Lifestyle and genetics in obesity and type 2 diabetes.

Obesity and type 2 diabetes mellitus are multifactorial health threats caused by a complex interplay between genetic predisposition and the environment with dramatically increasing worldwide prevalence. The role of heritability in their etiology is well recognized, however, the numerous attempts made in order certain genetic variants determining individual susceptibility to be identified have had limited success, until recently. At present the advancements in human genetics and the utilization of the genome-wide association approach have led to the identification of over 20 genetic loci associated with, respectively obesity and type 2 diabetes. Most of the genes identified to date, however, have modest effect on disease risk suggesting that both diseases are unlikely to develop without the individual being exposed to obesity- and/or type 2 diabetes-promoting environment. Indeed, unhealthy lifestyle, characterized by physical inactivity and food overconsumption is an unequivocally established risk factor for obesity and type 2 diabetes. Numerous epidemiological studies and randomized controlled trials, on the other hand, have demonstrated that lifestyle modification is effective in obesity and type 2 diabetes prevention. Furthermore, gene-lifestyle interaction studies suggest that genetic susceptibility to obesity and type 2 diabetes may be partially or totally kept under control by healthy lifestyle or lifestyle modification and that lifestyle determines whether an individual is likely to develop the disease. Inherited factors, however, seem to influence individual response to a lifestyle intervention program and even the motivation for lifestyle change. Personalized interventions according to genotype may be, therefore, considered in the future. By then lifestyle modification targeting dietary change and increased physical activity may be recommended for successful obesity and type 2 diabetes prevention irrespectively of genetic susceptibility.

The lipid triad in type 2 diabetes - prevalence and relevance of hypertriglyceridaemia/low high-density lipoprotein syndrome in type 2 diabetes.

Cardiovascular disease is the major cause of morbidity and mortality in type 2 diabetes mellitus. Among the established risk factors, the lipid triad (elevated triglycerides, decreased high-density lipoprotein cholesterol, and small dense low-density lipoprotein cholesterol) is a powerful risk factor for atherosclerosis in type 2 diabetes. The prevalence of hypertriglyceridaemia (HTG) in type 2 diabetes is two to three times higher than in non-diabetics. The Copenhagen Male study, the AMORIS study, and several other trials showed hypertriglyceridaemia to be an independent predictor of coronary heart disease (CHD). HTG may promote risk both directly and indirectly through association with alterations of lipoprotein size and composition. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) demonstrated that raising high-density lipoprotein cholesterol (HDL-C) in patients with low (HDL-C) and low-density lipoprotein cholesterol (LDL-C) is associated with a significant reduction in CHD risk. It was shown in the Diabetes Intervention Study, AFCAPS/TexCAPS, and PROCAM studies that decreased HDL-C and elevated triglycerides are independent risk factors for atherosclerosis, particularly in patients with diabetes mellitus. Several epidemiological studies demonstrated that total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) ratios or low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratios could be better predictors of atherosclerosis than any single lipid parameter. Intima-media thickness (IMT), a well established marker of early atherosclerosis, is associated with HTG/low HDL-cholesterol. In the Risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study total and HDL-cholesterol were independent determinants of IMT in subjects at risk for type 2 diabetes. Postprandial HTG was also shown to be correlated with increased IMT in type 2 diabetic patients.

Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients.

