PUFA supplements and type 2 diabetes in the elderly.

The prevalence of type 2 diabetes is increasing continuously, especially in older people. Such a rapidly rising risk has been linked to physical inactivity and evolutionary changes in dietary patterns (mainly characterized by a greater intake in dietary fat). Increased physical activity in any age group is associated with a lower risk of developing type 2 diabetes. Epidemiological studies also reported a lower incidence of type 2 diabetes in individuals who consumed n-3 polyunsaturated fatty acids (PUFA), while intake of total, saturated and/or monounsaturated fat was associated with increased risk of type 2 diabetes in glucose-intolerant individuals. Furthermore, the beneficial effects of PUFA consumption on cardiovascular disease were mainly attributed to their effects on reducing triglyceride levels, increasing high density lipoprotein cholesterol, and improving endothelial function through anti-inflammatory mechanisms and reduced platelet aggregation. In addition to common diabetic complications such as dyslipidemia and cardiovascular disease, elderly people with type 2 diabetes are at greater risk of specific geriatric syndromes, such as cognitive decline and physical disability. The threats of physical disability, loss of independence and loss of cognitive performance which diminish quality of life may ultimately be the greatest concern for those with type 2 diabetes. In this review we will address: i) specific dietary fat intake patterns and the development of insulin resistance and type 2 diabetes, ii) the effects of PUFA supplementation on glucose metabolism, diabetic dyslipidemia and cardiovascular disease, iii) the potential advantages of PUFA supplementation on cognitive decline and physical disability in the elderly.

Dipeptidyl peptidase 4 (DPP-4) inhibitors and their role in Type 2 diabetes management.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are a new pharmacological class of drugs for treating Type 2 diabetes. They improve the capacity of the organism to control glycemia by increasing the levels of active incretins. Their mechanism of action is thus radically different from those of other anti-diabetic drugs currently available. DDP-4 inhibitors use a physiological mechanism to control hyperglycemia, by stimulating the secretion of insulin from beta-cells, decreasing the secretion of glucagon from pancreatic alpha-cells, and at the same time reducing the production of glucose by the liver. DDP-4 inhibitors have shown significant efficacy in maintaining reduced levels of glycosylated hemoglobin for up to 1 year. In vitro and animal studies have shown that they can inhibit apoptosis of beta-cells and favor their regeneration and differentiation. The oral DPP-4 inhibitors vildagliptin, sitagliptin, and saxagliptin are efficacious both alone and in association with other oral anti-diabetic agents and may be administered in a single daily dose. Lastly, they have substantial advantages with respect to other anti-diabetic drugs, since they involve a low risk of hypoglycemia and do not affect body weight.

Should we recommend the therapeutical use of vitamin E in diabetic patients?

The therapeutic application of vitamin E was initially restricted to thrombocytopenic purpura and later extended to coronary artery diseases and peripheral vascular arteriosclerosis due to the potency of its effects. Several recent studies have pointed out that vitamin E supplementation is useful for reducing low-density lipoprotein oxidation and thus might be protective towards coronary heart disease. Such data has been confirmed in many in vitro data, while in vivo results of reports from epidemiological studies are much more controversial. More consistent is the evidence showing vitamin E to improve endothelial function especially in diabetic patients. Finally, chronic vitamin E has been demonstrated to improve the metabolic control in diabetic patients. Whether chronic vitamin E administration at pharmacological doses and for long time, is safe is still debated. A sure response to such a query will open the possibility for recommending vitamin E as a therapeutic agent in diabetic patients.

Circulating adhesion molecules in humans: role of hyperglycemia and hyperinsulinemia.

