Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0028754 (obesity)
124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fasting serum total immunoreactive insulin (IRI), true insulin, and true proinsulin (PI) were measured in 169 Pima Indians. The relationship of these variables to glucose tolerance, obesity, and parental diabetes was studied. Seventy-seven subjects had normal glucose tolerance, 46 had impaired glucose tolerance (IGT), and 46 had noninsulin-dependent diabetes mellitus (NIDDM) by WHO criteria. In subjects with normal glucose tolerance, the geometric mean ratio of PI to IRI (PI/IRI) was 10.8% (arithmetic mean, 12.5%), similar to that reported in other ethnic groups with lower prevalence rates of NIDDM. Parental diabetes had no effect on PI/IRI. Obese persons (body mass index, greater than or equal to 27 kg/m2) with normal glucose tolerance had PI/IRI of 9.3% compared with 16.3% for the nonobese (P less than 0.001), and PI/IRI was negatively correlated with body mass index (r = -0.34; P = 0.002). Proinsulin was disproportionately elevated in NIDDM (geometric mean PI/IRI, 19.9%; arithmetic mean, 23.6%), and the degree of elevation was related to the severity of hyperglycemia, but not the duration of diabetes. Subjects with IGT were more obese and had higher fasting plasma glucose (5.7 vs. 5.2 mmol/L; P = 0.025), true insulin (250 vs. 125 pmol/L; P less than 0.001), and PI concentrations (26 vs. 15 pmol/L; P less than 0.001) than those with normal glucose tolerance but similar mean PI/IRI (9.4 vs. 10.8%; P = 0.4). These findings indicate that Pima Indians with NIDDM have a disproportionate elevation of PI consistent with the hypothesis that beta-cell dysfunction associated with hyperglycemia leads to the release of proinsulin-rich immature granules.
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PMID:Disproportionately elevated proinsulin in Pima Indians with noninsulin-dependent diabetes mellitus. 218 54

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.
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PMID:Management of dyslipidemia in NIDDM. 219 Jul 70

Many clinical studies have shown an increased insulin response to oral glucose in patients with ischemia of the heart, lower limbs, or brain. Hyperinsulinemia also occurs in patients with angiographically proved atherosclerosis without ischemia and thus appears to be related to arterial disease and not to be a nonspecific response to tissue injury. Fasting insulin levels and insulin responses to intravenous stimuli, including glucose, tolbutamide, and arginine, are normal, suggesting a gastrointestinal factor may be involved in the increased insulin response to oral glucose. In patients with atherosclerosis, insulin sensitivity appears to be normal or enhanced with respect to both glucose and lipid metabolism. Five population studies have shown that insulin responses to glucose are higher in populations at greater risk of cardiovascular disease. Many of the hyperinsulinemic populations also had upper-body obesity, hypertriglyceridemia, lower high-density lipoprotein (HDL) levels, and hypertension. These prospective studies support an independent association between hyperinsulinemia and ischemic heart disease, although their results differ in detail. Hyperinsulinemia is associated with raised triglyceride and decreased HDL cholesterol levels. Total and low-density lipoprotein (LDL) cholesterol is less closely related to hyperinsulinemia. Upper-body adiposity is associated (in separate studies) with coronary heart disease, diabetes, hyperinsulinemia, and hypertriglyceridemia. Insulin and blood pressure are closely related in both normotensive and hypertensive people. Although obesity and diabetes are often found in hypertensive people, hyperinsulinemia also occurs in nonobese nondiabetic hypertensive people. Thus, hyperinsulinemia is closely associated with a cluster of cardiovascular risk factors, i.e., hypertriglyceridemia, low HDL levels, hypertension, hyperglycemia, and upper-body obesity. There is a possibility that insulin has a role in the sex differences in ischemic heart disease incidence and their absence in diabetes, but additional work is required for its clarification. Long-term treatment with insulin results in lipid-containing lesions and thickening of the arterial wall in experimental animals. Insulin also inhibits regression of diet-induced experimental atherosclerosis, and insulin deficiency inhibits the development of arterial lesions. Insulin stimulates lipid synthesis in arterial tissue; the effect of insulin is influenced by hemodynamic factors and may be localized to certain parts of the artery. In physiological concentrations, insulin stimulates proliferation and migration of cultured arterial smooth muscle cells but has no effort on endothelial cells cultured from large vessels. Insulin also stimulates cholesterol synthesis and LDL binding in both arterial smooth muscle cells and monocyte macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin and atheroma. 20-yr perspective. 199 42

