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

To assess the metabolic disturbances, and, in particular, the occurrence of high blood ketone body concentration in post-absorptive Type 2 (non-insulin-dependent) diabetic patients as compared to a matched normal population, a study was carried out in a group of 78 Type 2 diabetic outpatients matched for age and sex and in 78 normal individuals. In all subjects we measured HbA1c, and fasting levels of glucose, FFA, lactate, pyruvate, glycerol, alanine, 3-hydroxybutyrate, acetoacetate, uric acid, total cholesterol, triglycerides, creatinine, growth hormone, cortisol, glucagon, free insulin, and C-peptide. Multistix strips were used for urine ketone determination. As expected HbA1c, and plasma glucose were higher in Type 2 diabetics. This was associated with multiple metabolic disturbances as shown by higher circulating concentrations of FFA, glycerol and gluconeogenic precursors. Similarly, blood levels of ketones (351 +/- 29 vs 159 +/- 15 umol/l; P < 0.0001) were increased, in spite of higher plasma free-insulin (77 +/- 7 vs. 49 +/- 14 pmol/l; p < 0.0001) and C-peptide concentration (0.63 +/- 0.03 vs. 0.46 +/- 0.07 nmol/l; P < 0.05) and no differences in plasma levels of cortisol, and growth hormone. Plasma glucagon levels were higher in Type 2 diabetics. Blood ketone body levels were directly correlated with both plasma glucose and FFA concentrations. These observations clearly show that Type 2 diabetes is a pathologic condition characterised by multiple metabolic disturbances which are fully apparent in the basal state. Furthermore, we emphasise that Type 2 diabetic patients, though not insulin deficient, may present a significant increase in their fasting levels of ketone bodies.
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PMID:High blood ketone body concentration in type 2 non-insulin dependent diabetic patients. 877 73

The aim of this study was to investigate whether the EcoRI polymorphism of the apolipoprotein B (apoB) gene influences the relationships between features of the insulin resistance syndrome and the dense LDL phenotype and apoB concentrations. A sample of 65 men was divided into two groups on the basis of the EcoRI genotype. Forty-four subjects were (+/+) homozygotes for the presence of the EcoRI restriction site that is associated with a glutamic acid at codon 4154. Twenty-one men were (+/-) heterozygotes for the absence of the restriction site resulting from a glutamic acid to a lysine substitution at codon 4154. In the (+/-) group, fasting plasma FFA levels were positively correlated with plasma apoB, LDL-apoB, and the LDL particle score that was calculated from the migration distances of LDL subspecies and their relative band intensities, reflecting the proportion of small dense LDL particles. However, these associations were not found among (+/+) subjects. The two genotypic groups were further divided into two subgroups on the basis of fasting FFA concentrations, and the LDL particle score and the LDL-apoB levels were compared. High FFA levels were associated with a higher proportion of small dense LDL particles, as reflected by a higher mean LDL particle score, irrespective of the genotype. However, the apoB-EcoRI polymorphism appeared to influence the association between high FFA levels and LDL-apoB concentrations because (+/-) heterozygotes with high FFA levels had higher LDL-apoB concentrations than (+/-) heterozygotes with low FFA levels. In addition, the integrated area under the curve of plasma insulin concentrations, measured in response to a 75-g oral glucose challenge, and the amount of visceral adipose tissue, measured by computed tomography, were positively associated with the LDL particle score only in (+/-) heterozygotes. When subjects were divided on the basis of insulin area (low vs. high) or visceral adipose tissue (low vs. high), (+/-) heterozygotes with high insulin area or with high levels of visceral adipose tissue had a higher mean LDL particle score than (+/-) heterozygotes with low insulin area or low visceral adipose tissue. However, among (+/+) homozygotes, low or high levels of insulin or visceral adipose tissue could not discriminate between men with large or small LDL particles. Therefore, (+/-) heterozygotes may be more susceptible to develop the dense LDL phenotype in presence of hyperinsulinemia and visceral obesity. Results of the present study suggest that the apoB-EcoRI polymorphism may exacerbate the alterations in the LDL particle (size and concentration) found among visceral obese-hyperinsulinemic men.
Diabetes 1996 Oct
PMID:The apoB-100 gene EcoRI polymorphism influences the relationship between features of the insulin resistance syndrome and the hyper-apoB and dense LDL phenotype in men. 882 78

