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Biomedical subjects

Michael Stumvoll

Publications and source records attributed to Michael Stumvoll.

At least 19 recordsLinked to original sources
PubMed2003

[Insulin secretion and aging. Implications for insulin therapy in the geriatric patient with diabetes mellitus].

Diabetes mellitus has become a global epidemic. With diabetes prevalence highest in old age groups and aging populations, it is the prevalence among the elderly, above all, where most dramatic increases can be expected. The present paper summarizes the age-related metabolic abnormalities resulting in diabetes mellitus, specifically the progressive decline in beta-cell function. In addition, insulin therapy in the elderly is described. Among the many different insulins and therapeutic algorithms, advantages and disadvantages pertaining to the elderly will be highlighted. Specifics in frequency, pathophysiology, and avoidance of severe hypoglycemia in the elderly are discussed.

Age Factors↗
PubMed2003

Elevated plasma nonesterified fatty acids are associated with deterioration of acute insulin response in IGT but not NGT.

High concentrations of nonesterified fatty acids (NEFA) are a risk factor for developing type 2 diabetes in Pima Indians. In vitro and in vivo, chronic elevation of NEFA decreases glucose-stimulated insulin secretion. We hypothesized that high fasting plasma NEFA would increase the risk of type 2 diabetes by inducing a worsening of glucose-stimulated insulin secretion in Pima Indians. To test this hypothesis, fasting plasma NEFA concentrations, body composition, insulin action (M), acute insulin response (AIR, 25-g IVGTT), and glucose tolerance (75-g OGTT) were measured in 151 Pima Indians [107 normal glucose tolerant (NGT), 44 impaired glucose tolerant (IGT)] at the initial visit. These subjects, participants in ongoing studies of the pathogenesis of obesity and type 2 diabetes, had follow-up measurements of body composition, glucose tolerance, M, and AIR. In NGT individuals, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were negatively associated with AIR after adjustment for age, sex, percent body fat, and M (P = 0.03). Longitudinally, high fasting plasma NEFA concentrations at the initial visit were not associated with change in AIR. In individuals with IGT, cross-sectionally, high fasting plasma NEFA concentrations at the initial visit were not associated with AIR. Longitudinally, high fasting plasma NEFA concentrations at the initial visit were associated with a decrease in AIR before (P < 0.0001) and after adjustment for sex, age at follow-up, time of follow-up, change in percent body fat and insulin sensitivity, and AIR at the initial visit (P = 0.0006). In conclusion, findings in people with NGT indicate that fasting plasma NEFA concentrations are not a primary etiologic factor for beta-cell failure. However, in subjects who have progressed to a state of IGT, chronically elevated NEFA seem to have a deleterious effect on insulin-secretory capacity.

Adolescent↗
PubMed2003

Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala.

The Pro12Ala polymorphism of the peroxisome proliferator-activated receptor (PPARgamma(2)) is associated with reduced risk for type 2 diabetes. Although increased insulin sensitivity of glucose disposal and lipolysis has been reported, the exact mechanism by which the risk reduction is conferred is not clear. Because the conclusion of greater insulin sensitivity hinged upon lower insulin levels in some studies, it is possible that more efficient insulin clearance is involved. We therefore estimated insulin clearance during a euglycemic hyperinsulinemic clamp (insulin infusion rate divided by steady-state insulin concentration, 229 normal glucose tolerant [NGT] subjects), an oral glucose tolerance test (OGTT) (mean C-peptide divided by mean insulin concentrations, 406 NGT, 54 impaired glucose tolerant or mildly diabetic subjects), and a hyperglycemic clamp (120 minutes, 10 mmol/L, C-peptide divided by insulin in the steady-state, 56 NGT subjects). In the carriers of the Ala allele (prevalence approximately 24%), insulin clearance in all 3 protocols was significantly greater ( approximately 10%), than in controls. While the results from the euglycemic clamp reflect both hepatic and peripheral insulin clearance, those from the OGTT and the hyperglycemic clamp reflect mainly hepatic insulin extraction. Free fatty acids (FFA) during the steady state of the euglycemic hyperinsulinemic clamp were significantly lower in carriers of the Ala allele (26 +/- 5 micromol/L) than in controls (46 +/- 3 micromol/L, P =.02). In conclusion, the Pro12Ala polymorphism is associated with increased insulin clearance. This could be the result of reduced FFA delivery, which has been shown to improve hepatic insulin removal and sensitivity. Because PPARgamma(2) is mainly expressed in adipose tissue, one of the main regulatory effects of the polymorphism may well be the more efficient suppression of (possibly intra-abdominal) lipolysis.

