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A Vaag

Publications and source records attributed to A Vaag.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hyperglycaemia enhances renal magnesium excretion in type 1 diabetic patients.

Magnesium depletion is a common feature of diabetes mellitus, apparently related to glycaemic control. The aim of the study was to investigate the isolated effect of hyperglycaemia upon renal magnesium excretion. Urinary magnesium excretion rates were measured in 10 patients with Type 1 diabetes mellitus on two different days with different levels of blood glucose concentration but equal plasma insulin concentration. On a hyperglycaemic day, an i.v. infusion of 20% glucose was started at the end of a euglycaemic baseline period, increasing blood glucose concentration from 5.3 mmol/L to 12.3 mmol/L. There was no major glucosuria. On the hyperglycaemic day the renal magnesium excretion and clearance were raised by a factor of 2.4 compared to the euglycaemic day. Plasma magnesium concentration decreased 3% during hyperglycaemia. In conclusion, blood glucose excursions influence magnesium homeostasis independently of insulin levels in Type 1 diabetic patients. This effect is primarily due to an increased renal magnesium clearance during hyperglycaemia.

Adult↗
PubMed2000

Impaired insulin-stimulated expression of the glycogen synthase gene in skeletal muscle of type 2 diabetic patients is acquired rather than inherited.

To examine whether defective muscle glycogen synthase (GYS1) expression is associated with impaired glycogen synthesis in type 2 diabetes and whether the defect is inherited or acquired, we measured GYS1 gene expression and enzyme activity in muscle biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and in 12 matched control subjects. The effect of insulin on GYS1 fractional activity, when expressed as the increment over the basal values, was significantly impaired in diabetic (15.7 +/- 3.3%; P < 0.01), but not in nondiabetic (23.7 +/- 1.8%; P = NS) twins compared with that in control subjects (28.1 +/- 2.3%). Insulin increased GYS1 messenger ribonucleic acid (mRNA) expression in control subjects (from 0.14 +/- 0.02 to 1.74 +/- 0.10 relative units; P < 0.01) and in nondiabetic (from 0.24 +/- 0.05 to 1.81 +/- 0.16 relative units; P < 0.01) and diabetic (from 0.20 +/- 0.07 to 1.08 + 0.14 relative units; P < 0.01) twins. The effect of insulin on GYS1 expression was, however, significantly reduced in the diabetic (P < 0.003), but not in the nondiabetic, twins compared with that in control subjects. The postclamp GYS1 mRNA levels correlated strongly with the hemoglobin A1c levels (r = -0.61; P < 0.001). Despite the decrease in postclamp GYS1 mRNA levels, the GYS1 protein levels were not decreased in the diabetic twins compared with those in the control subjects (2.10 +/- 0.46 vs. 2.10 +/- 0.34 relative units; P = NS). We conclude that 1) insulin stimulates GYS1 mRNA expression; and 2) impaired stimulation of GYS1 gene expression by insulin in patients with type 2 diabetes is acquired and most likely is secondary to chronic hyperglycemia.

Aged↗
PubMed2000

The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients.

The effect of 3 days of intensive treatment with acipimox, an antilipolytic nicotinic acid derivative, on plasma leptin levels was studied in eight patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, cross-over study. Acipimox reduced plasma free fatty acids (FFA) markedly and lowered plasma triglycerides, glucose and insulin. Plasma leptin levels were elevated in all eight patients during 3 days of acipimox treatment (mean increase+/-s.e.: 2.38+/-0.57ng/ml, P<0.005) and the 24h mean effect of acipimox on leptin levels increased during the experimental period (P<0.03). The effect on plasma insulin and glucose resembled a mirror image of the effect on plasma leptin during 3 days of treatment. The suggestion that leptin mediates insulin resistance and may be involved in the development of the diabetic syndrome cannot be supported by the present results. It has been reported that FFA stimulates leptin secretion. Surprisingly, despite a markedly reduced FFA level, leptin concentration increased in the present study. We suggest that a primary acipimox effect is to increase leptin secretion, and that this prevails over the reduced FFA stimulus.

