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J C Levy

Publications and source records attributed to J C Levy.

At least 37 records · Page 2Linked to original sources
PubMed2001

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

Chromosome Mapping↗
PubMed2001

Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom.

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.

Alleles↗
PubMed2001

Butyrylcholinesterase K variant on chromosome 3 q is associated with Type II diabetes in white Caucasian subjects.

AIMS/HYPOTHESIS: To determine the association of three genes associated with Alzheimer's disease--butyrylcholinesterase (BcHE) on chromosome 3 q, alpha2 macroglobulin (alpha2M) on chromosome 12 p and apolipoprotein E (ApoE) on chromosome 19 q--with Type II (non-insulin-dependent) diabetes mellitus. METHODS: Frequencies of BcHE K variant, alpha2M insertion and/or deletion polymorphism, the ApoE common polymorphisms and promoter variants at ApoE-491 and -291, were examined by fluorescent RFLP in DNA from 276 United Kingdom Prospective Diabetes Study Type II diabetic subjects and 351 non-diabetic subjects from the Diabetes In Families study. Genetic data in diabetic subjects was analysed in relation to clinical characteristics and islet function as assessed by the requirement for insulin therapy 6 years after randomisation. RESULTS: The BcHE K variant allele was more common among Type II diabetic subjects (D) than non-diabetic subjects (ND) (22.8 % D vs 15.8 % ND; p = 0.00 017). Subjects homozygous for the variant were more frequent in the diabetic group (5.8 % D vs 2.6 % ND: p = 0.00 056). The K variant allele frequency was not associated with a requirement for insulin therapy (29.0 % insulin-requiring vs 21.8 % non-insulin-requiring; p = 0.121). There were no associations of alpha2M and ApoE polymorphisms or ApoE promoter variants with clinical characteristics or insulin requirement in diabetic subjects. There were differences in total cholesterol (p = 0.0005) and LDL-cholesterol (p = 0.0009) among non-diabetic subjects in relation to ApoE-491 genotypes. CONCLUSION/INTERPRETATION: The association of the BcHE gene (3q26) with Type II diabetes could be related to an identified susceptibility locus on chromosome 3q27 but appears to be independent of islet function. The absence of diabetes-specific associations with alpha2M, ApoE or ApoE promoter variants suggest that these are not important in the onset of hyperglycaemia.

Adult↗
PubMed2001

Insulin signalling through ultradian oscillations.

Periodic oscillations appear to be a characteristic of insulin secretion at various different levels. Very rapid pulsations are seen in the isolated beta-cell and islet, while rapid (10- to 15-min) pulsations are seen both in the intact organism and in the isolated pancreas. Ultradian oscillations, particularly evident in situations of sustained exogenous glucose loading, appear to be a characteristic of intact organisms and have been hypothesized to be intrinsic to the normal glucose-insulin feedback system. Many of the features seen in experimental situations and in abnormalities of the system can be predicted by computer modelling of this system, supporting this hypothesis. A further theoretical feature of this hypothesis, borne out by experiment, is the ability to entrain insulin pulsatility by oscillations in an exogenous glucose infusion. Identification of defective ultradian oscillations and entrainment can identify subtle abnormalities of insulin sensitivity and pancreatic function, and restoration of normal function can be demonstrated after pharmaceutical intervention.

Activity Cycles↗
PubMed2001

Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166).

OBJECTIVE: This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal. RESEARCH DESIGN AND METHODS: A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min. RESULTS: The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide. CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.

Blood Glucose↗
PubMed2000

Parallel changes of proinsulin and islet amyloid polypeptide in glucose intolerance.

Elevated proinsulin secretion and islet amyloid deposition are both features of Type 2 diabetes but their relationship to beta-cell dysfunction is unknown. To determine if islet amyloid polypeptide (IAPP) secretion is disproportionate with other beta-cell products at any stage of glucose intolerance, 116 subjects were studied. Non-diabetic subjects with equivalent body mass index (BMI) were assigned to three groups, (i) normal fasting glucose, fpg<5.5 mmol l(-1); (ii) intermediate fasting glucose, fpg> or =5.5<6.15 mmol l(-1); (iii) impaired fasting glucose (IFG), fpg> or =6.1<7.0 mmol l(-1). Diabetic subjects were divided according to therapy (9 diet, 19 tablet, and 11 insulin). IAPP, C-peptide and proinsulin were measured fasting and at the end of a 1-h glucose infusion. Fasting C-peptide, IAPP and proinsulin were significantly elevated in the IFG group compared with the other non-diabetic groups (P<0.02); fasting IAPP/C-peptide and proinsulin/C-peptide were 1-2% in all non-diabetic groups. Fasting and 1-h proinsulin and proinsulin/C-peptide were higher in diabetic compared with non-diabetic subjects (P<0.01). IAPP and IAPP/C-peptide in diabetic groups were similar to that in non-diabetic subjects but reduced in the insulin-treated group (P<0.01). Proinsulin was disproportionately increased compared with C-peptide and IAPP in Type 2 diabetes particularly in severe beta-cell failure implying more than one concurrent beta-cell pathology.