AIM: The aim of our double-blind, placebo-controlled study was to compare the effect of acarbose and glibenclamide on the insulin sensitivity in type 2 diabetes. METHODS: We investigated 77 patients (mean age 58.7 years, mean BMI 27.3 kg/m2), treated by diet alone for at least 4 weeks. The subjects were randomized into three treatment groups for 16 weeks: 100 mg t.i.d. acarbose (n = 25) or 1 mg t.i.d. glibenclamide (n = 27) or one t.i.d. placebo (n = 25). Before and after therapy, the levels of fasting plasma glucose, glycosylated haemoglobin, fasting insulin, plasma glucose and insulin 1 h after a standardized breakfast were measured and insulin sensitivity determined by euglycaemic hyperinsulinaemic clamp test. RESULTS: After the treatment period, BMI in the acarbose and placebo group decreased significantly, whereas in the glibenclamide group a significant increase was observed. Fasting plasma glucose was only significant reduced under glibenclamide. The postprandial glucose decreased significantly after acarbose (13.8 vs. 11.4 mmol/l, p < 0.05) and glibenclamide treatment (14.6 vs. 11.4 mmol/l, p < 0.05) and was unchanged under placebo (13.8 vs. 13.7 mmol/l). The fasting insulin levels remained unchanged in all three groups, whereas postprandial insulin values increased significantly under glibenclamide. Neither acarbose nor glibenclamide significantly changed insulin sensitivity [acarbose: glucose disposal rate before treatment 2.3 mg/kg body weight/min/insulin, after treatment 3.2; glibenclamide 2.2 vs. 2.1; placebo 2.6 vs. 3.0]. CONCLUSIONS: Our results show a more substantial improvement of glucose control under glibenclamide than under acarbose which, however, was not associated with an increase of insulin sensitivity.

[Significance of postprandial glucose peaks for development of diabetic macroangiopathy]. / Bedeutung der postprandialen Glukosespitzen für die Entstehung der diabetischen Makroangiopathie.

Type-2 diabetes is associated with an excessively high mortality and morbidity due to cardiovascular disease. Numerous studies have demonstrated the relevance of postprandial hyperglycemia for atherosclerosis. Moreover, the form of isolated postprandial diabetes seems to be much more common than expected. Even mild postprandial hyperglycemia in the form of impaired glucose tolerance was shown to be associated with an increased rate of cardiovascular disease. This indicates the necessity of using OGTT in the screening of high-risk populations in order to detect asymptomatic diabetic subjects and enable appropriate treatment in time. Not using the OGTT would mean missing a large cohort of undiagnosed diabetic subjects, particularly among older people. Since an OGTT cannot be generally conducted, we recommend its performance in risk subjects and especially in elderly women. This would make it possible to institute preventive measures.

Control of post-prandial hyperglycemia--an essential part of good diabetes treatment and prevention of cardiovascular complications.

AIM: This article reviews the relationship between the control of post-prandial hyperglycemia and diabetes-related complications. DATA SYNTHESIS: Hyperglycemia is a modifiable risk factor that has a deleterious effect on the development and progression of microvascular and macrovascular complications in patients with type 2 diabetes. The UK Prospective Diabetes Study revealed how reductions in hemoglobin A1c (HbA1c) correlate with a significant reduction in all-cause mortality and the incidence of myocardial infarction. The Diabetes Intervention Study showed that poor control of fasting glycemia does not increase the risk of myocardial infarction or mortality, whereas poor control of post-prandial glucose is associated with a high all-cause mortality rate. HbA1c is the standard measure for metabolic control and therapeutic efficacy, but does not reflect fluctuations in glycemic control. Plasma glucose concentrations in healthy subjects remain within a narrow range, which suggests that the fluctuations in glucose levels caused by inappropriate treatment may have negative consequences. These fluctuations have been associated with acute adverse effects (particularly excessive post-prandial hyperglycemia, pre-meal hypoglycemia and weight gain) that counteract the positive effect of lowering fasting plasma glucose and HbA1c. Post-prandial hyperglycemia and spikes also have deleterious effects on insulin secretion and sensitivity. Prandial oral antidiabetic agents such as alpha-glucosidase inhibitors (acarbose, miglitol) and rapidly acting insulin secretagogues (nateglinide, repaglinide) have recently been introduced to improve the control of post-prandial hyperglycemia. CONCLUSION: Near-normal post-prandial glycemic control is associated with lower rates of cardiovascular and all-cause mortality than excessive post-challenge hyperglycemia. In addition to the aggressive control of HbA1c and fasting plasma glucose, the strict normalisation of postprandial hyperglycemia is an essential part of good diabetes treatment. There is growing evidence from epidemiological and clinical studies that this also reduces the risk of cardiovascular complications.

Intima-media thickness and atherosclerotic plaques in familial defective apolipoprotein B-100 and familial hypercholesterolemia.