The study investigated a possible association between fasting plasma insulin (FPI) levels and ventricular premature complexes (VPCs). One hundred eighty-six subjects without coronary artery disease (CAD), diabetes, hypertension, and left ventricular hypertrophy were recruited. All subjects underwent 24-hour electrocardiographic monitoring and oral glucose tolerance testing. The subjects were slightly overweight, normotensive, and nondiabetic. Subjects at the third tertile of FPI concentrations were the oldest and heaviest, with prevalent upper-body fat distribution, and had enhanced fasting plasma triglyceride and potassium concentrations, lower fasting plasma high-density lipoprotein (HDL) cholesterol concentration, and a greater number of VPCs versus subjects at the first and second tertiles. Independently of age, sex, body mass index (BMI), and waist to hip ratio (WHR), VPCs were correlated with FPI concentration (r = .19, P < .01). Multiple logistic regression analyses in which the presence or absence of VPCs was the dependent variable demonstrated that FPI concentrations were associated with VPCs independently of age, sex, BMI, WHR, daily physical activity (DPA), left ventricular mass index (LVMI), plasma low-density lipoprotein (LDL)/HDL cholesterol ratio, and triglyceride concentration (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0 to 1.6). After addition to the model of fasting plasma free fatty acids ([FFA] OR, 0.7; 95% CI, 0.6 to 1.3) or potassium (OR, 0.7; 95% CI, 0.6 to 1.1) concentrations, the association between FPI concentrations and VPCs is no longer significant. In conclusion, FPI concentrations are associated with VPCs in nondiabetic, normotensive, nonischemic subjects.
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PMID:Hyperinsulinemia is associated with ventricular premature complexes. 884 80

Most obese patients with noninsulin-dependent diabetes mellitus (NIDDM) are initially treated with diet, then with oral hypoglycemic agents, eventually with insulin. However several reports indicate that in these patients insulin therapy has little chance to control glucose metabolism, promotes weight gain and arterial hypertension, and is likely to aggravate insulin resistance. In this randomized, double-blind trial vs. placebo (P) we evaluated in 29 obese NIDDM patients poorly controlled by insulin (daily insulin doses 48.7 +/- 4.0 U/day, HbA1c 10 +/- 0.27%, mean daily blood glucose levels 12.3 +/- 0.3 mmol/L, fasting C-peptide 1.8 +/- 0.2, C-peptide after 1 mg iv glucagon 3.2 +/- 0.3 ng/mL, means +/- SE), the clinical and metabolic effects of benfluorex (B), a lipid-lowering drug able to improve insulin sensitivity. After a 2-3 week run-in period (1 tablet P at dinner and diet 800 cal/day to lose 5% of the initial body weight (BWi), patients received a 1000 kcal/day diet and were randomized to B, 150 mg/ tablet, or P (3 tablets/day); the time limit was set at a 10% decrease of BWi or at 90 days. At the end of run-in there was a significant reduction of BWi (P < 0.001), fasting (P = 0.002) and mean daily blood glucose levels (P < 0.001), triglycerides (P = 0.02), cholesterol (P < 0.001) and daily insulin doses (P < 0.001). At the end of the double-blind trial, weight-loss was greater (P < 0.05), faster (P = 0.018), and more frequent (P < 0.05) with B than with P, and systolic blood pressure (P < 0.05) decreased only with B. Considering only patients with a 10% decrease of BWi (B = 15, P = 10), HbA1c (P < 0.001) decreased only with B, while fasting insulin levels decreased with both B (P < 0.01) and with P (P < 0.05). Insulin sensitivity was evaluated by means of a double infusion test (LDIGIT, insulin 25 mU/Kg/h plus glucose 4 mg/kg/min, lasting 150 min) at the end of run-in and at the end of the double-blind trial; at the end of the double-blind trial steady state blood glucose (SSBG, P < 0.05), free fatty acids (FFA, P < 0.05) and blood beta-hydroxybutyrate (P < 0.05) decreased only with B, while blood glycerol decreased both with both P (P < 0.05) and B (P < 0.06). At the end of the double-blind trial, C-peptide release was unchanged with either P or B. In conclusion, benfluorex potentiates the effects of hypocaloric diet on weight loss and on glycemic control in obese NIDDM patients treated with insulin, and this effect seems to be the result of an improved insulin sensitivity.
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PMID:Benfluorex in obese noninsulin dependent diabetes mellitus patients poorly controlled by insulin: a double blind study versus placebo. 885 30