Area Under Curve↗
PubMed1999

Does zygosity influence the metabolic profile of twins? A population based cross sectional study.

OBJECTIVE: To study the influence of zygosity on the metabolic variables involved in the pathophysiology of type 2 diabetes. DESIGN: Population based cross sectional study. SETTING: Odense University Hospital, Denmark. PARTICIPANTS: 125 monozygotic twin pairs and 178 dizygotic twin pairs of the same sex born between 1921 and 1940. MAIN OUTCOME MEASURES: Clinical characteristics of monozygotic and dizygotic twins with or without a family history of type 2 diabetes. RESULTS: Absolute prevalences of type 2 diabetes and impaired glucose tolerance according to the World Health Organisation criteria were similar in both the monozygotic and the dizygotic twins as were measurements of height, weight, body mass index, waist to hip ratio, and fasting plasma glucose and insulin concentrations. During the oral glucose tolerance test, monozygotic twins had a higher incremental plasma insulin area under the curve than dizygotic twins (10.05 (SD 0.68) v 9.89 (0.72) pmol/lxminutes, P<0.01) indicating insulin resistance. In twins with normal glucose tolerance and without first degree relatives or co-twins with type 2 diabetes or impaired glucose tolerance, both the glucose and insulin areas under the curve were higher among monozygotic twins (glucose 214.4 (88.3) v 189.8 (78.4) mmol/lxminutes, P<0.05; insulin 20 040 (14 865-32 554) v 17 625 (12 330-23 640) pmol/lxminutes, P=0.08). CONCLUSION: Zygosity influences both plasma glucose and plasma insulin concentrations during an oral glucose tolerance test. This supports an intrauterine influence on glucose homeostasis and perhaps on insulin resistance in humans.

Aged↗
PubMed1999

Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance--a population-based twin study.

To elucidate the relative importance of genetic and environmental factors on the development of Type II (non-insulin dependent) diabetes mellitus, we examined a sample of twins (n = 606) ascertained from the population-based Danish Twin Register. Based on a standard 75 g oral glucose tolerance test and current WHO criteria we identified 62 pairs in which one or both had Type II diabetes. The probandwise concordance (monozygotic: 0.50; dizygotic: 0.37) for Type II diabetes per se was not very different. When including the twins with impaired glucose tolerance (IGT), however, the probandwise concordance for abnormal glucose tolerance was significantly different between monozygotic (0.63) and dizygotic (0.43) twin pairs, (p < 0.01). These findings were supported by the heritability estimates for Type II diabetes per se (26%) and for abnormal glucose tolerance (61%). The metabolic variables, insulin resistance and insulin secretion, and anthropometric variables, body mass index and waist to hip ratio, known to be associated with the development of glucose intolerance had a heritability of 26, 50, 80 and 6% respectively. This study confirms the notion of a multifactorial aetiology of Type II diabetes. It supports the contribution of non-genetic aetiological components in the development of Type II diabetes per se. The study also indicates a role for genes in the aetiology of abnormal glucose tolerance. We therefore propose that genetic predisposition is important for the development of abnormal glucose tolerance. Non-genetic factors, however, might play a predominant role in controlling whether a genetically predisposed individual progresses to overt Type II diabetes.

Body Constitution↗
PubMed1999

Intracellular skeletal muscle glucose metabolism is differentially altered by dexamethasone treatment of normoglycemic relatives of type 2 diabetic patients.

