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PubMed2005

Insulin Promoter Factor 1 variation is associated with type 2 diabetes in African Americans.

BACKGROUND: Defective insulin secretion is a key defect in the pathogenesis of type 2 diabetes (T2DM). The beta-cell specific transcription factor, insulin promoter factor 1 gene (IPF1), is essential to pancreatic development and the maintenance of beta-cell mass. We hypothesized that regulatory or coding variants in IPF1 contribute to defective insulin secretion and thus T2DM. METHODS: We screened 71 Caucasian and 69 African American individuals for genetic variants in the promoter region, three highly conserved upstream regulatory sequences (PH1, PH2 and PH3), the human beta-cell specific enhancer, and the two exons with adjacent introns. We tested for an association of each variant with T2DM Caucasians (192 cases and 192 controls) and African Americans (341 cases and 186 controls). RESULTS: We identified 8 variants in the two populations, including a 3 bp insertion in exon 2 (InsCCG243) in African Americans that resulted in an in-frame proline insertion in the transactivation domain. No variant was associated with T2DM in Caucasians, but polymorphisms at -3766 in the human beta-cell enhancer, at -2877 bp in the PH1 domain, and at -108 bp in the promoter region were associated with T2DM in African American subjects (p < 0.01), both individually and as haplotypes (p = 0.01 correcting by permutation test). No SNP altered a binding site for the expected beta-cell transcription factors. The rare alleles of InsCCG243 in exon 2 showed a trend to over-representation among African American diabetic subjects (p < 0.1), but this trend was not significant on permutation test. CONCLUSION: The common alleles of regulatory variants in the 5' enhancer and promoter regions of the IPF1 gene increase susceptibility to type 2 diabetes among African American individuals, likely as a result of gene-gene or gene-environment interactions. In contrast, IPF1 is not a cause of type 2 diabetes in Caucasians. A previously described InsCCG243 variant may contribute to diabetes susceptibility in African American individuals, but is of low penetrance.

Adult↗
PubMed2005

Association of CETP TaqI and APOE polymorphisms with type II diabetes mellitus in North Indians: a case control study.

BACKGROUND: Genetic variants of proteins involved in lipid metabolism may play an important role in determining the susceptibility for complications associated with type II diabetes mellitus (T2DM). Goal of the present study was to determine the association of cholesteryl ester transfer protein TaqI B, D442G, and APOE Hha I polymorphisms with T2DM and its complications. METHODS: Study subjects were 136 patients and 264 healthy controls. All polymorphisms were detected using PCR-RFLP and statistical analysis done with chi2 test and ANOVA. RESULTS: Although CETP TaqI B polymorphism was not associated with the T2DM, yet B1B2 genotype was significantly (p = 0.028) associated with high risk of hypertension in diabetic patients (OR = 3.068, 95% CI 1.183-7.958). In North Indians D442G variation in CETP gene was found to be absent. Frequency of APOE HhaI polymorphism was also not different between patients and controls. In diabetic patients having neuropathy and retinopathy significantly different levels of total-cholesterol [(p = 0.001) and (p = 0.029) respectively] and LDL-cholesterol [(p = 0.001) and (p = 0.001) respectively] were observed when compared to patients with T2DM only. However, lipid levels did not show any correlation with the CETP TaqI B and APOE Hha I genetic polymorphisms. CONCLUSION: CETP TaqI B and APOE HhaI polymorphism may not be associated with type II diabetes mellitus in North Indian population, however CETP TaqI B polymorphism may be associated with hypertension along with T2DM.

Journal Article↗
PubMed2003

Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

BACKGROUND: Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease. HYPOTHESIS: Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress. TESTING OF THE HYPOTHESIS: The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1) The L-arginine substrate. (2) The eNOS enzyme. (3) The BH4 cofactor. IMPLICATIONS OF THE HYPOTHESIS: If we view T2DM as a vascular disease initially with a later manifestation of hyperglycemia, we may be able to better understand and modify the multiple toxicities associated with insulin resistance, metabolic syndrome, prediabetes, overt T2DM, and accelerated atherosclerosis (atheroscleropathy). The importance of endothelial nitric oxide synthase, endothelial nitric oxide, tetrahydrobiopterin (BH4), L-arginine, and redox stress are discussed in relation to endothelial cell dysfunction and the development and progression of atheroscleropathy and T2DM. In addition to the standard therapies to restore endothelial cell dysfunction and stabilization of vulnerable atherosclerotic plaques, this article will discuss the importance of folic acid (5MTHF) supplementation in this complex devastating disease process. Atheroscleropathy and hyperglycemia could be early and late manifestations, respectively, in the natural progressive history of T2DM.