The kinetics of in vivo insulin-mediated glucose uptake in human obesity have not been previously studied. To examine this, we used the glucose-clamp technique to measure whole-body and leg muscle glucose uptake in seven lean and six obese men during hyperinsulinemia (approximately 2000 pM) at four glucose levels (approximately 4.5, approximately 8.3, approximately 13.5, and approximately 23.5 mM). To measure leg glucose uptake, the femoral artery and vein were catheterized, and blood flow was measured by thermodilution (leg glucose uptake = arteriovenous glucose difference x blood flow). With this approach, we found that rates of whole-body and leg glucose uptake were significantly lower in obese than in lean subjects at each glucose plateau. Leg blood flow rates increased from 4.3 +/- 0.4 to 6.5 +/- 0.8 dl/min over the range of glucose in lean subjects (P less than 0.05) but remained unchanged in obese subjects. The apparent maximal capacity (Vmax), based on whole-body and leg glucose uptake, was reduced in obese compared with lean subjects, but the apparent Km was similar in the lean and obese subjects (6-9 mM, NS). To assess the affinity of muscle for glucose extraction independent of changes in muscle plasma flow, we determined the mean half-maximal effective glucose concentration (EG50) and found it was similar in the lean and obese subjects (6.0 +/- 0.3 vs. 6.0 +/- 0.8 mM, NS). We conclude that 1) the kinetics of in vivo insulin-mediated glucose uptake in skeletal muscle in human obesity are characterized by reduced Vmax but normal Km; 2) the EG50 for insulin-mediated glucose extraction in skeletal muscle was 6 mM in both lean and obese subjects, consistent with a Km characteristic of the glucose-transport system; 3) obese subjects were unable to generate increases in blood flow in response to hyperglycemia under hyperinsulinemic conditions, and this contributed significantly to lower rates of leg and whole-body glucose uptake.
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PMID:Kinetics of in vivo muscle insulin-mediated glucose uptake in human obesity. 219 40

Diabetes develops spontaneously in some, but not all, obese middle-aged monkeys. Longitudinal study of spontaneously obese rhesus monkeys has now shown the separation in time of the onset of various abnormalities associated with non-insulin-dependent diabetes mellitus (NIDDM). Glucose tolerance and acute and late insulin release were assessed at 6-mo to 1-yr intervals over a period of 7 yr in six young, lean, normal animals and 14 middle-aged obese, initially normoglycemic monkeys. Over 2-5 yr, while under study, five of the obese subjects developed overt diabetes [fasting plasma glucose greater than 140 mg/dl and decreased glucose disappearance rates (KG) less than 1.5]. Progressively increasing hyperinsulinemia leading to a 10-fold increase in basal plasma insulin levels (mean +/- SE = 443 +/- 69 microU/ml) and a fivefold increase in insulin response to glucose occurred independent of degree of obesity and before hyperglycemia. Later, basal and stimulated insulin levels declined before significant hyperglycemia. We conclude that in the monkey beta-cell function is clearly enhanced, not reduced, in the earliest stages of the progression to NIDDM but is reduced just before overt diabetes.
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PMID:Beta-cell hyperresponsiveness: earliest event in development of diabetes in monkeys. 220 82

To investigate the time course of glucose metabolism in obesity 33 patients (21 to 69 years old; body mass index [BMI], 25.7 to 53.3 kg/m2) with different degrees of glucose intolerance or diabetes who had been studied initially and 6 years later were submitted to the same 100-g oral glucose tolerance test (OGTT) with indirect calorimetry. From a group of 13 obese subjects with normal glucose tolerance (NGT), four developed impaired glucose tolerance (IGT); from a group of nine patients with IGT, three developed non-insulin-dependent diabetes mellitus (NIDDM); five of six obese NIDDM subjects with high insulin response developed NIDDM with low insulin response. Five patients had diabetes with hypoinsulinemia initially. As previously seen in a cross-sectional study, the 3-hour glucose storage measured by continuous indirect calorimetry remained unaltered in patients with IGT, whereas it decreased in NIDDM patients. A further decrease in glucose storage was observed with the lowering of the insulin response in the previously hyperinsulinemic diabetics. These results confirm cross-sectional studies that suggest successive phases in the evolution of obesity to diabetes: A, NGT; B, IGT (the hyperglycemia normalizing the glucose storage over 3 hours); C, diabetes with increased insulin response, where hyperglycemia does not correct the resistance to glucose storage anymore; and D, diabetes with low insulin response, with a low glucose storage and an elevated fasting and postload glycemia.
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PMID:Impaired glucose tolerance and diabetes in obesity: a 6-year follow-up study of glucose metabolism. 221 53

