Sex influenced association of directly measured insulin sensitivity and serum transaminase levels: Why alanine aminotransferase only predicts cardiovascular risk in men?

BACKGROUND: Non alcoholic fatty liver disease (NAFLD) is an independent cardiovascular (CV) risk factor which is closely associated with insulin resistance measured by both direct or indirect methods. Gender specific findings in the relationship between alanine aminotransferase (ALT) and CV disease, the prevalence of NAFLD and type 2 diabetes (T2DM) have been published recently. The aim of the present study was to explore the gender aspects of the association between insulin sensitivity, liver markers and other metabolic biomarkers in order to elucidate the background behind the sex influenced difference in both NAFLD, T2DM and their association with CV risk. PATIENTS AND METHODS: 158 female (47 normal and 111 impaired glucose intolerant) and 148 male (74 normal and 74 impaired glucose tolerant) subjects were included (mean age: 46.5 ± 8.31 vs. 41.6 ± 11.3, average Hba1c < 6.1 %, i.e. prediabetic population, drug naive at the time of the study). Subjects underwent a hyperinsulinemic normoglycemic clamp to determine muscle glucose uptake (M3), besides liver function tests and other fasting metabolic and anthropometric parameters were determined. RESULTS: Significant bivariate correlations were found between clamp measured M3 and all three liver enzymes (ALT, aspartate aminotransferase and gamma-glutamyl transferase) in both sexes. When data were adjusted for possible metabolic confounding factors correlations ceased in the male population but stayed significant in the female group. Feature selection analysis showed that ALT is an important attribute for M3 in the female but not in male group (mean Z: 3.85 vs. 0.107). Multiple regression analysis confirmed that BMI (p < 0.0001) and ALT (p = 0.00991) significantly and independently predicted clamp measured muscle glucose uptake in women (R(2) = 0.5259), while in men serum fasting insulin (p = 0.0210) and leptin levels (p = 0.0294) but none of the liver enzymes were confirmed as significant independent predictors of M3 (R(2) = 0.4989). CONCLUSION: There is a gender specific association between insulin sensitivity, metabolic risk factors and liver transaminase levels. This might explain the sex difference in the predictive role of ALT elevation for CV disease. Moreover, ALT may be used as a simple diagnostic tool to identify insulin resistant subjects only in the female population according to our results.

[The effect of genetic risk of diabetes on the correlations in bone and energy homeostasis]. / A genetikai diabeteskockázat hatása a csontanyagcsere-energia-háztartás kapcsolatokra.

INTRODUCTION: Type 2 diabetes is associated with increased risk of bone fractures, and the connection between bone remodeling and carbohydrate homeostasis is decoupled. It is not known whether these phenomena are the consequence of the deteriorating glucose metabolism, and the increasing insulin resistance or they belong to the genetic risk of type 2 diabetes. AIM: The aim of the authors was to clarify the impact of genetic risk on bone and carbohydrate homeostasis connections. METHOD: Hyperinsulinemic-normoglycemic clamps, and oral and iv. glucose loads were done to select 18 metabolically healthy females with first degree type 2 diabetic relatives -and 26 without diabetic relatives. RESULTS: The connections between total body glucose utilization and the activity of the bone metabolic unit were missing in healthy females with the genetic risk of type 2 diabetes, like in those with manifest diabetes. In this risk group the level of low-density-large molecular sized LDL lipids were decreased, while the high-density LDL group with low molecular size was increased. The latter change was in significant connection with increased interleukin-6 levels and increased bone resorption within the bone metabolic unit. CONCLUSIONS: These data suggest that the missing connection between glucose and bone metabolism is not the consequence of the developing insulin resistance and deteriorating glucose metabolism, but rather it belongs to the inherited diabetes risk. The etiology of this early alteration, which develops prior to glucose intolerance and insulin resistance is unknown and needs further investigations.

[Metabolic alteration in healthy men with first degree type 2 diabetic relatives]. / Anyagcsere-eltérések a 2-es típusú cukorbetegek egészséges, elso fokú férfi rokonaiban.

INTRODUCTION: The recognition of prediabetic patients with the genetic risk of type 2 diabetes is very important as prediabetes is the last stage when manifestation of diabetes could be prevented by life style modification or drug intervention. This suggests the need for diagnostic processes to trace the risk of patients in time. AIMS: The authors looked for metabolic differences between age and BMI in adjusted healthy men with or without first degree type 2 diabetic relatives. METHODS: The study included 73 healthy men (21 with and 52 without) first-degree relatives with type 2 diabetes. RESULTS: Total body and muscle tissue glucose utilization, glucose tolerance did not differ between the two groups, but free fatty acid levels were not suppressed by glucose load in subjects with diabetic relatives. In addition the body fat content, leptin and IL-6 levels were higher, while adiponectin and the free fatty acid/adiponectin ratio were significantly lover in healthy men with diabetic relatives. In this group HDL cholesterol, and the large buoyant LDL fraction were lower whereas the high density LDL - small molecular lipid fraction was higher than those measured in subjects without diabetic relatives. CONCLUSIONS: These data suggest that deteriorations of insulin sensitivity and glucose tolerance is preceded by disturbances of fatty acid metabolism. The observed alteration in free fatty acid/adiponectin ratio, and/or the absence of free fatty acid suppression during glucose tolerance tests could be a screening tool for diabetes risk among men.