BACKGROUND: We assessed the role of glucose and insulin in the regulation of circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1) in normal subjects and in patients with type 2 diabetes. METHODS AND RESULTS: Plasma glucose concentrations were acutely raised in 10 normal subjects and 10 newly diagnosed, complication-free type 2 diabetic patients and maintained at 15 mmol/L for 2 hours. In normal subjects, plasma sICAM-1, but not sVCAM-1, levels rose significantly (P<0.01) at 1 hour and returned to basal values at 2 hours. In another study, octreotide was infused during the hyperglycemic clamp to block the release of endogenous insulin; this prevented the late fall of plasma sICAM-l levels observed in under control clamp conditions. The diabetic patients had plasma sICAM-1 levels significantly higher (P<0.01) than those of the control subjects; plasma sVCAM-1 levels were similar. Both sICAM-l and sVCAM-1 concentrations did not change significantly during the control hyperglycemic clamp; however, octreotide infusion increased plasma sICAM-1 levels, which remained significantly (P<0.05) above baseline during the whole clamp. In an additional 10 type 2 diabetic patients, overnight euglycemia (plasma glucose 5.5 mmol/L) obtained with the aid of an artificial pancreas or supplementation with l-arginine (10 g PO for 30 days), the natural precursor of NO, normalized the increased plasma sICAM-1 levels. CONCLUSIONS: Acute hyperglycemia increases circulating sICAM-1 levels in normal subjects, whereas the correction of hyperglycemia with insulin or l-arginine supplementation restored to normal levels the increased plasma sICAM-1 levels of type 2 diabetic patients.

Effects of vitamin E and glutathione on glucose metabolism: role of magnesium.

Vitamin E is an antioxidant that has been demonstrated to improve insulin action. Glutathione, another natural antioxidant, may also be important in blood pressure and glucose homeostasis, consistent with the involvement of free radicals in both essential hypertension and diabetes mellitus. Our group has recently suggested that the effects of reduced glutathione on glucose metabolism may be mediated, at least in part, by intracellular magnesium levels (Mg([i])). Recent evidence suggests that vitamin E enhances glutathione levels and may play a protective role in magnesium deficiency-induced cardiac lesions. To directly investigate the effects of vitamin E supplementation on insulin sensitivity in hypertension, in relation to the effects on circulating levels of reduced (GSH) and oxidized (GSSG) glutathione and on Mg([i]), we performed a 4-week, double-blind, randomized study of vitamin E administration (600 mg/d) versus placebo in 24 hypertensive patients and measured whole-body glucose disposal (WBGD) by euglycemic glucose clamp, GSH/GSSG ratios, and Mg([i]) before and after intervention. The relationships among WBGD, GSH/GSSG, and Mg([i]) in both groups were evaluated. In hypertensive subjects, vitamin E administration significantly increased WBGD (25.56+/-0.61 to 31.75+/-0.53 micromol/kg of fat-free mass per minute; P<0.01), GSH/GSSG ratio (1.10+/-0.07 to 1.65+/-0.11; P<0.01), and Mg([i]) (1.71+/-0.042 to 1.99+/-0.049 mmol/L; P<0.01). In basal conditions, WBGD was significantly related to both GSH/GSSG ratios (r=0.58, P=0.047) and Mg([i]) (r=0.78, P=0.003). These data show a clinical link between vitamin E administration, cellular magnesium, GSH/GSSG ratio, and tissue glucose metabolism. Further studies are needed to explore the cellular mechanism(s) of this association.

Hypertension, diabetes mellitus, and insulin resistance: the role of intracellular magnesium.