Young first-degree relatives of type 2 diabetic patients are insulin-resistant, with the insulin resistance mainly located in skeletal muscle due to decreased insulin-induced nonoxidative glucose metabolism and muscle glycogen synthase activation. We investigated whether the mechanism differs for dexamethasone (dex)-induced insulin resistance in first-degree relatives of type 2 diabetics versus healthy control subjects by quantifying intracellular glucose processing in muscle biopsies taken before and after 5 days of dex treatment (4 mg/d) in 20 normal glucose-tolerant relatives of type 2 diabetic patients and 20 matched controls (age, 29.4 +/- 1.7 v 29.4 +/- 1.6 years; body mass index, 25.1 +/- 1.0 v 25.1 +/- 0.9 kg/m2). In addition, an intravenous glucose tolerance test (IVGTT) combined with continuous indirect calorimetry was performed. Following 5 days of dex treatment, glucose tolerance deteriorated in both the relatives and the control subjects. Fasting dry-weight muscle glucose and fasting intracellular muscle glucose concentrations increased in response to dex only in the relatives (2.43 +/- 0.21 v 2.97 +/- 0.26 mmol/kg dry weight, P < .05; 0.28 +/- 0.07 v 0.45 +/- 0.08 mmol/L intracellular water, P < .05); no increases were observed in the control subjects. Fasting dry-weight muscle lactate also increased post-dex only in the relatives (7.37 +/- 0.40 v 10.77 +/- 1.22 mmol/kg dry weight, P < .001). Both basal muscle glucose and lactate concentrations from the IVGTT study correlated with the 2-hour post-dex glucose value obtained during the OGTT study in the relatives (R = .76 and R = .74, respectively, both P < .0001) but not in the control subjects. Basal intramuscular glycogen synthase activity decreased approximately 25% in both the relatives and control subjects post-dex; the decrement was significant (P < .01) only in control subjects. Indirect calorimetry during the post-dex IVGTT demonstrated increased glucose oxidation (P < .03) and reduced lipid oxidation (P < .03) in the relatives only. We postulate that the insulin resistance induced by dex in first-degree relatives of type 2 diabetic patients is associated with a preferential channeling of glucose into the glycolytic pathway (increased glucose oxidation and lactate production), probably associated with a preexisting downregulation of the glycosen synthase pathway.

Adult↗
PubMed1999

Impact of ubiquinone (coenzyme Q10) treatment on glycaemic control, insulin requirement and well-being in patients with Type 1 diabetes mellitus.

AIM: To investigate the effect of ubiquinone (coenzyme Q10) on glycaemic control and insulin requirement in patients with Type 1 diabetes mellitus (DM). METHODS: We investigated 34 patients with Type 1 DM in a randomized, double-blind, placebo-controlled study. Patients received either 100 mg Q10 or placebo daily for 3 months. The insulin doses were adjusted according to patients' home measurements of blood glucose concentrations and reported experience of hypoglycaemia. RESULTS: At randomization no differences existed between the Q10 and the placebo groups in age, body mass index (BMI), HbA1c, daily insulin dose or mean daily blood glucose concentration. Serum Q10 concentration increased in the Q10 group (mean +/- SD: 0.9+/-0.2 vs. 2.0+/-1.0 microg/ml, P<0.005), with no change in the placebo group (0.9+/-0.3 vs. 0.9+/-0.3 microg/ml, not significant (NS)). Following intervention no differences existed between the Q10 and the placebo groups regarding HbA1c (7.86+/-0.88 vs. 7.84+/-0.84%), mean daily blood glucose concentrations (8.06+/-1.86 vs. 8.53+/-1.88 mM), mean insulin dose (52.1+/-13.2 vs. 52.6+/-21.4 U), hypoglycaemic episodes (2.0+/-1.8 vs. 2.5+/-2.1 episodes/week), or cholesterol concentrations (4.81+/-0.91 vs. 4.78+/-1.07 mM). Furthermore, no differences existed in the well-being of the patients reported from a visual analogue scale (physical: 0.67+/-0.21 vs. 0.71+/-0.18, psychological: 0.70+/-0.25 vs. 0.73+/-0.24). CONCLUSION: Q10 treatment does not improve glycaemic control, nor does it reduce insulin requirement, and it can therefore be taken by patients with Type 1 DM without any obvious risk of hypoglycaemia. No major beneficial or unfavourable effects on the investigated parameters could be demonstrated and no major changes in the sense of well-being occurred in the patients.

Adult↗
PubMed1999

Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle.