We have previously shown that during glucose clamps in moderately hyperglycemic depancreatized dogs: 1) peripheral insulin infusion, resulting in greater systemic insulinemia and greater suppression of glucagon than equidose portal infusion, inhibited glucose production (GP) to a greater extent; and 2) portal and half-dose peripheral infusions, resulting in matched peripheral insulinemia and similar suppression of glucagon, inhibited GP equally. These findings are consistent with an indirect effect of insulin in suppressing GP in diabetic dogs, which might be partly mediated by the differential suppression of glucagon. To address this question, we performed the experimental protocols of the previous study under conditions of constant glucagon levels (approximately 550 ng/liter), achieved by a high rate portal glucagon infusion (5 ng/kg.min). As in the previous study (basal glucagon levels, approximately 170 ng/liter), we used depancreatized dogs and assessed GP with HPLC-purified [6(-3)H]glucose. After obtaining constant basal hyperglycemia (approximately 10 mM) with portal infusions of insulin (4.8 +/- 0.5 pmol/kg.min) and glucagon, an additional infusion of insulin was administered for 180 min, either portally (portal; n = 7) or peripherally (peripheral; n = 8) at the same rate (5.4 pmol/kg.min) or at half that rate peripherally (1/2 periph; n = 5). Plasma glucose and glucose specific activities were clamped at basal levels. Systemic insulin levels increased by 215 +/- 16,310 +/- 26, and 184 +/- 15 pM, and estimated hepatic insulin levels increased by 398 +/- 20, 310 +/- 26, and 184 +/- 15 pM with portal, peripheral, and 1/2 periph, respectively. GP was suppressed to the same extent with portal and peripheral (53 +/- 6% and 50 +/- 6%), but less with 1/2 periph (35 +/- 5%). FFA levels were suppressed to a greater extent with peripheral than portal or 1/2 periph, whereas the responses of lactate alanine and glycerol to insulin infusion were similar in the three groups. Thus, in the present report, unlike in our previous study, 1) suppression of GP was proportional to the hepatic insulin levels; and 2) systemic insulin levels did not dominate suppression of GP. We, therefore, conclude that in hyperglycemic depancreatized dogs 1) glucagon, at concentrations seen in poorly controlled diabetes, can unmask a direct effect of hepatic insulin levels on GP; and 2) the suppression of glucagon may play a role in the peripheral effect of exogenously delivered insulin on GP. This is the first in vivo study to show that the main direct effect of insulin on the liver is to counteract the effect of glucagon.
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PMID:Direct and indirect effects of insulin in suppressing glucose production in depancreatized dogs: role of glucagon. 904 1

Here we report that free fatty acid-induced suppression of insulin output in prediabetic Zucker diabetic fatty (ZDF) rats is mediated by NO. When normal islets were cultured in 2 mM FFA, NO production and basal insulin secretion increased slightly. In cultured prediabetic ZDF islets, FFA induced a fourfold greater rise in NO, upregulated mRNA of inducible nitric oxide synthase (iNOS), and reduced insulin output; both nicotinamide and aminoguanidine, which lower NO, prevented the FFA-mediated increase in iNOS mRNA, reduced NO, and minimized the loss of insulin secretion. In vivo nicotinamide or aminoguanidine treatment of prediabetic ZDF rats prevented the iNOS expression in islets and decreased beta cell dysfunction while blocking beta cell destruction and hyperglycemia. We conclude that NO-lowering agents prevent adipogenic diabetes in obese rats.
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PMID:Role of nitric oxide in obesity-induced beta cell disease. 921 5

