Stephan Jacob

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. β‐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 β blockers, both nonselective and selective, are vasoconstrictive due to unopposed α₁ activity; however, vasodilating β 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 β blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.

Subjects with type 2 diabetes experience an increased cardiovascular morbidity and mortality, related to a high prevalence of hypertension, dyslipidemia, and obesity. Antihypertensive treatment with β-adrenergic receptor blockers may have deleterious metabolic consequences, including worsening of lipid profiles and insulin sensitivity. The centrally-acting sympatholytic agent moxonidine may improve these variables. In this randomised, double-blind multicenter study, the effects of two widely used antihypertensive agents - moxonidine (MOX) and the β₁-selective adrenergic receptor blocker metoprolol (MET) - on blood pressure and metabolic control were directly compared in hypertensive subjects with type 2 diabetes. Patients received either MOX (0.2 - 0.6 mg/d) or MET (50 - 150 mg/d) for 12 weeks, intending comparable blood pressure control. In total 200 patients were randomized. Here we report results from the per protocol population consisting of 127 patients (MOX 66, MET 61) but similar results were found in the ITT population. Reductions in systolic (SBP) and diastolic (DBP) blood pressures after 12 weeks were similar in both groups: In the MOX group, mean SBP (± SD) decreased from 154 ± 12 to 142 ± 17 mmHg and mean DBP from 91 ± 9 to 83 ± 9 mmHg. In the MET group, mean SBP decreased from 152 ± 13 to 140 ± 15 mmHg, and mean DBP from 90 ± 8 to 84 ± 10 mmHg. Mean HbA_1C values did not differ between groups after 12 weeks (MOX 8.1 ± 1.4 Hb%, MET 8.1 ± 1.5 Hb%, intention-to-treat population). However, fasting plasma glucose decreased in the MOX group (median change - 5 mg/dl), but increased in the MET group (+ 16 mg/dl; p < 0.05). Median changes in the insulin resistance index (HOMA_IR) were + 0.56 µIU × mol/L² in the MET group, and - 0.27 µIU × mol/L² in the MOX group. Correspondingly, fasting triglycerides increased with a median change of + 29.5 mg/dL in the MET group, but decreased in the MOX group (- 27.5 mg/dl; p < 0.05). These results indicate that MOX, unlike MET, may elicit beneficial adaptations in glucose and lipid metabolism in hypertensive subjects with type 2 diabetes, although mean HbA_1c values did not differ. In long-term treatment in this high-risk population, MOX thus may decrease global vascular disease risk to a greater extent than MET.

Vascular events still represent the leading cause of death in the western world. The pathogenesis of atherothrombotic events is multifactorial. Epidemiological studies indicate that the presence of several concomitant risk factors, especially in the metabolic syndrome, markedly exacerbates the vascular risk. In the prevention and management of cardiovascular disease, a multi-dimensional risk factor approach is therefore required to reduce the “vascular burden”. Consequently it is absolutely necessary to identify and to subsequently monitor these factors during intervention/therapy. The present MMDS represents a tool for the daily clinical routine to assess and document important cardiovascular risk factors. This data set is the result of a consensus of the two German working groups of the German Cardiology Society and the German Diabetes Society. The identification and detection of all relevant vascular risk factors should result in improved patient care and a more comprehensive documentation of cardiovascular risk factors in clinical studies.

Carnitine palmitoyl transferase (CPT) II is a key enzyme in transporting FFA into the mitochondrial matrix for β 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.