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1.
Acta Reumatol Port ; 42(4): 310-317, 2017.
Article in English | MEDLINE | ID: mdl-29017177

ABSTRACT

AIMS: To reveal the prevalence of Diabetes Mellitus (DM) in patients with newly diagnosed Rheumatoid Arthritis (RA) and evaluate the association between clinical characteristics of RA and DM as well as treatment response in newly diagnosed RA patients with DM. METHODS: Newly diagnosed, adult, RA patients, who were registered in Danish Danbio since 1st January 2010, were included. Patients' demographics, serology results including rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP) and antinuclear antibody (ANA) as well as disease activity score in 28 joints-C-reactive protein (DAS28-CRP) at the time of diagnosis and after 4 months (±1-2 months) of treatment initiation were extracted from Danbio Registry. To reveal the presence of DM, patients' electronic medical records were reviewed. The prevalence of DM in our patients was compared (using an age- and gender-matched analysis) with that expected from Danish population. RESULTS: of 439 included patients, 60.1% were female, mean of age 64.6±15.0 years and RA disease duration 2.6±1.7 years. Prevalence of DM was 57/439 (12.9%), herein type II DM 52 (91.2%) and type I DM 5 (8.8%). Except for two patients, diagnosis of DM was established prior to the diagnosis of RA. The prevalence of DM in newly diagnosed RA patients of all ages was significantly increased versus that expected from Danish population (RR=2.21, CI=1.40-3.42, P min 0.001). In addition, prevalence of DM was significantly increased with more than twice of the expected for RA patients aged 65-84. Both genders showed increased risk of DM after subgroup analysis. The presence of DM in RA patients was significantly associated with age (P min 0.001) and RA disease duration ≥4 years (P =0.05). We did not find any significant associations between presence of DM and gender, RF, anti-CCP as well as ANA. Additionally, presence of DM in the RA patients was not a negative predictor of treatment response measured by the European League Against Rheumatism (EULAR) response criteria and ∆DAS28-CRP. CONCLUSION: Newly diagnosed RA patients are at higher risk of DM (13% versus 5.7% in Denmark), and a high index of suspicion must be kept.


Subject(s)
Arthritis, Rheumatoid/complications , Diabetes Mellitus/epidemiology , Diabetes Mellitus/etiology , Adult , Aged , Aged, 80 and over , Child , Cohort Studies , Female , Humans , Male , Middle Aged , Prevalence , Risk Factors , Young Adult
2.
J Clin Endocrinol Metab ; 99(10): E1943-50, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25050902

ABSTRACT

AIMS/HYPOTHESIS: The pathophysiological role of gut incretin hormone argumentation on acute insulin release in the genesis of type 2 diabetes (TDM2) is uncertain. We examined retrospectively at 0 year and 10 years the endogenous incretin hormone action (IHA) on acute insulin release and glucose tolerance in normoglycemic relatives (REL) of TDM2 and control (CON) subjects. METHODS: At 0 year and 10 years, glucose tolerance, paired oral glucose tolerance test (OGTT)- and i.v. glucose tolerance test (IVGTT)-induced acute (0-30 min) insulin release (insulinogenic index IGIOGTT and IGIIVGTT), and IHA were calculated in 19 REL and 18 CON subjects by cross-correlation linear regression slope analyses of the OGTT (0-30 min) matched insulin/glucose profiles vs the early (0-5 min) and delayed (10-30 min) IVGTT profiles. RESULTS: At 0 year, REL and CON IGIOGTT and IGIIVGTT were similar, but the REL 2- to 5-min IVGTT-induced insulin responses were reduced (P < .03). By 10 years, glucose tolerance deteriorated in nine dysglycemic REL (RELDGT), with raised fasting glucose and 2-hour OGTT glucose. Retrospective analyses of RELDGT at 0 year demonstrated raised proinsulin/insulin molar ratios and fasting glucose and a reduced IVGTT insulin/glucose slope, but the RELDGT IHA was similar to normoglycemic REL (RELNGT) and CON. By 10 years, RELDGT OGTT insulin/glucose slopes were reduced (P = .03-.01), but more so for the early (P < .01-.003) and delayed (P < .005-.002) IVGTT slopes, compared to the normoglycaemic REL and CON subjects. CONCLUSIONS: IHA on acute insulin release is maintained in normoglycemic REL and CON subjects over 10 years. The apparent deterioration in IHA in RELDGT is consistent with a progressive failure of acute ß-cell function over 10 years.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Incretins/metabolism , Insulin/blood , Insulin/metabolism , Adult , Blood Glucose/metabolism , Disease Progression , Family , Female , Glucose Intolerance/metabolism , Glucose Intolerance/physiopathology , Glucose Tolerance Test , Humans , Insulin Secretion , Insulin-Secreting Cells/metabolism , Longitudinal Studies , Male , Retrospective Studies
3.
J Diabetes Sci Technol ; 7(3): 587-95, 2013 May 01.
Article in English | MEDLINE | ID: mdl-23759390

