[Significance of triglycerides for other metabolic parameters in the familial metabolic syndrome]. / Bedeutung der Triglyzeride für weitere metabolische Parameter bei familiärem metabolischem Syndrom.

BACKGROUND: The relationship between the various degrees of glucose tolerance and metabolic parameters have already been examined in various studies. Whether and to what extent the triglycerides (TG) affect other metabolic parameters in the different degrees of glucose tolerance is not certain. We therefore studied the importance of the triglycerides within a defined glycemic state in patients with an elevated familial risk for metabolic diseases. METHODS: We examined 866 patients (380 men, 486 women, mean age 44,4 years) in the "Familial Metabolic Syndrome Study" (FAMES). The patients were assigned to various degrees of glucose tolerance, according to the result of an oral glucose tolerance test. All degrees were divided into subgroups in respect of the triglyceride level (TG < 1,7 or TG >/= 1,7 mmol/l). In these subgroups we measured various metabolic parameters like fasting glucose, insulin resistance, insulin and proinsulin levels, HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), uric acid, HbA (1c), and free fatty acids (FFA). RESULTS: In patients with normal glucose tolerance the hypertriglyceridemia is already associated with other components of the metabolic syndrome like elevated HbA (1c), free fatty acids, proinsulin and insulin levels, worsened insulin sensitivity, elevated uric acid and LDL-C levels as well as a lowered HDL-C level. The patients with diabetes and hypertriglyceridemia also showed higher levels of FFA, proinsulin and insulin, a lower HDL-C level and a more prominent insulin resistance. CONCLUSION: Hypertriglyceridemia is an indicator for insulin resistance and elevated levels of other components of the metabolic syndrome within the various degrees of glucose tolerance.

Insulin-resistant patients with type 2 diabetes mellitus have higher serum leptin levels independently of body fat mass.

In obese people, an increase of plasma leptin levels is well-known and is seen as a consequence of the increased body fat mass. Moreover, a relationship between fasting concentrations of leptin and insulin has been described. Hyperinsulinemia is considered to be indicative of insulin resistance. We aimed at elucidating the interrelations between leptin, insulin and insulin resistance in type 2 diabetic patients. Under metabolic ward conditions, we investigated 21 moderately overweight men with type 2 diabetes. The patients had a mean age of 49.1 years, a mean body mass index (BMI) of 26.8 kg/m(2), and a mean diabetes duration of 82.5 months. All patients were treated with diet alone. We measured fasting leptin and insulin levels, body composition by determination of total body water, and insulin resistance by euglycemic hyperinsulinemic clamp technique. At univariate analysis, fasting leptin level significantly and positively correlated with BMI (r=0.49, p=0.02) and with fasting insulin (r=0.69, p=0.001), while it negatively correlated with the glucose disposal rate (r=-0.62, p=0.002). Furthermore, leptin was inversely correlated with HDL-cholesterol (r=-0.45, p=0.04). When excluding the influence of body fat mass or of BMI in partial correlation analysis, the correlations between leptin and insulin or insulin sensitivity remained significant. The relationship between insulin resistance (as measured directly in the clamp experiments) and leptin concentrations was also shown by subdividing the diabetic patients according to tertiles of insulin sensitivity. The highest fasting leptin levels were observed in those patients with the most expressed insulin resistance. Our data point to a functional relationship between insulin resistance and leptin concentrations in insulin-resistant type 2 diabetic men, independently of body composition. This relationship is believed to be mediated by insulin.

[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.

Relation of free and specifically bound leptin to insulin secretion in patients with impaired glucose tolerance (IGT).

Impaired glucose tolerance (IGT) is frequently associated with an increased fat mass and an altered fat distribution. The adipocyte derived hormone, leptin has been shown to interact with insulin at various levels and may be intimately involved in this process. However, only limited data concerning the interaction of insulin, glucose tolerance and leptin are available and no data exist on the potential influence of bound vs. free circulating leptin. We therefore studied free and bound leptin in 136 patients (77 males, 59 females) with IGT, in relation to plasma glucose, insulin, proinsulin and C-peptide levels as well as serum free and bound leptin concentrations during an oral glucose tolerance test (oGTT). The expected positive relation of free serum leptin levels with body mass index (BMI) was found. Free leptin concentrations were higher in women than in men. Analysis in tertiles revealed a significant relation between free leptin (16-58, 60-160, and 169-932 pmol/l) and mean fasting insulin levels (65, 93, and 100 pmol/l). This relationship remained significant in a multiple regression analysis with BMI and gender as covariates. Similar independent relationships to leptin serum levels were observed for HbA1c and plasma C peptide levels and the proinsulin/insulin ratio but not for plasma glucose and proinsulin levels. These data suggest a fine tuning of leptin by small changes in circulating insulin levels observed in impaired glucose tolerance.

Glibenclamide, but not acarbose, increases leptin concentrations parallel to changes in insulin in subjects with NIDDM.

