Life Extension Magazine

Life Extension Magazine September 2004

LE Magazine September 2004
image
Insulin

Insulin sensitivity and sodium excretion in normotensive offspring and hypertensive patients.
Insulin resistance and hyperinsulinemia have been suggested to precede and promote hypertension, possibly by impairing sodium balance. We examined insulin sensitivity and the influence of acute hyperinsulinemia on sodium excretion after acute sodium loading in hypertension-prone individuals. Insulin sensitivity and sodium excretion in response to a 1,000-mL isotonic saline bolus were examined in 24 strictly normotensive offspring of at least 1 hypertensive parent, 19 controls without a family history of hypertension, and 8 untreated, young hypertensive patients. After the saline bolus, urinary sodium excretion was measured at baseline and during a 2-hour euglycemic, hyperinsulinemic clamp, and insulin sensitivity was determined. Insulin, pressor hormones, and atrial natriuretic peptide (ANP), were measured by radioimmunoassay (RIA) or high-performance liquid chromatography (HPLC). Results are given as means +/- SEM. Offspring and controls were well matched in age (23.7 +/- 0.5; 24.6 +/- 0.5 years, respectively), blood pressure (113.0 +/- 2.9/68.5 +/- 1.9; 110.6 +/- 2.5/71.7 +/- 2.2 mm Hg, respectively), bone mass index (BMI), plasma glucose, and lipid parameters. Insulin sensitivity index did not significantly differ between offspring and controls (0.102 +/- 0.012; 0.112 +/- 0.018 micromol/min/kg/body weight [BW]/pmol, respectively), but was markedly reduced in hypertensives (0.045 +/- 0.006, P <.001). In response to sodium loading, natriuresis increased significantly (P <.05) in both offspring and controls to a similar extent, despite the presence of hyperinsulinemia, but failed to increase in hypertensives. In normotensive offspring of hypertensive patients who have not yet developed any features of the metabolic syndrome, insulin sensitivity is not impaired. Acute hyperinsulinemia impairs the ability to excrete an acute sodium load in hypertensive patients, but not in offspring of hypertensives with normal insulin sensitivity.

Metabolism. 2001 Aug;50(8):929-35

Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia.
There is increasing evidence that the post-prandial state is an important contributing factor in the development of atherosclerosis. In subjects with impaired glucose tolerance, whereas fasting glycemia is in reference range, the post-prandial phase is characterized by a rapid and large increase in blood glucose levels. The possibility that this post-prandial "hyperglycemic spike" may be relevant to the development of cardiovascular disease in these subjects has received recently much attention. The oral glucose tolerance test, although highly non-physiological, has been used largely as model of the post-prandial state, and epidemiological studies have shown that impaired oral glucose tolerance is associated with an increased risk of cardiovascular disease, because the glycemia level after 2 hours of the glucose challenge is a direct and independent risk factor. Most of the cardiovascular risk factors are modified in the post-prandial phase and are directly affected by an acute increase of glycemia. The mechanisms through which acute hyperglycemia exerts its effects may be identified in the production of free radicals, which favours the development of an endothelial dysfunction, a prothrombotic and proinflammatory condition. Future studies may evaluate whether correcting the post-prandial hyperglycemia in the impaired glucose tolerance state can form part of the strategy for the prevention and management of cardiovascular diseases in these subjects.

Am Heart J. 2004 May;147(5):803-7

Glucomannan: properties and therapeutic applications.
Glucomannan is a dietary fiber employed quite frequently in the western countries since two decades now, as its ingestion plays an important role in human health. However, eastern people have used this fiber for more than a thousand years. This dietary fiber is the main polysaccharide obtain from the tubers of the Amorphophallus konjac plant, a member of the family Araceae found in east Asia. The chemical structure of glucomannan consists, mainly, in mannose and glucose in the ratio 8:5 linked by beta (1-->4) glycosidic bonds. This soluble fiber has a extraordinarily high waterholding capacity, forming highly viscous solutions when dissolved in water. It has the highest molecular weight and viscosity of any known dietary fiber. It has been demonstrated that this product is highly effective in the treatment of obesity due to the satiety sensation that it produces; as a remedy for constipation, because it increases the faeces volume; as hypocholesterolemic agent, interfering in the transport of cholesterol and of bile acids and as hypoglycemic and hypoinsulinemic agent, probably, by delaying gastric emptying and slowering glucose delivery to the intestinal mucosa. To the beneficial properties of this fiber, several disadvantages can be added as the production of flatulence, abdominal pain, esophageal obstruction, lower gastrointestinal obstruction or even the possible modification of the bioavailability of other drugs. This paper reviews the main characteristics of glucomannan, as well as its properties, physiologic effects and therapeutic uses.