Adult↗
PubMed2003

Relationship of serum adiponectin and leptin concentrations with body fat distribution in humans.

OBJECTIVE: We investigated whether serum concentrations of adiponectin are determined by body fat distribution and compared the findings with leptin. RESEARCH METHODS AND PROCEDURES: Serum concentrations of adiponectin and leptin were measured by radioimmunoassay (n = 394) and analyzed for correlation with sex, age, and body fat distribution, i.e., waist-to-hip ratio, waist and hip circumference, and subcutaneous adipose tissue area of the lower leg as assessed by magnetic resonance imaging. RESULTS: After adjusting for sex and percentage of body fat, adiponectin was negatively (r = -0.17, p < 0.001) and leptin was positively (r = 0.22, p < 0.001) correlated with waist-to-hip ratio. Leptin, but not adiponectin, correlated with both waist (r = 0.49, p < 0.001) and hip circumference (r = 0.46, p < 0.001). Furthermore, leptin, but not adiponectin, correlated with the proportion of subcutaneous fat of the lower leg cross-sectional area (r = 0.37, p < 0.001). DISCUSSION: These data suggest that both adipocytokines are associated with central body fat distribution, and serum adiponectin concentrations are determined predominantly by the visceral fat compartment.

Adiponectin↗
PubMed2003

Relative importance of liver, kidney, and substrates in epinephrine-induced increased gluconeogenesis in humans.

Splanchnic and renal net balance measurements indicate that lactate and glycerol may be important precursors for epinephrine-stimulated gluconeogenesis (GNG) in liver and kidney, but the effects of epinephrine on their renal and hepatic conversion to glucose in humans have not yet been reported. We therefore used a combination of renal balance and isotopic techniques in nine postabsorptive volunteers to measure systemic and renal GNG from these precursors before and during a 3-h infusion of epinephrine (270 pmol. kg-1. min-1) and calculated hepatic GNG as the difference between systemic and renal rates. During infusion of epinephrine, renal and hepatic GNG from lactate increased 4- to 6-fold and accounted for approximately 85 and 70% of renal and hepatic glucose release, respectively, at the end of study; renal and hepatic GNG from glycerol increased approximately 1.5- to 2-fold and accounted for approximately 7-9% of renal and hepatic glucose release at the end of study. The increased renal GNG from lactate and glycerol was due not only to their increased renal uptake (approximately 3.3- and 1.4-fold, respectively) but also increased renal gluconeogenic efficiency (approximately 1.8- and 1.5-fold). The increased renal uptake of lactate and glycerol was wholly due to their increased arterial concentrations, since their renal fractional extraction remained unchanged and renal blood flow decreased. We conclude that 1) lactate is the predominant precursor for epinephrine-stimulated GNG in both liver and kidney, 2) hepatic and renal GNG from lactate and glycerol are similarly sensitive to stimulation by epinephrine, and 3) epinephrine increases renal GNG from lactate and glycerol by increasing substrate availability and the gluconeogenic efficiency of the kidney.

Adult↗
PubMed2003

Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity.

