Thursday, 28 March 2013
Sunday, 10 February 2013
6 February 2013 Last updated at 01:45 GMT
Study finds obesity can 'lead to lack of vitamin D'
Friday, 25 January 2013
Mechanistic Insights into Diuretic-Induced Insulin Resistance
- From the Pritzker School of Medicine, Department of Medicine, Hypertensive Diseases Unit, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, Ill.
- Correspondence to George L. Bakris, Hypertensive Diseases Unit, University of Chicago School of Medicine, 5841 S Maryland Ave, MC 1027, Chicago, IL 60637. E-mail firstname.lastname@example.org
The incidence of diabetes mellitus and hypertension continues to rise worldwide. The proportion of patients with hypertension at risk for developing diabetes mellitus is also growing secondary to aging and increased obesity rates.1 Several guidelines recommend thiazide diuretics as either first-line or add-on antihypertensive therapy to achieve blood pressure goals.2 Concern over negative metabolic effects associated with thiazide diuretics, however, dates back >3 decades.3 A substantial fraction of patients with hypertension have additional cardiovascular risk factors, and many have elevated fasting glucose and are at risk for developing diabetes mellitus.4 Impaired fasting glucose itself increases the risk for cardiovascular events.5
Any medication that worsens insulin sensitivity, ie, thiazide diuretics or most β-blockers will hasten the development of diabetes mellitus in those with impaired fasting glucose.6 Large observational studies demonstrate that thiazide diuretics and most β-blockers increase the incidence of new-onset diabetes mellitus compared with renin-angiotensin system (RAS) blockers or calcium channel blockers.7 To further support this observation, a network-based meta-analysis of hypertensive agents showed that RAS blockers were the agents least likely to be associated with the development of diabetes mellitus, whereas thiazides had a higher incidence of diabetes mellitus compared with placebo.7
The mechanism traditionally associated with this increased risk of diuretic-associated diabetes mellitus is a reduction in serum potassium. A meta-analysis of 59 studies involving 83 thiazide diuretic treatment arms found a significant correlation between the degree of diuretic-induced hypokalemia and an increase in plasma glucose.8 Moreover, there is evidence that prevention of hypokalemia with K+ supplementation or potassium-sparing agents lessens the degree to which plasma glucose is increased consequent to diuretic therapy.8 The mechanism of this glucose increase by diuretics may relate to insulin secretion. Mechanisms related to insulin release were reviewed recently, and it was noted that hyperkalemia stimulates insulin secretion and induces cellular uptake of potassium.9 This suggests that low plasma potassium could impair insulin secretion and thereby increase plasma glucose. Ironically, the significant hypokalemia associated with hyperaldosteronism is not associated with hyperglycemia. The presence of insulin resistance and an impaired glucose response to an oral glucose load, however, are reported in hyperaldosteronism.9 Thus, the exact relationship between hypokalemia and worsening of insulin resistance is unclear but appears most pronounced in those with preexisting impaired glucose tolerance and not all people.
Given this background, combining an agent that reduces potassium loss, ie, an RAS blocker with a thiazide diuretic, should reduce the risk of new-onset diabetes mellitus. Unfortunately, the Study of Trandolapril/Verapamil SR and Insulin Resistance failed to support this hypothesis. It demonstrated a 4-fold increase in diabetes mellitus at 1 year in comparison with a fixed-dose combination of an RAS blocker with a calcium channel blocker.10 This result was not attributable to differences in serum potassium between groups, because serum potassium values were >4.0 mEq/L in both groups. Thus, mechanisms other than changes in potassium may be operative to worsen glycemic control and are summarized elsewhere.9
One mechanism proposed for the prevention of worsening glycemic control by RAS blockers is their peroxisome proliferator-activated receptor-γ stimulating effects; however, this was not observed in this or any other trial, because candesartan had a neutral effect on glucose.11 Moreover, the peroxisome proliferator-activated receptor-γ stimulating effect observed by some RAS blockers appears relevant only in animal models or at a cellular level.12
The current study by Eriksson et al13 provides a potentially novel mechanism by which diuretics worsen insulin resistance. Twenty-six obese, hypertensive subjects were randomly assigned to candesartan, hydrochlorothiazide (HCTZ), or placebo (in random sequence), each for 12 weeks, using a 3-way crossover design. Insulin sensitivity and secretion, hepatic fat accumulation, inflammatory markers, and the ratio of subcutaneous:visceral abdominal fat were measured. Insulin sensitivity was assessed using a hyperinsulinemic, euglycemic clamp. Significant reductions in insulin sensitivity were present with HCTZ compared with candesartan. Serum potassium levels were within the normal range in all of the groups but 0.3 mEq/L lower among those randomly assigned to HCTZ. The authors reported that differences in potassium level between groups did not correlate with changes in insulin sensitivity. The epidemiological data, however, suggest that the risk for new-onset diabetes mellitus is increased if the serum potassium levels fall below 3.5 mEq/L7,9; levels in the current study were well above this value.