To identify abnormally expressed genes contributing to muscle insulin resistance in type 2 diabetes, we screened the mRNA populations from normal and diabetic human skeletal muscle using cDNA differential display and isolated abnormally expressed cDNA clones of mitochondrial-encoded NADH dehydrogenase 1 (ND1), cytochrome oxidase 1, tRNA(leu), and displacement loop. We then measured mRNA expression of these mitochondrial genes using a relative quantitative polymerase chain reaction method in biopsies taken before and after an insulin clamp in 12 monozygotic twin pairs discordant for type 2 diabetes and 12 matched control subjects and in muscle biopsies taken after an insulin clamp from 13 subjects with type 2 diabetes, 15 subjects with impaired glucose tolerance, and 14 subjects with normal glucose tolerance. Insulin infusion increased mRNA expression of ND1 from 1.02 +/- 0.04 to 2.55 +/- 0.30 relative units (P < 0.001) and of cytochrome oxidase 1 from 0.80 +/- 0.01 to 1.24 +/- 0.10 relative units (P < 0.001). The ND1 response to insulin correlated with glucose uptake (r = 0.46, P = 0.002). Although the rate of insulin-mediated glucose uptake was decreased in the diabetic versus the nondiabetic twins (5.2 +/- 0.7 vs. 8.5 +/- 0.8 mg x kg(-1) fat-free mass x min(-1), P < 0.01), insulin-stimulated ND1 expression was not significantly different between them (2.4 +/- 0.5 vs. 2.7 +/- 0.5 relative units). Neither was there any significant intrapair correlation of ND1 expression between the monozygotic twins (r = -0.15, NS). We conclude that insulin upregulates mitochondrial-encoded gene expression in skeletal muscle. Given the positive correlation between ND1 expression and glucose uptake and the lack of intrapair correlation between monozygotic twins, mitochondrial gene expression may represent an adaptation to intracellular glucose flux rather than an inherited trait.

Aged↗
PubMed1999

On the pathophysiology of late onset non-insulin dependent diabetes mellitus. Current controversies and new insights.

The development of late onset non-insulin dependent diabetes mellitus (NIDDM) is due to a complicated interplay between genes and environment on one side, and the interaction between metabolic defects in various tissues including the pancreatic beta cell (decreased insulin secretion), skeletal muscle (insulin resistance), liver (increased gluconeogenesis), adipose tissue (increased lipolysis) and possibly gut incretin hormones (defective glucagon like peptide 1 (GLP1) secretion) on the other side. Evidence for a genetic component includes the finding of a variety of metabolic defects in various tissues in non-diabetic subjects with a genetic predisposition to NIDDM, higher concordance rates for abnormal glucose tolerance including NIDDM in monozygotic compared with dizygotic twins, and the more recent demonstration of different NIDDM susceptibility genes at the sites of Insulin Receptor Substrate 1 (IRS1), the beta-3 adrenergic receptor, and the sulfonylurea receptor. However, the latter susceptibility genes only explain a minor proportion of NIDDM in the general population, and the quantitative extent to which genetic versus non-genetic factors contribute to NIDDM is presently unsolved. Environmental components include both an early intrauterine component associated with low birth weight, and later postnatal components including low physical activity, high fat diet, and the subsequent development of obesity and elevated plasma and tissue free fatty acid levels. Our finding of lower birth weights in monozygotic twins compared with their non-diabetic genetically identical co-twins excludes the possibility that the association between NIDDM and low birth weight as demonstrated in several studies may solely be explained by a coincidence between a certain gene causing both a low birth weight and an increased risk of NIDDM. Young first degree relatives of patients with NIDDM are characterized by hyperinsulinaemia and peripheral insulin resistance, which in turn may be explained by a decreased insulin activation of the enzyme glycogen synthase in skeletal muscle. Therefore, a defective skeletal muscle glycogen synthase activation may represent an early phenotypic expression of a genetic defect contributing to an increased risk of later development of NIDDM. However, elderly insulin resistant non-diabetic co-twins (64 years old) of twins with overt NIDDM does not--in contrast to their NIDDM co-twins--have a significantly decreased insulin activation of glycogen synthase in skeletal muscle. This demonstrates that the defective muscle glycogen synthase insulin activation has an apparent non-genetic component, and that this key defect of metabolism can be escaped or postponed even in non-diabetic subjects with a presumably 100% genetic predisposition to NIDDM. The insulin activation of glycogen synthase in skeletal muscle is compensated or apparently normalised in NIDDM patients when studied during their ambient fasting hyperglycaemia and a subsequent isoglycaemic (hyperglycaemic) physiologic insulin infusion. This indicates that the prevailing hyperglycaemia in NIDDM subjects compensates for the defective insulin activation of glycogen synthase present in those subjects when studied during eulycaemia. Our data and those of others also indicates that hyperglycaemia in NIDDM compensates for the defects in insulin secretion, the disproportionately elevated hepatic glucose production, and to some extent for the increased lipid oxidation and the decreased glucose oxidation present in NIDDM patients. Accordingly, NIDDM subjects exhibit all of those defects of metabolism when studied during "experimental decompensation" when the ambient hyperglycaemia is normalized by a prior and later withdrawn intravenous insulin infusion. However, shortly after the withdrawal of the intravenous insulin infusion, the plasma glucose concentration increased spontaneously in the NIDDM patients. (ABSTRACT TRUNCATED)