[Metabolic differences in healthy first-degree female relatives of type 2 diabetic patients]. / Anyagcsere-eltérések a 2-es típusú cukorbetegek egészséges, elsofokú norokonaiban.

INTRODUCTION: Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the "prediabetic" state, urging the development of diagnostic tests to recognize the group at risk in time. AIM: The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes. METHOD: Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated. RESULTS: Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives. CONCLUSIONS: These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically susceptible females.

[Effects of catalase gene (RS769217) polymorphism on energy homeostasis and bone status are gender specific]. / Nemhez kötött a katalázgén-polimorfizmus (RS769217) hatása az energia-háztartásra és a csontok állapotára.

The pathogenic role of oxidative stress has already been proven both in energy homeostasis and bone metabolism. The effects of +22348C>T (RS769217) polymorphism of catalase (EC 1.11.1.6, hydrogenperoxid-hydrogenperoxid oxidoreduktase) gene were investigated on glucose disposal and bone mineral density in groups of healthy (n = 24) and glucose intolerant (n = 27) females and healthy (n = 64) and glucose intolerant (n = 26) males. Glucose intolerant groups included IFG, IGT and non-treated type 2 diabetic patients. There were no differences in allele frequencies between the genders and groups in this transdanubian Hungarian population. The effects of CAT gene polymorphisms on glucose metabolism and bone status were gender specific. Females with mutant CAT (CT+TT) gene had better HOMA-IR (CC: 2.95+/-1.8 versus CT+TT: 2.06+/-0.9, p<0.05), but bone density did not differ between the CC and CT+TT haplotypes. The homozygote TT females had significantly better whole body glucose disposal. (M-1 mg/kg/min: CC: 9,43+/-4,4 versus TT: 13,23+/-1,6mg/kg body weight/min, p<0.05). The appearance of T allel among males caused lower femur density (CC: 1,11+/-0,17 versus CT+TT: 1,03+/-0,16, p<0.05 g/cm 2 ) and better HOMA-IR (CC: 2.42+/-2.3 versus CT+TT: 1.50+/-0.2, p<0.05), with no change in whole body glucose disposal. Osteocalcin - which has been proven to be the connection between energy homeostasis and bone metabolism - had identical serum levels in both haplotypes, but the significant correlation between muscle tissue glucose utilization and osteocalcin levels (r = +0.4424, p<0.05, n = 23) disappeared in the presence of T allele. Multiple correlation showed significant connection between leptin/adiponectin and femur BMD in CC female group, and between leptin/adiponectin and lumbar BMD in CC male group. The correlations disappeared with the appearance of T allele. Our results differ from the data obtained in Korean postmenopausal women and stress the need of population/ethnic specific replication of genetic data.

[Occurrence of GRB10 (+11275G > A) polymorphism in Hungarian population and its relationship to glucose metabolism]. / A GRB10 gén (+11275G > A) polimorfizmusának hazai elôfordulása és kapcsolata a cukoranyagcserével.

In our backstage experiment with differential display method among the differentially expressed genes we found the gene of GRB10 (Growth factor Receptor-Bound protein 10). The GRB10 protein binds to insulin and insulin-like growth factor receptors and acts as a negative regulatory protein. Besides, GRB10 gene polymorphisms are connected to the development of type 2 diabetes mellitus. In this experiment we investigated the allele frequency of RS 2237457, +11275G > A polymorphism in Hungarian healthy and type 2 diabetic populations (healthy: n = 77, diabetics: n = 85). We also searched for the connections between the genotype and glucose homeostasis measured by hyperinsulinemic - normoglycemic clamps in healthy volunteers (n = 88), glucose intolerant (IFG n = 15; IGT n = 29) and non-treated type 2 diabetic patients (n = 9). We did not find significant differences in allele frequencies between the Hungarian healthy and diabetic populations (healthy: g vs. a: 62% vs. 38%; 2DM g vs. a: 70% vs. 30%). In case of females, glucose utilization did not depend on GRB10 gene polymorphisms. Insulin production after oral glucose load was increased among males with gg alleles, and not after iv. glucose administration. The glucose disposal in muscle tissue was lower and the metabolic clearance rate was also lower calculated either for total body or muscle tissue in this group. In both genders gg alleles were associated with a disadvantageous lipid profile of decreased levels of large, buoyant LDL molecules and HDL levels in females. Metabolic changes related to the polymorphism of GRB10 gene support a gender specific role of this gene in insulin sensitivity and insulin signal transduction. It may be hypothesized on the basis of the differences in insulin release after oral and iv. glucose loads that GRB10 is involved in incretin signaling pathway.

[The role of osteocalcin in the connection of bone and glucose metabolism in humans]. / Az osteocalcin helye a humán cukor- és csontanyagcsere kapcsolatában.

