[Patient with beer belly or hypertension. Check for a metabolic syndrome!].
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Body Composition↗
Biomedical subjects
Stephan Jacob
Publications and source records attributed to Stephan Jacob.
Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome.
Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. beta-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional beta blockers, both nonselective and selective, are vasoconstrictive due to unopposed alpha1 activity; however, vasodilating beta blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating beta blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.
Adrenergic beta-Antagonists↗
The management of hypertension in the overweight and obese patient: is weight reduction sufficient?
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Anti-Obesity Agents↗
Isomer-specific actions of conjugated linoleic acid on muscle glucose transport in the obese Zucker rat.
The fatty acid-conjugated linoleic acid (CLA) enhances glucose tolerance and insulin action on skeletal muscle glucose transport in rodent models of insulin resistance. However, no study has directly compared the metabolic effects of the two primary CLA isomers, cis-9,trans-11-CLA (c9,t11-CLA) and trans-10,cis-12-CLA (t10,c12-CLA). Therefore, we assessed the effects of a 50:50 mixture of these two CLA isomers (M-CLA) and of preparations enriched in either c9,t11-CLA (76% enriched) or t10,c12-CLA (90% enriched) on glucose tolerance and insulin-stimulated glucose transport in skeletal muscle of the insulin-resistant obese Zucker (fa/fa) rat. Animals were treated daily by gavage with either vehicle (corn oil), M-CLA, c9,t11-CLA, or t10,c12-CLA (all CLA treatments at 1.5 g total CLA/kg body wt) for 21 consecutive days. During an oral glucose tolerance test, glucose responses were reduced (P < 0.05) by 10 and 16%, respectively, in the M-CLA and t10,c12-CLA animals, respectively, whereas insulin responses were diminished by 21 and 19% in these same groups. There were no significant alterations in these responses in the c9,t11-CLA group. Insulin-mediated glucose transport activity was enhanced by M-CLA treatment in both type I soleus (32%) and type IIb epitrochlearis (58%) muscles and by 36 and 48%, respectively, with t10,c12-CLA. In the soleus, these increases were associated with decreases in protein carbonyls (index of oxidative stress, r = -0.616, P = 0.0038) and intramuscular triglycerides (r = -0.631, P = 0.0028). Treatment with c9,t11-CLA was without effect on these variables. These results suggest that the ability of CLA treatment to improve glucose tolerance and insulin-stimulated glucose transport activity in insulin-resistant skeletal muscle of the obese Zucker rat are associated with a reduction in oxidative stress and muscle lipid levels and can be specifically ascribed to the actions of the t10,c12 isomer. In the obese Zucker rat, the c9,t11 isomer of CLA is metabolically neutral.
Abdomen↗
Modulation of metabolic control by angiotensin converting enzyme (ACE) inhibition.
Angiotensin converting enzyme (ACE) inhibitors are a widely used intervention for blood pressure control, and are particularly beneficial in hypertensive type 2 diabetic subjects with insulin resistance. The hemodynamic effects of ACE inhibitors are associated with enhanced levels of the vasodilator bradykinin and decreased production of the vasoconstrictor and growth factor angiotensin II (ATII). In insulin-resistant conditions, ACE inhibitors can also enhance whole-body glucose disposal and glucose transport activity in skeletal muscle. This review will focus on the metabolic consequences of ACE inhibition in insulin resistance. At the cellular level, ACE inhibitors acutely enhance glucose uptake in insulin-resistant skeletal muscle via two mechanisms. One mechanism involves the action of bradykinin, acting through bradykinin B(2) receptors, to increase nitric oxide (NO) production and ultimately enhance glucose transport. A second mechanism involves diminution of the inhibitory effects of ATII, acting through AT(1) receptors, on the skeletal muscle glucose transport system. The acute actions of ACE inhibitors on skeletal muscle glucose transport are associated with upregulation of insulin signaling, including enhanced IRS-1 tyrosine phosphorylation and phosphatidylinositol-3-kinase activity, and ultimately with increased cell-surface GLUT-4 glucose transporter protein. Chronic administration of ACE inhibitors or AT(1) antagonists to insulin-resistant rodents can increase protein expression of GLUT-4 in skeletal muscle and myocardium. These data support the concept that ACE inhibitors can beneficially modulate glucose control in insulin-resistant states, possibly through a NO-dependent effect of bradykinin and/or antagonism of ATII action on skeletal muscle.