The existence of metabolically relevant intramyocellular lipids (IMCL) as assessed by the noninvasive (1)H-magnetic resonance spectroscopy (MRS) has been established. In the present studies, we analyzed the relationships between IMCL in two muscle types [the predominantly nonoxidative tibialis muscle (tib) and the predominantly oxidative soleus muscle (sol)] and anthropometric data, aerobic capacity (VO(2)max, bicycle ergometry, n = 77) and insulin sensitivity (hyperinsulinemic euglycemic clamp, n = 105) using regression analysis. In univariate regression, IMCL (tib) was weakly but significantly correlated with percentage of body fat (r = 0.28, P = 0.01), whereas IMCL (sol) was better correlated with waist-to-hip ratio (r = 0.41, P < 0.0001). No significant univariate correlation with age or maximal aerobic power was observed. After adjusting for adiposity, IMCL (tib) was positively correlated with measures of aerobic fitness. A significant interaction term between VO(2)max and percentage of body fat on IMCL (tib) (P = 0.04) existed (whole model r(2) = 0.26, P = 0.001). In contrast, aerobic fitness did not influence IMCL (sol). No correlation between insulin sensitivity as such and IMCL (tib) (r = -0.13, P = 0.2) or IMCL (sol) (r = 0.03, P = 0.72) was observed. Nethertheless, a significant interaction term between VO(2)max and IMCL on insulin sensitivity existed [P = 0.04 (tib) and P = 0.02 (sol)]; [whole model (sol) r(2) = 0.61, P < 0.0001, (tib) r(2) = 0.60, P < 0.0001]. In conclusion, obesity and aerobic fitness are important determinants of IMCL. IMCL and insulin sensitivity are negatively correlated in untrained subjects. The correlation between the two parameters is modified by the extent of aerobic fitness and cannot be found in endurance trained subjects. Thus, measurements of aerobic fitness and body fat are indispensable for the interpretation of IMCL and its relationship with insulin sensitivity.

Adipose Tissue↗
PubMed2003

Thiazolidinediones -- some recent developments.

The role of thiazolidinediones (currently rosiglitazone and pioglitazone) in the treatment of Type 2 diabetes is firmly established. The mechanism of action involves binding to the peroxisome proliferator-activated receptor-gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also other cell types such as endothelial cells, macrophages and monocytes, vascular smooth muscle cells and colonic epithelium. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g., increased free fatty acids, decreased adiponectin) in a way that results in net improvement of insulin sensitivity (i.e., in muscle and liver). A direct or indirect effect on AMP-dependent protein kinase may also be involved. Prevention of lipid accumulation in tissues critical to glycaemia such as visceral adipocytes, liver, muscle and beta-cells at the expense of lipids accumulating at the less harmful subcutaneous site may be central to their net metabolic effect. The sustained beneficial effect of troglitazone on beta-cell function in women with previous gestational diabetes in addition to the insulin-sensitising properties point to an important role of this class of drugs in the prevention of Type 2 diabetes. Original safety concerns based on animal and in vitro studies (e.g., fatty bone marrow transformation, colonic cancer, adipogenic transdifferentiation of blood cells) remain theoretical issues but become less pressing practically with prolonged uneventful clinical use. Hepatotoxicity for troglitazone and fluid retention, which can aggravate pre-existing heart failure, are the most important side effects. In summary, with the thiazolidinediones, a novel concept for the treatment of insulin resistance and possibly preservation of beta-cell function is available that could become effective in the prevention of Type 2 diabetes. Moreover, their anti-inflammatory properties also make them interesting in the prevention and treatment of atherosclerosis and possibly other inflammatory conditions (e.g., inflammatory bowel disease). Long-term data will be necessary for a final risk-benefit assessment of these substances.

Adipose Tissue↗
PubMed2003

Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism.

