Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with approximately two fold increase in coronary heart disease (CHD) in men and fourfold increase in CHD in women. In most studies, the duration of diabetes and severity of glycemia are only weakly related to CHD in NIDDM, suggesting that the prediabetic period may be important for the increased CHD in NIDDM subjects. Both hyperinsulinemia and/or insulin resistance predict the development of NIDDM. A number of studies have shown that increased cardiovascular risk factors (especially high triglyceride, blood pressure, and small dense low-density lipoprotein (LDL) and low high-density liproprotein (HDL) cholesterol) precede the onset of NIDDM. Recent data from the San Antonio Heart Study suggest that the atherogenic pattern of cardiovascular risk factors is more marked in prediabetic women than in prediabetic men, thus partially explaining the higher risk of CHD in prediabetic women than in prediabetic men. The atherogenic changes in cardiovascular risk factors appear to be mainly due to increased hyperinsulinemia and insulin resistance in nondiabetic subjects. Interventions to reduce cardiovascular disease in NIDDM subjects should emphasize the primary prevention of NIDDM and very aggressive treatment of traditional cardiovascular risk factors in prediabetic subjects. Treatment of hypertension and dyslipidemia in high-risk patients for NIDDM should avoid agents that further worsen insulin resistance (nicotinic acid, beta blockers, and thiazides), as subjects with hypertension and dyslipidemia are already at increased risk of NIDDM.
J Diabetes Complications
PMID:The prediabetic problem: development of non-insulin-dependent diabetes mellitus and related abnormalities. 910 90

A 34-year-old male with a history of angina pectoris suddenly developed weakness in the right upper and lower limbs, and consulted our hospital. Computed tomography (CT) and magnetic resonance imaging (MRI) suggested cerebral infarction. Cerebral angiography revealed stenosis at the M1 portion of the left middle cerebral artery. Hypertension, diabetes, tobacco or hyperlipidemia were not considered as risk factors for cerebral infarction. The lipoprotein (a) [Lp(a)] level was high. In the present case, medication with a nicotinic acid agent, niceritrol, for hyperlipoproteinemia and low density lipoprotein (LDL) apheresis were performed. Concerning family history, the patient's mother and younger sister had hyperlipoproteinemia. Recent studies have reported that increased Lp(a) levels are an independent risk factor even in cerebral infarction and coronary artery disease. Measurement of Lp(a) levels and treatment for increased Lp (a) levels may be important.
 ...
PMID:[Juvenile cerebral infarction with familial hyperlipoproteinemia (a)--case report]. 916 61

Islet amyloid polypeptide forms islet amyloid deposits in non-insulin-dependent diabetes mellitus. We have generated transgenic mice which express human islet amyloid polypeptide in their pancreatic beta cells yet do not develop islet amyloid deposits despite producing levels of the amyloidogenic human peptide 2 - 3 fold higher than the native (mouse) peptide. To determine whether marked overproduction of islet amyloid polypeptide is a potential cause of islet amyloid formation, we increased expression of this transgene by producing homozygous transgenic animals and by making heterozygous mice experimentally insulin resistant with nicotinic acid. Pancreatic content of islet amyloid polypeptide-like immunoreactivity in homozygous and nicotinic acid-treated mice was 2-fold (25 +/- 7 fmol/microg; n = 6) and 3.5-fold (47 +/- 20 fmol/microg; n = 3) higher, respectively, than that of untreated heterozygous animals (13+/-2 fmol/microg; n = 11; both p < 0.05). Despite this marked increase in production of islet amyloid polypeptide, neither group of mice developed gross islet amyloid deposits even after 16 months of age. We conclude that overproduction of islet amyloid polypeptide, even as produced by extreme insulin resistance, is not in itself sufficient for islet amyloid formation.
 ...
PMID:Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation. 923 Mar 54

The aim was to examine the feasibility and efficacy of a multifactorial risk factor intervention program in hypertensive patients at high cardiovascular risk. Treated hypertensive men, aged 50 to 72 years, with at least one of the following: serum cholesterol concentration > or = 6.5 mmol/L, diabetes mellitus, or smoking were randomized to multifactorial risk factor intervention (n = 253) or usual care (n = 255). The specific intervention was based on group meetings to encourage a lipid lowering diet and smoking cessation. Cholestyramine, nicotinic acid, fibrates, and later statins were used either as single drug therapy or in combination, following agreed guidelines in patients in whom the nonpharmacological intervention was judged to be insufficient. Usual care was given according to clinical practice. The median follow-up time was 6.6 years. Sixty-four patients (25.1%) died in the usual care group, compared with 41 patients (16.2%) in the intervention group (P = .016; 95% confidence interval, relative risk 0.42 to 0.92). The overall risk for fatal and nonfatal cardiovascular events was 29% lower in the intervention group than in the usual care group (P = .041). Relative to usual care, the intervention program lowered mean in-trial serum concentrations of total cholesterol (6.3%, P < .0001), LDL cholesterol (9.1%, P < .0001), and blood glucose (0.2 mmol/L, P < .05). Among smokers, at entry, cotinine-adjusted quit rates were 28% in the intervention group and 11% in the usual care group (P = .012) after 3 years. This study illustrates the very high cardiovascular risk in hypertensive patients 50 to 72 years of age with additional risk factors. The results indicate, however, that the gloomy prognosis may be improved by a dedicated risk factor intervention program.
 ...
PMID:Mortality rates in treated hypertensive men with additional risk factors are high but can be reduced: a randomized intervention study. 950 45