Perhaps the most interesting finding in this study was the increase in hepatic fat content after treatment with HCTZ; this fat increase correlated with the magnitude of insulin sensitivity decrease. Insulin secretion was not affected by HCTZ or candesartan, despite older studies implying decreased insulin secretion with HCTZ as the mechanism for worsened metabolic control.9
Given this new information, an additional mechanism to explain why thiazide diuretics worsen insulin resistance needs consideration. Before we embrace this concept, however, one needs to ask why this occurred. The increased shift of fat in liver, with resultant relative increases in visceral adiposity, is an intriguing perspective of this study. Hepatic fat accumulation is associated with insulin resistance, at the level of liver and skeletal muscle.14 The changes in content of visceral and hepatic fat could contribute to worsening of insulin sensitivity, but which occurs first? Is it possible that decreased insulin sensitivity and elevated insulin levels promote hepatic fat storage and visceral fat accumulation? In the Mechanisms for the Diabetes Preventing Effect of Candesartan Study, there was some correlation (r2=0.26; P=0.04) between the increased hepatic fat content and the observed decrease in insulin sensitivity.13
Other possible mechanisms that contributed to decreases in insulin sensitivity include increased inflammatory response or oxidative stress with diuretics, resulting in altered adipocyte activity.15 Inflammatory markers, such as high-sensitivity C-reactive protein and serum amyloid A, were higher in the diuretic group compared with the other groups. Changes in adiponectin levels may have also contributed to this shift in fat; however, adiponectin levels were not different between groups. Thus, there is no clear reason why this shift in fat occurred with HCTZ, but, if confirmed, this would provide another reason for the higher risk of new-onset diabetes.
Apart from the cost and inconvenience of new medications now required to treat the diabetes mellitus, the main concern is whether the cardiovascular risk–reduction that diuretics confer is lost in this subgroup of obese older patients who prematurely develop diabetes mellitus. Three posthoc analyses of large cardiovascular outcome trials evaluated whether the development of new-onset diabetes mellitus predicted a higher cardiovascular event rate.16–18 The results of 2 these analyses demonstrated no significant increase in risk, whereas another showed that those who developed diabetes mellitus had an intermediate cardiovascular risk less than those with diabetes mellitus but higher than those who did not develop diabetes mellitus.18 These analyses have major limitations, however, not the least of which is that they are posthoc, and most people in the analysis were not obese. There is, however, one ongoing trial that will address this issue and is due to be completed by 2010.19
In short, thiazide diuretics are associated with decreased insulin sensitivity over a relatively short time period in obese subjects with impaired fasting glucose. The mechanisms by which this occurs appear to be multifactorial. The current study provides new data to help us understand the interaction between thiazide diuretics and the adipocyte. This information, coupled with the results of a large multicentered cardiovascular outcome study that favors RAS blockade combined with a calcium channel blocker rather than a diuretic, may provide an option other than diuretics as initial agents in high-risk patients.20 Nevertheless, more detailed mechanistic studies are needed to explain further why insulin resistance is worsened with thiazide diuretics.
