidence interval = 2.36, 1.63–3.42) and diabetes (2.10, 1.28–3.45): macroalbuminuria was independently associated with hypertension (6.39, 3.93–10.4), diabetes (3.49, 1.93–6.28) and abdominal obesity (4.56, 2.40–8.64) and had a weaker association with insulin resistance (1.99, 1.12–3.54). Dyslipidaemia and impaired glucose tolerance were neither independently associated with microalbuminuria or macroalbuminuria, nor was insulin resistance or abdominal obesity independently associated with microalbuminuria.¶Conclusion/interpretation. There was a strong clustering of albuminuria with components of the metabolic syndrome. Diabetes, hypertension and abdominal obesity are major contributors to high rates of albuminuria among Australian Aboriginal people. [Diabetologia (2000) 43: 1397–1403]     

Clustering of cardiovascular risk factors with diabetes in Chinese patients: the effects of sex and hyperinsulinaemia

SUMMARY
Objective   This study was designed to investigate factors which affect the clustering of cardiovascular risk factors with diabetes in Chinese patients.
Research Design and Methods: Six hundred and fifty-four patients with diabetes were assessed comprehensively for diabetes complications and cardiovascular risk factors in a metropolitan hospital in Beijing, China. Insulin resistance and secretion were also evaluated by measurement of glucose and insulin levels before and after a meal tolerance test. Results were analysed according to patient groups stratified by the number of cardiovascular risk factors coexisting with diabetes.
Results   Cardiovascular risk factors were common in Chinese diabetic patients. The clustering of three or more of these factors with diabetes occurred more often than by chance alone and was associated with postprandial hyperinsulinaemia. Patients with a high number of risk factors were more prone to macrovascular events but did not have higher albuminuria. Using the commonly adopted lower threshold for diagnosing obesity and central obesity in women, there were more women with multiple risk factors. However, this disappeared if the same criteria were used for men and women. Even in the presence of diabetes, cardiovascular risk factors were inadequately controlled in most patients.
Conclusions   The concurrence of diabetes and other cardiovascular risk factors which constitute the metabolic syndrome is a common phenomenon in urban Chinese diabetic patients. It is associated with hyperinsulinaemia and possibly the female sex. This study emphasises the importance of public health measures to control cardiovascular risk factors in patients with diabetes.     

Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk in Type II diabetes

Aims/hypothesis. Cardiovascular complications and particularly coronary heart disease are the main causes of morbidity and mortality in Type II (non-insulin-dependent) diabetes mellitus. Some studies have shown that hypertriglyceridaemia in diabetes is an independent cardiovascular risk factor. In the ECTIM study high apolipoprotein C3 and lipoprotein B:C3 concentrations (lipoparticles playing a role in triglyceride metabolism) were associated with myocardial infarction in non-diabetic subjects.¶Methods. We studied the relations between macroangiopathy and different cardiovascular risk factors and lipid variables in 188 Type II diabetic subjects.¶Results. Multivariate analysis showed that triglycerides, apo C3 and Lp B:C3, sex, duration of diabetes, microalbuminuria and age were independently associated with macroangiopathy. The study group was divided into quartiles according to apo C3 and Lp B:C3 concentrations: the prevalence of macroangiopathy and coronary heart disease were increased in upper quartiles.¶Conclusion/interpretation. Triglycerides apo C3 and Lp B:C3 were independent cardiovascular risk markers in our group of Type II diabetic patients. [Diabetologia (2000) 43: 703–708]     

Impaired insulin secretion in non-diabetic offspring of probands with latent autoimmune diabetes mellitus in adults