Magnesium is one of the most abundant ions present in living cells and its plasma concentration is remarkably constant in healthy subjects. Plasma and intracellular magnesium concentrations are tightly regulated by several factors. Among them, insulin seems to be one of the most important. In fact, in vitro and in vivo studies have demonstrated that insulin may modulate the shift of magnesium from extracellular to intracellular space. Intracellular magnesium concentration has also been shown to be effective on modulating insulin action (mainly oxidative glucose metabolism), offset calcium-related excitation-contraction coupling, and decrease smooth cell responsiveness to depolarizing stimuli, by stimulating Ca2+-dependent K+ channels. A poor intracellular magnesium concentration, as found in non-insulin-dependent diabetes mellitus (NIDDM) and in hypertensive (HP) patients, may result in a defective tyrosine-kinase activity at the insulin receptor level and exaggerated intracellular calcium concentration. Both events are responsible for the impairment in insulin action and a worsening of insulin resistance in non-insulin-dependent diabetic and hypertensive patients. By contrast, in NIDDM patients daily magnesium administration, restoring a more appropriate intracellular magnesium concentration, contributes to improve insulin-mediated glucose uptake. Similarly, in HP patients magnesium administration may be useful in decreasing arterial blood pressure and improving insulin-mediated glucose uptake. The benefits deriving from daily magnesium supplementation in NIDDM and HP patients are further supported by epidemiological studies showing that high daily magnesium intake to be predictive of a lower incidence of NIDDM and HP. In conclusion, a growing body of studies suggest that intracellular magnesium may play a key role on modulating insulin-mediated glucose uptake and vascular tone. We further suggest that a reduced intracellular magnesium concentration might be the missing link helping to explain the epidemiological association between NIDDM and hypertension.

Metabolic benefits deriving from chronic vitamin C supplementation in aged non-insulin dependent diabetics.

OBJECTIVE: Our study investigated the metabolic benefits deriving from chronic pharmacological vitamin C administration in aged non-insulin dependent (Type II) diabetic patients. METHODS: Forty type II diabetic patients (age: 72 +/- 0.5 years) underwent placebo and vitamin C (0.5 g twice daily) administration in double-blind, randomized, cross-over fashion. All patients were treated by oral hypoglycaemic agents which continued throughout the study. After baseline observations, treatment periods lasted 4 months and were separated by a 30-day wash-out period. RESULTS: Patients' antropometric data were unchanged throughout the study. Chronic vitamin C administration vs placebo was associated with a significant decline in fasting plasma free radicals (0.26 +/- 0.06 vs 0.49 +/- 0.07 p < 0.03) and insulin (90 +/- 4 vs 73 +/- 6 pmol/L p < 0.04), total- (7.3 +/- 0.5 vs 5.8 +/- 0.4 mmol/L p < 0.03), LDL-cholesterol (5.6 +/- 0.6 vs 4.1 +/- 0.3 mmol/L p < 0.05) and triglycerides (2.58 +/- 0.07 vs 2.08 +/- 0.04 mmol/L p < 0.04) levels. In 20 patients, chronic vitamin C administration improved whole body glucose disposal and nonoxidative glucose metabolism. Percent increase in plasma vitamin C levels correlated with the percent decline in plasma LDL-cholesterol (r = 0.44; p < 0.007) and insulin levels (r = 0.42; p < 0.006). Finally percent increase in plasma vitamin C levels was correlated with the percent decline in plasma free radicals and increase in GSH levels. CONCLUSIONS: Chronic vitamin C administration has beneficial effects upon glucose and lipid metabolism in aged non-insulin dependent (type II) diabetic patients.

Chronic intake of pharmacological doses of vitamin E might be useful in the therapy of elderly patients with coronary heart disease.