In animals, the adipocyte-derived hormone adiponectin has been shown to improve insulin sensitivity, a key factor in the pathogenesis of type 2 diabetes. In Pima Indians, high plasma adiponectin levels are associated with increased insulin sensitivity and reduced risk of type 2 diabetes. It is unclear whether this is also the case in white individuals and whether an additional beneficial effect on lipid metabolism exists. We therefore analyzed in nondiabetic individuals the associations between plasma adiponectin concentrations and insulin sensitivity measured by a euglycemic-hyperinsulinemic clamp (n = 262) and estimated by an oral glucose tolerance test (OGTT; n = 636) and serum lipid parameters using correlational analysis. Plasma adiponectin concentrations were positively correlated with insulin sensitivity, both measured with the clamp (r = 0.28, P = 0.0015 in women; r = 0.42, P < 0.0001 in men) and estimated from the OGTT (r = 0.37, P < 0.0001 in women; r = 0.41, P < 0.0001 in men) before and after adjusting for sex and percentage of body fat (all P < 0.001). Fasting triglycerides and the free fatty acid (FFA) concentrations during the OGTT (area under the curve) and at 120 min were negatively correlated in both women and men, whereas HDL was positively correlated with plasma adiponectin concentrations (all P < 0.004). Most notable, these relationships remained significant after adjusting for insulin sensitivity of glucose disposal in addition to sex and percentage of body fat (all P < 0.05). In conclusion, high adiponectin predicts increased insulin sensitivity. This relationship is independent of low body fat mass and affects not only insulin-stimulated glucose disposal but also lipoprotein metabolism and insulin-mediated suppression of postprandial FFA release. This suggests pleiotropic insulin sensitizing effects of adiponectin in humans.

Adiponectin↗
PubMed2003

Altered homeostatic adaptation of first- and second-phase beta-cell secretion in the offspring of patients with type 2 diabetes: studies with a minimal model to assess beta-cell function.

We adapted a minimal model to assess beta-cell function during a hyperglycemic glucose clamp and to uncover peculiar aspects of the relationship among beta-cell function, plasma glucose, and insulin sensitivity (IS) in offspring of Caucasian patients with type 2 diabetes (OfT2D). We pooled two data sets of OfT2D (n = 69) and control subjects (n = 45) with normal glucose regulation. Plasma C-peptide was measured during a hyperglycemic clamp ( approximately 10 mmol/l) to quantify model-based first-phase secretion and glucose sensitivity of second-phase secretion (beta). IS was quantified during the hyperglycemic clamp. In the pooled data, first-phase secretion was linearly and negatively related to fasting plasma glucose, but not IS; OfT2D lay on a distinct line shifted to the left of the control subjects. In contrast, beta was negatively related to IS, and OfT2D lay on a distinct line shifted more and more to the left of the control subjects, as IS was worse. Thus, in OfT2D lower beta-cell adaptive responses exist between ambient glycemia and first-phase insulin secretion and between IS and second-phase secretion. Under conditions leading to decreased insulin sensitivity, these disturbed relationships may lead to progression to diabetes in OfT2D.

Adult↗
PubMed2003

Acute hyperglycemia causes intracellular formation of CML and activation of ras, p42/44 MAPK, and nuclear factor kappaB in PBMCs.

Twenty-three nondiabetic volunteers were divided into three groups. In group A (n = 9), the glucose infusion was adjusted to maintain blood glucose at 5 mmol/l (euglycemic clamp). In group B (n = 9), the glucose infusion was adjusted to maintain blood glucose at 10 mmol/l (hyperglycemic clamp) over 2 h. Group C consisted of five volunteers who were studied as the control group. Peripheral blood mononuclear cells (PBMCs) were isolated before and at the end of a 2-h clamp. In group C, PBMCs were isolated before and after 2 h without performing a clamp. The euglycemic clamp as well as "no clamp" had no effects on all parameters studied. In contrast, a significant increase in carboxymethyllysine (CML) content and p21(ras) and p42/44 mitogen-activated protein kinase (MAPK) phosphorylation was observed at the end of a 2-h hyperglycemic clamp. The nuclear factor (NF)-kappaB (but not Oct-1) binding activity increased significantly in the hyperglycemic clamp. Western blots confirmed NF-kappaB-p65-antigen translocation into the nucleus. IkappaBalpha did not change significantly in both groups. Hyperglycemia-mediated NF-kappaB activation and increase of CML content, p21(ras), and p42/44 MAPK phosphorylation was also seen in ex vivo-isolated PBMCs stimulated with 5 or 10 mmol/l glucose. Addition of insulin did not influence the results. Inhibition of activation of ras, MAPK, or protein kinase C blocked hyperglycemia-mediated NF-kappaB activation in ex vivo-isolated PBMCs stimulated with 10 mmol/l glucose. Similar data were obtained using an NF-kappaB-luciferase reporter plasmid. Therefore, we can conclude that an acute hyperglycemia-mediated mononuclear cell activation is dependent on activation of ras, p42/p44 MAPK phosphorylation, and subsequent NF-kappaB activation and results in transcriptional activity in PBMCs.