Familial defective apolipoprotein B-100 (FDB) is a genetic disorder characterized by a decreased binding of low-density lipoprotein (LDL) particles to the LDL receptor due to defective apo B-100. Impaired LDL clearance could also be due to defects of the LDL receptor (familial hypercholesterolemia, FH). FDB was suggested to be clinically indistinguishable from classical FH. The measurement of the intima-media thickness (IMT) is an accepted method for the direct evaluation of early atherosclerosis. Thus, the aim of this study was to examine the IMT in patients with FDB in comparison to FH. Our data indicate that IMT in FDB does not differ from IMT in FH.

Subclinical inflammation is strongly related to insulin resistance but not to impaired insulin secretion in a high risk population for diabetes.

Subclinical inflammation was shown to be a strong predictor of cardiovascular events and was suggested to be a part of the metabolic syndrome (MS). The aim of the present study was to investigate the relationship of the inflammatory parameters-leukocyte count, C-reactive protein (CRP), and fibrinogen level-to insulin resistance and insulin secretion, as well as to other components of the MS in a population at risk for diabetes. A total of 396 subjects (142 men and 254 women) were analyzed from the follow-up of the Risk Factors in Impaired Glucose tolerance (IGT) for Atherosclerosis and Diabetes (RIAD) study, who were at risk for type 2 diabetes, such as family history of diabetes, obesity, and/or hyper/dyslipoproteinemia. Subjects under lipid-lowering treatment or with acute infections were not eligible. A variety of risk factors within the MS were examined: lipids, glycemic parameters, coagulation, insulin fractions. and microalbuminuria. CRP was determined by a highly sensitive method, using an immunological agglutination test, and fibrinogen was measured by the method of Clauss. Insulin resistance was evaluated by the homeostasis model assessment (HOMA) and insulin secretion by HOMA and by insulin areas under curve in an oral glucose tolerance test (OGTT), insulin increment at 30 mnutes of OGTT, and insulin increment/glucose increment at 30 minutes of OGTT. By univariate analysis, fibrinogen level (r = 0.180, P <.001), leukocyte count (r = 0.162, P =.001), and CRP (r = 0.251, P <.001) were all highly significantly correlated to insulin resistance, but not to insulin secretion. A significant rise was found for the majority of the components of the MS in quartiles of the examined inflammatory parameters. In multivariate analysis of all analyzed metabolic parameters, including age, sex, physical activity, and smoking, body mass index (BMI) was found a strong independent determinant of all inflammatory markers examined. Thus, in a population at risk for type 2 diabetes we demonstrate that subclinical inflammation underlies the metabolic syndrome, through association to one of its primary anomalies-insulin resistance, whereas no association was found to impaired insulin secretion.

[Predictors of abnormal glucose tolerance in persons at risk of type 2 diabetes: the RIAD study]. / Prädiktoren von Glukosetoleranzstörungen in einer Risikopopulation für Typ-2-Diabetes: die RIAD-Studie.

BACKGROUND AND OBJECTIVE: Early detection of glucose intolerance is an important issue in diabetes care. In the metabolic syndrome it is associated with an increased incidence of cardiovascular events. So far it is not clear which anthropometric and metabolic/hormonal parameters are of importance in the conversion of normal to impaired glucose tolerance. PATIENTS AND METHODS: The participants of the RIAD (Risk factors in IGT for Atherosclerosis and Diabetes) study had to meet the following criteria: related to type 2 diabetic patients, obesity and/or dyslipidaemia. A total of 358 subjects (age: 40-70 years) with normal glucose tolerance (NGT) in an oral glucose tolerance test (OGTT, 75 g glucose), were examined after a follow-up of 2.90 +/- 0.47 years. 284 of them remained with normal glucose tolerance, while 64 developed an impaired glucose tolerance (IGT) and ten type 2 diabetes (T2DM). The data of the initial screening examination were analysed in three groups (NGT-NGT; NGT-IGT; NGT-T2DM). Plasma glucose (PG), insulin, C-peptide and proinsulin were measured in the fasting state, as well as every 30 minutes during an OGTT, and also basal plasminogen activator inhibitor (PAI) and inflammatory parameters. RESULTS: Subjects who converted to IGT or diabetes show, already in the stage of normal glucose tolerance, clear tendency for the development of the metabolic syndrome. They were more obese and had higher fasting and 2 hPG values. The early phase insulin secretion, calculated as a ratio of DeltaInsulin 30'/DeltaPG 30', was lower in the IGT and the diabetes groups (n. s.). Both groups showed a significantly increased insulin resistance. Both converter groups revealed significantly higher PAI (Plasminogen-Activator-Inhibitor) levels and a striking but not significant increase in inflammatory parameters. CONCLUSIONS: Subjects who develop IGT and type 2 diabetes, will already in the stage of NGT show an impairment of insulin secretion and higher insulin resistance. Both processes seem to develop parallel to each other and determine the progress of the glucose intolerance. Fasting and 2h post-challenge glucose were the most important predictors of subsequent glucose intolerance.