Thirty elderly (mean +/- SEM: 73.8 +/- 2.1 y) nondiabetic, moderately obese (body mass index = 28.3 +/- 0.6 kg/m2) patients with stable effort angina underwent an oral-glucose-tolerance test and a euglycemic hyperinsulinemic glucose clamp before and after vitamin E supplementation (900 mg/d for 4 mo). The study was of a randomized, placebo-controlled, double-blind, and crossover design. Anthropometric indexes were stable throughout the study. Despite similar fasting and 2-h plasma glucose concentrations, vitamin E administration (compared with placebo) lowered fasting (88 +/- 14 and 68 +/- 9 pmol/L, P < 0.02) and 2-h (348 +/- 43 and 263 +/- 28 pmol/L, P < 0.05) plasma insulin concentrations, plasma triglyceride concentrations (1.34 +/- 0.06 and 1.07 +/- 0.03 mmol/L, P < 0.05), and the ratio of plasma LDL to HDL cholesterol (7.64 +/- 0.31 and 5.52 +/- 0.38, P < 0.02). Vitamin E administration was associated with higher nonoxidative glucose metabolism (18.1 +/- 0.5 and 10.6 +/- 0.7 mumol.kg lean body mass-1.min-1, P < 0.03) than was placebo administration during the euglycemic glucose clamp. We conclude that chronic intake of pharmacological doses of vitamin E might be useful in the therapy of elderly insulin-resistant patients with coronary heart disease.

Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients.

The aim of the present study was to investigate the effects of magnesium supplementation on glucose uptake and substrate oxidation in noninsulin-dependent (type II) diabetic patients. Nine elderly non-obese noninsulin-dependent (type II) diabetic patients, treated by diet only, participated in the study, which was designed as randomized, double blind, and cross-over. Each patient was followed up for a prestudy period of 3 weeks before inviting him/her to receive placebo or magnesium supplementation (15.8 mmol/day) for 4 weeks. At the end of each treatment period, a euglycemic hyperinsulinemic glucose clamp with simultaneous D-[3-3H]glucose infusion and indirect calorimetry was performed. Magnesium supplementation resulted in significantly increased plasma and erythrocyte magnesium levels, whereas body weight and fasting plasma glucose did not change. In the last 60 min of the glucose clamp, insulin-mediated glucose disappearance, total body glucose disposal (24.5 +/- 0.4 vs. 28.2 +/- 0.7 mumol/kg.min; P < 0.005), and glucose oxidation (13.0 +/- 0.4 vs. 16.3 +/- 0.8 mumol/kg.min; P < 0.01) were increased after chronic magnesium supplementation. Endogenous glucose production, nonoxidative glucose disposal, lipid and protein oxidation, and insulin MCR were not affected. In conclusion, a 4-week magnesium supplementation improves insulin sensitivity and glucose oxidation in the course of a euglycemic-hyperinsulinemic glucose clamp in noninsulin-dependent diabetic patients. Long term studies are needed to determine whether magnesium supplementation is useful in the management of type II diabetes.

[Magnesium and glucose metabolism]. / Magnésium et métabolisme glucidique.

The interrelationships between magnesium and carbohydrate metabolism have regained considerable interest over the last few years. Insulin secretion requires magnesium: magnesium deficiency results in impaired insulin secretion while magnesium replacement restores insulin secretion. Furthermore, experimental magnesium deficiency reduces the tissues sensitivity to insulin. Subclinical magnesium deficiency is common in diabetes. It results from both insufficient magnesium intakes and increase magnesium losses, particularly in the urine. In type 2, or non-insulin-dependent, diabetes mellitus, magnesium deficiency seems to be associated with insulin resistance. Furthermore, it may participate in the pathogenesis of diabetes complications and may contribute to the increased risk of sudden death associated with diabetes. Some studies suggest that magnesium deficiency may play a role in spontaneous abortion of diabetic women, in fetal malformations and in the pathogenesis of neonatal hypocalcemia of the infants of diabetic mothers. Administration of magnesium salts to patients with type 2 diabetes tend to reduce insulin resistance. Long-term studies are needed before recommending systematic magnesium supplementation to type 2 diabetic patients with subclinical magnesium deficiency.

Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients.