Age of Onset↗
PubMed1998

Impact of family history of diabetes on the assessment of beta-cell function.

Numerous factors impinge on beta-cell function, and include the genetic background and insulin sensitivity of the individual. The aim of the present study was to evaluate the impact of a family history of non-insulin-dependent diabetes mellitus (NIDDM) on beta-cell function and to determine whether the relationships between beta-cell function and insulin sensitivity and age are influenced by a family history of diabetes. Thirty-three healthy control subjects (CON), 20 normal glucose-tolerant first-degree relatives of known NIDDM patients (REL), and 12 nondiabetic identical twins with an identical twin with known NIDDM were studied. Insulin and C-peptide responses to an acute intravenous glucose (AIRg) and glucagon bolus (at euglycemia [AIR[G.GON]]) were measured, as well as each individual's insulin sensitivity. Fasting insulin and C-peptide levels were similar in all groups. AIRg was significantly reduced by 65% in the nondiabetic twins compared with the CON and REL groups, with the latter group being similar to CON, whereas for the AIR[G.GON], the insulin responses in the twin subjects were reduced only by 35% compared with CON. Following stepwise (default) multiple regression analysis, three independent variables (insulin sensitivity, 23%; family history of NIDDM, 20%; and fasting glucose, 7%) were identified, and these combined to fit a model for prediction of acute beta-cell responses to glucose that yielded an R2 (adjusted) value of 50%. Following analysis of covariance (ANCOVA), a positive family history of NIDDM and insulin sensitivity but not the age of the subject were confirmed as separate factors affecting AIRg. In conclusion, in subjects with normal or mild glucose intolerance, the individual's genetic background and insulin sensitivity are important determinants of insulin secretion.

Adolescent↗
PubMed1998

Irreversibility of the defect in glycogen synthase activity in skeletal muscle from obese patients with NIDDM treated with diet and metformin.