ABSTRACT

BACKGROUND: The increasing number of patients with diabetes poses a major challenge for the health care system. One instrument to meet these challenges could be the use of telemedicine, which, at the same time, may reduce treatment costs. Since 2005, diabetes patients on the island of Aeroe have been offered expert diabetes care using teleconsultations. This article describes the impact of the telemedicine solution on essential diabetes treatment parameters, patient satisfaction, and cost-effectiveness. METHODS: Telemedicine consultations were conducted with the patient and nurse specialist placed in a consultation room of Aeroe Hospital in audiovisual contact with the physician situated at the hospital on the mainland. Consultations were supported by an electronic patient record and a Web-based quality-monitoring diabetes database. RESULTS: Inclusion criteria in this retrospective study were at least 6 months of telemedicine diabetes control with a minimum of two visits and two hemoglobin A1c (HbA1c) values. Results were compared with data from the Danish National Diabetes Registry (DVDD). Data are given in medians. In total, 23 type 1 diabetes mellitus (T1DM) patients, aged 65 (56-74) versus 48 years, diabetes duration 21.0 (10.7-31.3) versus 20.5 years, and 55 type 2 diabetes mellitus (T2DM) patients, aged 67 (64-70) versus 65 years, diabetes duration 14.0 (10.5-17.5) versus 11.7 years, were included. After teleconsultation, HbA1c in T1DM patients was 8.0% (7.4-8.6%) versus 7.9% [64 (57-71) versus 63 mmol/mol], not significant, and in T2DM patients was 7.4% (7.1-7.7%) versus 7.6% [57 (54-61) versus 60 mmol/mol], p < .05. Body mass index, blood pressure, and lipid values were comparable with the DVDD. Patient satisfaction was especially related to the major reduction in transportation time (7 h). Reductions in traveling costs and saved working days were the most important factors in making the telemedicine set-up economically efficient. CONCLUSION: Telemedicine consultation for remote outpatient diabetes control is feasible, and the interdisciplinary interventions achieved high treatment quality results in essential diabetes treatment parameters. In addition, the telemedicine set-up was associated with improved cost-effectiveness and patient satisfaction.


Subject(s)
Diabetes Mellitus/blood , Diabetes Mellitus/economics , Patient Satisfaction , Remote Consultation/economics , Telemedicine/economics , Aged , Cost-Benefit Analysis , Denmark , Diabetes Mellitus/therapy , Female , Follow-Up Studies , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Remote Consultation/methods , Retrospective Studies , Telemedicine/methods
4.
Diabetes Metab Res Rev ; 29(6): 492-8, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23568564

ABSTRACT

BACKGROUND: This study aimed to compare the metabolic and insulin secretory responses to dexamethasone with the metabolic responses observed at 10 years in normoglycaemic relatives of type 2 diabetic and healthy control subjects. METHODS: Twenty relatives and 20 matched control subjects were studied twice at 0 year (pre- and post-dexamethasone) and at 10 years, employing a 75-g oral glucose tolerance test (OGTT), with serial measurements of glucose and insulin, for determination of glucose tolerance and calculations of acute insulin release (ΔI30 /ΔG30 ; insulinogenic index) and insulin sensitivity (SIHOMA ). RESULTS: Following dexamethasone, the relatives group developed varying degrees of glucose intolerance, associated with reduced insulin sensitivity and insulinogenic index. By 10 years, fasting glucose and 2-h OGTT glucose were raised in the relatives group, especially in the relatives most metabolically affected by dexamethasone, including a reduced insulinogenic index. Multiple regression analysis of the data in relatives demonstrated that the 2-h OGTT glucose and fasting glucose values at 10 years depended on the 0-year post-dexamethasone 2-h OGTT glucose, post-dexamethasone fasting glucose and post-dexamethasone insulin sensitivity, r(2) adj = 56% (p < 0.001) and r(2) adj = 60% (p < 0.0001), respectively. No pre-dexamethasone metabolic or insulin secretory responses entered these models. CONCLUSIONS: In relatives, fasting and 2-h OGTT glucose concentrations and ß-cell responses to acute dexamethasone-induced insulin resistance are similar to those observed at 10 years, especially in relatives who develop the most disturbed dexamethasone-induced glucose intolerance and impaired acute insulin secretion. The combined 0-year, post-dexamethasone fasting and 2-h OGTT glucose concentrations and insulin resistance, measured as SIHOMA , are the best predictors in relatives of future dysglycaemia.