Different effects of acarbose and glibenclamide on proinsulin and insulin profiles in people with Type 2 diabetes.

AIM: In a double-blind, placebo-controlled study, we compared the effect of acarbose (A) and glibenclamide (G) on post-prandial (pp) and 24-h profiles of proinsulin and insulin. METHODS: Twenty-seven patients with Type 2 diabetes mellitus insufficiently controlled with diet alone were randomised to receive acarbose, 100 mg thrice daily, glibenclamide, 1 mg thrice daily, or placebo. Before and after 16 weeks of treatment, 24-h profiles of proinsulin, insulin and glucose (fasting, 1 h after breakfast and every 3-h for a 24-h period) were measured under metabolic ward conditions with standardised meals. RESULTS: With acarbose, a reduced 24-h level of proinsulin was observed compared with glibenclamide (AUC 1096 +/- 118 vs. 1604 +/- 174 pmol/l per h, P<0.05) at 16 weeks. The breakfast increment of proinsulin was lower with acarbose than glibenclamide (6.8 vs. 19.3 pmol/l, P<0.05) as was the level at that time (37.3 +/- 5.3 vs. 56.4 +/- 7.5 pmol/l, P<0.05). A lower AUC of insulin after treatment was also observed with acarbose than glibenclamide (7.9 +/- 0.9 vs. 14.8 +/- 4.5 nmol/l per h, P<0.05), as also for 1-h increment (81 +/- 26, vs. 380 +/- 120 pmol/l, P<0.01) and 1-h level (325 +/- 30 vs. 621 +/- 132 pmol/l, P<0.01). Acarbose reduced 1-h breakfast glucose increment (baseline 6.3 +/- 0.6, 16-week 3.5 +/- 0.6 mmol/l, P<0.01) and 1-h glucose level (18.1 +/- 1.1 and 14.5 +/- 1.3 mmol/l, P<0.01), whereas glibenclamide did not (6.6 +/- 0.7 vs. 5.4 +/- 0.6 mmol/l and 18.9 +/- 1.5 vs. 15.3 +/- 1.3 mmol/l). CONCLUSIONS: Measurement of circadian excursions of proinsulin and insulin reveals distinct differences in meal-time proinsulin and insulin increment and level between acarbose and glibenclamide whereas fasting levels of these insulin fractions remained unaffected.

[Intima-media thickness in healthy probands without risk factors for arteriosclerosis]. / Intima-Media-Dicke bei Gesunden ohne Risikofaktoren für Arteriosklerose.