OBJECTIVE: To assess the reversibility of the defect in glycogen synthase (GS) activity in skeletal muscle from obese patients with NIDDM treated with a hypocaloric diet and metformin. RESEARCH DESIGN AND METHODS: Eighteen obese patients newly diagnosed with NIDDM were included in a randomized placebo-controlled double-blind parallel group trial and followed for 3 months. Euglycemic-hyperinsulinemic clamp including indirect calorimetry and biopsy of m. vastus lateralis was performed before and after treatment with a hypocaloric diet plus metformin or placebo. The patients were studied at basal, low, and high insulin concentrations. RESULTS: The impaired GS activity in muscle biopsies was not reversed either by acute normalization of glycemia (for 8 h) or by chronic reduction of hyperglycemia by diet plus metformin. In both treatment groups, comparable effects on glycemic control and weight loss were found together with marked insulin suppression of nonesterified fatty acids and increased glucose oxidation. Total glucose disposal at euglycemic-hyperinsulinemic clamp increased significantly in the metformin group by 25% at high insulin level (259 +/- 31 vs. 207 +/- 21 mg x m(-2) x min(-1), P < 0.05). An insignificant increase by 13% was found in the placebo group. There were no significant changes in nonoxidative glucose metabolism. GS activity and glucose utilization showed no significant differences between the two treatment groups when regression coefficients, expressed as incremental changes by increments of insulin, were compared. CONCLUSIONS: Defective GS activity in obese NIDDM patients is not secondary to hyperglycemia. Metformin and diet had no significant influence on GS activity. The added effect of metformin to that of a hypocaloric diet in improving insulin-stimulated glucose utilization is marginal when blood glucose reduction is obtained by weight loss.

Adult↗
PubMed1996

Intracellular glucose and fat metabolism in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM): acquired versus genetic metabolic defects?

UNLABELLED: Intracellular glucose and lipid metabolism was studied in 12 identical twin pairs discordant for non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 13 control subjects without family history of diabetes during low (baseline) and high plasma insulin concentrations, using the hyperinsulinaemic clamp technique combined with indirect calorimetry, tritiated water glycolytic flux rates and biopsy skeletal muscle glycogen synthase activity determinations. Baseline and insulin stimulated rates of lipid oxidation were elevated--and glucose oxidation decreased--in the NIDDM twins compared with the non-diabetic co-twins and controls (all p < 0.05). Baseline and insulin stimulated rates of glucose and lipid oxidation were similar in non-diabetic twins and controls. Exogenous glycolytic flux was decreased in NIDDM twins compared with both their non-diabetic co-twins and controls during clamp insulin measurements (p < 0.02), but similar in all study groups during baseline measurements. Insulin stimulated glucose disposal, exogenous glucose storage (glucose disposal-exogenous glycolytic flux) and skeletal muscle glycogen synthase activity were all significantly decreased in NIDDM twins compared with both their non-diabetic co-twins and controls. Furthermore, glucose disposal and glucose storage were decreased in the non-diabetic twins (n = 12) compared with controls (p < 0.05 both). However, insulin stimulated fractional skeletal muscle glycogen synthase activity was not significantly decreased in non-diabetic twins compared with controls. IN CONCLUSION: (1) the glucose fatty acid cycle plays a major role in the secondary--but not the primary--abnormalities of glucose metabolism in NIDDM; (2) insulin resistance in non-diabetic identical co-twins of NIDDM patients is restricted exclusively to the pathway of exogenous glucose storage; (3) however, the decreased glucose storage is not explained solely by an impairment of insulin stimulated skeletal muscle glycogen synthase activity; and finally (4) the impairment of skeletal muscle glycogen synthase activity in NIDDM has an apparent non-genetic component and can be escaped (or postponed) in individuals (twins) with a 100% genetic predisposition to NIDDM.

Analysis of Variance↗
PubMed1996

Glucose processing during the intravenous glucose tolerance test.