Aims/hypothesis. This study was undertaken to investigate metabolic and genetic characteristics of latent autoimmune diabetes in adults (LADA).¶Methods. We evaluated insulin secretory capacity with oral and intravenous glucose tolerance tests (early insulin response) and hyperglycaemic clamp (insulin secretory capacity) and the rates of whole body glucose uptake with the euglycaemic clamp, HLA-DQB1 genotypes (time-resolved fluorescence) and islet cell antibodies (ICA) (immunofluoresence) and antibodies to glutamic acid decarboxylase (GAD) (radio-immunoprecipitation) in 36 non-diabetic offspring (LADA-offspring) of patients with Type II (non-insulin-dependent) diabetes mellitus who tested positive for ICA and/or GAD antibodies during the 10-year follow-up from the diagnosis and in 19 healthy control subjects without a family history of diabetes.¶Results. The early insulin response during the first 10 min of an intravenous glucose tolerance test was about 40 % lower in the LADA-offspring than in the control group (p = 0.008). Insulin secretory capacity in the hyperglycaemic clamp was also about 30 % lower in the LADA-offspring (p = 0.048). The rates of whole body glucose uptake were similar in both groups. The frequency of low risk HLA-DQB1 genotypes was higher in the LADA-offspring than among Finnish healthy blood donors (p = 0.033). The risk conferring genotypes were associated with the lowest tertile of insulin secretory capacity in the LADA-offspring (p = 0.032). There were no associations between the autoantibodies and early insulin response or insulin secretory capacity within the study groups.¶Conclusion/interpretation. We conclude that LADA is a familial disease involving most likely gene defects leading to a slow progressive beta-cell destruction and insulin deficiency. [Diabetologia (2000) 43: 69–78]     

Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse

Aims/hypothesis. The Nagoya-Shibata-Yasuda (NSY) mouse closely mimics human Type II (non-insulin-dependent) diabetes mellitus in that the onset is age-dependent, the animals are not severely obese, and both insulin resistance and impaired insulin response to glucose contribute to disease development. The aim of this study was to clarify the influence of age on the pathogenesis of diabetes and to analyse a candidate gene for Type II diabetes in this strain.¶Methods. Several phenotypic characteristics related to diabetes mellitus were monitored longitudinally in male NSY and control C3H/He mice. The nucleotide sequence of Glut4, a candidate gene for Nidd1nsy (a susceptibility gene for Type II diabetes) on Chromosome 11, encoding insulin-sensitive glucose transporter, was determined in NSY and C3H mice.¶Results. Glucose intolerance worsened with age, and fasting blood glucose and fasting plasma insulin concentration increased with age in NSY mice. Pancreatic insulin content increased until 24 weeks of age but then decreased at 48 weeks of age in NSY mice. The hypoglycaemic response to insulin was statistically significantly smaller in NSY than in C3H/He mice. The nucleotide sequence of GLUT4 cDNA was identical in NSY and C3H/He mice, but both were different from the sequence reported previously.¶Conclusion/interpretation. Insulin secretion and insulin resistance, as well as ageing possibly play an important part in the disease development in NSY mice. A decline of pancreatic insulin content in older age might cause the relative insulin deficiency in this strain. Nucleotide sequencing suggests that Glut4 is unlikely to be a candidate gene for Nidd1nsy. [Diabetologia (2000) 43: 932–938]     

Risk factors for cardiovascular disease in individuals with diabetes

Coronary heart disease (CHD) is the leading cause of death among individuals with diabetes. However, information on CHD and its association with known risk factors in populations with high rates of diabetes is limited. The purpose of the Strong Heart Study is to quantify CHD and its risk factors among three geographically diverse groups of American Indians who have a high prevalence of diabetes. The study group consisted of 4549 adults between 45 and 74 years of age in 13 Indian communities in Arizona, Oklahoma, and South and North Dakota. Rates of diabetes ranged from 33% to 72% in men and women in the three centers. The prevalence rates of definite myocardial infarction (MI) and definite CHD were higher in man than in women in all three centers (P<0.0001) and higher in those with diabetes (P=0.002 andP=0.0003 in women and men, respectively). Diabetes was associated with a relatively greater increase in prevalence of MI (PR=3.8 vs 1.9) and CHD (PR=4.6 vs 1.8) in women than in men. Logistic regression analysis indicated that prevalent CHD was significantly related to age, diabetes, hypertension, albuminuria, percent body fat, smoking, high concentrations of plasma insulin, and low concentrations of high-density lipoprotein (HDL)-cholesterol. These findings from the baseline Strong Heart Study examination emphasize the relative importance of diabetes-associated variables as risk factors for CHD among populations with high rates of diabetes.Invited lecture presented during the 6th International Milano Meeting on Diabetes held in Milan on 21–23 March, 1996     

