UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
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Type 2 diabetes is a familial disease, but recent analysis of nuclear families indicates it is unlikely to be due to a single dominant gene with high penetrance and that it could be polygenic. Insulin resistance is a major feature, with obesity being a major determinant. Beta cell deficiency is a sine qua non of Type 2 diabetes. It is possible that obesity, insulin resistance independent from obesity and impaired beta cell function are independently inherited factors. None of these can be said to be 'primary' as diabetes usually results from the interaction of several geometric and environmental factors. This makes linkage analysis of Type 2 diabetes of uncertain benefit, since heterogeneity can occur within a pedigree. The only mutation so far discovered is of glucokinase producing maturity-onset diabetes of the young, that has a clearly defined and unusual phenotype. Identification of genes that cause classical Type 2 diabetes is likely to come from population association studies, molecular scanning techniques and direct sequencing of candidate genes rather than linkage analysis.
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PMID:Type II diabetes: search for primary defects. 148 47

Twenty obese and 20 lean LA/N-cp male rats and 20 male Sprague-Dawley rats were fed a diet containing either 54 percent sucrose or starch for six weeks. After a 14-16 hour fast, rats were killed. Liver and kidney enzyme activities were determined in the LA/N-cp rats while plasma urea and selected amino acids were determined in all rats. Liver glucose-6-phosphatase (G6PASE), fructose-1,6-bisphosphatase (FBPASE), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malic enzyme (ME), glucokinase (GK), pyruvate kinase (PK), phosphofructokinase (PFK), glutamic-oxaloacetic-transaminase (GOT), glutamic-pyruvic transaminase (GPT), arginase (ARGASE), arginine-synthase (ARG-SYN) and ornithine transcarbamylase (OTC) levels were significantly affected by phenotype (obese greater than lean). All the above changes in enzyme levels were exaggerated by sucrose-feeding with the exception of PK, PFK, GOT, GPT, ARGASE and ARG-SYN. Kidney cortex G6PASE, PEPCK and ARGASE activities were higher in the obese rats as compared to the lean littermates. Sucrose feeding resulted in higher cortex G6PASE, FBPASE and PEPCK as compared to starch-fed rats. A phenotype effect was noted with plasma glutamate, urea, leucine, isoleucine and valine (obese greater than lean) and a diet effect was seen with aspartate, phenylalanine, leucine and valine (sucrose greater than starch) concentration. Sprague-Dawley rats had higher plasma urea and lower alanine than lean LA/N-cp males. Metabolic obesity in the LA/N-cp rat appears to involve an elevated capacity for pathways of glycolysis, gluconeogensis, lipogenesis and amino acid catabolism in the liver.
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PMID:Effect of dietary carbohydrate on liver and kidney enzyme activities and plasma amino acids in the LA/N-cp rat. 204 12

Substrate cycles (SC) are formed by a 'forward pathway' (FP) and a 'backward pathway' (BP), the difference between FP and BP forming the 'metabolic flux' (MF) through the route of which the cycle is part. SC modulate regulatory effects, i.e. amplify or reduce the % change in MF compared to the % change in FP and BP, thus affecting the sensitivity to regulatory factors, including hormones. A formula is given to calculate (with an approximation of +/- 0.5) the 'flux response index' (FRI), i.e. the factor by which the % change in FP plus the % change in BP must be multiplied to obtain the % change in metabolic flux, when FP and BP undergo opposite, non-unidirectional changes (as is often the case in metabolic regulation). The formula is: FRI = [( FP + BP)/(FP-BP)]/2. By this formula we evaluated the hepatic activities of glucose-6-phosphatase and glucokinase (which roughly reflect hepatic glucose production and uptake, respectively), i.e. the two enzymes that catalyze the cycle between glucose-6-phosphate (glucose-6-P) and glucose. Based on data obtained in normal, nonobese diabetic and obese diabetic subjects as well as in normal, streptozotocin-diabetic, and obese diabetic (ob/ob) mice, we found that FRI was reduced in non-obese diabetic humans and animals whereas it was increased in obese-diabetic humans and mice, compared to normal controls. Thus, diabetes without obesity decreases, and obesity with diabetes increases, the sensitivity of the glucose-6-P/glucose cycle to regulatory agents.
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PMID:A formula for quantifying the effects of substrate cycles (futile cycles) on metabolic regulation. Its application to glucose futile cycle in liver as studied by glucose-6-phosphatase/glucokinase determinations. 215 82