Amyloid↗
PubMed2000

Determinants of within-subject variation of fasting serum leptin concentrations in healthy subjects.

The hormone leptin is considered to contribute to body weight regulation through modulation of feeding behavior and energy expenditure. The aim of the present study was 1) to assess the day-to-day within-subject variation (biovariability) of serum leptin concentrations in healthy subjects and 2) to investigate whether this variation is associated with food intake, exercise, anthropometric measurements or various metabolic covariates (insulin, C-peptide and glucagon, glucose, lactate, 3-hydroxybutyrate (3-OHB), triglycerides, non-esterified-fatty acids and glycerol). Serum leptin levels were taken daily on 12 consecutive days after an overnight fast in 12 healthy subjects with a mean (SD) age of 22.7 (1.5) yr. and a BMI of 22.8 (1.6) kg/m2. Food intake, exercise, anthropometric measurements and various metabolic covariates were also determined during this period. The overall mean of serum leptin concentration was 33.3 pmol/L with a within-subject SD range of 27-41 pmol/L and a between-subject SD range of 18-61 pmol/L. The within-subject variance of serum leptin as a proportion of total variance was 9.5%. Within-subject variation of serum leptin concentrations is small in relation to between-subject variation in healthy, normal weight subjects. This has implications for the power of interventional or prospective studies. In men, 6.7% of the variation in serum leptin concentration was associated with body weight measured on the same day (p= 0.037). In women, however, 66% of the variation was negatively associated with 3-OHB measured on both the same and the previous day (p=0.0003 and 0.002), and positively associated with triglyceride concentration measured on the previous day (p=0.0017) and insulin measured on the same day (p=0.0002). Within-subject associations in women could be due to phasic changes in unmeasured variables, possibly related to the menstrual cycle or might suggest that energy balance may exert a delayed influence on serum leptin levels, with plasma 3-OHB and triglycerides acting as markers for the state of the fat stores that regulate leptin secretion. The differences between the genders remain unexplained, however.

3-Hydroxybutyric Acid↗
PubMed2000

No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians.

Several studies have identified evidence for linkage between type 2 diabetes and the regions on chromosomes 12 and 20 containing the maturity-onset diabetes of the young (MODY) genes, hepatocyte nuclear factor-1alpha (HNF-1alpha) and HNF-4alpha. Two studies examining the HNF-1alpha region have demonstrated evidence for linkage at genome-wide levels of significance, whereas four studies examining the HNF-4alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration of linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore assessed the evidence for linkage to these regions using a large cohort of United Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed for microsatellite markers across the MODY regions and, in a subset of families, for markers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence for excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to the general population risk, of 1.75 and 1.25 could be excluded for the HNF-1alpha and HNF-4alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the problems of replicating previous positive linkage results across different ethnic groups.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗
PubMed2000

Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.

Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.

Adult↗
PubMed1999

The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with Type II diabetes mellitus.