BACKGROUND AND OBJECTIVE: Ultrasound examination of the intima-media thickness (IMT) is a well accepted, highly reproducible method for the evaluation of early atherosclerosis. However, for the exact interpretation of these measurements reference values for IMT should be determined. The present work provides for the first time normal values for IMT of the common carotid artery and the arteries of the lower limbs (common femoral, superficial and popliteal arteries) in a German population of healthy subjects without risk factors. SUBJECTS AND METHODS: A total of 112 subjects (50 men, 62 women), aged 40 to 70, were examined, according to the following inclusion criteria: no diabetes or marked elevation of postprandial plasma glucose; non-smokers; no hypertension, obesity, dys/hyperlipidaemia or albuminuria; no history of coronary heart disease, stroke and peripheral arterial occlusion. IMT was measured and standardized by the method of Pignoli. Total cholesterol, triglycerides, HDL-cholesterol, HbA1c, plasma glucose (fasting and postprandial) and albuminuria were examined by routine methods. RESULTS: The mean values of double measurements bilaterally in the distal part of the common carotid artery in men were 0.79 (0.73 ... 0.84) mm (40-54 years) and 0.87 (0.81 ... 0.93) mm (55-70 years). In women the values were: -0.70 (0.67 ... 0.75) mm and 0.82 (0.75 ... 0.90) mm, resp. In the group aged 40-54 years the men showed significantly higher IMT of all examined vessels in comparison to the women. In the group aged 55-70 years somewhat higher IMT of the common carotid artery and significantly higher IMT of the arteries of the lower extremity were observed in men. In multivariate analysis age was found to be a significant determinant of IMT of all examined vessels. CONCLUSION: Intima-media thickening of the common carotid artery in men aged 40-70 years is to be accepted if a single measurement of IMT exceeds > or = 1 mm. For women, aged 40-54 years, IMT is defined as pathological if one IMT is above 0.85 mm, and for those aged 55-70 years if IMT exceeds 1 mm.

Postchallenge plasma glucose and glycemic spikes are more strongly associated with atherosclerosis than fasting glucose or HbA1c level.

OBJECTIVE: To observe the relationship of fasting plasma glucose (FPG), postchallenge plasma glucose (PG) (30, 60, 90, and 120 min during an oral glucose tolerance test [OGTT], as well as maximal PG during an OGTT, postchallenge glucose spikes [PGS], and glucose under the OGTT curve), and HbA1c to intima-media thickness (IMT) as a marker of atherosclerosis. RESEARCH DESIGN AND METHODS: OGTT, ultrasound measurement of carotid IMT, and various atherosclerosis risk factors, such as family history of diabetes, obesity, and/or hyperlipoproteinemia, but without known diabetes, were analyzed in 582 individuals aged 40-70 years and at risk for type 2 diabetes. RESULTS: In univariate analysis, all examined glycemic parameters were significantly correlated to IMT. The 2-h postchallenge plasma glucose showed the strongest odds ratio (OR) of 1.88 (1.34-2.63) in relation to abnormal IMT. All PG variables, except for 30-min glucose in OGTT, showed a significant OR, whereas the OR for HbA1c and FPG was not significant. In logistic regression analysis, 2-h PG was identified as the strongest determinant of IMT from all glycemic parameters. The 2-h PG and PGS, but not FPG, were associated with a significant rise of IMT in tertiles of HbA1c. Glycemic parameters were strongly related to each other and to many atherosclerosis risk factors. In multivariate analysis including a variety of atherosclerosis risk factors, 2-h PG was a significant independent determinant of IMT. CONCLUSIONS: PG and PGS are more strongly associated with carotid IMT than FPG and HbA1c level and modify substantially the risk for atherosclerosis, estimated by HbA1c alone, in a cohort at risk for diabetes and in the early diabetes stage.

Prevalence and atherosclerosis risk in different types of non-diabetic hyperglycemia. Is mild hyperglycemia an underestimated evil?