The aim of this study was to investigate the metabolic effects of short-term fasting in obese diabetic patients and to correlate the observed changes with the activity of hepatic key enzymes in an animal model of obesity-associated diabetes (ob/ob mice, C57BL/6J strain). In obese diabetic patients (ODP), a 72-h fast (causing slight change in body weight) decreased fasting glycemia by 3.82 +/- 0.79 mmoles/l and significantly improved glucose tolerance (OGTT) while reducing basal and stimulated insulinemia, whereas in obese non-diabetic patients (ONDP) only a small decrease in fasting glycemia (1.24 +/- 0.51 mmoles/l) occurred. This suggests that in ODP hyperphagia is a factor contributing to maintain hyperglycaemia and glucose intolerance (in the face of hyperinsulinaemia, indicating insulin resistance). In fed obese hyperglycaemic mice (OHM), which are a good model of the human obesity-associated diabetes, hepatic fructose-1,6-diphosphatase (F16Pase) and glucose-6-phosphatase (G6Pase), involved in glucose production, showed increased activity (+52 and +200 per cent, respectively) compared to control mice (CM), and the ratios of F16Pase and G6Pase to the opposing enzymes phosphofructokinase (PFK1) and glucokinase (GK), i.e. the F16Pase/PFK1 and G6Pase/GK ratios, were increased by 38 and 101 per cent, respectively, suggesting increase in gluconeogenesis and perhaps in glycogenolysis. In the 48-h fasted OHM, F16Pase activity was decreased (-30 per cent) compared to the fed animals, while the activity of G6Pase showed a smaller and statistically not significant change (-22 per cent). In contrast, in the CM a 48-h fasting was associated with a trend toward increased F16Pase (+22 per cent) and G6Pase (+173 per cent). However, since PFK1 and GK decreased to a similar extent in OHM and CM, the F16Pase/PFK1 and G6Pase/GK ratios, basally elevated in the OHM, did not change with fasting, whereas in the CM they showed a striking elevation (+71 and +274 per cent, respectively). The basally elevated F16Pase/PFK1 and G6Pase/GK ratios (functionally linked to glucose production) in the OHM may contribute to maintain hyperglycaemia; in these mice, the lack of further increase in the glucose production-related F16Pase/PFK1 and G6Pase/GK ratios (which occurs in CM) with fasting might allow that the interruption of the afflux of dietary carbohydrates ameliorates the glycaemic level. Similar mechanisms might occur also in the ODP.
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PMID:Metabolic effects of short-term fasting in obese hyperglycaemic humans and mice. 283 Nov 63

Glucose cycling (GC; G in equilibrium G6P) equals 14% of glucose production in postabsorptive man. Our aim was to determine glucose cycling in six lean and six overweight mild type II diabetics (fasting glycemia: 139 +/- 10 and 152 +/- 7 mg/dl), in postabsorptive state (PA) and during glucose infusion (2 mg/kg per min). 14 control subjects were weight and age matched. GC is a function of the enzyme that catalyzes the reaction opposite the net flux and is the difference between hepatic total glucose output (HTGO) (2-[3H]glucose) and hepatic glucose production (HGP) (6-[3H]-glucose). Postabsorptively, GC is a function of glucokinase. With glucose infusion the flux is reversed (net glucose uptake), and GC is a function of glucose 6-phosphatase. In PA, GC was increased by 100% in lean (from 0.25 +/- 0.07 to 0.43 +/- .08 mg/kg per min) and obese (from 0.22 +/- 0.05 to 0.50 +/- 0.07) diabetics. HGP and HTGO increased in lean and obese diabetics by 41 and 33%. Glucose infusion suppressed apparent phosphatase activity and gluconeogenesis much less in diabetics than controls, resulting in marked enhancement (400%) in HTGO and HGP, GC remained increased by 100%. Although the absolute responses of C-peptide and insulin were comparable to those of control subjects, they were inappropriate for hyperglycemia. Peripheral insulin resistance relates to decreased metabolic glucose clearance (MCR) and inadequate increase of uptake during glucose infusion. We conclude that increases in HGP and HTGO and a decrease of MCR are characteristic features of mild type II diabetes and are more pronounced during glucose infusion. There is also an increase in hepatic GC, a stopgap that controls changes from glucose production to uptake. Postabsorptively, this limits the increase of HGP and glycemia. In contrast, during glucose infusion, increased GC decreases hepatic glucose uptake and thus contributes to hyperglycemia. Obesity per se did not affect GC. An increase in glucose cycling and turnover indicate hepatic insulin resistance that is observed in addition to peripheral resistance. It is hypothesized that in pathogenesis of type II diabetes, augmented activity of glucose-6-phosphatase and kinase may be of importance.
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PMID:Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity. 329 Feb 57