UNLABELLED: The lack of osteoblast derived osteocalcin in mice causes reduced pancreatic beta-cell proliferation, decreased expression of insulin gene and adiponectin gene in adipocytes as well. METHODS: The relationship between insulin sensitivity, osteocalcin and bone state in 45 healthy (20 females, 25 males) and 92 glucose intolerant (51 females, 41 males) subjects was examined. Body composition, bone density, markers of bone resorption and formation as well as glucose uptake (M value for insulin sensitivity) measured by hyperinsulinemic normoglycemic clamp were determined separately in males and females. RESULTS: Osteocalcin levels were similar in the two genders, however, glucose intolerant men had lower osteocalcin levels than healthy men (24.5+/-11 vs. 18.1+/-9 ng/ml, p < 0.05). In the healthy group, we found positive correlation between osteocalcin and muscle M values (females: r = +0.319, p < 0.05, males: r = 0.481, p < 0.01), although this relationship disappeared in the glucose intolerant groups. Osteocalcin did not show correlation with adiponectin level in any of the genders. Based on a multivariate regression analysis, in all females significant independent predictors of osteocalcin level were fasting blood glucose, whole and lean body mass glucose uptake, metabolic clearance rate, estradiol and LDL-cholesterol levels (determined 92% of its value), while in all men these were serum calcium, OGTT glucose area under the curve, free fatty acid levels, insulogenic index, HOMA-R and waist/hip ratio (determined 95% of its value). The BMU index characterizing bone resorption/formation correlated significantly with the M values only in women. CONCLUSION: This study confirmed the relationship between insulin sensitivity and osteocalcin in healthy human population, although basic difference was found between the two genders which was not related to osteocalcin.

[Effect of progressive insulin resistance on the correlation of glucose metabolism and bone status]. / A progrediáló inzulinrezisztencia hatása a glükózanyagcsere csontállapot kapcsolatokra.

A paradox is hidden in the increasing number of patients with insulin resistance, Type 2 diabetes and osteoporosis, as the world wide diabetes epidemic is driven by the same obesity which protects the bones in the obese females. Our aim was to investigate the connection between the early glucose intolerance, insulin resistance and bone density and metabolism. After metabolic status of matched 20 healthy and 51 glucose intolerant women (age: 49 +/- 9 y.) was determined, hyperinsulinemic-euglycemic clamps were done, while adipo- and cytokine levels were measured. Bone mineral density over lumbar spine and the femur neck were measured by DEXA. No differences in bone density were observed between groups at any sites measured. Tight correlations were found between total body glucose utilization and bone density in healthy group (lumbar spine r = -0.4921, p < 0.05, femur neck: r = -0.4972, p < 0.05), while with deterioration of glucose metabolism this correlation disappeared (lumbar spine: r = -0.022, ns; femur neck: r = -0.3136, ns). The adiponectin was the only adipokine which correlated with lumbar spine density in both groups ( r = -0.5081, p < 0.05; -0.2804, p < 0.05), but not with femur density, where this connection disappeared with glucose intolerance ( r = -0.6742, p < 0.01; -0.1723, ns). Relations of bone metabolic markers indicated that bone resorption decreases with worsening of insulin resistance. In conclusion inverse correlations were found between bone density and glucose metabolism, or insulin sensitivity in healthy women in perimenopause, but this connection disappeared with the deterioration of glucose metabolism and progression of insulin resistance measured by the "gold standard" insulin-glucose clamps. Decreasing insulin sensitivity of bones and escape from "metabolic control" may result in frequently observed hyperdensity in Type 2 diabetics.

Serum osteocalcin is associated with improved metabolic state via adiponectin in females versus testosterone in males. Gender specific nature of the bone-energy homeostasis axis.

OBJECTIVE: The osteoblast-derived protein osteocalcin (OCN) is known to be involved in glucose metabolism by increasing adiponectin secretion from adipocytes. Recently, OCN was also found to enhance testosterone production in mouse testes, suggesting that OCN effects on energy metabolism may be mediated through testosterone. Our aim was to assess a possible gender difference in the metabolic effect of OCN in humans. METHODS: We included 135 women and 155 men exhibiting changes in glucose tolerance in our study. Oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) and a hyperinsulinemic normoglycemic clamp were performed. For clamp indices, whole body (M1) and muscle (M2) glucose uptake values were used. Leptin, adiponectin serum lipid, lipoprotein, total serum OCN and testosterone levels, and body composition were determined. RESULTS: Higher OCN values were associated with improving metabolic state in both genders. Adiponectin and OCN correlated significantly only in females (r=+0.254, p=0.0029), while in men, testosterone and OCN values showed a significant positive correlation (r=+0.243, p=0.0023), independent of age, BMI, HbA1c and body composition. In women, adiponectin was confirmed by feature selection analysis as being an independent determinant of OCN, in addition to age and three of the IVGTT glucose values. In men, besides M1, BMI, M2, leptin, body fat percent, and the 90-minute OGTT glucose reading testosterone, but not adiponectin were identified as independent contributors for OCN. CONCLUSION: We confirmed the 'classic' adiponectin-mediated insulin-sensitising effect of OCN only in females. In men, a testosterone-mediated OCN metabolic effect is more likely.