OBJECTIVE: To hypothesize if glibenclamide, which increases insulin levels, also increases leptin concentrations. RESEARCH DESIGN AND METHODS: Leptin is a hormone that regulates weight in mice. In obese humans, leptin concentrations are increased, suggesting resistance to the effects of this hormone. Although short-term infusion of insulin during the hyperinsulinemiceuglycemic clamp does not increase leptin concentration, the effect of oral antidiabetic agents on leptin concentration is unknown. Differing effects can be expected, since glibenclamide acts via stimulation of insulin secretion, whereas acarbose inhibits alpha-glucosidases of the small intestine and has no direct effect on insulin levels. We examined the effect of acarbose (n = 4), glibenclamide (n = 6), and placebo (n = 6) on insulin and leptin levels during 24-h periods before and after 16 weeks of therapy. RESULTS: We observed a significant diurnal variation in leptin concentrations. This was inversely related to insulin levels during the 24-h follow-up with usual diet. Neither the placebo nor acarbose altered leptin concentrations. However, glibenclamide increased leptin concentrations parallel to insulin levels. There were only minor changes in body weight during the l6-week follow-up: decrease in the placebo group (change -0.5 kg/m2, P = 0.07) and acarbose (change -0.7 kg/m2, P = 0.046) and increase in the glibenclamide group (change 0.8 kg/m2, P = 0.27). However, individual subjects who gained weight had increases in their leptin concentrations. The diurnal variation in leptin concentrations was preserved after glibenclamide. CONCLUSIONS: Glibenclamide increases circadian leptin and insulin concentrations, whereas acarbose does not. This observation may help to explain weight gain in subjects treated with glibenclamide and stable weight in those treated with acarbose in the long run.

Anomalies of lipoprotein pattern and fibrinolysis in acromegalic patients: relation to growth hormone levels and insulin-like growth factor I.

The influence of hGH and IGF-I levels on lipid-, lipoprotein metabolism and fibrinolysis were studied in 23 patients with active acromegaly (14 women and 9 men, mean age 49.8 +/- 2.1 years) compared to a sex, BMI and age-matched control group. Mean Lp(a) levels were significantly higher in acromegalics than in controls (469.8 +/- 140.1; n = 23 vs. 162.7 +/- 64.9 mg/l; n = 111; p < 0.01). We found elevated apolipoprotein A-I and Apo E-concentrations in acromegalic patients compared to controls (apo A-I: 1.79 +/- 0.06 vs. 1.46 +/- 0.04 g/l; p < 0.01; apo E: 98.35 +/- 6.4 vs. 72.53 +/- 3.38 mg/l; p < 0.05). 30% of the acromegalics showed increased plasminogen activator inhibitor activity (PAI) while 66% had increased tissue-type plasminogen activator (t-PA) concentrations. There was a correlation between hGH and Lp(a) (r = 0.414; p = 0.05), between hGH and PAI (r = -0.59; p < 0.005) and IGF-I and t-PA activity (r = -0.44; p < 0.05). In a subgroup of nine acromegalics Lp(a) was reduced by 32.2 +/- 6.7% (p < 0.05) after a six-month octreotide therapy and HDL2-cholesterol-concentration increased from 0.17 +/- 0.04 to 0.24 +/- 0.04 mmol/l (p < 0.05). In conclusion, our results demonstrate that elevated Lp(a)-concentrations and changes in fibrinolysis contribute to the cardiovascular complications and should therefore be controlled in acromegalic patients.

Impact of hormone replacement therapy on postprandial lipoproteins and lipoprotein(a) in normolipidemic postmenopausal women.

In 43 normolipidemic postmenopausal women we studied fasting and postprandial (oral fat load with 50 g fat per square meter; blood sampling for 5 h) lipoprotein components and lipoprotein(a) levels before and with the administration of conjugated equine estrogens opposed by medrogestone (on days 11-21). Data was compared intraindividually; the second testing was performed during the last 5 days of the combined estrogen/progestogen phase of the third cycle. Fasting low-density lipoprotein (LDL) and total cholesterol concentrations decreased significantly; high-density lipoprotein (HDL) cholesterol, including subfractions HDL2 and HDL3, was not changed. Fasting triglyceride concentrations increased. All lipoprotein fractions measured showed a postprandial elevation with the exception of chylomicron cholesterol concentrations. There was a significant effect of hormone replacement therapy on the postprandial course of total cholesterol (decrease; P < 0.001), VLDL cholesterol (increase; P = 0.025), and the triglyceride proportion in the LDL plus HDL fraction (increase; P < 0.001). With hormone replacement therapy the postprandial curve of total triglycerides was increased only 1 h after the fat load while chylomicron triglyceride concentrations were lowered after 5 h. VLDL triglycerides were not influenced. In all patients with lipoprotein(a) levels above 10 mg/dl, this parameter decreased (about 25%). Although increasing fasting triglyceride concentrations, hormone replacement therapy does not bring about an exaggerated postprandial increase in triglycerides. Postprandial chylomicron clearance is evidently promoted. Hormone replacement therapy leads to a small increase in triglycerides in the LDL plus HDL fraction by inhibiting hepatic lipase activity. Moreover, the decrease in lipoprotein(a) levels may contribute to the antiatherosclerotic effect.