Journal Article↗
PubMed2005

Serum resistin is associated with C-reactive protein & LDL cholesterol in type 2 diabetes and coronary artery disease in a Saudi population.

AIMS: Resistin is an adipocyte-derived factor implicated in obesity-associated type 2 diabetes (T2DM). This study examines the association between human serum resistin, T2DM and coronary heart disease. METHODS: One hundred and fourteen Saudi Arabian patients (male: female ratio 46:68; age 51.4 (mean +/- SD)11.7 years; median and range: 45.59 (11.7) years and BMI: 27.1 (mean +/- SD) 8.1 Kgm2 median and range: 30.3 (6.3) were studied. Serum resistin and C-reactive protein (CRP), a marker of inflammation CRP levels, were measured in all subjects. (35 patients had type 2 diabetes mellitus (T2DM); 22 patients had coronary heart disease (CHD). RESULTS: Serum resistin levels were 1.2-fold higher in type 2 diabetes and 1.3-fold higher in CHD than in controls (p = 0.01). In addition, CRP was significantly increased in both T2DM and CHD patients (p = 0.007 and p = 0.002 respectively). The use of regression analysis also determined that serum resistin correlated with CRP levels (p = 0.04, R2 0.045). CONCLUSION: The findings from this study further implicate resistin as a circulating protein associated with T2DM and CHD. In addition this study also demonstrates an association between resistin and CRP, a marker of inflammation in type 2 diabetic patients.

Adult↗
PubMed2004

Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis.

The contribution of increased gluconeogenesis (GNG) to the excessive rate of endogenous glucose production (EGP) in type 2 diabetes (T2DM) is well established. However, the separate effects of obesity (total body fat), visceral adiposity, and T2DM have not been investigated. We measured GNG (by the (2)H(2)O technique) and EGP (with 3-(3)H-glucose) after an overnight fast in 44 type 2 diabetic and 29 gender/ethnic-matched controls. Subjects were classified as obese (body mass index 30 kg/m(2) or greater) or nonobese (body mass index < 30 kg/m(2)); diabetic subjects were further subdivided according to the severity of fasting hyperglycemia [fasting plasma glucose (FPG) < 9 mm or >or= 9 mm]. EGP was similar in nondiabetic controls and T2DM with FPG less than 9 mm but was increased in T2DM with FPG >or= 9 mm (P < 0.001). Within the diabetic groups, obesity had an independent effect to further increase basal EGP (P < 0.01). In both nonobese diabetic groups, both the percent GNG and gluconeogenic flux were increased, compared with nonobese nondiabetic controls. In both diabetic groups, obesity further increased both percent GNG and gluconeogenic flux. In obese and nonobese T2DM, the increase in gluconeogenic flux was not accompanied by a reciprocal decrease in glycogenolysis, indicating a loss of hepatic autoregulation. By multivariate analysis, gluconeogenic flux was positively correlated with percent body fat, visceral fat, and the fasting plasma free fatty acid and glucose concentrations (all P <or= 0.02). We conclude that obesity per se, and visceral fat accumulation in particular, as well as poorly controlled diabetes are potent stimuli to augment gluconeogenic flux.

Abdomen↗
PubMed2004

Sustained reduction in plasma free fatty acid concentration improves insulin action without altering plasma adipocytokine levels in subjects with strong family history of type 2 diabetes.

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment. We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without increasing adiponectin levels or altering the secretion of other adipocytokines by the adipocyte. These results suggest that lipotoxicity already is well established in individuals who are genetically predisposed to develop T2DM and that drugs that cause a sustained reduction in the elevated plasma FFA concentration may represent an effective modality for the prevention of T2DM in high-risk, genetically predisposed, normal glucose-tolerant individuals despite the lack of an effect on adipocytokine concentrations.

Adiponectin↗
PubMed2004

beta-Cell function and insulin sensitivity in early adolescence: association with body fatness and family history of type 2 diabetes mellitus.