Subject(s)
Dexamethasone/administration & dosage , Diabetes Mellitus, Type 2/metabolism , Glucose Intolerance/diagnosis , Insulin/metabolism , Adult , Blood Glucose/drug effects , Blood Glucose/metabolism , Case-Control Studies , Diabetes Mellitus, Type 2/blood , Family , Female , Follow-Up Studies , Glucose Intolerance/complications , Glucose Intolerance/metabolism , Glucose Tolerance Test/methods , Humans , Insulin Secretion , Male , Prognosis
5.
NDT Plus ; 4(3): 158-163, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21629670

ABSTRACT

Mutations in the arginine vasopressin receptor 2 (AVPR2) gene can cause X-linked nephrogenic diabetes insipidus (NDI) characterized by the production of large amounts of urine and an inability to concentrate urine in response to the antidiuretic hormone vasopressin. We have identified a novel mutation in the AVPR2 gene (L170P) located in the fourth transmembrane domain in a Danish NDI male. Analysis of the mutant receptor in Madin-Darby Canine Kidney cell culture revealed that AVPR2-L170P was retained in the endoplasmic reticulum, and the expression was dramatically downregulated compared to wild-type AVPR2. Inhibition of the lysosome resulted in increased intracellular accumulation of AVPR2-L170P, indicating that AVPR2-L170P is downregulated via the lysosome. Inhibition of the proteasome resulted in plasma membrane localization of AVPR2-L170P, although the overall levels of AVPR2-L170P were unchanged.

6.
Diabetes Metab Res Rev ; 26(7): 569-78, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20830736

ABSTRACT

BACKGROUND: We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SG(MM) and SI(MM); simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SG(CLAMP) and SI(CLAMP)). METHODS: Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SG(CLAMP) was calculated in two ways based on data from study (2) alone (Day 2 SG(CLAMP210-240')) or from data from study day (2) and (3) (Day 2-3 SG(CLAMP330-360')). RESULTS: SG(MM) was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SG(CLAMP) protocols correlated (r = 0.72, p = 0.003), but SG(CLAMP210-240') was significantly (p = 0.001) higher than SG(CLAMP330-360'). Employing the Day 2 and 3 SG(CLAMP) protocol, the whole body SG(CLAMP330-360') was similar to SG(MM) (1.80 ± 0.82 versus 1.73 ± 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SG(CLAMP210-240') did not correlate with SG(MM) (r = 0.24). SI(MM) and SI(CLAMP) were similar (0.093 ± 0.060 versus 0.087 ± 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). CONCLUSIONS: The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SG(CLAMP), and significant concordance coefficients are observed between SG(MM), and SG(CLAMP330-360'), and SI(MM) and SI(CLAMP).


Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/drug therapy , Glucose Clamp Technique , Glucose Tolerance Test , Glucose/administration & dosage , Insulin Resistance , Insulin/administration & dosage , Adult , Diabetes Mellitus, Type 2/metabolism , Female , Humans , Insulin/blood , Male , Young Adult
7.
Am J Physiol Endocrinol Metab ; 299(1): E14-22, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20442319

