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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Obesity is a major risk factor for morbidity and mortality, and a series of pharmacologic approaches are available for helping to manage the problem. Obesity is caused by an imbalance between caloric intake and energy expenditure, which is influenced by both environmental and genetic factors. Pharmacologic treatments include anorexigenic agents, which fall into two broad categories: those that act via brain catecholamine pathways and those that act via serotonin pathways. The most recent oral agents approved are dexfenfluramine, which is currently being marketed, and sibutramine. Both agents inhibit the control reuptake of serotonin but in addition may have effects on thermogenesis. Under investigation are agents that increase energy expenditure: the beta 3-adrenergic receptor agonists and drugs that prevent the intestinal absorption of free fatty acids and cholesterol. In development are innovative approaches to influence leptin and its receptors, various obesity genes, and biologic substances thought to influence satiety (neuropeptide Y, enterostatin, cholecystokinin, bombesin, and amylin). Obesity has now become a major target for drug development not only for affecting obesity per se but also for managing and preventing comorbid conditions such as diabetes and cardiovascular disease.
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PMID:The pharmacologic approach to the treatment of obesity. 920 52

The aim of this study was to determine whether serum leptin concentrations are reduced in response to short-term energy restriction in centrally obese individuals with impaired glucose tolerance or non-insulin-dependent diabetes mellitus. Twenty African Americans [16 females and 4 males, 44 +/- 7 y (x +/- SD), 107.2 +/- 23.8 kg, 39 +/- 7% body fat] consumed a 7-d energy-restricted diet (4.03 +/- 0.72 MJ/d) of whole foods. Oral-glucose-tolerance tests (OGTTs) were performed before and immediately after the diet to assess changes in serum leptin, glucose, and insulin concentrations. Baseline leptin concentration correlated significantly with percentage body fat (r = 0.80), body mass index (r = 0.72), fat mass (4 = 0.64), waist-height ratio (r = 0.6), body weight (r = 0.59, all P < 0.01), waist circumference (r = 0.49), and basal insulin concentration (r = 0.48, both P < 0.05). Seven days of energy restriction resulted in significant reductions (P < 0.005) in leptin (-6.1 +/- 8.4 micrograms/L), basal glucose (-0.9 +/- 0.8 mmol/L), OGTT glucose area under the curve (-158 +/- 164 mmol/L), and basal insulin concentration (-34 +/- 69 pmol/L, P < 0.05). In addition, there was a trend for a reduction in OGTT insulin area under the curve (-15,567 +/- 3,658 pmol/L, P = 0.05), and a tendency for basal insulin and leptin to change together (r = 0.41, P = 0.07). Despite the weight loss of 3.1 +/- 1.3 kg (P < 0.0001), the loss of fat mass was calculated to be only -1.0 +/- 0.1 kg. These results suggest that negative energy balance or improved insulin action was responsible for the changes in leptin, glucose, and insulin concentrations. In summary, short-term energy restriction effectively reduced serum leptin concentrations and improved glucose tolerance and insulin action in obese individuals with impaired or diabetic glucose tolerance.
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PMID:Response of serum leptin concentrations to 7 d of energy restriction in centrally obese African Americans with impaired or diabetic glucose tolerance. 984 63

Plasma leptin level is known to correlate with the degree of obesity. To determine the influences of renal function and insulin resistance on plasma leptin concentrations, we measured plasma leptin concentrations and performed the euglycaemic hyperinsulinaemic clamp studies in 57 patients with non-insulin-dependent diabetes mellitus with a wide range of renal function. In simple regression analyses, plasma leptin concentration showed significant positive correlations with percentage of body fat measured by dual energy X-ray absorptiometry, body mass index, waist to hip ratio and fasting plasma insulin. Leptin level was higher in females than males. Multiple regression analyses indicated that percent body fat, waist to hip ratio, plasma insulin, gender and renal function (1/creatinine), but not insulin sensitivity, were significant and independent determinants of plasma leptin level. These results suggest that plasma leptin level is regulated or affected by multiple factors including renal function. Insulin resistance appeared to increase leptin levels indirectly by raising plasma insulin.
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PMID:Renal function and insulin resistance as determinants of plasma leptin levels in patients with NIDDM. 922 47