Angiotensin-Converting Enzyme Inhibitors↗
Lipid content in the musculature of the lower leg assessed by fat selective MRI: intra- and interindividual differences and correlation with anthropometric and metabolic data.
PURPOSE: To assess the muscular lipid content (LC) in different muscle groups of the lower leg by a magnetic resonance imaging technique working with chemical shift selective excitation, and comparison with anthropometric and metabolic data. MATERIALS AND METHODS: Examinations were performed in 67 volunteers (54 male/13 female, age 29 +/- seven years) on a 1.5 T whole body imager, applying a highly selective spectral-spatial technique for fat selective MRI. LC was measured in six calf muscles and correlated with body mass index (BMI), percent body fat (PFAT), and insulin sensitivity (IS) of the subjects. RESULTS: Mean muscular LC of all subjects was between 2.0% (Tibialis posterior [TP]) and 3.8% (Peroneus muscles) with female subjects showing a significantly higher LC in all muscle groups (P < 0.05 each). LCs correlated moderately with BMI (R between 0.39 [TP] and 0.53 [GM]) and with PFAT (R between 0.38 [TP] and 0.62 [GM]). Insulin-resistant subjects showed slightly but not significantly increased LC compared to insulin-sensitive subjects in BMI-matched subgroups. CONCLUSION: The fat-selective MRI technique allows a reliable non-invasive measure of muscular lipids - even in muscle groups with inherent low LC - within a relatively short measurement time of about three minutes. The presented data reveal interesting interrelationships between LC and anthropometric and metabolic data, and therefore provide new insight into muscular fat metabolism.
Adult↗
Interactions of conjugated linoleic acid and lipoic acid on insulin action in the obese Zucker rat.
The fatty acid conjugated linoleic acid (CLA) and the antioxidant R-(+)-alpha-lipoic acid (R-ALA) individually enhance glucose tolerance and insulin action on skeletal muscle glucose transport in the insulin-resistant obese Zucker rat. To date, no study has assessed the potential interactions between these 2 interventions in treating insulin resistance. The present study was designed to determine whether chronic treatment with CLA and R-ALA in combination would enhance skeletal muscle glucose transport to a greater extent than either intervention individually. CLA, R-ALA, or a combination treatment of R-ALA and CLA were administered to female obese Zucker rats for 20 days at low or high doses. Whereas low-dose R-ALA (10 mg/kg body weight) alone did not alter muscle glucose transport, low-dose CLA (0.3 g/kg) induced a significant increase (38%, P <.05) in insulin-mediated glucose transport in epitrochlearis, but not in soleus. Low-dose combination therapy brought about the greatest enhancement of insulin-mediated glucose transport in epitrochlearis (77%) and soleus (54%), with the latter effect being associated with a 50% reduction in protein carbonyls (an index of tissue oxidative stress) and a 33% diminution in muscle triglycerides. High-dose treatments with CLA (1.5 g/kg), R-ALA (50 mg/kg), and the combination of CLA and R-ALA elicited increases in insulin-mediated glucose transport in epitrochlearis (57%, 58%, and 77%) and soleus (32%, 35%, and 54%). However, whereas the individual high-dose treatments with CLA and R-ALA reduced protein carbonyls (63% and 49%) and triglycerides (29% and 28%) in soleus, no further reductions were observed with the high-dose combination treatment groups. These findings support a significant interaction between low doses of CLA and R-ALA for enhancement of insulin action on skeletal muscle glucose transport, possibly via reductions in muscle oxidative stress and in lipid storage.
Animals↗
Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity.