OBJECTIVE: To investigate the potential metabolic benefits deriving from daily vitamin E administration in type II diabetic patients. RESEARCH DESIGN AND METHODS: Twenty-five type II diabetic patients were invited to randomly take placebo or vitamin E (d-alpha-tocopherol; 900 mg/day) along a similar 3-mo period in a double-blind, crossover procedure. A wash-out period of 30 days separated the two treatment periods. At the end of each treatment period blood samples were drawn for plasma metabolites determination, and an intravenous glucose tolerance test (25 g of glucose as bolus in 3 min) was performed. During this study oral hypoglycemic agents were not discontinued or changed in their dosage. RESULTS: Chronic vitamin E administration reduced plasma glucose (8.3 +/- 0.3 vs. 7.5 +/- 0.2 mM, P > 0.05), triglycerides (2.27 +/- 0.08 vs. 1.67 +/- 0.09 mM, P < 0.02), free fatty acids (786 +/- 116 vs. 483 +/- 64 mM), total cholesterol (6.74 +/- 0.09 vs. 5.50 +/- 0.10 mM, P < 0.05), low-density lipoprotein cholesterol (4.73 +/- 0.11 vs. 3.67 +/- 0.07 mM, P < 0.04), and apoprotein B (1.7 +/- 0.3 vs. 1.0 +/- 0.1 g/L) levels but did not affect beta-cell response to glucose. HbA1 levels (7.8 +/- 0.3 vs. 7.1 +/- 0.5%, P < 0.05) were also significantly lowered after chronic vitamin E administration. CONCLUSIONS: Daily vitamin E supplements seem to produce a minimal but significant improvement in the metabolic control in type II diabetic patients. More studies are necessary before conclusions can be drawn about the safety of vitamin E during long-term administration.

Pharmacologic doses of vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients.

Ten control (healthy) subjects and 15 non-insulin-dependent diabetics underwent an oral glucose-tolerance test and a euglycemic hyperinsulinemic glucose clamp before and after vitamin E supplementation (900 mg/d for 4 mo). In control subjects (placebo-treated vs vitamin E-supplemented subjects, respectively) vitamin E reduced the area under the curve for glucose (344 +/- 21 vs 287 +/- 13 mmol.L-1 x min-1; P < 0.05) and increased total body glucose disposal (39.0 +/- 0.3 vs 47.6 +/- 0.4 mumol.kg lean body mass-1 x min-1; P < 0.05) and non-oxidative glucose metabolism (23.4 +/- 0.2 vs 30.8 +/- 0.3 mumol.kg lean body mass-1 x min-1; P < 0.05). In diabetics (placebo-treated vs vitamin E-supplemented subjects, respectively) vitamin E supplementation reduced glucose area under the curve (614 +/- 129 vs 544 +/- 98 mmol.L-1 x min-1; P < 0.03) and increased glucose disappearance (19.4 +/- 0.4 vs 26.4 +/- 0.7 mumol.kg lean body mass-1.min-1; P < 0.03), total glucose disposal (19.0 +/- 0.7 vs 28.1 +/- 0.4 mumol.kg lean body mass-1 x min-1; P < 0.02), and nonoxidative glucose metabolism (8.5 +/- 0.3 vs 13.9 +/- 0.3 mumol.kg lean body mass-1 x min-1; P < 0.02). Therefore we conclude that administration of pharmacologic doses of vitamin E is a useful tool to reduce oxidative stress and improve insulin action.

Daily magnesium supplements improve glucose handling in elderly subjects.

We demonstrated similar plasma concentrations and urinary losses but lower erythrocyte magnesium concentrations (2.18 +/- 0.04 vs 1.86 +/- 0.03 mmol/L, P less than 0.01) in twelve aged (77.8 +/- 2.1 y) vs 25 young (36.1 +/- 0.4 y), nonobese subjects. Subsequently, aged subjects were enrolled in a double-blind, randomized, crossover study in which placebo (for 4 wk) and chronic magnesium administration (CMA) (4.5 g/d for 4 wk) were provided. At the end of each treatment period an intravenous glucose tolerance test (0.33 g/kg body wt) and a euglycemic glucose clamp with simultaneous [D-3H]glucose infusion and indirect calorimetry were performed. CMA vs placebo significantly increased erythrocyte magnesium concentration and improved insulin response and action. Net increase in erythrocyte magnesium significantly and positively correlated with the decrease in erythrocyte membrane microviscosity and with the net increase in both insulin secretion and action. In aged patients, correction of a low erythrocyte magnesium concentration may allow an improvement of glucose handling.