The impact of the dynamic changes in plasma glucose and insulin levels observed during a frequently sampled intravenous (IV) glucose tolerance test (FSIGT) on whole-body glucose processing and muscle glycogen metabolism is not known. Paired randomized FSIGTs were performed in eight healthy subjects (age, 31 years; range, 28 to 35; BMI, 25.4 kg/m2; range, 22.3 to 32.1), one with muscle biopsy samples and one without. The mean time average (0- to 40- and 0- to 120-minute) insulin levels during the test were 26.6 and 11.4 mU/1, respectively. Glucose oxidation increased following the IV glucose bolus (basal 1.34 +/- 0.21 v mean value at 0 to 120 minutes 2.09 +/- 0.22 mg/kg fat-free mass [FFM]/min, P < .02). In contrast, fractional glucose-6-phosphate [G-6-P]) (0.1/10 mmol/L) skeletal muscle glycogen synthase activity in muscle biopsies obtained before and following the IV glucose bolus (-30, 30,60, and 120 minutes, respectively) were unchanged (38.1% +/- 2.3%, 38.3% +/- 2.9%, 38.1% +/- 2.3%, 35.4% +/- 2.3%, NS). Skeletal muscle glycogen concentration decreased slightly (449 +/- 54, 439 +/- 55, and 383 +/- 29, and 438 +/- 48 mmol/kg dry weight, P =.05), indicating no net storage of glucose into glycogen during the FSIGT. G-6-P decreased (0.77 +/- 0.08, 0.64 +/- 0.07, 0.66 +/- 0.07, and 0.54 +/- 0.04 mmol/kg dry weight, P < .05). Levels of the insulin-regulatable glucose transporter, GLUT-4, were unchanged. Insulin sensitivity (Si), glucose effectiveness, and insulin secretion parameters (01 and 02) were not affected by the muscle biopsy procedure. In conclusion, the FSIGT is associated predominantly with increased whole-body glucose oxidation with no apparent activation of muscle glucose storage as glycogen. Thus, the Si measured by the FSIGT, although similar in magnitude to the clamp-derived parameter, represents primarily glucose oxidation, in contrast to the euglycemic clamp, which involves glucose oxidation and storage.

Adult↗
PubMed1996

Insulin resistance in growth hormone-deficient adults: defects in glucose utilization and glycogen synthase activity.

Fourteen GH-deficient (GHD) adults were compared with 12 age-, sex-, and body mass index-matched control subjects using a baseline tritiated glucose equilibration period and euglycemic-hyperinsulinemic (approximately 55 mU/L) clamp in conjunction with paired muscle biopsies for measurement of glycogen synthase fractional velocity (FV0.1). Despite similar basal rates of total glucose disposal (Rd), there was a 64% reduction in the insulin-stimulated rise (delta) in Rd in the GHD adults compared to that in controls [16.6 +/- 2.8 vs. 44.7 +/- 6.0 mumol/kg fat free mass (FFM)/min; P < 0.001], which was mainly due to a decreased glucose storage (GS) rate (delta GS, 12.6 +/- 2.9 vs. 39.5 +/- 7.5 mumol/kg FFM/min; P < 0.01). Furthermore, the insulin sensitivity indexes of Rd (0.39 +/- 0.07 vs. 0.85 +/- 0.11; P < 0.05) and GS (0.25 +/- 0.07 vs. 0.72 +/- 0.13 mumol/kg FFM/min per mU/L; P < 0.02) were reduced in GHD adults compared to the control values. The insulin sensitivity of the glycolytic pathway was also reduced by approximately 50% in GHD adults (P = 0.07 vs. controls). Insulin-stimulated FV0.1 was decreased in GHD adults (0.31 +/- 0.02 vs. 0.47 +/- 0.03; P < 0.005) despite similar basal FV0.1. Using multiple and stepwise regression analysis, duration of GH deficiency, fasting triglycerides and fasting insulin accounted for 67% of the variance in the insulin sensitivity index of Rd. In conclusion, the severe insulin resistance in GHD adults is mainly due to the inhibition of the GS pathway and glycogen synthase activity in peripheral tissues, which is related to the duration of GH deficiency, fasting triglycerides, and fasting insulin.

Adult↗
PubMed1995

Multiple defects of both hepatic and peripheral intracellular glucose processing contribute to the hyperglycaemia of NIDDM.