ABSTRACT

Obesity and insulin resistance are related to both enlarged intramyocellular triacylglycerol stores and accumulation of lipid intermediates. We investigated how lipid overflow can change the oxidation of intramyocellular lipids (ICL(OX)) and intramyocellular lipid storage (ICL). These experiments were extended by comparing these processes in primary cultured myotubes established from healthy lean and obese type 2 diabetic (T2D) individuals, two extremes in a range of metabolic phenotypes. ICLs were prelabeled for 2 days with 100 microM [(14)C]oleic acid (OA). ICL(OX) was studied using a (14)CO(2) trapping system and measured under various conditions of extracellular OA (5 or 100 microM) and glucose (0.1 or 5.0 mM) and the absence or presence of mitochondrial uncoupling [carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)]. First, increased extracellular OA availability (5 vs. 100 microM) reduced ICL(OX) by 37%. No differences in total lipolysis were observed between low and high OA availability. Uncoupling with FCCP restored ICL(OX) to basal levels during high OA availability. Mitochondrial mass was positively related to ICL(OX), but only in myotubes from lean individuals. In all, a lower mitochondrial mass and lower ICL(OX) were related to a higher cell-associated OA accumulation. Second, myotubes established from obese T2D individuals showed reduced ICL(OX). ICL(OX) remained lower during uncoupling (P < 0.001), even with comparable mitochondrial mass, suggesting decreased mitochondrial function. Furthermore, the variation in ICL(OX) in vitro was significantly related to the in vivo fasting respiratory quotient of all subjects (P < 0.02). In conclusion, the rate of ICL(OX) is dependent on the availability of extracellular fatty acids and mitochondrial function rather than mitochondrial mass.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Fatty Acids/metabolism , Mitochondria, Muscle/metabolism , Muscle, Skeletal/metabolism , Obesity/metabolism , Adult , Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone/pharmacology , Cross-Over Studies , Female , Glucose/pharmacology , Humans , Male , Microscopy, Fluorescence , Middle Aged , Muscle Fibers, Skeletal/metabolism , Oleic Acid/administration & dosage , Oleic Acid/metabolism , Statistics, Nonparametric , Uncoupling Agents/pharmacology
8.
J Clin Endocrinol Metab ; 94(11): 4547-56, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19837931

ABSTRACT

CONTEXT: Insulin-stimulated glucose disposal is impaired in obesity and type 2 diabetes mellitus (T2DM) and is tightly linked to impaired skeletal muscle glucose uptake and storage. Impaired activation of glycogen synthase (GS) by insulin is a well-established defect in both obesity and T2DM, but the underlying mechanisms remain unclear. DESIGN AND PARTICIPANTS: Insulin action was investigated in a matched cohort of lean healthy, obese nondiabetic, and obese type 2 diabetic subjects by the euglycemic-hyperinsulinemic clamp technique combined with muscle biopsies. Activity, site-specific phosphorylation, and upstream signaling of GS were evaluated in skeletal muscle. RESULTS: GS activity correlated inversely with phosphorylation of GS site 2+2a and 3a. Insulin significantly decreased 2+2a phosphorylation in lean subjects only and induced a larger dephosphorylation at site 3 in lean compared with obese subjects. The exaggerated insulin resistance in T2DM compared with obese subjects was not reflected by differences in site 3 phosphorylation but was accompanied by a significantly higher site 1b phosphorylation during insulin stimulation. Hyperphosphorylation of another Ca(2+)/calmodulin-dependent kinase-II target, phospholamban-Thr17, was also evident in T2DM. Dephosphorylation of GS by phosphatase treatment fully restored GS activity in all groups. CONCLUSIONS: Dysregulation of GS phosphorylation plays a major role in impaired insulin regulation of GS in obesity and T2DM. In obesity, independent of T2DM, this is associated with impaired regulation of site 2+2a and likely site 3, whereas the exaggerated insulin resistance to activate GS in T2DM is linked to hyperphosphorylation of at least site 1b. Thus, T2DM per se seems unrelated to defects in the glycogen synthase kinase-3 regulation of GS.


Subject(s)
Diabetes Mellitus, Type 2/enzymology , Glycogen Synthase/antagonists & inhibitors , Insulin/pharmacology , Obesity/enzymology , Adenosine Monophosphate/physiology , Blotting, Western , Calcium/physiology , Female , Glucose/metabolism , Glucose Tolerance Test , Homeostasis , Humans , Kinetics , Male , Middle Aged , Muscle, Skeletal/enzymology , Phosphoric Monoester Hydrolases/metabolism , Phosphorylation , Reference Values , Signal Transduction
9.
Circulation ; 114(11): 1169-76, 2006 Sep 12.
Article in English | MEDLINE | ID: mdl-16952981