The existence of metabolically relevant intramyocellular lipids (IMCL) as assessed by the noninvasive (1)H-magnetic resonance spectroscopy (MRS) has been established. In the present studies, we analyzed the relationships between IMCL in two muscle types [the predominantly nonoxidative tibialis muscle (tib) and the predominantly oxidative soleus muscle (sol)] and anthropometric data, aerobic capacity (VO(2)max, bicycle ergometry, n = 77) and insulin sensitivity (hyperinsulinemic euglycemic clamp, n = 105) using regression analysis. In univariate regression, IMCL (tib) was weakly but significantly correlated with percentage of body fat (r = 0.28, P = 0.01), whereas IMCL (sol) was better correlated with waist-to-hip ratio (r = 0.41, P < 0.0001). No significant univariate correlation with age or maximal aerobic power was observed. After adjusting for adiposity, IMCL (tib) was positively correlated with measures of aerobic fitness. A significant interaction term between VO(2)max and percentage of body fat on IMCL (tib) (P = 0.04) existed (whole model r(2) = 0.26, P = 0.001). In contrast, aerobic fitness did not influence IMCL (sol). No correlation between insulin sensitivity as such and IMCL (tib) (r = -0.13, P = 0.2) or IMCL (sol) (r = 0.03, P = 0.72) was observed. Nethertheless, a significant interaction term between VO(2)max and IMCL on insulin sensitivity existed [P = 0.04 (tib) and P = 0.02 (sol)]; [whole model (sol) r(2) = 0.61, P < 0.0001, (tib) r(2) = 0.60, P < 0.0001]. In conclusion, obesity and aerobic fitness are important determinants of IMCL. IMCL and insulin sensitivity are negatively correlated in untrained subjects. The correlation between the two parameters is modified by the extent of aerobic fitness and cannot be found in endurance trained subjects. Thus, measurements of aerobic fitness and body fat are indispensable for the interpretation of IMCL and its relationship with insulin sensitivity.
Adipose Tissue↗
MRI of muscular fat.
An MRI technique with high selectivity and sensitivity to the signal components in the chemical shift range of methylene and methyl protons of fatty acids has been developed for noninvasive assessment of muscular fat in vivo. A spoiled gradient-echo sequence with spatial-spectral excitation by six equidistant pulses with 2 degrees -(-9 degrees )-17 degrees -(-17 degrees )-9 degrees -(-2 degrees ) and a multi-echo train (TE = 16, 36, 56, 76, 96, and 116 ms) allowed a series of images to be recorded with a receiver bandwidth of 78 Hz per pixel. SIs from phantoms with lipid contents between 0.1% and 100% were compared to those from pure water. Thirty healthy volunteers underwent fat-selective imaging of their lower leg, and parallel localized proton spectroscopy of the tibialis anterior and the soleus muscle by a single-voxel stimulated echo acquisition mode (STEAM) technique (TR = 2 s, TE = 10 ms, TM = 15 ms). Results show a high correlation (r = 0.91) between fat imaging and the spectroscopic approach in the soleus muscle, considering the percentage total fat content of musculature. The correlation coefficient was clearly lower (r = 0.55) in the tibialis anterior muscle due to signal contaminations from adjacent subcutaneous fat in the images, inhomogeneous fat distribution, and generally lower lipid content in this muscle. Applications of the new imaging technique showed marked intra- and interindividual variability in the spatial distribution of lipids in the musculature of the lower leg. No significant correlation of the muscular fat with the thickness of the subcutaneous fat layer was found. In addition, the body mass index does not appear to determine muscular fat content, except in very obese cases.
Adult↗
Metabolic characterization of a woman homozygous for the Ser113Leu missense mutation in carnitine palmitoyl transferase II.
Carnitine palmitoyl transferase (CPT) II is a key enzyme in transporting FFA into the mitochondrial matrix for beta oxidation. The clinical manifestation of CPT II deficiency is characterized mainly by myopathic symptoms. Conceivably, the inability of skeletal muscle to oxidize (long-chain) FFAs could also have far-reaching metabolic consequences, such as insulin resistance secondary to increased muscle lipids, about which relatively little is known. We therefore performed a series of metabolic studies in a 43-yr-old woman homozygous for the Ser113Leu mutation in the CPT II gene, the single most common genetic cause of CPT II deficiency, and compared the results with data from a male and female control group taken from the Tübingen family study database. The metabolic studies included oral glucose tolerance test (OGTT), euglycemic hyperinsulinemic clamp to measure insulin sensitivity, indirect calorimetry to measure substrate oxidation, stable isotopes for determination of glycerol turnover, and magnetic resonance spectroscopy for measurement of intramyocellular lipids. Compared with the female control group, the patient was normal glucose tolerant but severely insulin resistant, basal lipolysis was markedly reduced, and carbohydrate oxidation was maximally increased in the basal state and did not increase further during insulin stimulation. Conversely, lipid oxidation was virtually absent and did not decrease during insulin stimulation. Surprisingly, intramyocellular lipids were well within the range of the control group. In conclusion, genetic CPT II deficiency is characterized by insulin resistance, which is not explained by increased intramyomellular lipids. However, it may be partially explained by glucose oxidation already maximally increased in the basal state, which cannot be increased any further by insulin. Reduced basal lipolysis may represent a compensatory mechanism for the reduced oxidative FFA disposal characteristic for this disease.
Adult↗