Congestive heart failure (CHF) is an insulin-resistant state which constitutes the main risk factor for the development of non-insulin-dependent diabetes mellitus (NIDDM). Our study investigated the predictive role of CHF on the development of NIDDM in 1,339 elderly subjects with a mean ( +/- SD) age of 74.2 +/- 6.4 years. CHF had a 9.5% prevalence, and 14.7% of the subjects had NIDDM. After stratification by age, subjects between 80 and 84 years had the highest prevalence of CHF and a total of 29.6% of CHF patients had NIDDM. In multiple logistic regression analysis, CHF was associated with NIDDM [odds ration (OR) = 2.0, 95% confidence interval (CI) - 1.6-2.5] independent of age, sex, family history of diabetes, body mass index, (BMI), waist/hip ratio, and diastolic blood pressure. When only untreated CHF patients were taken into account, the association between CHF and NIDDM was even stronger (OR = 4.0, 95% CI = 3.4-5.8). When untreated CHF patients were grouped into those with low (I and II) and high (III and IV) New York Heart Association (NYHA) classes, the association of CHF and NIDDM was stronger with the worsening of CHF. In a longitudinal study, CHF predicted NIDDM independently of age, sex, family history of diabetes, BMI, waist/hip ratio, systolic and diastolic blood pressure, and therapy for CHF (OR = 1.4, 95% CI = 1.1-1.8). CHF was associated with a higher prevalence of NIDDM and was a risk factor for its development. Elevated FFA concentrations may play a pivotal role.
Diabetes Metab 1997 Jun
PMID:Congestive heart failure predicts the development of non-insulin-dependent diabetes mellitus in the elderly. The Osservatorio Geriatrico Regione Campania Group. 923 98

Insulin resistance is a precursor to and primary cause of Type 2 diabetes mellitus. In addition, insulin resistance is associated with other chronic diseases, including gestational diabetes, cardiovascular disease, and cancer. Resistance to insulin's effects on carbohydrate metabolism include diminished actions of insulin to enhance glucose uptake and suppress endogenous glucose production. This chapter introduces new concepts related to the mechanism by which insulin stimulates glucose utilization in vivo and demonstrates that these processes are mechanistically linked to glucose production. Insulin acts rapidly in vitro to stimulate glucose uptake; in contrast, its effects in vivo are relatively slow in the conscious animal or human subject. The explanation for this difference between in vitro and in vivo dynamics is the delay associated with insulin transport across capillary endothelium of insulin-sensitive tissues (primarily muscle). Also, interstitial insulin is attenuated in concentration compared to plasma insulin at basal as well as under hyperinsulinemic conditions (plasma:interstitial ratio, 3:2). The sluggishness of insulin action and the attenuation in insulin concentration can be explained by a model in which transendothelial insulin transport is restricted and interstitial insulin binds to insulin-sensitive cells, where the hormone is internalized and degraded. Whether insulin transport occurs by a hormone-specific mechanism (i.e., via receptors on endothelial cells) was tested by comparing transport at physiological with pharmacological insulin concentrations-evidence supports a nonspecific mechanism of transport across endothelium (i.e., diffusion or transcytosis). Transendothelial transport alters the in vivo patterns of insulin signaling-biphasic plasma insulin after glucose injection is reflected in a simple, rapid increase in interstitial insulin to an elevated concentration. The time course of insulin's effect to suppress endogenous glucose output is a mirror image of its effect to enhance glucose uptake; however, there is no transendothelial barrier to insulin action at the liver. The similarity in action dynamics at periphery and liver was explained by a mechanism in which insulin crosses into peripheral tissue and alters a "second (blood-borne) signal" that, in turn, suppresses liver glucose production. Of various possible alternative candidates for the second signal, declining plasma free fatty acids appear to signal suppression of glucose production. We have proposed the "single gateway hypothesis" to explain insulin's action on carbohydrate metabolism in vivo: insulin crosses the endothelial boundary in skeletal muscle (to stimulate glucose disposal) and traverses the endothelial barrier in adipose tissue to suppress lipolysis. The declining free fatty acids are proposed to be a major factor in the insulin-mediated decline in glucose output. This mechanism can be contrasted with the classical concept that portal insulin controls the liver directly. Recent evidence supports the concept that, under normal levels of glucagonemia, less than 25% of the suppression of hepatic glucose output by insulin is due to a direct effect of insulin via the portal vein and that most of the effect (approximately 75%) is explained by the indirect single gateway mechanism. These results raise the question of whether hepatic insulin resistance in Type 2 diabetes can be explained by insulin resistance at the adipocyte, which causes a failure of reduction of FFA by insulin, leading to overproduction of glucose by the liver. The possible role of the single gateway mechanism in diabetes is under investigation.
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PMID:New concepts in extracellular signaling for insulin action: the single gateway hypothesis. 923 59