Animals↗
PubMed2003

Palmitate-induced activation of the hexosamine pathway in human myotubes: increased expression of glutamine:fructose-6-phosphate aminotransferase.

The nutrient sensing capacity of the hexosamine biosynthetic pathway (HBP) has been implicated in the development of insulin resistance of skeletal muscle. To study the molecular mechanism of the free fatty acid (FFA)-induced activation of the HBP myotubes obtained from muscle biopsies of metabolically characterized, subjects were stimulated with different fatty acids for 20 h. Incubation with the saturated fatty acids palmitate and stearate (0.5 mmol/l) resulted in a three- to fourfold increase in mRNA expression of glutamine:fructose-6-phosphate aminotransferase (GFAT), the key and rate-limiting enzyme of the hexosamine pathway. Unsaturated fatty acids or 30 mmol/l glucose had little or no effect. Palmitate increased the amount of GFAT protein nearly two-fold, and subsequently, the concentration of UDP-N-acetylglucosamine, the end product of the HBP, was 1.3-fold enhanced in the palmitate-stimulated myotubes. The nonmetabolized fatty acid bromopalmitate had no effect. The DNA binding activity of the transcription factor Sp1, a target downstream of the HBP, was increased by palmitate and completely lost after enzymatic removal of O-GlcNAc. No correlation was found between the palmitate-induced increase in GFAT protein and the insulin resistance in the respective subjects. The findings reveal a new mechanism for how FFAs induce the activation of the HBP.

Cells, Cultured↗
PubMed2003

Glucose allostasis.

In many organisms, normoglycemia is achieved by a tight coupling of nutrient-stimulated insulin secretion in the pancreatic beta-cell (acute insulin response [AIR]) and the metabolic action of insulin to stimulate glucose disposal (insulin action [M]). It is widely accepted that in healthy individuals with normal glucose tolerance, normoglycemia can always be maintained by compensatorily increasing AIR in response to decreasing M (and vice versa). This has been mathematically described by the hyperbolic relationship between AIR and M and referred to as glucose homeostasis, with glucose concentration assumed to remain constant along the hyperbola. Conceivably, glucose is one of the signals stimulating AIR in response to decreasing M. Hypothetically, as with any normally functioning feed-forward system, AIR should not fully compensate for worsening M, since this would remove the stimulus for the compensation. We provide evidence from cross-sectional, longitudinal, and prospective data from Pima Indians (n = 413) and Caucasians (n = 60) that fasting and postprandial glucose concentrations increase with decreasing M despite normal compensation of AIR. For this physiologic adaptation to chronic stress (insulin resistance), we propose to use the term "glucose allostasis." Allostasis (stability through change) ensures the continued homeostatic response (stability through staying the same) to acute stress at some cumulative costs to the system. With increasing severity and over time, the allostatic load (increase in glycemia) may have pathological consequences, such as the development of type 2 diabetes.

Adolescent↗
PubMed2003

Genetic variation in the human winged helix/forkhead transcription factor gene FOXC2 in Pima Indians.