Type II (non-insulin-dependent) diabetes mellitus has a substantial genetic component; however, its molecular basis remains largely unknown. The mode of inheritance is likely to be polygenic, with penetrance influenced by environmental factors. Although the familial aggregation of Type II diabetes is acknowledged, there is little data concerning the prevalence of diabetes in the relatives of subjects with diabetes in comparison with the general population, and our objective was to address this question in the defined geographic region of Oxfordshire, England. We studied 139 first degree relatives of 90 probands with Type II diabetes who attended routine diabetes clinics in Oxfordshire and documented the fasting plasma glucose, triglyceride and HDL-cholesterol concentrations and BMI of these subjects. The probands were selected without regard to family history of diabetes. The control population data were derived from two large-scale Oxford community studies which documented the prevalences of known and newly diagnosed diabetes. The prevalences of newly diagnosed and known diabetes were calculated for each group. The mean BMI, and concentrations of fasting glucose, triglyceride and HDL-cholesterol were compared and prevalence ratios for obesity (defined as BMI > 30 kg/m2), hyperglycaemia (defined as fasting plasma glucose > or = 6.1 mmol/l), and dyslipidaemia (defined as triglyceride > 2.0 mmol/l, HDL < 1.0 mmol/l) were calculated. There was a fourfold higher prevalence of hyperglycaemia in the first degree relatives of subjects with Type II diabetes compared with the control population: the prevalence ratio after adjustment for age, sex and BMI was 4.32 (95 % confidence interval 2.29-8.17). The relatives had a considerably higher fasting plasma glucose concentration than the control population (5.18+/-0.67 mmol/l (mean +/- 1 SD) vs 4.76+/-1.59 mmol/l, p = 0.0001), and this difference remained statistically significant after adjustment for age, sex and obesity. The relatives were significantly more obese, had higher fasting plasma insulin concentrations and had lower HDL-cholesterol concentrations. In conclusion, there is a strong familial aggregation of hyperglycaemia and obesity in the relatives of subjects with Type II diabetes and these subjects have higher fasting plasma insulin concentrations and lower HDL-cholesterol than the general population. These data indicate the particular relevance of screening the first degree relatives of subjects with Type II diabetes, as intervention strategies which aim to improve the metabolic profile are indicated for a large proportion of these subjects.

Adult↗
PubMed1999

Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes.

AIMS/HYPOTHESIS: Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. METHODS: Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio - DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. RESULTS: Reciprocal fasting plasma insulin (FPI(-1)), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI(-1), HOMA %S, 2-h CIGMA %S and S(I) FSIVGTT intercorrelated more than 90% of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. CONCLUSION/INTERPRETATION: The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative.

Adult↗
PubMed1999

Knowledge of risk of developing diabetes mellitus among siblings of Type 2 diabetic patients.

AIMS: We set out to investigate the extent to which siblings of diabetic subjects perceived themselves likely to develop Type 2 diabetes mellitus (DM) when offered screening tests. METHODS: Nondiabetic siblings, aged 35-74 years, of Type 2 diabetic patients who were more than 35 years old at diagnosis had fasting plasma glucose measured in a study to determine heritability of diabetes. Questionnaires assessing perceived likelihood of developing, seriousness and knowledge about diabetes were completed. Logistic regression assessed factors predicting perceptions of diabetes risk. RESULTS: Factors predicting diabetes on screening were male sex, increasing age and body mass index (BMI) > or = 30. Eighty-nine per cent of 540 eligible siblings completed questionnaires. Thirty-eight per cent saw themselves at increased risk of diabetes and 34% thought diabetes a serious problem. Predictors of perceiving an increased likelihood of developing diabetes were female sex, age 35-54 years vs. 55-74 years and having a parent with diabetes. BMI did not affect perceptions of likelihood. CONCLUSION: A perception of reduced vulnerability to diabetes may occur due to unawareness of risk or minimization of risk. Feelings of invulnerability may affect emotional response to a subsequent result. It is not known whether providing more information about the risk of developing diabetes prior to screening would affect outcomes

Adult↗
PubMed1999

Skin mini-erosion technique for monitoring metabolites in interstitial fluid: its feasibility demonstrated by OGTT results in diabetic and non-diabetic subjects.

The aim of this study was to evaluate a new interstitial fluid (IF) sampling technique and its application in diabetology. IF and venous whole blood were sampled serially during an oral glucose tolerance test (OGTT) on days 1 and 3 after formation of a mini-erosion in eight non-diabetic controls and eight Type 2 diabetic subjects. Glucose, lactate, glycerol, 3-hydroxybutyrate and insulin were assayed in IF and plasma. With solitary exceptions, the IF sample volumes were in excess of those required for measurement of all five substances. However, mean IF sampling rates differed significantly both between the non-diabetic and diabetic groups and between days 1 and 3 (p < 0.001 in all cases). In both groups, the OGTT curves of glucose, glycerol and 3-hydroxybutyrate were similar to the respective curves for plasma, whereas for lactate concentrations they were markedly greater in IF than in plasma (40% and 93% in the control group and 57% and 100% greater in the diabetic group on days 1 and 3, respectively). The reverse was true of insulin concentrations in the non-diabetic group, which were 57% and 74% lower in IF than in plasma on days 1 and 3, respectively. In the non-diabetic group, the baseline (pre-OGTT) insulin level in IF increased from 49 +/- 22% (SD) of that in plasma on day 1 to 74 +/- 19% of that in plasma on day 3 (p=0.005). Sampling site re-epithelialization was rapid. In conclusion, the feasibility of transdermal sampling of IF via a skin mini-erosion has been demonstrated in both diabetic and non-diabetic subjects.