ABSTRACT

BACKGROUND: Macrophage CD36 scavenges oxidized low-density lipoprotein, leading to foam cell formation, and appears to be a key proatherogenic molecule. Increased expression of CD36 has been attributed to hyperglycemia and to defective macrophage insulin signaling in insulin resistance. Premature atherosclerosis is the major cause of morbidity and mortality in type 2 diabetes. Here, we report the identification of a soluble form of CD36 (sCD36) in plasma and hypothesize that sCD36 would be elevated in patients with type 2 diabetes and insulin resistance. METHODS AND RESULTS: sCD36 in plasma was demonstrated by immunopurification and Western blotting. We established ELISA assays to determine sCD36 in plasma and measured sCD36 in obese type 2 diabetic patients, obese nondiabetic relatives, and obese and lean control subjects. sCD36 was markedly elevated in type 2 diabetic patients compared with both lean (5-fold) and obese (2- to 3-fold) control subjects. There was a strong, inverse correlation between sCD36 and insulin-stimulated glucose disposal and a direct correlation with fasting plasma glucose, fasting insulin, and body mass index. CONCLUSIONS: Our study demonstrates sCD36 in plasma for the first time. sCD36 is highly related to risk factors of accelerated atherosclerosis in type 2 diabetes such as insulin resistance and glycemic control, and we propose that sCD36 might represent a marker of the metabolic syndrome and a potential surrogate marker of atherosclerosis.


Subject(s)
CD36 Antigens/blood , Diabetes Mellitus, Type 2/blood , Insulin Resistance , Lipoproteins, LDL/blood , Receptors, Scavenger/blood , Adult , Atherosclerosis/blood , Atherosclerosis/physiopathology , Biomarkers/blood , Blood Glucose/analysis , Case-Control Studies , Female , Humans , Insulin/blood , Lipoproteins, LDL/metabolism , Male , Middle Aged , Obesity/blood , Regression Analysis , Risk Factors
10.
Biochim Biophys Acta ; 1741(1-2): 206-14, 2005 Jun 30.
Article in English | MEDLINE | ID: mdl-15894466

ABSTRACT

In myotubes established from patients with type 2 diabetes (T2D), lipid oxidation and insulin-mediated glucose oxidation are reduced, whereas in myotubes from obese non-diabetic subjects, exposure to palmitate impairs insulin-mediated glucose oxidation. To determine the underlying mechanisms of these metabolic malfunctions, we studied mitochondrial respiration, uncoupled respiration and oxidative enzyme activities (citrate synthase (CS), 3-hydroxy-acyl-CoA-dehydrogenase activity (HAD)) before and after acute exposure to insulin and/or palmitate in myotubes established from healthy lean and obese subjects and T2D patients. Basal CS activity was lower (14%) in diabetic myotubes compared with myotubes from lean controls (P=0.03). Incubation with insulin (1 microM) for 4 h increased the CS activity (26-33%) in myotubes from both lean (P=0.02) and obese controls (P<0.001), but not from diabetic subjects. Co-incubation with palmitate (0.6 mM) for 4 h abolished the stimulatory effect of insulin on CS activity in non-diabetic myotubes. No differences were detected in mitochondrial respiration and HAD activity between myotubes from non-diabetic subjects and T2D patients, and none of these measures responded to high levels of insulin and/or palmitate. These results provide evidence for an intrinsic defect in CS activity, which may play a role in the pathogenesis of T2D. Moreover, the data suggest that insulin resistance at the CS level can be induced by exposure to high free fatty acid levels.


Subject(s)
Citrate (si)-Synthase/metabolism , Diabetes Mellitus, Type 2/enzymology , Insulin/pharmacology , Muscle, Skeletal/drug effects , 3-Hydroxyacyl CoA Dehydrogenases/metabolism , Cells, Cultured , Diabetes Mellitus, Type 2/metabolism , Glucose/metabolism , Humans , Insulin Resistance , Middle Aged , Muscle Fibers, Skeletal/drug effects , Muscle Fibers, Skeletal/metabolism , Muscle, Skeletal/metabolism , Obesity/enzymology , Obesity/metabolism , Oxidation-Reduction , Oxygen Consumption , Palmitic Acid/metabolism
11.
Diabetes ; 54(4): 1108-15, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15793250

ABSTRACT

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism and are also involved in glucose metabolism. However, the functional role of LXRs in human skeletal muscle is at present unknown. This study demonstrates that chronic ligand activation of LXRs by a synthetic LXR agonist increases the uptake, distribution into complex cellular lipids, and oxidation of palmitate as well as the uptake and oxidation of glucose in cultured human skeletal muscle cells. Furthermore, the effect of the LXR agonist was additive to acute effects of insulin on palmitate uptake and metabolism. Consistently, activation of LXRs induced the expression of relevant genes: fatty acid translocase (CD36/FAT), glucose transporters (GLUT1 and -4), sterol regulatory element-binding protein-1c, peroxisome proliferator-activated receptor-gamma, carnitine palmitoyltransferase-1, and uncoupling protein 2 and 3. Interestingly, in response to activation of LXRs, myotubes from patients with type 2 diabetes showed an elevated uptake and incorporation of palmitate into complex lipids but an absence of palmitate oxidation to CO(2). These results provide evidence for a functional role of LXRs in both lipid and glucose metabolism and energy uncoupling in human myotubes. Furthermore, these data suggest that increased intramyocellular lipid content in type 2 diabetic patients may involve an altered response to activation of components in the LXR pathway.