Metabolic effects of nitrendipine.

A randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and clinical efficacy of nitrendipine in the treatment of isolated systolic hypertension in elderly patients. The subjects were 20 elderly patients with isolated systolic hypertension who received 20 mg of nitrendipine or placebo daily for 60 days. In the nitrendipine-treated patients, both systolic and diastolic blood pressures were reduced significantly during treatment (from a mean of 180 to 155 mmHg and 92 to 80 mmHg); heart rate did not change significantly. Standard laboratory test results did not change in either group during treatment and results of a posttreatment oral glucose tolerance test were similar in the two treatment groups.

Magnesium and glucose homeostasis.

Magnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects.

Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects.

Hypomagnesemia and low erythrocyte magnesium content are both common findings in non-insulin-dependent diabetic subjects. Moreover, intracellular magnesium may play a crucial role in modulating B-cell response to glucose by interfering with potassium permeability. Eight elderly, moderately obese, non-insulin-dependent diabetic subjects were treated with either magnesium supplementation (3 g/day) to the diet or placebo. Both treatment schemes lasted 4-weeks and were separated by a 'wash-out' of 3 weeks. At the end of each treatment period, in glucose test (0.33 g/kg for 3 min) and an iv arginine (5 g) test were performed to determine the B-and A-cell responses. Dietary magnesium supplementation vs placebo produced a slight but significant decrease in basal plasma glucose (8.6 +/- 0.3 vs 8.0 +/- 0.1 mmol/l, p less than 0.05) and an increase in acute insulin response after iv glucose (3.7 +/- 2.3 vs - 14.7 +/- 0.9 pmol.l 1. (10 min)-1, p less than 0.01) and after iv arginine (151 +/- vs 81 +/- 15 pmol.l-1. (10 min)-1, p less than 0.01), respectively. Plasma glucagon levels were unaffected by chronic dietary magnesium supplementation as well under basal conditions as in response to arginine. Net increase in acute insulin response after iv glucose and after iv arginine was significantly correlated to the net increase in erythrocyte magnesium content after dietary magnesium supplementation. We conclude that magnesium administration may be a useful adjuvant to the classic hypoglycemic agents in the treatment of non-insulin-dependent diabetic subjects.

Improved insulin response and action by chronic magnesium administration in aged NIDDM subjects.

In eight aged non-insulin-dependent diabetes mellitus (NIDDM) subjects, insulin response and action were studied before and after chronic magnesium supplementation (2 g/day) to diet. Chronic magnesium supplementation to diet versus placebo produced 1) a significant increase in plasma (0.83 +/- 0.05 vs. 0.78 +/- 0.06 mM, P less than .05) and erythrocyte (2.03 +/- 0.06 vs. 1.88 +/- 0.09 mM, P less than .01) magnesium levels, 2) an increase in acute insulin response (AIR) (4.0 +/- 0.6 vs. -1.6 +/- 0.6 mU/L, P less than .05) to glucose pulse, and 3) an increase in glucose infusion rate (GIR) (3.6 +/- 0.6 vs. 2.9 +/- 0.5 mg.kg-1.min-1, P less than .025) calculated in the last 60 min of a euglycemic-hyperinsulinemic (100 mU.m2.min-1 during 180 min) glucose clamp. Net increase in AIR, glucose disappearance rate after glucose pulse, and GIR were significantly and positively correlated to the net increase in erythrocyte magnesium content calculated after chronic magnesium supplementation to diet. In conclusion, our data suggest that NIDDM subjects may benefit from therapeutic chronic administration of magnesium salts.