- The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- ↵ Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, Zinman B. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care. 2007; 30: 753–759. FREE Full Text
- ↵ Sarafidis PA, Bakris GL. State of hypertension management in the United States: confluence of risk factors and the prevalence of resistant hypertension. J Clin Hypertens (Greenwich). 2008; 10: 130–139. CrossRefMedline
- ↵ Pollare T, Lithell H, Berne C. A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med. 1989; 321: 868–873. Medline
- ↵ Ostergren J. Renin-angiotensin-system blockade in the prevention of diabetes. Diabetes Res Clin Pract. 2007; 76 (suppl 1): S13–S21. CrossRefMedline
- ↵ Lin-Tan DT, Lin JL, Wang LH, Wang LM, Huang LM, Liu L, Huang JY, Huang YL. Fasting glucose levels in predicting 1-year all-cause mortality in patients who do not have diabetes and are on maintenance hemodialysis. J Am Soc Nephrol. 2007; 18: 2385–2391. Abstract/FREE Full Text
- ↵ Sarafidis PA, McFarlane SI, Bakris GL. Antihypertensive agents, insulin sensitivity, and new-onset diabetes. Curr Diab Rep. 2007; 7: 191–199. Medline
- ↵ Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007; 369: 201–207. CrossRefMedline
- ↵ Zillich AJ, Garg J, Basu S, Bakris GL, Carter BL. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension. 2006; 48: 219–224. Abstract/FREE Full Text
- ↵ Carter BL, Einhorn PT, Brands M, He J, Cutler JA, Whelton PK, Bakris GL, Brancati FL, Cushman WC, Oparil S, Wright JT Jr. Thiazide-induced dysglycemia: call for research from a working group from the national heart, lung, and blood institute. Hypertension. 2008; 52: 30–36. FREE Full Text
- ↵ Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, Bacher P, Sowers J. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006; 29: 2592–2597. Abstract/FREE Full Text
- ↵ Bahadir O, Uzunlulu M, Oguz A, Bahadir MA. Effects of telmisartan and losartan on insulin resistance in hypertensive patients with metabolic syndrome. Hypertens Res. 2007; 30: 49–53. CrossRefMedline
- ↵ Clasen R, Schupp M, Foryst-Ludwig A, Sprang C, Clemenz M, Krikov M, Thone-Reineke C, Unger T, Kintscher U. PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. Hypertension. 2005; 46: 137–143. Abstract/FREE Full Text
- ↵ Eriksson JW, Jansson P-A, Carlberg B, Hägg A, Kurland L, Svensson MK, Ahlström H, Ström C, Lönn L, Öjbrandt K, Johansson L, Lind L. Hydrochlorothiazide, but not candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation: the Mechanisms for the Diabetes Preventing Effect of Candesartan Study. Hypertension. 2008: 52; 1030–1037. Abstract/FREE Full Text
- ↵ Deivanayagam S, Mohammed BS, Vitola BE, Naguib GH, Keshen TH, Kirk EP, Klein S. Nonalcoholic fatty liver disease is associated with hepatic and skeletal muscle insulin resistance in overweight adolescents. Am J Clin Nutr. 2008; 88: 257–262. Abstract/FREE Full Text
- ↵ Zhou MS, Schulman IH, Jaimes EA, Raij L. Thiazide diuretics, endothelial function, and vascular oxidative stress. J Hypertens. 2008; 26: 494–500. Medline
- ↵ Barzilay JI, Davis BR, Cutler JA, Pressel SL, Whelton PK, Basile J, Margolis KL, Ong ST, Sadler LS, Summerson J. Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2006; 166: 2191–2201. Abstract/FREE Full Text
- ↵ Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005; 95: 29–35. CrossRefMedline
- ↵ Aksnes TA, Kjeldsen SE, Rostrup M, Omvik P, Hua TA, Julius S. Impact of new-onset diabetes mellitus on cardiac outcomes in the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial population. Hypertension. 2007; 50: 467–473. Abstract/FREE Full Text
- ↵ Zidek W, Schrader J, Luders S, Matthaei S, Hasslacher C, Hoyer J, Bramlage P, Sturm CD, Paar WD. First-line antihypertensive treatment in patients with pre-diabetes: Rationale, design and baseline results of the ADaPT investigation. Cardiovasc Diabetol. 2008; 7: 22.
- ↵ Jamerson K, Weber MA, Bakris G, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velaquez E. The effects on cardiovascular morbidity and mortality of combined therapy with amlodipine plus benazepril compared with hydrochlorothiazide plus benazepril in hypertensive patients at high risk. N Engl J Med. In press.
Friday, 4 January 2013
Consuming fructose appears to cause changes in the brain that may lead to overeating, a new study suggests.