Sex differences in risk for coronary heart disease mortality associated with diabetes and established coronary heart disease

BACKGROUND: The sex-specific independent effect of diabetes mellitus and established coronary heart disease (CHD) on subsequent CHD mortality is not known. METHODS: This is an analysis of pooled data (n = 5243) from the Framingham Heart Study and the Framingham Offspring Study with follow-up of 20 years. At baseline (1971-1975), 134 men and 95 women had diabetes, while 222 men and 129 women had CHD. Risk for CHD death was analyzed by proportional hazards models, adjusting for age, hypertension, serum cholesterol levels, smoking, and body mass index. The comparative effect of established CHD vs diabetes on the risk of CHD mortality was tested by testing the difference in log hazards. RESULTS: The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for death from CHD were 2.1 (95% CI, 1.3-3.3) in men with diabetes only, and 4.2 (95% CI, 3.2-5.6) in men with CHD only compared with men without diabetes or CHD. The HR for CHD death was 3.8 (95% CI, 2.2-6.6) in women with diabetes, and 1.9 (95% CI, 1.1-3.4) in women with CHD. The difference between the CHD and the diabetes log hazards was +0.73 (95% CI, 0.72-0.75) in men and -0.65 (95% CI, -0.68 to -0.63) in women. CONCLUSIONS: In men, established CHD signifies a higher risk for CHD mortality than diabetes. This is reversed in women, with diabetes being associated with greater risk for CHD mortality. Current treatment recommendations for women with diabetes may need to be more aggressive to match CHD mortality risk.     

Low serum concentration of sulfatide and presence of sulfated lactosylceramid are associated with Type 2 diabetes. The Skaraborg Project.

AIMS: The glycosphingolipid sulfatide (sulfated galactosyl-ceramide) increases exocytosis of beta-cell secretory granules, activates K(ATP)-channels and is thereby able to influence insulin secretion through its presence in the islets. A closely related compound, sulfated lactosylceramide (sulf-lac-cer), is present in the islets during fetal and neonatal life when, as in Type 2 diabetes, insulin is secreted autonomically without the usual first phase response to glucose. The aim was to examine whether serum concentrations of these glycolipids are associated with Type 2 diabetes. METHODS: A case-control study, comprising 286 women and 283 men, was designed using a population-based sample of patients with Type 2 diabetes and a population survey. RESULTS: Low serum concentrations of sulfatide were associated with Type 2 diabetes, independent of traditional risk factors for diabetes in a sex-specific analysis: odds ratio (OR) 2.1 (95% confidence interval 1.1, 3.9) in men, and 2.3 (1.2, 4.3) in women, comparing the lowest and the highest tertiles. Type 2 diabetes was also associated with detectable amounts of sulf-lac-cer in serum: OR 1.7 (0.9, 3.4) in men, and 7.6 (3.8, 15.2) in women. After adjustment for confounding from other diabetes risk factors, these associations remained basically unchanged. The connections between sulfatide and Type 2 diabetes, and sulf-lac-cer and Type 2 diabetes were independent of each other. Insulin resistance (HOMA-IR) was negatively correlated with sulfatide concentration and positively correlated with sulf-lac-cer (both P < 0.0001, independently). CONCLUSIONS: We report a new, robust and highly significant independent association between Type 2 diabetes and serum concentrations of sulfatide in both sexes, and sulf-lac-cer in females. The associations were also independent of other known diabetes risk factors.