Subjects with diabetes have a greatly increased risk of CHD, which is only partially related to their elevated glucose. Other factors such as insulin resistance and dyslipidemia are likely to be important. The type of dyslipidemia that is most characteristic of type 2 diabetic subjects is elevated triglycerides and decreased HDL cholesterol levels, although all lipoproteins have compositional abnormalities. Surprisingly few good prospective studies of lipoprotein levels in relation to CHD have been done in diabetic subjects. Available studies suggest that low HDL cholesterol may be the most important risk factor for CHD in observational studies. In studies in which total cholesterol and triglyceride were done, cholesterol and triglycerides were risk factors for CHD, although triglycerides were often a stronger predictor. However, the strength of triglyceride as a risk factor for CHD may depend partially on its association with other variables (e.g., hypertension, plasminogen activator inhibitor 1 [PAI-1], etc.). In clinical trials in diabetic subjects, LDL reduction with statins has led to significant reductions in CHD incidence. In addition, overall mortality was reduced with statin therapy, although the results were not statistically significant. Gemfibrozil has led to reductions in CHD incidence in diabetic subjects, although the results were not statistically significant perhaps because of low sample size. Regarding lipoproteins and CHD risk in diabetic patients, the very positive results of statin trials point to LDL cholesterol being more important than previous realized. Apparently, having a borderline high LDL cholesterol (between 130 and 160 mg/dl) in a diabetic patient is equivalent to a much higher LDL cholesterol in terms of CHD risk for a nondiabetic subject. Therefore, the primary target of therapy in diabetic patients is lowering LDL cholesterol (or possibly, non-HDL cholesterol). Statins are the preferred pharmacological agent in this situation. Once LDL cholesterol levels have been lowered, attention can be given to treatment of residual hypertriglyceridemia and low HDL. The goal here is weight reduction and increased exercise. However, for selected patients, combining a fibric acid (or low-dose nicotinic acid) with a statin also can be considered. Reduction of LDL levels should take priority over reduction of triglycerides in combined hyperlipidemia because of the proven safety of the statin class of drugs as well as greater reduction in CHD incidence.
Diabetes Care 1998 Jan
PMID:Management of dyslipidemia in adults with diabetes. 953 88

The objective of this study was to determine whether basal plasma free fatty acid (FFA) concentrations affect basal insulin secretion rates (ISRs). Effects of FFA levels on basal ISRs were evaluated by lowering basal plasma FFA levels with nicotinic acid (NA) (100-150 mg p.o., q 30 min x 4 h) in type 2 diabetic patients and in normal volunteers. Lowering of FFAs (from approximately 600 to approximately 100 micromol/l) lowered ISRs in type 2 diabetic patients during isoglycemic clamping (from 139 to 101 pmol/min; -23%; P < 0.02) and euglycemic clamping (from 99 to 63 pmol/min; -36%; P < 0.03) and in normal subjects during euglycemic clamping (from 127 to 96 pmol/min; -25%; P < 0.03). In addition, peripheral insulin concentrations decreased by approximately 30% in diabetic and nondiabetic subjects. NA had no direct effect on ISRs; that is, NA did not change ISRs when plasma FFAs were prevented from decreasing with a lipid/heparin infusion. We concluded that 1) basal plasma FFAs exerted physiologically important, long-lasting effects supporting 25-33% of basal insulin secretion in nondiabetic and diabetic subjects; 2) basal plasma FFAs were responsible for some of the hyperinsulinemia in normoglycemic obese subjects; and 3) NA had no direct effect on insulin secretion.
Diabetes 1998 Oct
PMID:Acute lowering of plasma fatty acids lowers basal insulin secretion in diabetic and nondiabetic subjects. 975 99