The prevalence of type 2 diabetes mellitus (T2DM) among adolescents has increased 5- to 10-fold over the past decade. T2DM results from pancreatic beta-cell dysfunction and insulin resistance. Using rapid iv glucose tolerance testing, we examined beta-cell function and insulin resistance in 72 predominantly Latino eighth grade students (41 males and 31 females; mean +/- sem age, 13.6 +/- 0.1 yr). Thirty-six percent of the children had body mass indexes above the 85th percentile for age and gender, and 50% had a first- or second-degree relative with T2DM. Overweight children were five times more likely to be in the highest quartile for insulin resistance. Children with a family history of T2DM were five times more likely to be in the lowest quartile for insulin secretory capacity, 4.5 times more likely to be in the lowest quartile for glucose disposal, and three times more likely to be in the lowest quartile for insulin resistance. These findings are consistent with a model for the physiology of T2DM in which a familial beta-cell dysfunction is unmasked by increasing insulin resistance secondary to overweight in this predominantly Latino population.

Adipose Tissue↗
PubMed2004

beta-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.

The nature of the progressive beta-cell failure occurring as normal glucose tolerant (NGT) individuals progress to type 2 diabetes (T2DM) is incompletely understood. We measured insulin sensitivity (by a euglycemic insulin clamp) and insulin secretion rate (by deconvolution of plasma C-peptide levels during an oral glucose tolerance test) in 188 subjects [19 lean NGT (body mass index [BMI] </= 25 kg/m(2)), 42 obese NGT, 22 BMI-matched impaired glucose tolerance [IGT], and 105 BMI-matched T2DM]. Main determinants of beta-cell function on the oral glucose tolerance test were derived from a mathematical model featuring the following: 1) glucose concentration-insulin secretion dose response (glucose sensitivity), 2) a secretion component proportional to the derivative of plasma glucose concentration (rate sensitivity); and 3) a potentiation factor. When NGT and T2DM were subgrouped by 2-h plasma glucose concentrations, insulin secretion rate revealed an inverted U-shaped pattern, rising through NGT up to IGT and falling off thereafter. In contrast, beta-cell glucose sensitivity dropped in a monophasic, curvilinear fashion throughout the range of 2-h plasma glucose. Within the NGT range (2-h glucose of 4.1-7.7 mmol/liter), beta-cell glucose sensitivity declined by 50-70% (P < 0.02). Insulin sensitivity decreased sharply in the transition from lean to obese NGT and then declined further in IGT and mild T2DM to level off in the higher three quartiles of diabetic hyperglycemia. In T2DM, defective beta-cell potentiation and rate sensitivity also emerged (P </= 0.05). In the whole data set, insulin sensitivity and the dynamic parameters of beta-cell function explained 89% of the variability of 2-h plasma glucose levels. The following conclusions were reached: 1) beta-cell glucose sensitivity falls already within the NGT range in association with rising 2-h plasma glucose concentrations, although absolute insulin secretion rates increase; and 2) throughout the glucose tolerance range, dynamic parameters of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) and insulin sensitivity are independent determinants of 2-h plasma glucose levels.

Adult↗
PubMed2004

Molecular screening and association analyses of the interleukin 6 receptor gene variants with type 2 diabetes, diabetic nephropathy, and insulin sensitivity.

IL-6 levels and polymorphisms have been implicated in type 2 diabetes mellitus (T2DM) and insulin resistance. The IL-6 receptor (IL-6R) comprises two subunits, IL-6R and gp130, of which IL-6R confers specificity to IL-6 action and is located in a region of replicated linkage to T2DM on chromosome 1q21. We screened this gene for variation in Northern European Caucasian and African-American ethnic groups. We identified 11 variants with a minor allele frequency over 5%, including two amino acid changes (D358A and V385I) and four variants in the 3' untranslated region. No variant was associated with obesity or measures of insulin sensitivity, but two single nucleotide polymorphisms in the 3' untranslated region showed a trend to an association with T2DM in all Caucasians, and three single nucleotide polymorphisms, including D358A, showed a trend (P < 0.06) to an association with T2DM among the subset of Northern European Caucasians. Variant V385I was unique to African-Americans and was significantly associated with diabetes and diabetic nephropathy (P < 0.05). Among individuals heterozygous for the four variants in the transcribed sequence, one allele was significantly overrepresented, thus suggesting the existence of a regulatory variant controlling mRNA stability or expression. IL-6R is not likely to explain the linkage to diabetes in this region, but our work supports a minor role of variants in T2DM risk and suggests that sequence variants may alter IL-6R mRNA levels and possibly levels of soluble IL-6R.