Metabolic alterations in ventromedial hypothalamus (VMH)-lesioned rats were investigated by examining daily changes of enzyme activities and urea concentrations three weeks after the operation. VMH-lesions in female adult rats caused a significant elevation in the activity of acetyl-CoA carboxylase in the liver and parametrial adipose tissue. These changes suggest an increased lipogenesis. VMH-lesions also elicited an increase in activities of glucokinase (GK), pyruvate kinase (PK) and fructose 1,6-bisphosphatase (FBPase), and a decrease in activities of phosphofructokinase (PFK), glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver. The apparently inconsistent changes in activities of key glycolytic enzymes, GK, PK and PFK, and key gluconeogenic enzymes, G6Pase, PEPCK and FBPase in the liver may be explained by the fact that they were favorable for glucose oxidation through pentose phosphate cycle and provide NADPH for lipogenesis in the liver. Furthermore, VMH-lesions induced an increase in urea contents of the liver and serum, and elicited an increase in activity of liver tyrosine aminotransferase (TAT) and a decrease in activity of liver histidase. These changes suggest an accelerated amino acid and protein catabolism, and favor an increment in the supply of the substrate for lipogenesis. Daily rhythms of TAT, histidase activities and serum urea concentration observed in the control rats were abolished by VMH-lesions. These findings suggest that VMH-lesions elicit the loss of these daily rhythms, probably through the disturbance of the circadian rhythm of feeding behavior at this dynamic phase (three weeks after operation) of obesity.
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PMID:Shift of metabolism in rats with ventromedial hypothalamic lesions with respect to changes in daily rhythms of enzyme activity. 614 67

The specific activity of hepatic glucokinase (ATP: D-glucose 6-phosphotransferase, EC 2.7.1.2) in db/db mice and ob/ob mice was higher than in normal mice. All enzymes had a similar Km and, thus, the difference in activity was not due to differences in the affinity of enzyme molecules to substrates. Mixing liver extracts with high or low enzyme activities yielded additive results, as expected, which ruled out the involvement of an inhibitor or activator of the enzyme. Fasting normal mice of either strain for three days decreased glucokinase activity. However, fasting db/db or ob/ob mice for as long as 10 days had no effect on enzyme activity, indicating that glucokinase in db/db or ob/ob mice was out of regulation or constitutive. The constant, abnormally high glucokinase activity may be a contributing factor to the obesity of ob/or or db/db mice. These mice provide a model system to study the regulation of this rate-limiting enzyme of glucose metabolism.
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PMID:Constitutive hepatic glucokinase activity in db/db and ob/ob mice. 701 1

This chapter focuses on the biochemical mechanisms that mediate glucose-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summarize evidence supporting the idea that glucose metabolism is required for GSIS and that the GLUT-2 facilitated glucose transporter and the glucose phosphorylating enzyme glucokinase play important roles in measuring changes in extracellular glucose concentration. The idea that glucose metabolism is linked to insulin secretion through a sequence of events involving changes in ATP:ADP ratio, inhibition of ATP-sensitive K+ channels, and activation of voltage-gated Ca2+ channels is critically reviewed, and the relative importance of ATP generated from glycolytic versus mitochondrial metabolism is evaluated. We also present the growing concept that an important signal for insulin secretion may reside at the linkage between glucose and lipid metabolism, specifically the generation of the regulatory molecule malonyl CoA that promotes fatty acid esterification and inhibits oxidation. Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term exposure of islets to high levels of fatty acids results in beta-cell dysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insulin-dependent diabetes mellitus (NIDDM).
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PMID:Metabolic coupling factors in pancreatic beta-cell signal transduction. 757 98