So far little is known about the importance of different types of non-diabetic hyperglycemia for the development of macrovascular disease. The aim of this work was to examine the intima-media thickness (IMT) of the common carotid artery (CCA), a well-accepted marker of atherosclerosis, as well as various risk factors for atherosclerosis in non-diabetic subjects with isolated fasting (IFH; n=67), isolated postchallenge (IPH; n=82) and combined hyperglycemia (CH; n=88) in comparison to normoglycemic (NG; n=265) controls. Subjects were participants of the RIAD study (Risk Factors in IGT for Atherosclerosis and Diabetes). IMT in the IPH (IMTmean: 0.89+/-0.02 mm; IMTmax: 1.01+/-0.02 mm; mean+/-SEM) and CH group (IMTmean: 0.91+/-0.02 mm; IMTmax: 1.03+/-0.02 mm) was significantly increased vs. the NG (IMTmean: 0.82+/-0.01 mm; IMTmax: 0.94+/-0.01 mm) and IFH group (IMTmean: 0.81+/-0.02 mm; IMTmax: 0.90+/-0.03 mm). IMT of the IFH group was similar to the normoglycemic controls. Subjects in the first and second tertile for postchallenge plasma glucose have similar carotid IMT irrespective of the level of fasting plasma glucose. The individuals of the third tertile for 2 h plasma glucose, whether in the first, second or third tertile of fasting plasma glucose, showed the same carotid IMT, which was significantly higher than all other groups, except for the one with lowest tertile for fasting and postchallenge plasma glucose. Except for total cholesterol and von Willebrand factor the levels of all other risk parameters were significantly higher in the hyperglycemic groups in comparison to the normoglycemic controls. Among the hyperglycemic subjects the CH group was at the highest risk for atherosclerosis with significantly increased levels of plasma triglycerides, fibrinogen, PAI-1, albuminuria, HDL-triglycerides, free fatty acids, insulin and proinsulin, and significantly reduced HDL-cholesterol in comparison to the normoglycemic controls. In summary, postchallenge hyperglycemia within the non-diabetic range is associated with atherosclerosis, as measured by the increased intima-media thickness of the common carotid artery. Furthermore, cardiovascular risk factors are significantly raised in all types of non-diabetic hyperglycemia.

Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes.

AIMS: Only scarce information exists on the distribution and atherosclerosis risk in different types of hyperglycaemia at diabetes detection. This study aimed to analyse the occurrence of isolated fasting (IFH), isolated post-challenge (IPH) and combined hyperglycaemia (FH/PH) among subjects detected to have diabetes and the association of these types of hyperglycaemia with cardiovascular risk factors and carotid intima-media thickness (IMT). METHODS: A total of 785 middle-aged subjects of the Risk Factors in Impaired Glucose Tolerance (IGT) for Atherosclerosis and Diabetes (RIAD) study underwent a 75-g oral glucose tolerance test and examination of various atherosclerosis risk factors. IMT was measured by B-mode ultrasound. RESULTS: One hundred and nineteen (15.2%) asymptomatic diabetic subjects were detected: of these, 35.3% with IFH, 26% with IPH and 38.7% with FH/PH. The level of risk factors was higher in diabetic vs. non-diabetic subjects. HbA1c and cardiovascular risk factors were in the same range for IFH and IPH except for active plasminogen activator inhibitor (PAI)-1 which was significantly higher in IFH. A higher risk burden was found in the FH/PH group vs. both IFH and IPH. IMT was as follows: non-diabetic subjects 0.85 +/- 0.18 mm, IFH 0.91 +/- 0.20 mm, IPH 0.94 +/- 0.18 mm, FH/PH 0.98 +/- 0.17 mm (P < 0.05 vs. non-diabetes). 2 h post-challenge glucose (2hPG) correlated more closely (r = 0.23, P < 0.001) to IMT than fasting plasma glucose (FPG) (r = 0.14, P = 0.004). The importance of 2hPG was confirmed by the direct comparison of FPG and 2hPG in a three dimensional analysis. A significant increase of IMT was only observed in the subgroups with abnormal post-challenge hyperglycaemia for both combinations with normal FPG and IFG. FPG category did not significantly add to IMT in either group of post-challenge hyperglycaemia. Regression analysis in the whole sample revealed 2hPG but not FPG as a significant determinant of IMT. Further significant risk factors were age, male sex, total cholesterol, HDL-cholesterol and hypertension. CONCLUSIONS: The RIAD study population at high risk for Type 2 diabetes mellitus, post-challenge hyperglycaemia was found to relate more strongly than fasting hyperglycaemia with carotid IMT.

[Prevalence of newly diagnosed type 2 diabetes, impaired glucose tolerance and abnormal fasting glucose in a high risk population. Data from the RIAD study using new diagnostic criteria for diabetes]. / Prävalenz von neuentdecktem Typ 2 Diabetes, gestörter Glukosetoleranz und gestörter Nüchternglukose in einer Risikopopulation. Daten der RIAD-Studie nach Anwendung neuer Diagnosekriterien für Diabetes.