[Different effects of fibrates on the lipoprotein profile. Comparison of the effectiveness of gemfibrozil and bezafibrate in various types of hyperlipoproteinemia]. / Differente Effekte von Fibraten auf das Lipoproteinprofil. Wirkungsvergleich von Gemfibrozil und Bezafibrat bei verschiedenen Hyperlipoproteinämie-Typen.

AIMS: To compare the efficacy and tolerability of Gemfibrozil and Bezafibrate in patients with hyperlipoproteinemia, types IIa, IIb and IV. METHOD: In an open, randomized parallel study, the tolerability and efficacy of Gemfibrozil (G) and Bezafibrate (B) were investigated over a period of 12 weeks in 178 hyperlipidemic (HLP) patients first submitted to an 8-week "wash-out" (diet only) phase. In HLP type IIa patients, LDL cholesterol was lowered (G: -13%, B: -10%). In HLP type IIb, a decrease in triglyceride (TG) levels (G: -41%, B: -31%), an increase in HDL-cholesterol (G: +19%, B: +5%), and a decrease in the total cholesterol/HDL cholesterol ratio (G: -32%, B: -9%) predominated. Patients with type IV HLP responded to both fibrates with an appreciable reduction in TG levels (G: -45%, B: -42%). The effects of the preparations differed significantly with respect to the elevation of HDL cholesterol and a decrease in the total cholesterol/HDL cholesterol ratio in HLP type IIb patients. The respective lipid baseline concentration appeared to be of importance for the sense and extent of the changes induced.

Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone.

OBJECTIVE: Acarbose inhibits alpha-glucosidases of the small intestine and thus delays glucose release from complex carbohydrates. Therefore, its efficacy and acceptability as a first-line drug in non-insulin-dependent diabetes mellitus (NIDDM) insufficiently treated with diet alone was tested in a randomized double-blind placebo-controlled study. RESEARCH DESIGN AND METHODS: Ninety-four NIDDM subjects, aged 43-70 yr with average body mass index of 28 kg/m2 and undergoing a pretreatment period of at least 3 mo with diet alone, were treated with 100 mg acarbose three times daily or placebo for 24 wk. The patients were recruited after a 4-wk screening period of dietary reinforcement. The inclusion limits for patients termed diet not satisfactory were fasting blood glucose (FBG) greater than or equal to 7.8 mM and/or postprandial blood glucose (BG) greater than or equal to 10 mM. RESULTS: FBG was lowered in the acarbose group from 9.8 to 8.4 mM and in the placebo group from 10.2 to 9.6 mM after 24 wk (P = 0.007 vs. placebo). The most impressive therapeutic effect was a highly significant reduction of postprandial hyperglycemia for at least 5 h after the test meal (1-h postprandial BG with acarbose 10.4 mM and placebo 13.5 mM at 24 wk, P less than 0.001) accompanied by a significant decrease in HbA1 (acarbose 8.65%, placebo 9.32%, P = 0.003). Whereas C-peptide and fasting serum insulin were not significantly affected by acarbose, postprandial insulin increment was approximately 30% lower after 24 wk compared with placebo. Furthermore, acarbose significantly reduced 1-h postprandial triglyceride levels. After an initial phase of greater than 4 wk (when 76.6% in the acarbose group vs. 28% on placebo complained about flatulence, P less than 0.001), the drug was well accepted. At the end of the study, only 32% showed mild or moderate gastrointestinal sensations. CONCLUSIONS: Extrapolation shows that acarbose is an efficient and acceptable drug for the treatment of NIDDM with poor metabolic control by diet alone. It has beneficial effects on postprandial hyperinsulinemia and postprandial hypertriglyceridemia.

Efficacy of a combined bezafibrate retard-colestyramine treatment in patients with hypercholesterolemia.

In a placebo-controlled randomized study the effect of combined bezafibrate-colestyramine therapy in comparison with monotherapy with both drugs was investigated. 47 patients with primary hypercholesterolemia received 400 mg bezafibrate (Cedur) retard/d, subsequently bezafibrate retard plus colestyramine (24 g/d) or colestyramine plus placebo in a double-blind fashion. The combination therapy was most effective (LDL decrease 36%, HDL-C increase 31%, apoprotein B decrease 28%), bezafibrate and colestyramine were equally effective with regard to LDL-C and apoprotein B, but only bezafibrate decreased triglycerides (-37%) and increased HDL-C (+24%). Bezafibrate was well-tolerated, but gastro-intestinal side-effects were frequent during therapy with colestyramine, and 16 patients tolerated only a reduced dosage of this drug. From the results presented it can be concluded that combined therapy with bezafibrate retard plus colestyramine is highly effective in the treatment of severe hypercholesterolemia.