The clinical characteristics of subjects with a missense glucokinase mutation, gly299-->arg, were studied in a large pedigree, BX, initially characterized by some members having Maturity Onset Diabetes of the Young (MODY). Glucose tolerance, beta cell function and insulin sensitivity were measured with Homeostasis Model Assessment (HOMA) and with a 'Continuous Infusion of Glucose with Model Assessment' (CIGMA) test. Diabetic complications were clinically assessed. Subjects with glucokinase gly299-->arg were the same age, height, and obesity as the subjects without the mutation. Diabetes was usually asymptomatic at diagnosis and was treated with diet alone in 15 of the 18 subjects. Five of the 11 adult females had been diagnosed when they developed gestational diabetes. The fasting plasma glucose concentrations at the time of study were 4.3-12.6 mmol l-1, with the higher levels being in the more obese (p < 0.05) and in the older subjects (p < 0.05). In subjects with the mutation, beta cell function was impaired, being geometric mean 63% (normal-100%) compared with 126% in the subjects without the mutation (p < 0.001) measured by HOMA and in a subset assessed by CIGMA 59% and 127% (p < 0.01), respectively. There was no difference in fasting insulin concentrations, insulin sensitivity, lipid concentrations or blood pressure between the groups. The haemoglobin A1c was raised (mean 6.5% compared with 5.5% in the subjects without the mutation), but microvascular and macrovascular complications were uncommon. The subjects with the mutation did not have microalbuminuria but had an impaired vibration perception threshold compared with subjects without the mutation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical characteristics of subjects with a missense mutation in glucokinase. 775 56

Pancreatic insulin secretion rates can be accurately derived by mathematical deconvolution of peripheral C-peptide concentrations either by using individual C-peptide kinetic parameters obtained by analysis of the decay curve of biosynthetic human C-peptide or by using published group parameters with appropriate adjustments for age and degree of obesity. Since the cross-reactivity of proinsulin and related peptides is low (< 10%) in many C-peptide assays, this experimental approach avoids the spurious increase in insulin immunoreactivity resulting from cross-reactivity with proinsulin and related peptides in the insulin assay. Application of this technique has demonstrated that the phenotypic expression of beta-cell dysfunction differs in subjects with different genetic mechanisms of non-insulin-dependent diabetes mellitus (NIDDM). Subjects who have maturity-onset diabetes of the young (MODY) due to mutations in the glucokinase gene demonstrate different patterns of altered insulin secretion when compared with subjects who have mutations in the MODY1 gene on chromosome 20. Glucokinase mutations affect the ability of the beta-cell to detect and respond to small increases in glucose above the basal level. However, compensatory mechanisms operative in vivo, which include a priming effect of glucose on insulin secretion, limit the severity of the observed insulin secretory defect, resulting in a generally mild clinical course in these subjects. In contrast, mutations in the MODY1 gene are associated with an inability to increase insulin secretion as the plasma glucose concentration increases above 7-8 mmol/l and the normal priming effect of glucose on insulin secretion is lost. These characteristics of the dose-response relationships between glucose and insulin secretion result in a more severe degree of hyperglycemia than observed in subjects with glucokinase mutations, and these subjects more frequently need insulin treatment. These alterations are evident in prediabetic subjects with normal glucose levels who carry the MODY1 mutation, suggesting that defective beta-cell function is the primary pathogenetic defect in the diabetic syndrome in these subjects. Studies performed in the classic form of NIDDM demonstrate that subjects with mild glucose intolerance and normal fasting glucose concentrations and glycosylated hemoglobin levels consistently demonstrate defective beta-cell function. These results are consistent with studies in the Zucker diabetic fatty rat, an animal model of NIDDM in which prediabetic animals demonstrate extensive alterations in expression of multiple genes involved in the regulation of insulin secretion. It thus appears that abnormal beta-cell function is present at a relatively early stage in the evolution of NIDDM, even before the onset of overt hyperglycemia.
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PMID:Lilly Lecture 1994. The beta-cell in diabetes: from molecular genetics to clinical research. 778 37

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