BACKGROUND AND OBJECTIVE: In 1997 the American Diabetes Association (ADA) introduced new criteria for the diagnosis of type 2 diabetes mellitus, reducing the upper limit of normal fasting blood sugar from 140 to 126 mg/dl. A level of between 110 and 126 < mg/dl (6.1-7.0 mmol/l) was added as a new category, "impaired fasting glucose" (IFG) as an at-risk factor. It was the aim of this study to determine what effect these new criteria will have on the prevalence of type 2 diabetes and other glucose tolerance stages in the German population. PATIENTS AND METHODS: The analysis was based on data collected in the "Risk-factors in IGT for atherosclerosis and diabetes" (RIAD) study. 1139 persons of an at-risk population group (aged 40-70 years) were investigated. Most of them were relatives of diabetics and/or themselves had obesity and/or dyslipidaemia. All known diabetics were excluded. All subjects underwent an oral glucose test with 75 g glucose, and plasma glucose values were used for classifying them into different glucose tolerance stages. RESULTS: According to the new ADA criteria, confirmed by WHO in 1998, the prevalence of type 2 diabetes mellitus was shifted from 11% to 15.1%, that of IGT from 28.8% to 26.2%. An impaired fasting glucose was found in 27.1% of the population cohort, 9.2% of whom had 2-hour plasma glucose levels corresponding to the diabetes criteria. Men in the first age decade (40-49 years) had a 14% prevalence of previously undetected type 2 diabetes, double that in women. Hyperlipidaemia, hypertension and obesity were significantly more common in diabetics and persons with IGT than in normoglycaemic persons. CONCLUSIONS: The prevalence of previously unknown type 2 diabetes is very high in this at-risk part of the population. Using the criteria for impaired fasting glucose, 9.2% diabetics would remain undetected. We, therefore, support the recommendation that an oral glucose tolerance test be performed in those of the population aged over 45 years and in younger at-risk persons so that any indicated treatment can be initiated at the earliest. Measurement of fasting glucose is adequate in the population aged under 45 years not at special risk.

Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals.

Postprandial (pp) hyperglycemia--frequently associated with an increase in cardiovascular risk factors--may be damaging for the endothelium. So far, little information exists how glucose, insulin and lipids may affect atherosclerosis in the pp state. Therefore, we evaluated the relationship of pp hyperglycemia, insulin secretion and coronary risk factors to intima-media thickness (IMT) in a non-diabetic risk population. In 403 subjects (147 males, 256 females), aged 40-70 years, in the majority relatives of index cases with type 2 diabetes--a 75 g oral glucose tolerance test was performed together with measurement of insulin fractions, various risk factors and IMT of the common carotid artery. We found a continuous rise of 2h pp insulin fractions along the quintiles of 2h pp plasma glucose. A significant increase of body mass index, waist to hip ratio, triglycerides and decrease of HDL-cholesterol was observed in the top quintile of 2h pp plasma glucose (8.24 > or = pp plasma glucose < 11.1 mmol/l). Albuminuria was significantly enhanced in the 5th quintile. In parallel, IMT was significantly increased in the 5th quintile versus the bottom quintile of 2 h and maximal glucose (range 11.7-15.3 mmol/l) postprandially. After age and sex adjustment pp glucose and C-peptide, total cholesterol, triglycerides and HDL-cholesterol but not fasting plasma glucose were significantly correlated to IMT. In multivariate analysis age, male sex, pp plasma glucose, total and HDL-cholesterol were found to be independent risk factors for increased IMT. In conclusion, our data in a non-diabetic European risk population show that the two top quintiles of pp plasma glucose are associated with a clustering of standard risk factors. Corresponding to this clustering of risk factors IMT was significantly increased in the top quintile of 2 h and maximal pp plasma glucose. These data show that pp hyperglycemia may exert a noxious impact on the arterial wall together with a cluster of anomalies typical for the metabolic syndrome.

Impaired fasting glucose is not a risk factor for atherosclerosis.