FOXC2 is a winged helix gene that has been shown to counteract obesity, hypertriglyceridemia, and diet-induced insulin resistance in rodents. Therefore, FOXC2 was analyzed as a candidate gene for susceptibility to type 2 diabetes in Pima Indians. Four variants were identified by sequencing the coding region, as well as 638 bp of the 5' region and 300 bp of the 3' region of the gene. Two single nucleotide polymorphisms (SNPs) were found in the putative promoter region, a C-512T transition and a G-350T. In addition, two SNPs were found in the 3' region, a C1548T and a C1702T. The G-350T and the C1702T variants were in complete linkage disequilibrium, and the C1548T variant was relatively rare; therefore, only the C-512T and G-350T variants were additionally genotyped in 937 full-blooded Pima Indians. Neither of these polymorphisms were associated with type 2 diabetes; however, the C-512T variant was associated with BMI (P = 0.03) and percentage of body fat (P = 0.02) in male and female Pima subjects, as well as with basal glucose turnover and fasting plasma triglycerides in women. Our data indicate that variation in FOXC2 may have a minor role in body weight control and seems to be involved in the regulation of basal glucose turnover and plasma triglyceride levels in women, but this gene does not significantly contribute to the etiology of type 2 diabetes in Pima Indians.

Arizona↗
PubMed2003

Metabolic effects of the Gly1057Asp polymorphism in IRS-2 and interactions with obesity.

Insulin receptor substrate (IRS)-2 plays an important role in insulin signaling and its disruption results in diabetes in mice. In humans, the IRS-2 Gly1057Asp substitution was associated with lower risk of type 2 diabetes in lean individuals, but with a higher risk in obese individuals. To clarify the role of IRS-2 on the development of type 2 diabetes and obesity in Pima Indians, and particularly to investigate whether the effects of the Gly1057Asp polymorphism on metabolism are mediated by obesity, molecular scanning of the gene for mutations was performed and interaction of the polymorphism with obesity was tested. We identified the previously described Gly1057Asp mutation as well as a rare Asp819His mutation and four silent polymorphisms. The effect of the Gly1057Asp mutation on type 2 diabetes and obesity was tested in a large cohort of Pima Indians (n = 998). A subgroup of nondiabetic full-heritage Pima Indians (n = 233) had measurements of body composition, glucose tolerance, insulin action (M), endogenous glucose production (EGP; hyperinsulinemic clamp), acute insulin response (AIR, 25-g intravenous glucose tolerance test, n = 118 normal glucose-tolerant subjects), and percutaneous fat biopsy specimens from the periumbilical region (n = 160). A total of 132 nondiabetic subjects were included in longitudinal analyses. The frequency of the Asp1057 allele was 0.6. In cross-sectional analyses, subjects homozygous for the Asp1057 allele (Asp/Asp) had a higher prevalence of type 2 diabetes than heterozygote individuals and subjects homozygous for the Gly1057 allele (X/Gly, P = 0.04). There was no effect on BMI (P = 0.78) or gene-BMI interaction on the prevalence of type 2 diabetes (P = 0.57). In the nondiabetic subgroup, subjects with Asp/Asp had higher percent body fat (P = 0.01), BMI (P = 0.02), and waist circumference (P = 0.004), but there was no difference in metabolic characteristics (all P > 0.2). However, the relationship between percent body fat and fasting glucose, basal EGP, EGP during the clamp, AIR, and subcutaneous abdominal adipocyte size was significantly different in the Asp/Asp group (P for interaction = 0.02, 0.06, 0.0007, 0.08, and 0.006, respectively) compared with the X/Gly group, suggesting a more detrimental effect of Asp homozygosity on these traits with increasing percent body fat. In longitudinal analyses, among subjects in the upper tertile of change in percent body fat, those with Asp/Asp had a larger increase in fasting and postprandial glycemia and basal EGP and a larger decrease in M and AIR than subjects with X/Gly, independent of change in obesity (all P < 0.05). In conclusion, our findings suggest that the association of homozygosity for the Asp1057 allele in IRS-2 with type 2 diabetes in Pima Indians may be mediated by interaction of the polymorphism with obesity on several diabetes-related traits.

Adult↗
PubMed2003

Assessing the shape of the glucose curve during an oral glucose tolerance test.