3' Untranslated Regions↗
PubMed2005

High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes.

CONTEXT: Ketosis-prone diabetes (KPD) is mostly observed in males of West African descent and is characterized by phasic or permanent insulin dependence without apparent autoimmune process. OBJECTIVE: KPD subjects display a propensity to hyperglycemia-induced acute insulin deficiency, suggesting that they exhibit a propensity to oxidative stress in beta-cells. The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a defense mechanism against oxidative stress, and G6PD deficiency, an X-linked genetic disorder with male predominance, is frequent in West Africans. We hypothesized that mutations in the G6PD gene could predispose to KPD. DESIGN: We studied G6PD erythrocyte enzyme activity and the insulin secretory reserve (glucagon-stimulated C peptide) in a cohort of hospitalized West Africans with KPD (n = 59) or type 2 diabetes (T2DM; n = 59) and in normoglycemic controls (n = 55). We also studied the G6PD gene in an extended population of KPD patients (n = 100), T2DM patients (n = 59), and controls (n = 85). RESULTS: The prevalence of G6PD deficiency was higher in KPD than in T2DM and controls (42.3%; 16.9%; 16.4%; P = 0.01). In KPD, but not in T2DM, insulin deficiency was proportional to the decreased G6PD activity (r = 0.33; P = 0.04). We found no increase in the prevalence of G6PD gene mutations in KPD compared with T2DM and controls. Rather, we found a 20.3% prevalence of G6PD deficiency in KPD without gene mutation. CONCLUSIONS: This study suggests that 1) G6PD deficiency alone is not causative of KPD; and 2) alterations in genes controlling both insulin secretion and G6PD-mediated antioxidant defenses may contribute to the predisposition to KPD in West Africans.

Africa, Western↗
PubMed2006

Genetic variation in the visfatin gene (PBEF1) and its relation to glucose metabolism and fat-depot-specific messenger ribonucleic acid expression in humans.

CONTEXT AND OBJECTIVE: Visfatin is a peptide suggested to play a role in glucose homeostasis. In the present study, we investigated the role of genetic variation in the visfatin gene in the pathophysiology of obesity/type 2 diabetes mellitus (T2DM). DESIGN: The visfatin gene (PBEF1) was sequenced in DNA samples from 24 nonrelated Caucasian subjects. Identified genetic variants were used for association analyses of T2DM in a case-control study (503 diabetic subjects and 476 healthy controls) and T2DM-related traits in 626 nondiabetic subjects. The effect of genetic variation in the visfatin gene on its mRNA expression in a subgroup of 157 nondiabetic subjects with measurements of visfatin mRNA expression in visceral and sc fat depots was also analyzed. RESULTS: Seven single-nucleotide polymorphisms (SNPs) and one insertion/deletion were identified. Three SNPs (rs9770242, -948G-->T, rs4730153) that were representatives of their linkage disequilibrium groups were genotyped in Caucasians from Germany with a wide range of body fat distribution and insulin sensitivity for association analyses. No association of T2DM with any of the genotyped SNPs or their haplotypes was found. However, the ratio of visceral/sc visfatin mRNA expression was associated with all three genetic polymorphisms (P < 0.05). Moreover, the -948G-->T variant was associated with 2-h plasma glucose and fasting insulin concentrations (P < 0.05) in nondiabetic subjects. CONCLUSIONS: In conclusion, our data suggest that genetic variation in the visfatin gene may have a minor effect on visceral and sc visfatin mRNA expression profiles but does not play a major role in the development of obesity or T2DM.

Adipose Tissue↗
PubMed2006

Association of alpha2-Heremans-Schmid glycoprotein polymorphisms with subclinical atherosclerosis.