3-Hydroxybutyric Acid↗
PubMed1999

Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes.

Adequate comparisons of the relative performance of different tests of beta-cell function are not available. We compared discrimination of commonly used in vivo tests of beta-cell function across a range of glucose tolerance in seven subjects with normal glucose tolerance (NGT), eight subjects with impaired glucose tolerance (IGT), and nine subjects with type 2 diabetes. In random order, each subject underwent two of each of the following tests: 1) frequently sampled 0.3-g/kg intravenous glucose tolerance test (FSIVGTT) with MinMod analysis; 2) homeostasis model assessment (HOMA) from three samples at 5-min intervals with a model incorporating immunoreactive or specific insulin measurements; and 3) continuous infusion of 180 mg x min(-1) x m(-2) glucose with model assessment (CIGMA) of three samples at 50, 55, and 60 min (1-h CIGMA) and at 110, 115, and 120 min (2-h CIGMA). The discrimination of each test was assessed by the ratio of the within-subject SD to the underlying between-subject SD, the discriminant ratio (DR). The degree to which tests measured the same physiological variable was assessed using Pearson's correlation coefficient adjusted for attenuation due to test imprecision. An unbiased line of equivalence, taking into account the imprecision of both tests, was used to compare results. Beta-cell function assessed from HOMA and beta-cell function assessed from CIGMA (CIGMA%beta) (using immunoreactive insulin) had higher DRs than first-phase intravenous glucose tolerance test-derived incremental insulin peak, area, insulin-to-glucose index, and acute insulin response to glucose from FSIVGTT-MinMod. CIGMA%beta (immunoreactive insulin) had the highest DR. FSIVGTT-derived first-phase insulin response tests correlated only moderately with HOMA and CIGMA. Using specific rather than immunoreactive insulin for HOMA and CIGMA did not improve discriminatory power. Simple tests such as HOMA and CIGMA, using immunoreactive insulin, offer better beta-cell function discrimination across subjects with NGT, IGT, and type 2 diabetes than measurements derived from FSIVGTT first-phase insulin response.

Analysis of Variance↗
PubMed1999

Within- and between-subject variation in commonly measured anthropometric and biochemical variables.

BACKGROUND: The biological variation of some commonly assessed metabolic variables in healthy subjects has not been studied extensively. The aim of the study was to assess, in 12 healthy subjects (6 male and 6 female; mean (SD) age; 22.7 (1.5) years) following an overnight fast, the day-to-day variation of body fat (impedance method), triglycerides, nonesterified fatty acid (NEFAs), glycerol, 3-hydroxybutyrate (3-OHB), lactate, glucose, insulin (RIA), C-peptide, and glucagon on 12 consecutive days. METHODS: Between- and within-subject coefficients of variation (CVG and CVW) were estimated using a random effects analysis of variance, and assay variation was subtracted to give the coefficient of within-subject biological variation (CVI). Individuality indices were calculated as CVW/CVG. RESULTS: The overall means, CVI, and individuality indices were as follows: for body fat, 24.2%, 10%, and 0.3; for triglycerides, 0.61 mmol/L, 21%, and 1.1; for NEFAs, 376 micromol/L, 45%, and 1.4; for glycerol, 48 micromol/L, 36%, and 0.8; for 3-OHB, 43 micromol/L, 61%, and 1.5; for lactate, 0.88 mmol/L, 31%, and 1.1; for glucose, 4.9 mmol/L, 4.8%, and 0.7; for insulin, 52 pmol/L, 26%, and 1.0; for C-peptide, 0.39 nmol/L, 24%, and 0.9; and for glucagon, 53 ng/L, 19%, and 0.8. CONCLUSIONS: The data presented here are necessary for the evaluation of several important metabolic variables in individual and group studies. The biological variation of some metabolites makes it difficult to characterize the status of healthy subjects with a single measurement.