Subject(s)
DNA-Binding Proteins/metabolism , Diabetes Mellitus, Type 2/metabolism , Lipid Metabolism , Muscle, Skeletal/metabolism , Receptors, Cytoplasmic and Nuclear/metabolism , Anticholesteremic Agents/pharmacology , Cells, Cultured , Gene Expression , Glucose/metabolism , Glycogen/biosynthesis , Humans , Hydrocarbons, Fluorinated , Liver X Receptors , Middle Aged , Muscle, Skeletal/drug effects , Obesity/metabolism , Orphan Nuclear Receptors , Sulfonamides
12.
Diabetes ; 54(1): 275-83, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15616039

ABSTRACT

The etiology of type 2 diabetes is multifactorial, including genetic as well as pre- and postnatal factors that influence several different defects of glucose homeostasis, primarily in muscle, beta-cells, and liver. In the present twin study, we report heritability estimates (h(2)) for measures of insulin secretion, insulin resistance, hepatic glucose production (HGP), and intracellular glucose partitioning using gold standard methods (euglycemic-hyperinsulinemic clamp technique, tritiated glucose infusion, indirect calorimetry, and intravenous glucose tolerance testing) among 110 younger (22-31 years of age) and 86 older (57-66 years of age) twins. To obtain a valid estimate of beta-cell function, insulin secretion was adjusted for the individual degree of insulin action (disposition index). In both age-groups there was a major genetic component in the etiology of insulin secretion that was statistically significantly higher among older twins (young h(2) = 0.75 [0.55-0.86] and old h(2) = 0.84 [0.69-0.92], P < 0.05). The heritability estimates for peripheral insulin sensitivity (young h(2) = 0.53 [0.28-0.71] and old h(2) = 0.55 [0.20-0.76]) and nonoxidative glucose metabolism (young h(2) = 0.50 [0.32-0.64] and old h(2) = 0.48 [0.04-0.72]) were similar in younger and older twins, supporting the notion of both genetic and environmental etiological factors in the control of insulin action and nonoxidative glucose metabolism. The results suggested that HGP was predominantly controlled by nongenetic factors in both young and old twins. In conclusion, we provide further evidence for a role of genes in controlling insulin secretion, insulin action, and nonoxidative glucose metabolism. The relative contribution of genes versus environment on in vivo insulin secretion exhibited an age dependency with a slightly greater relative impact of genes among older as compared with younger twins.


Subject(s)
Glucose/metabolism , Glycolysis/genetics , Insulin/metabolism , Liver/physiology , Adult , Aging , Blood Glucose/metabolism , Denmark , Female , Glucose Clamp Technique , Humans , Insulin/genetics , Insulin Secretion , Liver/growth & development , Male , Middle Aged
13.
Diabetes ; 53(6): 1592-8, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15161766

ABSTRACT

Recently, various subtypes of familial hyperinsulinemic hypoglycemia with an autosomal-dominant inheritance have been etiologically characterized. In the present study, we have delineated the genetics and metabolic phenotype of a novel form of hypoglycemia in a large pedigree with an apparent autosomal-dominant transmission. After initial investigations of the proband, her mother, and a sister, the study was extended to 19 family members in three generations. Glucose tolerance was assessed by a 5-h oral glucose tolerance test (OGTT) and insulin sensitivity by euglycemic-hyperinsulinemic clamp in six affected family members and six control subjects. To identify the genetic cause of hypoglycemia, linkage analysis and mutation analysis of genomic DNA from all family members were performed. All affected family members were characterized by postprandial hypoglycemia, fasting hyperinsulinemia, and an elevated serum insulin-to-C-peptide ratio. The 5-h OGTT demonstrated hyperinsulinemic hypoglycemia, and the clamp studies showed reduced insulin sensitivity and clearance of serum insulin in affected family members compared with control subjects. Linkage analysis and subsequent mutation screening revealed a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate the coexistence of severe postprandial hypoglycemia, insulin resistance, and impaired insulin clearance and suggest that hypoglycemia should be considered as a phenotype linked to heterozygote mutations in the insulin receptor gene.