CONTEXT: Cardiovascular disease is significantly increased in individuals with type 2 diabetes mellitus (T2DM), especially in the presence of calcified atherosclerotic plaque. Fetuin A is an important mineralization inhibitor, and polymorphisms in the corresponding alpha2-Heremans-Schmid glycoprotein (AHSG) gene have been shown to be associated with serum fetuin A levels and free phosphate levels, as well as cardiovascular disease death. OBJECTIVE: This study investigated whether polymorphisms in AHSG contribute to the development of calcified atherosclerotic plaque in the coronary and carotid arteries and to carotid artery intima-media thickness. DESIGN: Eleven single nucleotide polymorphisms (SNPs) in AHSG were genotyped and evaluated for association with quantitative measures of subclinical atherosclerosis. PARTICIPANTS: Subjects were 829 T2DM-affected European Americans from 368 families in the Diabetes Heart Study. MAIN OUTCOME MEASURES: Participants were phenotyped for cardiovascular risk factors and atherosclerosis traits. The extent of coronary artery calcified plaque (CorCP) and carotid artery calcified plaque (CarCP) was measured using quantitative computed tomography, and carotid artery intima-media thickness was measured using high-resolution B mode ultrasonography. RESULTS: Four SNPs in AHSG were nominally associated with CorCP in European Americans with T2DM (P < 0.05). Two 3-SNP haplotypes in the exon 6-7 region were associated with CorCP in European Americans with T2DM (P < 0.06). CONCLUSIONS: Sequence variants in the AHSG gene affect the extent of CorCP in T2DM-affected European Americans, consistent with the known biological role of AHSG in vascular calcification. These data implicate AHSG in the development of vascular calcified plaque in diabetic subjects.

Adult↗
PubMed2006

Exercise-induced improvement in vasodilatory function accompanies increased insulin sensitivity in obesity and type 2 diabetes mellitus.

OBJECTIVE: The present study was undertaken to determine whether improved vasodilatory function accompanies increased insulin sensitivity in overweight, insulin-resistant subjects (OW) and type 2 diabetic patients (T2DM) who participated in an 8-wk exercise training regimen. DESIGN: Before and after training, subjects had euglycemic clamps to determine insulin sensitivity. Brachial artery catheterization was done on another occasion for measurement of vasodilatory function. A lean, healthy, untrained group was studied as nonexercised controls. RESULTS: Training increased oxygen consumption (VO2) peak [OW, 29 +/- 1 to 37 +/- 4 ml/kg fat-free mass (FFM).min; T2DM, 33 +/- 2 to 43 +/- 3 ml/kg FFM.min; P < 0.05] and improved insulin-stimulated glucose disposal (OW, 6.5 +/- 0.5 to 7.2 +/- 0.4 mg/kg FFM.min; T2DM, 3.8 +/- 0.3 to 4.2 +/- 0.3 mg/kg FFM.min; P < 0.05) in insulin resistance. OW and T2DM, before training, had decreased acetylcholine chloride (ACh)- and sodium nitroprusside-mediated vasodilation and decreased reactive hyperemia compared with lean controls. Training increased the vasodilatory response to ACh [OW (30 microg ACh/min), 12.2 +/- 3.4 to 19 +/- 4.2 ml/100 g.min; T2DM (30 microg ACh/min), 10.1 +/- 1.5 to 14.2 +/- 2.1 ml/100 g.min; P < 0.05] in both groups without affecting nitroprusside response. CONCLUSION: Because vasodilatory dysfunction has been postulated to contribute to insulin resistance, the exercise-induced improvement in vasodilatory function may signify changes in the endothelium that could contribute to the improvement in insulin sensitivity observed after aerobic exercise training.

Adult↗
PubMed2006

Impact of type 2 diabetes on myocardial insulin sensitivity to glucose uptake and perfusion in patients with coronary artery disease.

BACKGROUND AND HYPOTHESIS: Myocardial insulin resistance (IR) is a feature of coronary artery disease (CAD) with reduced left ventricular ejection fraction (LVEF). Whether type 2 diabetes mellitus (T2DM) with CAD and preserved LVEF induces myocardial IR and whether insulin in these patients acts as a myocardial vasodilator is debated. METHODS: We studied 27 CAD patients (LVEF > 50%): 12 with T2DM (CAD+DM), 15 without T2DM (CAD-NoDM). Regional myocardial and skeletal glucose uptake, myocardial and skeletal muscle perfusion were measured with positron emission tomography. Myocardial muscle perfusion was measured at rest and during hyperemia in nonstenotic and stenotic regions with and without acute hyperinsulinemia. RESULTS: Myocardial glucose uptake was similar in CAD+DM and CAD-NoDM in both nonstenotic and stenotic regions [0.38 +/- 0.08 and 0.36 +/- 0.11 micromol/g.min; P value nonsignificant (NS)] and (0.35 +/- 0.09 and 0.37 +/- 0.13 micromol/g.min; P = NS). Skeletal glucose uptake was reduced in CAD+DM (0.05 +/- 0.04 vs. 0.10 +/- 0.05 micromol/g.min; P = 0.02), and likewise, whole-body glucose uptake was reduced in CAD+DM (4.0 +/- 2.8 vs. 7.0 +/- 2.4 mg/kg.min; P = 0.01). Insulin did not alter myocardial muscle perfusion at rest or during hyperemia. Insulin increased skeletal muscle perfusion in CAD-NoDM (0.11 +/- 0.03 vs. 0.06 +/- 0.03 ml/g.min; P = 0.02), but not in CAD+DM (0.08 +/- 0.04 and 0.09 +/- 0.05 ml/g.min; P = NS). CONCLUSION: Myocardial IR to glucose uptake is not an inherent feature in T2DM patients with preserved LVEF. Acute physiological insulin exposure exerts no coronary vasodilation in CAD patients irrespective of T2DM.