Nutr Hosp. 2004 Jan-Feb;19(1):45-50

Inhibition of insulin secretion as a new drug target in the treatment of metabolic disorders.
The pattern of insulin release is crucial for regulation of glucose and lipid haemostasis. Deficient insulin release causes hyperglycemia and diabetes, whereas excessive insulin release can give rise to serious metabolic disorders, such as nesidioblastosis (Persistent Hyperinsulinemic Hypoglycemia of Infancy, PHHI) and might also be closely associated with development of type 2 diabetes and obesity. Type 2 diabetes is characterized by fasting hyperinsulinemia, insulin resistance and impaired insulin release, i.e. reduced first phase insulin release and decreased insulin pulse mass. The beta cell function of patients with type 2 diabetes slowly declines and will ultimately result in beta cell failure and increasing degrees of hyperglycemia. Type 2 diabetes, in combination with obesity and cardiovascular disorders, forms the metabolic syndrome. It has been possible to improve beta cell function and viability in preclinical models of type 1 and type 2 diabetes by reducing insulin secretion to induce beta cell rest. Clinical studies have furthermore indicated that inhibitors of insulin release will be of benefit in treatment or prevention of diabetes and obesity. Pancreatic beta cells secrete insulin in response to increased metabolism and by stimulation of different receptors. The energy status of the beta cell controls insulin release via regulation of open probability of the ATP sensitive potassium (K(ATP)) channels to affect membrane potential and the intracellular calcium concentration [Ca(2+)](i). Other membrane bound receptors and ion channels and intracellular targets that modulate [Ca(2+)](i)will affect insulin release. Thus, insulin release is regulated by e.g. somatostatin receptors, GLP-1 receptors, muscarinic receptors, cholecystokinin receptors and adrenergic receptors. Although the relationship between hyperinsulinemia and certain metabolic diseases has been known for decades, only a few inhibitors of insulin release have been characterized in vitro and in vivo. These include the K(ATP) channel openers diazoxide and NN414 and the somatostatin receptor agonist octreotide.

Curr Med Chem. 2004 Jun;11(12):1595-615

Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome.
BACKGROUND: Mild hypoandrogenism in men, usually defined by low levels of testosterone, is a peculiar feature of abdominal obesity that independently predicts the development of insulin resistance and diabetes mellitus. Little is known about the short- and long-term effects of weight loss on sex steroids in abdominally obese men, however. OBJECTIVES: We assessed the effect of rapid weight loss and sustained weight maintenance on the plasma concentrations of testosterone and other sex hormones in 58 abdominally obese men (age, 46.3 +/- 7.5 years; body mass index, 36.1 +/- 3.8 kg/m(2); waist girth, 121 +/- 10 cm) with the metabolic syndrome. RESULTS: The men lost on average 16.3 +/- 4.5 kg during a 9-week very low-calorie diet (VLCD) and maintained 14.3 +/- 9.1 kg weight loss after a 12-month maintenance period (vs. baseline, p < 0.001). Sex hormone-binding globulin (SHBG) increased from 27.6 +/- 11.9 to 48.1 +/- 23.5 nmol/l during the VLCD but decreased to 32.6 +/- 12.9 nmol/l during weight maintenance, which was still higher than at baseline (p < 0.001). Free testosterone (fT) increased from 185 +/- 66 to 208 +/- 70 pmol/l (p = 0.002) during the VLCD and remained high after 1 year of weight maintenance (212 +/- 84 pmol/l, p = 0.002). Total testosterone levels followed a pattern intermediate between fT and SHBG. Plasma estradiol and dehydroepiandrosterone sulphate concentrations changed only transiently or not at all. CONCLUSIONS: Rapid weight loss with successful weight maintenance in abdominally obese men with the metabolic syndrome brings about a sustained increase in fT levels. The dramatic increase in SHBG attenuated initially during weight maintenance but remained elevated. These findings may be important with regard to prevention of progressive metabolic decompensation and cardiovascular disease associated with obesity and the metabolic syndrome.

Diabetes Obes Metab . 2004 May;6(3):208-15