The majority of patients with diabetes mellitus can be classified as suffering from either Type 1 or Type 2 diabetes. The pathogenetic pathways for these two categories of diabetes appear to be distinct and separate. Both forms of diabetes have a genetic as well as environmental component in their pathogenesis. Type 1 diabetes has a weaker genetic link; its association with HLA antigens is well established. Type 2 diabetes has a stronger genetic association but the exact gene or genes responsible is unknown. The environmental trigger in Type 1 diabetes may be a viral infection while urbanisation, obesity, physical inactivity and stress may trigger the development of Type 2 diabetes. Type 1 diabetes is a chronic autoimmune disease where beta cell destruction may occur over a number of years before clinical diabetes is diagnosed. Type 2 diabetes is the result of an interplay of relative insulin deficiency or a defect in insulin release together with insulin resistance. Hyperglycaemia perpetuates the problem of beta cell defect and insulin resistance. The understanding of pathogenesis of diabetes is the key to prevention and treatment of diabetes mellitus.
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PMID:Pathogenesis of type 1 and type 2 diabetes mellitus. 222 10

There are three major obstacles to a recommendation for screening the elderly for NIDDM. The first is the conflicting evidence as to whether early detection and treatment reduce complications. The second is that treatment of hyperglycemia with attainment of euglycemia is difficult to achieve in the elderly. Nondrug therapy often fails because of lifelong eating habits, denture problems, fixed income, and physical handicaps. Drug therapy is fraught with the dangers of hypoglycemia and drug interactions. Compliance with therapy often is poor and leads to conflicts between physician and patient that may be detrimental in the treatment of other diseases in which intervention has proven worthwhile. The third obstacle is the lack of data regarding the adverse effects of labeling and noncompliance issues in the face of a positive screening test. Because obesity is a risk factor for NIDDM and hypertension in conjunction with NIDDM leads to atherosclerosis, screening and treatment for these two conditions are warranted whether or not NIDDM is present concurrently. Medicine is in a dynamic state of flux and, undoubtedly, conflicts over the benefits of early treatment and patient compliance will be resolved. Until then, there is no justification for screening for NIDDM in the elderly.
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PMID:Screening for non-insulin-dependent diabetes mellitus in the elderly. 222 50

Hyperglycemia is only one of several metabolic derangements that are prevalent in diabetes mellitus. Of these, hyperlipidemia, obesity, and co-existent hypertension may make more important contributions to complications than persistently elevated blood sugars. The role of hyperglycemia in the genesis of diabetic complications is uncertain and there is little evidence from prospective randomized controlled studies to support rigorous hypoglycemic treatment. Adverse consequences of pharmacologic therapy can be severe, including death, and are most frequent in the elderly. The group of elderly diabetic ambulatory patients is markedly heterogeneous and individualization of therapy is required. Obese persons require dietary therapy, and additional dietary manipulations are needed for patients with the complications of hyperlipidemia, hypertension, and nephropathy. Pharmacologic hypoglycemic therapy may be required to control symptoms, but its use in asymptomatic diabetic persons is for the most part unwarranted.
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PMID:Glycemic control in elderly people with diabetes. 222 56

Because basal hyperglycemia is a major feature in non-insulin-dependent diabetes mellitus, diabetes control can be monitored by the fasting blood glucose concentration. A hierarchical sequence of therapies is proposed in which the major aim is to maintain near-normal fasting blood glucose concentrations, in the expectation that this will help prevent development of long-term complications. When diet and tablet therapy are no longer effective in keeping the fasting blood glucose level less than 6 mM, a basal insulin supplement from a long-acting insulin such as ultralente can be added. When monitored by fasting blood glucose concentration, there is little risk of hypoglycemia, and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. A basal insulin supplement does not induce marked weight gain. The dose of insulin required can be predicted from the level of the fasting blood glucose and the degree of obesity, which provides an index of the accompanying insulin resistance. Based on current evidence, insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance, because the benefit from maintaining near-normal glucose concentrations probably outweighs a putative risk of hyperinsulinemia. In more severely affected patients, additional regular insulin to cover meals is needed. Lowering fasting blood glucose to normal with a basal insulin supplement reduces endogenous insulin production, and this may be advantageous if accompanying production of islet amyloid polypeptide and islet amyloid formation are also reduced.
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PMID:Insulin use in NIDDM. Rationale based on pathophysiology of disease. 222 8


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