The recently cloned obesity gene (ob) encodes a protein, leptin, which is secreted from adipose tissue and interacts with hypothalamic receptors to decrease appetite, increase energy expenditure, and reduce body lipid stores. The levels of ob mRNA are increased in several models of obesity, consistent with the hypothesis that obese animals may be resistant to the actions of leptin. The present study examined the impact of increased energy expenditure through exercise training on ob mRNA gene expression and body composition in the SHHF/Mc-fa(cp) male rat, a rodent model of obesity, insulin resistance, and type II diabetes. Six week old lean and obese animals were trained 8-12 weeks by treadmill running at 70% peak oxygen uptake, 5 days/wk, for 1.5 hr/day. After endurance training, exercised rats had significantly lower total body fat compared to sedentary rats of the same age, despite maintaining the same body weight. In the obese SHHF/Mcc-fa(cp) rat, the level of ob mRNA expression was markedly increased by four fold in subcutaneous adipose tissue compared to lean controls (p<0.05). In response to exercise training, there was a significant 85 % decrease in ob mRNA in exercised-training lean rats (p < 0.05) compared with non-exercised controls, while in obese-exercised rats, ob gene expression was significantly reduced only by 50% relative to non-exercised obese rats (p < 0.05). These results demonstrate that exercise training reduces fat mass and ob mRNA in lean and obese rats, and supports the hypothesis of a feedback loop between the adipocyte and hypothalamus that attempts to maintain body weight at a constant level by reducing ob gene expression in response to increased energy expenditure.
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PMID:Exercise training down-regulates ob gene expression in the genetically obese SHHF/Mcc-fa(cp) rat. 922 5

Leptin was overexpressed in the liver of normal Wistar rats by infusing recombinant adenovirus containing the cDNA encoding leptin. Plasma leptin levels rose to 12-24 ng/ml (vs. <2 ng/ml in control rats), and food intake and body weight fell. Visible fat disappeared within 7 days. Plasma insulin fell to <50% of normal in association with hypoglycemia, suggesting enhanced insulin sensitivity. Although beta-cells appeared histologically normal, the pancreases were unresponsive to perfusion with stimulatory levels of glucose and arginine. Since islet triglyceride content was 0, compared with 14 ng/islet in pair-fed control rats, we coperfused a 2:1 oleate:palmitate mixture (0.5 mmol/l). This restored insulin responses to supranormal levels. When normal islets were cultured with 20 ng/ml of leptin, they too became triglyceride-depleted and failed to respond when perifused with glucose or arginine. Perifusion of fatty acids restored both responses. We conclude that in normal rats, hyperleptinemia for 2 weeks causes reversible beta-cell dysfunction by depleting tissue lipids, thereby depriving beta-cells of a lipid-derived signal required for the insulin response to other fuels.
Diabetes 1997 Aug
PMID:beta-cell function in normal rats made chronically hyperleptinemic by adenovirus-leptin gene therapy. 923 51

Members of the peroxisome proliferator-activated receptor (PPAR) family might be involved in pathologies with altered lipid metabolism. They participate in the control of the expression of genes involved in lipid metabolism and adipocyte differentiation. In addition, thiazolidinediones improve insulin resistance in vivo by activating PPAR gamma. However, little is known regarding their tissue distribution and relative expression in humans. Using a quantitative and sensitive reverse transcription (RT)-competitive polymerase chain reaction (PCR) assay, we determined the distribution and relative mRNA expression of the four PPARs (alpha,beta, gamma1, and gamma2) and liver X receptor-alpha (LXR alpha) in the main tissues implicated in lipid metabolism. PPAR alpha and LXR alpha were mainly expressed in liver, while PPAR gamma1 predominated in adipose tissue and large intestine. We found that PPAR gamma2 mRNA was a minor isoform, even in adipose tissue, thus causing question of its role in humans. PPAR beta mRNA was present in all the tissues tested at low levels. In addition, PPAR gamma mRNA was barely detectable in skeletal muscle, suggesting that improvement of insulin resistance with thiazolidinediones may not result from a direct effect of these agents on PPAR gamma in muscle. Obesity and NIDDM were not associated with change in PPARs and LXR alpha expression in adipose tissue. The mRNA levels of PPAR gamma1, the predominant form in adipocytes, did not correlate with BMI, leptin mRNA levels, or fasting insulinemia in 29 subjects with various degrees of obesity. These results indicated that obesity is not associated with alteration in PPAR gene expression in abdominal subcutaneous adipose tissue in humans.
Diabetes 1997 Aug
PMID:Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. 923 57

Leptin, an adipocyte-derived hormone that directly regulates both adiposity and energy homeostasis, decreases food intake and appears to partition metabolic fuels toward utilization and away from storage. Because skeletal muscle expresses the leptin receptor and plays a major role in determining energy metabolism, we studied leptin's effects on glucose and fatty acid (FA) metabolism in isolated mouse soleus and extensor digitorum longus (EDL) muscles. One muscle from each animal served as a basal control. The contralateral muscle was treated with insulin (10 mU/ml), leptin (0.01-10 microg/ml), or insulin plus leptin, and incorporation of [14C]glucose or [14C]oleate into CO2 and into either glycogen or triacylglycerol (TAG) was determined. Leptin increased soleus muscle FA oxidation by 42% (P < 0.001) and decreased incorporation of FA into TAG by 35% (P < 0.01) in a dose-dependent manner. In contrast, insulin decreased soleus muscle FA oxidation by 40% (P < 0.001) and increased incorporation into TAG by 70% (P < 0.001). When both hormones were present, leptin attenuated both the antioxidative and the lipogenic effects of insulin by 50%. Less pronounced hormone effects were observed in EDL muscle. Leptin did not alter insulin-stimulated muscle glucose metabolism. These data demonstrate that leptin has direct and acute effects on skeletal muscle.
Diabetes 1997 Aug
PMID:Leptin directly alters lipid partitioning in skeletal muscle. 923 63