AIM: To determine a new category of dysfunctional glucose homeostasis - impaired fasting glucose (IFG) - introduced by the American Diabetes Association (ADA) and the World Health Organization (WHO) defining those with abnormal but nondiabetic fasting glucose values and with a possible risk for developing diabetes. It is not known whether IFG is a risk factor for atherosclerosis, as is impaired glucose tolerance (IGT). METHODS: In this case-control cross-sectional study in which the oral glucose tolerance (75-g OGTT) and the carotid intima-media thickness (IMT) with B mode ultrasound, as a marker of atherosclerosis, were measured, together with HbA1c, lipids, plasminogen activator (PAI), insulin and proinsulin concentrations in blood plasma. Out of 788 subjects of the risk factors in IGT for Atherosclerosis and Diabetes (RIAD) study we found 104 IFG cases that were compared to 104 controls with fasting plasma glucose (FPG)<6.1 mmol/l, matched for age, sex and body mass index. Subjects with 2h postprandial (pp) plasma glucose > or = 11.1 mmol/l were excluded. The rest were subdivided into those with 2h plasma glucose < 7.8 mmol/l (63 pairs, NGT) and those with plasma glucose > 7.8 mmol/l and < 11.1 mmol/l (41 pairs, IGT). RESULTS: The case and control groups showed no significant differences in the major risk factors except for waist-to-hip ratio (WHR) which was higher in the IFG with NGT. IFG with NGT exhibited significantly higher levels of HbA1c, true insulin and proinsulin. In IFG with IGT, only HbA1c and proinsulin were significantly increased vs. controls. IMT was in the same range for cases and controls in both subgroups. However, IMT mean and IMTmax were significantly increased in IFG with IGT vs. IFG with NGT (0.95 mm vs. 0.80 mm and 1.10 mm vs. 0.90 mm). Cumulative distribution analysis of IMT illustrates that IMT in IFG with IGT is more shifted to higher artery wall thickness than in IFG with NGT. CONCLUSIONS: In our case-control study IFG alone was not related to increased IMT. Only IFG in a combination with IGT exhibited atherosclerotic changes of the carotid arteries. IFG is not analogous to IGT as a risk factor for atherosclerosis.

Increased intimal-medial thickness in newly detected type 2 diabetes: risk factors.

OBJECTIVE: To examine carotid intimal-medial thickness (IMT) and its determinants in newly detected type 2 diabetic subjects, classified according to the new criteria of the American Diabetes Association, in comparison with age- and sex-matched control subjects with normal glucose tolerance. RESEARCH DESIGN AND METHODS: This study was case-controlled, with matched pairs for 71 newly diagnosed type 2 diabetic individuals. Subjects aged 40-70 years were recruited from a risk population for diabetes seen in the Risk Factors in IGT for Atherosclerosis and Diabetes (RIAD) Study. Standard risk factors, 75-g oral glucose tolerance test with real insulin, proinsulin, and C-peptide, and ultrasound measurement of the IMT of the common carotid artery were performed. RESULTS: The diabetic subjects, both men and women, displayed carotid intimal-medial thickening, even in the subgroup with fasting plasma glucose between 7.0 and 7.8 mmol/l. HbA1c was significantly increased in the diabetic patients (6.33 vs. 5.48%). Insulin, proinsulin, and C-peptide were also significantly higher. Among the coronary risk factors, triglycerides and plasminogen activator inhibitor were significantly increased. After age and sex adjustment. IMT in the diabetic group was correlated to triglycerides and the total-to-HDL cholesterol ratio. In the total group, IMT was significantly correlated to blood pressure, 2-h glucose in oral glucose tolerance testing, triglycerides, albuminuria, and the total-to-HDL cholesterol ratio, and inversely correlated to HDL cholesterol. No independent determinant of IMT was found in the diabetic group by multivariate analysis. CONCLUSIONS: Newly detected type 2 diabetic patients exhibit a higher degree of early atherosclerosis than normal glucose-tolerant subjects matched for age and sex. Our data suggest that hyperglycemia, together with a clustering of risk factors, and in particular dyslipidemia, may cause intimal-medial thickening in the early phases of diabetes.