Gestational diabetes mellitus (GDM) is associated with much increased risk of developing diabetes later on in life. Using the frequently sampled intravenous glucose tolerance test and the minimal model analyses we have therefore determined the early insulin response to glucose (EIR) and insulin sensitivity (Si), in women with GDM of different severity (n = 14) and in normal women (n = 10). During the last trimester of pregnancy. GDMs compared to controls had significantly lower EIR (p < 0.001) and Si (p < 0.01). The reduction in EIR was less marked in GDM patients treated with diet alone (n = 6) as compared to GMD patients (n = 8) who subsequently during pregnancy needed treatment also with insulin. The insulin treated GDM group only had higher fasting glucose level than controls (5.2 vs 4.2 mmol/l, p < 0.001). Both GDM subgroups had slightly elevated basal levels of FFA and 3-hydroxybutyrate. Si and EIR were inversely correlated in control women and their fasting glucose correlated both to EIR (r = 0.63, p < 0.05) and to Si (r = 0.59, p < 0.05). In the GDM subgroups Si and EIR were unrelated and there were no correlations between fasting glucose and Si or EIR. These results suggest that glucose intolerance in GDM patients in the last trimester of pregnancy is characterized by both an impaired insulin secretion and an increased resistance to insulin. The impairment of insulin secretion and action increases with the severity of hyperglycemia, and the relative insulin deficiency characterizing GDM patients is associated with a selected defect in insulin action mainly affecting gluco-regulation.
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PMID:Insulin sensitivity and insulin response in women with gestational diabetes mellitus. 928 77

Interleukin 1beta (IL-1beta)-induced beta cell cytotoxicity has been implicated in the autoimmune cytotoxicity of insulin-dependent diabetes mellitus. These cytotoxic effects may be mediated by nitric oxide (NO). Since long-chain fatty acids (FFA), like IL-1beta, upregulate inducible nitric oxide synthase and enhance NO generation in islets, it seemed possible that islets might be protected from IL-1beta-induced damage by lowering their lipid content. We found that IL-1beta-induced NO production varied directly and islet cell viability inversely with islet triglyceride (TG) content. Fat-laden islets of obese rats were most vulnerable to IL-1beta, while moderately fat-depleted islets of food-restricted normal rats were less vulnerable than those of free-feeding normal rats. Severely lipopenic islets of rats made chronically hyperleptinemic by adenoviral leptin gene transfer resisted IL-1beta cytotoxicity even at 300 pg/ml, the maximal concentration. Troglitazone lowered islet TG in cultured islets from both normal rats and obese, leptin-resistant rats and reduced NO production and enhanced cell survival. We conclude that measures that lower islet TG content protect against IL-1beta-induced NO production and cytotoxicity. Leptin or troglitazone could provide in vivo protection against insulin-dependent diabetes mellitus.
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PMID:Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity. 931 73


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