Marc T. Hamilton

Effect of Antihypertensive Agents on the Development of Type 2 Diabetes Mellitus

People with hypertension have a high prevalence of insulin resistance and are at relatively high risk of developing type 2 diabetes mellitus. It is becoming increasingly evident that antihypertensive agents have disparate metabolic effects. For example, recent clinical trials indicate that agents that interrupt the renin-angiotensin axis reduce the risk of developing diabetes compared with other classes of antihypertensive agents. Blockade of the effects of angiotensin II might improve blood flow to insulin-sensitive tissues. Furthermore, interruption of the renin-angiotensin system might provide metabolic benefit through such mechanisms as reduced oxidative stress and restored nitric oxide production, which could lead to improved insulin signaling. Alternatively, collective trials suggest that both diuretics and beta-blockers accelerate the appearance of new-onset type 2 diabetes mellitus in patients with hypertension. Therefore, the risk of new-onset diabetes-associated cardiovascular risks should be factored into future treatment recommendations for patients who require antihypertensive therapy. This will become even more important as the number of insulin-resistant patients with hypertension increases in parallel with the steady growth in the number of sedentary, obese, and aged persons in our population.

Induction of Lipoprotein Lipase Gene Expression in 3T3-L1 Preadipocytes by Atorvastatin, a Cholesterol- and Triglyceride-Lowering Drug

Atorvastatin is a drug of choice in the treatment of coronary heart disease, because this hepatic 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitor significantly decreases plasma cholesterol and triglyceride levels. However, little is known about the underlying molecular targets of this drug. Lipoprotein lipase (LPL), an enzyme with multiple functions in non-hepatic lipid metabolism, may be a potential candidate and LPL gene expression may increase in response to a treatment with atorvastatin. In order to verify this hypothesis, mouse 3T3-L1 preadipocytes were incubated with 1 and 10 µmol/l atorvastatin for 24 and 48 h and LPL mRNA concentration was measured by reverse transcription-polymerase chain reaction. Our data indicated that atorvastatin increased LPL mRNA concentration by a time- and dose-dependent mechanism. LPL mRNA concentration was significantly increased by 82% with 10 µmol/l atorvastatin after 48 h. LPL mRNA concentration was 28% greater (not significant) than control with 10 µmol/l atorvastatin after 24 h. No increase was obtained with 1 µmol/l atorvastatin after 24 or 48 h. The first 976 nucleotides of rat LPL promoter were transfected in 3T3-L1 preadipocytes. Addition of 10 µmol/l atorvastatin for 48 h resulted in a 44% increase of rat LPL promoter activity. This study demonstrates for the first time that a statin can regulate LPL gene expression transcriptionally in preadipocytes.

The role of skeletal muscle contractile duration throughout the whole day: reducing sedentary time and promoting universal physical activity in all people

A shared goal of many researchers has been to discover how to improve health and prevent disease, through safely replacing a large amount of daily sedentary time with physical activity in everyone, regardless of age and current health status. This involves contrasting how different muscle contractile activity patterns regulate the underlying molecular and physiological responses impacting health‐related processes. It also requires an equal attention to behavioural feasibility studies in extremely unfit and sedentary people. A sound scientific principle is that the body is constantly sensing and responding to changes in skeletal muscle metabolism induced by contractile activity. Because of that, the rapid time course of health‐related responses to physical inactivity/activity patterns are caused in large part directly because of the variable amounts of muscle inactivity/activity throughout the day. However, traditional modes and doses of exercise fall far short of replacing most of the sedentary time in the modern lifestyle, because both the weekly frequency and the weekly duration of exercise time are an order of magnitude less than those for people sitting inactive. This can explain why high amounts of sedentary time produce distinct metabolic and cardiovascular responses through inactivity physiology that are not sufficiently prevented by low doses of exercise. For these reasons, we hypothesize that maintaining a high metabolic rate over the majority of the day, through safe and sustainable types of muscular activity, will be the optimal way to create a healthy active lifestyle over the whole lifespan.