3-Hydroxybutyric Acid↗
PubMed1998

The relationship between the insulin resistance syndrome and insulin sensitivity in the first-degree relatives of subjects with non-insulin dependent diabetes mellitus.

Non-insulin dependent diabetes mellitus (NIDDM) has a substantial genetic component. Impaired insulin secretion, insulin insensitivity in muscle and adipose tissue, and elevated hepatic glucose production are the major pathophysiological features of NIDDM. Insulin insensitivity is also a feature of the insulin resistance syndrome, which describes the epidemiological association of glucose intolerance, upper body obesity, hyperinsulinaemia, hypertension, increased triglyceride levels and decreased high-density-lipoprotein (HDL)-cholesterol concentrations. Insulin insensitivity has been found to be a familial trait, and this raises the hypothesis that the insulin resistance syndrome may also occur as a familial trait in caucasian families in association with the development of NIDDM. The 90 first degree relatives of 50 caucasian subjects with NIDDM were studied with a continuous infusion glucose tolerance test to quantitate glucose tolerance, insulin sensitivity and beta-cell function. Body mass index (BMI), blood pressure, fasting triglyceride and HDL-cholesterol measurements were obtained, and the intercorrelations between these variables were examined. As a group the first degree relatives had a median insulin sensitivity of 65% (interquartile range 46-99%). Insulin sensitivity was univariately correlated with systolic and diastolic blood pressure, triglyceride and HDL-cholesterol. These associations were present in both the hyperglycaemic and the normoglycaemic relatives. The hyperglycaemic relatives were significantly more insulin insensitive than the normoglycaemic relatives, but this additional insulin insensitivity was not associated with significant differences in blood pressure, triglyceride or HDL-cholesterol concentrations. Our data indicate that the insulin insensitivity present in the first degree relatives of subjects with NIDDM is correlated with the cardiovascular risk factors which make up the insulin resistance syndrome, and that glycaemic status does not appear to be the major determinant of these associations. Interventions targeting obesity and insulin insensitivity in these subjects may reduce cardiovascular risk.

Adult↗
PubMed1998

Changes in amylin and amylin-like peptide concentrations and beta-cell function in response to sulfonylurea or insulin therapy in NIDDM.

OBJECTIVE: Amylin, a secretory peptide of beta-cells, is the constituent peptide of islet amyloid, which is characteristic of NIDDM, and changes in amylin secretion in response to therapies may influence the rate of production of islet amyloid. The primary objective of this study was to determine whether therapy with sulfonylurea or basal insulin in NIDDM would alter amylin secretion in a way that might affect the formation of islet amyloid. RESEARCH DESIGN AND METHODS: In a randomized crossover design, eight subjects with NIDDM underwent three 8-week periods of therapy with diet alone, sulfonylurea, or exogenous basal insulin, with evaluation of amylin, amylin-like peptide (ALP), and glucose and C-peptide concentrations, both during fasting and after a standard breakfast. Changes in beta-cell function (% beta) were assessed, in the basal state by homeostasis model assessment (HOMA) and in the stimulated state by hyperglycemic clamps. Seven nondiabetic control subjects each underwent a meal profile and hyperglycemic clamp. RESULTS: Both sulfonylurea and insulin therapy reduced basal glucose concentrations compared with diet alone, but neither reduced the increased postprandial glucose increments. Both sulfonylurea and insulin therapy increased basal % beta, assessed by HOMA, but only sulfonylurea increased the second-phase C-peptide responses to the hyperglycemic clamp. Sulfonylurea increased time-averaged mean postprandial amylin and ALP concentrations compared with diet alone (geometric mean [1-SD range] for amylin, 4.9 [2.0-11.8] vs. 3.0 [1.4-6.2] pmol/l, P = 0.003; for ALP, 16.4 [8.5-31.7] vs. 10.1 [4.9-20.8] pmol/l, P = 0.001). Insulin therapy reduced basal ALP concentrations compared with diet alone (2.9 [1.5-5.6] vs. 6.0 [2.6-13.6] pmol/l, P = 0.03), but had no effect on postprandial concentrations of amylin (3.0 [1.3-6.5] pmol/l) or ALP (10.0 [5.5-18.1] pmol/l). CONCLUSIONS: By increasing postprandial concentrations of the constituent peptides of islet amyloid, sulfonylurea therapy might increase the rate of deposition of islet amyloid and thereby accelerate the decline of % beta in NIDDM, compared with diet therapy alone.

Aged↗