OBJECTIVE: The oral glucose tolerance test (OGTT) is used to define the status of glucose tolerance based on the plasma glucose level at 120 min. The purpose of the present study was to identify parameters that determine the shape of the plasma glucose course measured at 0, 30, 60, 90, and 120 min during an OGTT. RESEARCH DESIGN AND METHODS: OGTT data from 551 subjects (485 with normal glucose tolerance [NGT] and 66 with impaired glucose tolerance [IGT]) were analyzed. We distinguished between "monophasic," "biphasic," and unclassified glucose shapes. A "shape" index based on the extent and the direction of the plasma glucose change in the second hour allowed us to treat shape as a continuous variable. RESULTS: In the biphasic group, the NGT-to-IGT ratio was slightly higher (173/20 vs. 209/40, P = 0.08) and the male-to-female ratio was lower (60/133 vs. 120/129, P = 0.0003). Subjects with a biphasic shape had significantly lower age, BMI, waist-to-hip ratio (WHR), HbA(1c), plasma glucose, and area under the insulin curve (insulin(AUC)) and a better estimated insulin sensitivity and secretion (using validated indexes) than monophasic subjects (all P < 0.05). By adjusting this shape index for glucose(AUC) (as continuous measure of glucose tolerance), correlations with age, BMI, WHR, HbA(1c), and insulin(AUC) were completely abolished. The adjusted shape index was still higher in female than in male subjects but lower in IGT than in NGT subjects (both P = 0.0003). Finally, we tested common polymorphisms in insulin receptor substrate (IRS)-1, IRS-2, calpain-10, hepatic lipase, and peroxisome proliferator-activated receptor-gamma for association with the shape index. CONCLUSIONS: We conclude that the plasma glucose shape during an OGTT depends on glucose tolerance and sex. In addition, genetic factors seem to play a role. The shape index may be a useful metabolic screening parameter in epidemiological and genetic association studies.

Administration, Oral↗
PubMed2003

Reduced skeletal muscle oxygen uptake and reduced beta-cell function: two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes.

OBJECTIVE: Studies on insulin sensitivity and insulin secretion in subjects with a familial predisposition for type 2 diabetes mellitus (T2DM) traditionally produce inconsistent results. This may be due to small sample size, subject selection, matching procedures, and perhaps lack of a measure of physical fitness. RESEARCH DESIGN AND METHODS: In the present study, we specifically tested the hypothesis that a family history of T2DM is associated with reduced VO(2max), measured by incremental bicycle ergometry, independent of insulin sensitivity estimated from an oral glucose tolerance test (OGTT; n = 424) and measured by a euglycemic-hyperinsulinemic clamp (n = 185). Subjects included in the study were young (34 +/- 10 years), healthy, and normal glucose tolerant with either a first-degree relative (FDR) with T2DM (n = 183), a second-degree relative with T2DM (n = 94), or no family history of T2DM (control subjects, n = 147). BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). RESULTS: BMI, percent body fat, waist-to-hip ratio (WHR), and habitual physical activity (HPA; standard questionnaire) were comparable among groups. FDRs had significantly lower VO(2max) than control subjects: 40.5 +/- 0.6 vs. 45.2 +/- 0.9 ml O(2)/kg lean body mass, P = 0.01 after adjusting for sex, age, BMI, HPA, and insulin sensitivity (euglycemic-hyperinsulinemic clamp). Insulin sensitivity per se was not affected by family history of T2DM after adjusting for age, sex, BMI, and percent body fat (P = 0.76). The appropriateness of beta-cell function for the individual insulin sensitivity (disposition index: product of a validated secretion parameter [OGTT] and sensitivity [clamp]) was significantly lower in FDRs (87 +/- 4 units) versus control subjects (104 +/- 6 units, P = 0.02 after adjusting for sex, age, and BMI). Analyses of the larger OGTT group produced essentially the same results. CONCLUSIONS: In conclusion, these data are compatible with the hypothesis that familial predisposition for T2DM impairs maximal oxygen consumption in skeletal muscle. Because habitual physical activity was not different, genetic factors may be involved. Conceivably, reduced VO(2max) precedes skeletal muscle insulin resistance, providing a partial explanation for discrepancies in the literature.

Adult↗