In the fasted rat, efficient glucose-stimulated insulin secretion (GSIS) is absolutely dependent on an elevated level of circulating free fatty acids (FFAs). To determine if this is also true in humans, nonobese volunteers were fasted for 24 h (n = 5) or 48 h (n = 5), after which they received an infusion of either saline or nicotinic acid (NA) to deplete their plasma FFA pool, followed by an intravenous bolus of glucose. NA treatment resulted in a fall in basal insulin concentrations of 35 and 45% and in the area under the insulin response curve (area under the curve [AUC]) to glucose of 47 and 42% in the 24- and 48-h fasted individuals, respectively. The 48-h fasted subjects underwent the same procedure with the addition of a coinfusion of Intralipid plus heparin (together with NA) to maintain a high concentration of plasma FFAs throughout the study. The basal level and AUC for insulin were now completely normalized (C-peptide profiles paralleled those for insulin). To assess the effect of an overnight fast, nonobese (n = 6) and obese (n = 6) subjects received an infusion of either saline or NA, followed by a hyperglycemic clamp (200 mg/dl). The insulin AUC in response to glucose was unaffected by lowering of the FFA level in nonobese subjects, but fell by 29% in the obese group. The data clearly demonstrate that in humans, the rise in circulating FFA levels after 24 and 48 h of food deprivation is critically important for pancreatic beta-cell function both basally and during subsequent glucose loading. They also suggest that the enhancement of GSIS by FFAs in obese individuals is more prominent than that seen in their nonobese counterparts.
Diabetes 1998 Oct
PMID:Circulating fatty acids are essential for efficient glucose-stimulated insulin secretion after prolonged fasting in humans. 975

Uncoupling proteins 3 and 2 (UCP3 and UCP2) are two newly cloned genes that have been implicated in the regulation of lipids as fuel substrate in skeletal muscle on the basis that their mRNA expressions are upregulated during starvation (when fat stores are being rapidly mobilized) and downregulated during the early phase of refeeding (when fat stores are being rapidly replenished). To test the hypothesis that circulating free fatty acids (FFAs) may have a physiological role as an interorgan signal linking these dynamic changes in the fat stores to skeletal muscle expression of UCP3 and UCP2, the mRNA levels of these UCP homologs were examined in fed and fasted rats treated with the antilipolytic agent nicotinic acid. In 46-h fasted rats, we observed a threefold increase in serum FFA levels and increases in UCP3 and UCP2 mRNA levels that were more marked in the gastrocnemius and tibialis anterior muscles (predominantly fast-twitch fibers) than in the soleus muscle (predominantly slow-twitch fibers). Treatment with nicotinic acid blunted the fasting-induced increase in serum FFA levels and prevented the increase in mRNA levels of UCP3 and UCP2 in the soleus muscle, but had little or no effect on the elevated mRNA levels of these UCP homologs in the gastrocnemius and tibialis anterior muscles. Furthermore, treatment of ad libitum-fed animals with nicotinic acid resulted in a twofold reduction in serum FFA levels (i.e., by a magnitude similar to that observed during early refeeding) and significant reductions in UCP3 and UCP2 mRNA levels in the soleus muscle, but not in the gastrocnemius or tibialis anterior muscles. These results revealed a muscle-type dependency in the way UCP2 and UCP3 gene expression in skeletal muscle is regulated, and suggest that the hypothesis that circulating FFAs function as an interorgan signal between fat stores and skeletal muscle UCP3 and UCP2 gene expression is adequate only for slow-twitch (oxidative) muscles. Consequently, a signal(s) other than circulating FFAs must be implicated in the link between dynamic changes in body fat stores and UCP expression in predominantly fast-twitch (glycolytic/oxidative-glycolytic) muscles, which constitute the major fiber type of the total skeletal muscle mass and which have high susceptibility to developing insulin resistance and impairment in substrate utilization in metabolic diseases.
Diabetes 1998 Nov
PMID:Interorgan signaling between adipose tissue metabolism and skeletal muscle uncoupling protein homologs: is there a role for circulating free fatty acids? 979 37

The electrical activity of pancreatic beta-cells in 48-h fasted mice has been recorded in vivo. Their electrical activity is exceedingly high at low levels of blood glucose when compared with control animals. For example, at a blood glucose concentration of 4.5 mmol/l, at which beta-cells are permanently hyperpolarized in control animals, fasted animals show continuous spiking activity. In fasted animals, hyperpolarization only occurs at glycemias below 2.2 mmol/l. As in fed animals, the electrical activity in fasted mice can be decreased or suppressed by the injection of diazoxide, indicating the participation of K(ATP) channels. The treatment of fasted animals with nicotinic acid, an inhibitor of lipolysis, produces a decrease in the levels of free fatty acids (FFAs) and a decrease in electrical activity, thereby restoring the dose-response curve for glucose in fasted animals to values close to those found in fed animals. Conversely, the injection of palmitic acid produces an increase in electrical activity without a change in blood glucose. These results point to FFAs as important regulators of electrical activity during fasting in vivo. They also indicate a dissociation of electrical activity and insulin release in fasted animals, since an increase in electrical activity is not associated with increased insulin secretion.
Diabetes 1998 Nov
PMID:Increased levels of free fatty acids in fasted mice stimulate in vivo beta-cell electrical activity. 979 39

Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.
 ...
PMID:Diabetic dyslipidemia. 991 65


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>