Subject(s)
Genetic Linkage , Hyperinsulinism/genetics , Hypoglycemia/genetics , Mutation , Receptor, Insulin/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Exercise , Glucose Clamp Technique , Glucose Tolerance Test , Haplotypes , Heterozygote , Humans , Hyperinsulinism/physiopathology , Hypoglycemia/physiopathology , Lod Score , Middle Aged , Pedigree , Phenotype , Point Mutation
14.
Diabetes Care ; 27(1): 148-54, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14693981

ABSTRACT

OBJECTIVE: Insulin resistance is a key characteristic of first-degree relatives of patients with type 2 diabetes. We therefore treated young, glucose-tolerant relatives with the insulin action enhancer troglitazone in order to determine the effects on insulin sensitivity, glucose metabolism, and glycogen synthase activity. RESEARCH DESIGN AND METHODS: Relatives were randomized in a double-blind manner and treated for 12 weeks with either 200 mg troglitazone or placebo. Before and after treatment, an oral glucose tolerance test (OGTT) and a euglycemic-hyperinsulinemic clamp (40 mU. m(-2). min(-1)) were performed, including 3-(3)H glucose infusion, glycolytic flux calculations, indirect calorimetry, and muscle biopsies. RESULTS: Twelve relatives received troglitazone and 12 placebo (aged 30.8 +/- 2.0 vs. 30.3 +/- 1.6 years, BMI 29.6 +/- 0.8 vs. 30.5 +/- 1.3 kg/m(2); means +/- SE). Area under the curve (AUC) for plasma glucose at the second OGTT was unchanged after troglitazone. In contrast, troglitazone reduced fasting (from 70.3 +/- 6.9 to 52.2 +/- 5.8 vs. 73.6 +/- 11.0 to 73.3 +/- 6.5 pmol/l, P < 0.02) and AUC plasma insulin (mean [CI] from 335.7 [230.9-488.1] to 277.4 [179.4-428.8] vs. 313.8 [218.2-451.2] to 353.9 [208.3-601.3] pmol/l, P < 0.05). Additionally, fasting plasma triglycerides were reduced by troglitazone (from 1.86 +/- 0.33 to 1.38 +/- 0.27 vs. 2.22 +/- 0.44 to 2.35 +/- 0.46 mmol/l, P < 0.01). Insulin-stimulated glucose disposal increased in the troglitazone group (from 208.3 +/- 23.7 to 263.5 +/- 30.4 vs. 197.1 +/- 20.0 to 200.8 +/- 20.8 mg. m(-2). min(-1), P < 0.02) mainly due to increased glucose storage (from 99.9 +/- 17.9 to 146.0 +/- 25.3 vs. 87.1 +/- 16.7 to 87.9 +/- 15.7 mg. m(-2). min(-1), P < 0.02), which took place without altering insulin-stimulated glycogen synthase activity. CONCLUSIONS: In glucose-tolerant first-degree relatives, treatment with troglitazone improved insulin sensitivity almost 50%, primarily due to increased glucose storage. It is suggested that the use of insulin action enhancers can be especially valuable in this group of subjects with a known high risk for developing type 2 diabetes.


Subject(s)
Chromans/pharmacology , Diabetes Mellitus, Type 2/genetics , Hypoglycemic Agents/pharmacology , Thiazolidinediones/pharmacology , Blood Glucose/drug effects , Chromans/therapeutic use , Denmark , Diabetes Mellitus, Type 2/epidemiology , Family , Glucose Clamp Technique , Glucose Tolerance Test , Humans , Hyperinsulinism , Hypoglycemic Agents/therapeutic use , Insulin/administration & dosage , Insulin/pharmacology , Lipids/blood , Obesity/physiopathology , Oxidation-Reduction , Risk Factors , Thiazolidinediones/therapeutic use , Troglitazone
15.
Diabetes ; 51(9): 2691-7, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12196460