"Increases in fructose consumption have paralleled the increasing prevalence of obesity, and high-fructose diets are thought to promote weight gain and insulin resistance," lead author Kathleen A. Page, MD, and colleagues from Yale University in New Haven, Connecticut, write.
In this study, they showed in healthy volunteers that although glucose ingestion resulted in reduced activation of the hypothalamus, insula, and striatum on MRI — areas that regulate appetite, motivation, and reward processing — as well as increased functional connections between the hypothalamic striatal network and increased satiety. Fructose ingestion had none of these effects.
"The disparate responses to fructose were associated with reduced systemic levels of the satiety-signaling hormone insulin and were not likely attributable to an inability of fructose to cross the blood-brain barrier into the hypothalamus or to a lack of hypothalamic expression of genes necessary for fructose metabolism," they conclude.
Their findings are published in the January 2 issue of the Journal of the American Medical Association.
Glucose vs Fructose
Fructose ingestion produces smaller increases in circulating satiety hormones compared with glucose ingestion, and central administration of fructose provokes feeding in rodents, whereas centrally administered glucose promotes satiety, the authors write. "Thus, fructose possibly increases food-seeking behavior and increases food intake."
In this study, the researchers used arterial spin labeling MRI to quantify regional cerebral blood flow in 20 healthy normal-weight adult volunteers before and after drinking a 75-g beverage of pure glucose or fructose.
They observed that glucose (but not fructose) ingestion reduced activation of the hypothalamus, insula, and striatum. Glucose ingestion also increased functional connections between the hypothalamic-striatal network and increased ratings of satiety and fullness.
Brain responses were markedly different after ingestion of an equal amount of fructose. Not only did fructose fail to diminish hypothalamic activity, but it also induced a small, transient increase in hypothalamic activity.
The striatum, as with the hypothalamus, also did not deactivate with fructose ingestion, which may cause decreased inhibitory responses. Fructose ingestion was also associated with reduced systemic levels of the satiety-signaling hormone insulin.
"These findings support the conceptual framework that when the human brain is exposed to fructose, neurobiological pathways involved in appetite regulation are modulated, thereby promoting increased food intake," Jonathan Q. Purnell, MD, and Damien A. Fair, PhD, from Oregon Health & Science University, Portland, write in an accompanying editorial.
They say the implications of this study, coupled with mounting evidence from epidemiologic, metabolic feeding, and animal studies, are that the "advances in food processing and economic forces leading to increased intake of added sugar and accompanying fructose in U.S. society are indeed extending the supersizing concept to the population's collective waistlines."
The study was supported in part by grants from the National Institutes of Health and the Yale Center for Clinical Investigation. The authors and editorialists have disclosed no relevant financial relationships.
Thursday, 3 January 2013
Cuba Maintains Infant Mortality Rate under Five
HAVANA, Cuba, Jan 3 (ACN) For five years in a row, Cuba has reported its infant mortality rate at less than five deaths in every one thousand live births, with 4.6 in 2012. The achievement reveals the human development level reached by the country.
According to Granma newspaper, the important indicator reached only 4.7 in 2008; 4.8 in 2010; 4.5 in 2011 and 4.6 in 2012.
This public health achievement makes Cuba one of the countries with the lowest infant mortality rates in the Americas and it is the result of the Cuban government’s political will and decision to maintain free of charge and accessible health services for all citizens, the paper explains.
The lowest infant mortality level was reported in central Sancti Spiritus province, with only 2.8, while another four territories reported indicators below the 4.6 national rate, such as Artemisa (west), 3.8; Holguin (east) and Cienfuegos (Center) both with 3.9; and Granma (east), 4.1.
Preliminary statistics released on Wednesday by the Public Health Ministry say that some 125 thousand 661 births took place in 2012, seven thousand 406 less births than in 2011.
The major cause for death in children below one year of age is the infection during the delivery process, particularly infections linked to premature babies, who are born before the 34th week.
Medical specialists told Granma newspaper that the rate of low weight at birth was kept at 6 percent in 2012, which is a favorable level, they said. This means that only six babies in every 100 births weigh less than 2500 grams (5.5 pounds). However, 3.8 percent of children still are born before complete pregnancy period.
The infant mortality rate is a demographic indicator telling the number of deaths of children before the first year of living, which is the most critical period in human survival. The indicator is an international tool to measure the quality of the assistance given to children in every country.