Non-insulin-dependent diabetic (NIDDM) patients were studied during a modified euglycaemic state when fasting hyperglycaemia was normalized by a prior (-210 to -150 min)--and later withdrawn (-150-0 min)--intravenous insulin infusion. Glucose metabolism was assessed in NIDDM patients (n = 10) and matched control subjects (n = 10) using tritiated glucose turnover rates, indirect calorimetry and skeletal muscle glycogen synthase activity determinations. Total and non-oxidative exogenous glycolytic flux rates were measured using appearance rates of tritiated water. A + 180 min euglycaemic hyperinsulinaemic (40 mU.m-2.min-1) clamp was performed to determine the insulin responsiveness of the various metabolic pathways. Plasma glucose concentration increased spontaneously during baseline measurements in the NIDDM patients (-120 to 0 min: 4.8 +/- 0.3 to 7.0 +/- 0.3 mmol/l; p < 0.01), and was primarily due to an elevated rate of hepatic glucose production (3.16 +/- 0.13 vs 2.51 +/- 0.16 mg.kg FFM-1.min-1; p < 0.01). In the NIDDM subjects baseline glucose oxidation was decreased (0.92 +/- 0.17 vs 1.33 +/- 0.14 mg.kg FFM-1.min-1; p < 0.01) in the presence of a normal rate of total exogenous glycolytic flux and skeletal muscle glycogen synthase activity. The simultaneous finding of an increased lipid oxidation rate (1.95 +/- 0.13 vs 1.61 +/- 0.07 mg.kg FFM-1.min-1; p = 0.05) and increased plasma lactate concentrations (0.86 +/- 0.05 vs 0.66 +/- 0.03 mmol/l; p = 0.01) are consistent with a role for both the glucose-fatty acid cycle and the Cori cycle in the maintenance and development of fasting hyperglycaemia in NIDDM during decompensation. Insulin resistance was demonstrated during the hyperinsulinaemic clamp in the NIDDM patients with a decrease in the major peripheral pathways of intracellular glucose metabolism (oxidation, storage and muscle glycogen synthase activity), but not in the pathway of non-oxidative glycolytic flux which was not completely suppressed during insulin infusion in the NIDDM patients (0.55 +/- 0.15 mg.kg FFM-1.min-1; p < 0.05 vs 0; control subjects: 0.17 +/- 0.29; NS vs 0). Thus, these data also indicate that the defect(s) of peripheral (skeletal muscle) glucose processing in NIDDM goes beyond the site of glucose transport across the cell membrane.

Biopsy↗
PubMed1995

Pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM).

In this review, the pathophysiologycal events leading to hyperglycemia in NIDDM patients are discussed, i.e. glucose effectiveness, insulin action (in muscle and liver) and insulin secretion. The natural history of the insulin resistance syndrome is demonstrated and a new staging system is proposed. We conclude that NIDDM is a life-long disease characterized by intraabdominal obesity and macrovascular events several years in advance of hyperglycemia, and that insulin resistance in skeletal muscle plays an important pathophysiological part and also may be used in prediction of the disease.

Adult↗
PubMed1995

Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus.

12 identical twin pairs discordant for non-insulin-dependent diabetes mellitus (NIDDM) were studied for insulin sensitivity (euglycemic insulin clamp, 40 mU/m2 per min), hepatic glucose production (HGP, [3-3H]glucose infusion), and insulin secretion (oral glucose tolerance test and hyperglycemic [12 mM] clamp, including glucagon administration). Five of the nondiabetic twins had normal and seven had impaired glucose tolerance. 13 matched, healthy subjects without a family history of diabetes were included as control subjects. The NIDDM twins were more obese compared with their non-diabetic co-twins. The nondiabetic twins were insulin resistant and had a delayed insulin and C-peptide response during oral glucose tolerance tests compared with controls. Furthermore, the nondiabetic twins had a decreased first-phase insulin response and a decreased maximal insulin secretion capacity during hyperglycemic clamping and intravenous glucagon administration. Nondiabetic twins and controls had similar rates of HGP. Compared with both nondiabetic twins and controls, the NIDDM twins had an elevated basal rate of HGP, a further decreased insulin sensitivity, and a further impaired insulin secretion pattern as determined by all tests. In conclusion, defects of both in vivo insulin secretion and insulin action are present in non- and possibly prediabetic twins who possess the necessary NIDDM susceptibility genes. However, all defects of both insulin secretion and glucose metabolism are expressed quantitatively more severely in their identical co-twins with overt NIDDM.

Age of Onset↗