ABSTRACT

We investigated whether the effect of troglitazone on glucose disposal is associated with altered insulin signaling. Nondiabetic first-degree relatives of type 2 diabetic patients (age 30 +/- 2 years, BMI 30 +/- 1 kg/m(2); n = 20) were randomized in a double-blind manner to 3 months of troglitazone (200 mg/day) or placebo treatment. Before and after treatment, 3-h euglycemic-hyperinsulinemic glucose clamps (40 mU. m(-2). min(-1)) were performed, and muscle biopsies were obtained immediately before and after the clamps. In the biopsies, insulin receptor kinase (IRK) activity, insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity, Ser(473) and Thr(308) phosphorylation of protein kinase B (PKB), and protein expression of IRS-1, IRS-2, phosphoinositol-dependent kinase-1 (PDK-1), PKB, and GLUT-4 were determined. After troglitazone treatment, insulin-stimulated glucose disposal was increased compared with pretreatment and placebo (279 +/- 37 vs. 211 +/- 26 and 200 +/- 25 mg. m(-2). min(-1); both P < 0.05). IRK and PI3K activities were not altered by troglitazone, but PKB Ser(473) phosphorylation was enhanced compared with pretreatment and placebo at the clamp insulin level (138 +/- 36 vs. 77 +/- 16 and 55 +/- 13 internal standard units; both P < 0.05) and with pretreatment at the basal level (31 +/- 9 vs. 14 +/- 4 internal standard units; P < 0.05). PKB Thr(308) phosphorylation also tended to be higher, but this was not statistically significant. Troglitazone did not alter insulin receptor number or IRS-1, IRS-2, PKB, PDK-1, or GLUT-4 protein expression. We conclude that increased PKB phosphorylation may contribute to the insulin-sensitizing effects of thiazolidinediones in human skeletal muscle.


Subject(s)
Blood Glucose/analysis , Chromans/pharmacology , Diabetes Mellitus, Type 2/etiology , Hypoglycemic Agents/pharmacology , Muscle, Skeletal/metabolism , Proto-Oncogene Proteins/metabolism , Thiazoles/pharmacology , Thiazolidinediones , 3-Phosphoinositide-Dependent Protein Kinases , Adult , Diabetes Mellitus, Type 2/genetics , Double-Blind Method , Female , Humans , Insulin/blood , Male , Osmolar Concentration , Phosphatidylinositol 3-Kinases/metabolism , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-akt , Reference Values , Risk Factors , Troglitazone
16.
Med Sci Sports Exerc ; 34(4): 655-61, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11932575

ABSTRACT

PURPOSE: We examined whether reported deviations from linearity of the oxygen uptake (.VO(2))-to-power output (W) relationship during intense cycling exercise correlated with the percentage Type II fibers in the exercising muscle. METHODS: Twelve trained young men with known fiber type distribution in the vastus lateralis muscle performed step-increment exercise (40 W.3 min(-1)) to exhaustion. RESULTS: .VO(2) increased linearly with W up to about 50% .VO(2max) with a regression equation of .VO(2) (mL.min-1) = 661 + 9.73 W and a correlation coefficient (r) of 1.000. Subsequent .VO(2) values were all greater than corresponding linear estimates (P < 0.001 or 0.0001). Peak exercise excess .VO(2) (measured minus estimated .VO(2) assuming linearity) averaged (SD) 434 (192) mL O(2).min-1 or 10.3 (4.7) % .VO(2max). A comprehensive curvilinearity index defined as the sum of measured minus estimated .VO(2) at the four highest completed exercise trials averaged 973 (460) mL O(2).min-1 or 21.5 (9.4) % .VO(2max). Correlations between percentage Type II fibers and either of the two expressions of curvilinearity were nonsignificant. Delta [H+] (arterialized capillary blood) from basal level to peak exercise correlated with the submaximal curvilinearity index (r = 0.59-0.64; P < 0.05) but not with peak excess .VO(2). There was a trend toward a correlation between delta La and curvilinearity index in % .VO(2max)(r = 0.52; P < 0.10) but not with any of the other curvilinearity expressions. The relative ventilatory activity expressed as .V(E)-to-.VO(2) ratio tended to correlate with peak excess .VO(2) (P < 0.10) but not with curvilinearity index. Signals from motion sensors indicate that coactivation of upper-body musculature coincided with deviation from linearity in the .VO(2)-W relationship. CONCLUSION: VO2 during step-increment cycling increases linearly with power output up to about 50% .VO(2max)and then curvilinearly. The degree of curvilinearity is not related to muscle fiber type distribution in the vastus lateralis, and only marginally and insignificantly related (P < 0.10) to the relative degree of hyperventilation or to lactate response. Acidosis, on the other hand, correlated significantly with curvilinearity index. The inclusion of isometrically working, upper-body muscular groups during high-intensity cycling may also contribute to the overshoot in oxygen cost.


Subject(s)
Exercise/physiology , Muscle, Skeletal/cytology , Muscle, Skeletal/physiology , Oxygen Consumption/physiology , Physical Exertion/physiology , Adult , Energy Metabolism/physiology , Exercise Test , Humans , Kinetics , Male , Muscle Fibers, Skeletal/cytology , Physical Fitness/physiology
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