Aged↗
PubMed2000

Recombinant human insulin-like growth factor I treatment for 1 week improves metabolic control in type 2 diabetes by ameliorating hepatic and muscle insulin resistance.

The administration of recombinant human insulin-like growth factor I (rhIGF-I) reduces hyperglycemia and insulin requirements in subjects with severe insulin resistance syndromes and in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms responsible for the improved metabolic control are incompletely understood. One proposed mechanism is that rhIGF-I therapy in T2DM may bypass early defects in insulin action (i.e. signal transduction), leading to improved hepatic and/or peripheral insulin sensitivity. To test this hypothesis, we used the euglycemic insulin clamp to measure the response to 7 days of rhIGF-I therapy (80 microg/kg, sc, twice daily) in eight poorly controlled T2DM subjects. rhIGF-I significantly improved fasting (203 +/- 12 vs. 134 +/- 14 mg/dL; P < 0.01) and day-long (0800-1700 h; 234 +/- 11 vs. 153 +/- 10 mg/dL; P < 0.01) plasma glucose levels. Basal endogenous glucose production decreased from 3.2 +/- 0.2 to 2.7 +/- 0.2 mg/kg lean body mass x min (P < 0.03) despite a concomitant decline in the fasting plasma insulin concentration from 13 +/- 5 to 5 +/- 1 microU/mL (P < 0.01). The decrement in basal endogenous glucose production was closely correlated with the decrement in fasting plasma glucose concentration (r = 0.78; P < 0.01). Whole body insulin-stimulated glucose disposal increased by 27% (from 5.6 +/- 0.8 to 7.1 +/- 0.8 mg/kg lean body mass x min; P < 0.01), but remained well below that observed in age- and weight-matched healthy subjects. The effects of rhIGF-I on endogenous glucose production and peripheral insulin sensitivity resemble those observed with intensified insulin regimens in T2DM. We conclude that 7 days of sc rhIGF-I improves glucose control by improving hepatic and muscle insulin sensitivity, but it remains markedly abnormal. This indicates that an intrinsic defect(s) responsible for insulin resistance in T2DM cannot be overcome by rhIGF-I treatment.

Blood Glucose↗
PubMed2002

Role of calpain-10 gene variants in familial type 2 diabetes in Caucasians.

The calpain-10 gene (CAPN10) has been implicated in type 2 diabetes (T2DM) susceptibility by both linkage and association in a Hispanic population from Starr County Texas. Common intronic variants seem to alter CAPN10 mRNA levels and were associated with insulin resistance but not diabetes in Pima Indians. The role of these variants in Caucasian populations is less clear. We found some evidence for linkage of T2DM to chromosome 2q approximately 20 cM proximal to the NIDDM1/CAPN10 locus. To test the hypothesis that CAPN10 is a diabetes susceptibility locus in Caucasian families at high risk for T2DM, we examined the influence of the three previously implicated CAPN10 variants on both diabetes risk and measures of insulin sensitivity and glucose homeostasis. We genotyped approximately 700 members of 63 families for 3 variants (SNP-43, SNP-19, and SNP-63). We tested each variant separately and as haplotype combinations for altered transmission from parents to affected children (transmission disequilibrium test), and we tested for an effect of each variant individually on measures of glucose and insulin during a glucose tolerance test in nondiabetic family members. Finally, we looked for an effect of each variant on measures of insulin sensitivity (S(I)) and insulin secretion estimated by frequently sampled iv glucose tolerance test and Minimal Model analysis. We could not confirm an increase in risk for T2DM susceptibility for any variant or for any haplotype combination, although we found marginal evidence for an increased risk of the 111/221 haplotype combination (P = 0.036) after ascertainment correction. However, both SNP-19 and SNP-63 increased fasting and/or postchallenge insulin levels, consistent with reduced insulin sensitivity. Furthermore, SNP-19 had modest effects on insulin sensitivity measured by homeostatic model, and on postchallenge glucose. The reduction in insulin sensitivity was confirmed by analysis of the subset of individuals who underwent iv glucose tolerance tests, where SNP-19 significantly altered the insulin sensitivity index. CAPN10 cannot be considered a major diabetes susceptibility gene in our population and seems unlikely to explain the observed linkage findings. However, CAPN10 influences insulin sensitivity and glucose homeostasis in nondiabetic members of kindreds at high risk for T2DM.