Leptin is the peptide product of the OB gene, which is associated with obesity in some strains of mice. Because dyslipidemias are frequently associated with obesity, we have begun to characterize the pathways connecting these related traits. In this investigation we tested for correlation of HDL phenotype measures with leptin concentrations using data from 1159 participants in the San Antonio Family Heart Study, a study of risk factors for cardiovascular disease in Mexican Americans living in and around San Antonio, Texas. In a subset of 288 unrelated individuals, we tested for correlation of leptin with nine different measures of HDL phenotype and found that only three were significantly related. However, stepwise regression analysis suggested that only two measures, HDL triglyceride concentrations (HDL-TG) and the proportion of apo A-I on HDL particles larger than HDL3 (Large HDL-apo A-I), were independently correlated with leptin. Because obesity and HDL phenotypes are both under strong genetic control, we conducted a trivariate genetic analysis, using the entire data set, to test the hypothesis that the phenotypic correlations were due to the effects of shared genes (i.e., pleiotropy). Heritabilities for the three traits were estimated to be 0.47 for leptin, 0.46 for HDL-TG, and 0.46 for Large HDL-apo A-I. Results from the genetic analyses revealed that the phenotypic correlation of leptin with HDL-TG was nongenetic (i.e., shared environment), while the phenotypic correlation with Large HDL-apo A-I was due to pleiotropy (i.e., shared genes). These results confirmed the result derived from the subset of unrelated individuals that the two measures of HDL are independently correlated with leptin. To our knowledge, this is the first report of a relationship between leptin and any aspect of lipoprotein phenotype. A better understanding of the genes responsible for this relationship may provide a molecular explanation for the aggregation of atherogenic phenotypes, such as diabetes, obesity, and dyslipoproteinemia.
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PMID:Serum leptin levels are independently correlated with two measures of HDL. 924 70

Leptin 167 an amino acid product of the recently discovered obesity gene "ob-gene", is a tissue hormone of adipose tissue. It is a hormonal satiety signal or a signal for terminating food intake. Its level rise after a meal or after administration. Rats with a mutation of the ob-gene have zero or very low leptin levels, are hyperphagic, obese and sterile, develop diabetes as a result of overeating. Administration of recombinant leptin arrests hyperphagia, the body weight declines and sexual function improve partly, in particular in males. It seems that leptin controls not only the function of the hypothalamic satiety centre but also the output of GnRh and other liberins as well as thermoregulation, muscular and sexual activity and thus energy expenditure. In the majority of obese rats and human the leptin levels are significantly higher compared with asthenic individuals, proportionate to the percentage of body fat and BMI. Obesity promotes also insulin resistance and penetration of the H-phenomenon into the phenotype. In the insulin resistance syndrome (5H-X) it may thus be assumed that there is a parallel leptin and insulin resistance, probably of the postreceptor type, and even a causal association, as the "db" gene is identical with the gene for leptin receptors.
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PMID:[Leptin and its biological and clinical significance. Is leptin and insulin resistance in the X-5H hormonal metabolic syndrome a parallel or causally-linked phenomenon?]. 924 68

The results of the Diabetes Intervention Study indicate that postprandial hyperglycaemia, but not fasting hyperglycaemia, is an independent risk factor for myocardial infarction and total mortality in newly detected non-insulin-dependent diabetes mellitus (NIDDM). Blood pressure and triglyceride levels were also found to be risk factors. Data from patients in the Study to Prevent NIDDM show that patients with impaired glucose tolerance (IGT) have higher fasting levels of triglycerides, and higher fasting and postprandial levels of pro-insulin, insulin, and C-peptide levels, compared with those who have normal glucose tolerance (NGT). Postprandial data at 2 h showed that hyperinsulinaemia was prolonged in subjects with IGT compared with their NGT counterparts. Postprandial pro-insulin levels at 2 h were also increased in subjects with IGT, and were found to have the best discriminating power between subjects with IGT and NGT. Those with IGT also secreted markedly higher levels of insulin, indicated by C-peptide levels, than those with NGT. These data support the possibility that subjects with IGT are at an increased risk of conditions such as atherosclerotic disease, even though they have not developed manifest NIDDM. Intervention with agents that can affect risk factors, such as triglyceride levels and postprandial hyperglycaemia, are expected to reduce the risk of atherosclerosis. One promising agent is acarbose, an antihyperglycaemic drug that significantly reduces postprandial insulin and triglyceride levels and has no effect on leptin levels. The ability of acarbose to improve glycaemic control without the potential for inducing hyperinsulinaemia and weight gain appears to give it an advantage over oral antidiabetic agents such as the sulphonylureas.
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PMID:The postprandial state and the risk of atherosclerosis. 947 69


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