Alleles↗
PubMed2002

Laparoscopic adjustable gastric banding for the treatment of morbid (grade 3) obesity and its metabolic complications: a three-year study.

Weight loss ameliorates arterial hypertension and glucose metabolism in obese patients, but the dietary approach is unsatisfactory because obesity relapses. Durable reduction of body weight, obtained through major nonreversible surgical procedures, such as jejunal and gastric bypass, allows improvement of glucose metabolism and arterial blood pressure in morbid (grade 3) obesity. Laparoscopic adjustable gastric banding (LAGB) is a minimally invasive and reversible surgical procedure that yields a significant reduction of gastric volume and hunger sensation. In this study, 143 patients with grade 3 obesity [27 men and 116 women; age, 42.9 +/- 0.83 yr; body mass index (BMI), 44.9 +/- 0.53 kg/m(2); normal glucose tolerance (NGT; n = 77); impaired glucose tolerance (IGT; n = 47); type 2 diabetes mellitus (T2DM; n = 19)] underwent LAGB and a 3-yr follow-up for clinical (BMI, waist circumference, waist to hip ratio, and arterial blood pressure) and metabolic variables (glycosylated hemoglobin, fasting insulin and glucose, insulin and glucose response to oral glucose tolerance test, homeostasis model assessment index, total and high-density lipoprotein cholesterol, triglycerides, uric acid, and transaminases). At baseline and 1 yr after LAGB, patients underwent computerized tomography and ultrasound evaluation of visceral and sc adipose tissue. One-year metabolic results were compared with 120 obese patients (51 men and 69 women; age, 42.9 +/- 1.11 yr; BMI, 43.6 +/- 0.46 kg/m(2); NGT, n = 66; IGT, n = 8; T2DM, n = 46) receiving standard dietary treatment. LAGB induced a significant and persistent weight loss and decrease of blood pressure. Greater metabolic effects were observed in T2DM patients than in NGT and IGT patients, so that at 3 yr glycosylated hemoglobin was no longer different in NGT and T2DM subjects. Clinical and metabolic improvements were proportional to the amount of weight loss. LAGB induced a greater reduction of visceral fat than sc fat. At 1-yr evaluation, weight loss and metabolic improvements were greater in LAGB-treated than diet-treated patients. We conclude that LAGB is an effective treatment of grade 3 obesity in inducing long-lasting reduction of body weight and arterial blood pressure, modifying body fat distribution, and improving glucose and lipid metabolism, especially in T2DM.

Adult↗
PubMed2001

Genetic determinants of type 2 diabetes.

Hyperglycemia of type 2 diabetes mellitus (T2DM) results from a complex interplay of genetic and environmental factors that influence a number of intermediate traits (e.g., beta-cell mass, insulin secretion, insulin action, fat distribution, obesity). The primary biochemical events leading to diabetes are still unknown in most cases. Although several monogenic forms of diabetes have been identified, T2DM seems to be a polygenic disorder in the majority of cases. T2DM is probably also multigenic, meaning that many different combinations of gene defects may exist among diabetic patients. Significant results were obtained in the identification of the genetic determinants of monogenic forms of diabetes with young age of onset. However, despite the evidence for a strong genetic background, little of the genetic risk factors for the more-common forms of polygenic T2DM are known to date. The goal of this chapter is to summarize and discuss the significant results of recent literature on the genetics of both the monogenic and polygenic forms of T2DM.

Age of Onset↗