Camilla Schalin-Jäntti

Association between Polymorphism of the Glycogen Synthase Gene and Non-Insulin-Dependent Diabetes Mellitus

BACKGROUND The storage of glucose as glycogen in skeletal muscle is frequently impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their nondiabetic relatives. Despite an intensive search for candidate genes associated with NIDDM, no data have been available on the gene coding for the key enzyme of this pathway, glycogen synthase. METHODS AND RESULTS Using a human complementary DNA probe, the restriction enzyme Xbal, and Southern blot analysis, we identified two polymorphic alleles, A1 and A2, in the glycogen synthase gene. The gene was localized to chromosome 19. The A1A2 or A2A2 genotype was found in 30 percent of 107 patients with NIDDM but in only 8 percent of 164 nondiabetic subjects without a family history of NIDDM (P < 0.001). The diabetic patients with the A2 allele had a stronger family history of NIDDM (P = 0.019), a higher prevalence of hypertension (P = 0.008), and a more severe defect in insulin-stimulated glucose storage (P = 0.001) than the diabetic patients with the A1 allele. The concentration of the glycogen synthase protein in biopsy specimens of skeletal muscle from the patients with the A2 allele was normal, however, suggesting that expression of the gene was unaltered. The Xbal polymorphism was due to a change of a single base in an intron. CONCLUSIONS The Xbal polymorphism of the glycogen synthase gene identifies a subgroup of patients with NIDDM characterized by a strong family history of NIDDM, a high prevalence of hypertension, and marked insulin resistance.

Impaired Activation of Glycogen Synthase in People at Increased Risk for Developing NIDDM

To study whether impaired activation of muscle glycogen synthase represents an early defect in the pathogenesis of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM), we quantitated rates of nonoxidative glucose metabolism and measured activities of glycogen synthase and phosphorylase and concentrations of free glucose and glucose-6-phosphate in muscle biopsies, obtained before and after a euglycemic insulin clamp, in 16 NIDDM patients, 18 first-degree relatives of NIDDM patients, and 16 nondiabetic control subjects. Insulin-stimulated glucose storage (20.1 ± 1.5 and 11.6 ± 1.7 vs. 27.9 ± 1.7 βmol·kg−1 lean body mass [LBM]·min−1 P < 0.01–0.001 [3.6 ± 0.3 and 2.1 ± 0.3 vs. 5.0 ± 0.3 mg·kg−1 LBM·min−1] and glycogen synthase activity, measured at 0.1 mM glucose-6-phosphate concentration (11.3 ± 1.3 and 11.6 ± 1.3 vs. 18.3 ± 2.0 nmol·min−1·mg−1 protein, P < 0.01), were impaired in relatives and diabetic subjects compared with control subjects. Glycogen synthase activity correlated with the rate of glucose storage (r = 0.53, P < 0.001). Glycogen phosphorylase fractional activity did not differ among the groups. Apart from increased intramuscular basal glucose concentrations in NIDDM patients, no consistent differences were observed in free glucose and glucose-6-phosphate concentrations between the groups. We conclude that impaired activation of muscle glycogen synthase by insulin is observed in patients with a genetic risk of developing NIDDM and may represent an early defect in the pathogenesis of NIDDM.

Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporter (GLUT-4) gene in human skeletal muscle.

SummaryTo study whether insulin resistance in Type 2 (non-insulin-dependent) diabetes mellitus is due to a defect in the expression of the insulin-responsive glucose transporter gene (GLUT-4) in human skeletal muscle, we measured the level of GLUT-4 mRNA and (in some of the subjects) its protein in muscle biopsies taken from 14 insulin-resistant patients with Type 2 diabetes, 10 first-degree relatives of the diabetic patients and 12 insulin-sensitive control subjects. Insulin sensitivity was measured with a +45 mU·

Hyperthyroidism Increases Brown Fat Metabolism in Humans

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Complementary Roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in Medullary Thyroid Cancer

·min−1 euglycaemic insulin clamp in combination with indirect calorimetry and infusion of [3-3H]glucose. GLUT-4 mRNA was measured using a human GLUT-4 cDNA probe and GLUT-4 protein with a polyclonal antibody specific for the 15 amino acid carboxyterminal peptide. Both Type 2 diabetic patients and their relatives showed impaired stimulation of total-body glucose disposal by insulin compared with control subjects (29.5±2.1 and 34.0±4.8 vs 57.9±3.1 μmol·kg lean body mass−1·min−1; p<0.01). This impairment in glucose disposal was primarily accounted for by a reduction in insulin-stimulated storage of glucose as glycogen (13.0±2.4 and 15.6±3.9 vs 36.9±2.2 μmol·kg lean body mass−1·min−1; p<0.01). The levels of GLUT-4 mRNA expressed both per μg of total RNA and per μg DNA, were higher in the diabetic patients compared with the control subjects (116±25 vs 53±10 pg/μg RNA and 177±35 vs 112±29 pg/μg DNA; p<0.05, p<0.01, respectively). The GLUT-4 mRNA levels in the relatives were not significantly different from that observed in the control subjects (90±16 pg/μg RNA and 117±23 pg/μg DNA; p = NS). The GLUT-4 protein levels did not significantly differ between control subjects, diabetic patients and relatives (494±85, 567±133 and 323±80 cpm/100 μg protein). No correlation was observed between the level of GLUT-4 mRNA andits protein. However, the level of GLUT-4 mRNA and the rate of total-body glucose disposal correlated positively in the control group and in the relatives (both p<0.05) but not in the diabetic subjects. A positive correlation between the level of GLUT-4 protein and total-body glucose disposal was also observed in the control subjects (r = 0.759; p<0.05) and in the relatives (r = 0.794; p<0.01) but not in the diabetic subjects. We conclude that insulin resistance in Type 2 diabetes is not related to a defect in the expression of the GLUT-4 gene in skeletal muscle. Nevertheless, the levels of GLUT-4 mRNA and GLUT-4 protein are related to the rate of total-body glucose disposal in subjects with normal fasting glucose concentrations.

DIAGNOSIS OF ENDOCRINE DISEASE: Thyroglobulin measurement using highly sensitive assays in patients with differentiated thyroid cancer: a clinical position paper

Abstract Background. The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3–20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Groups current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.

Post-ablative serum thyroglobulin is an independent predictor of recurrence in low-risk differentiated thyroid carcinoma: a 16-year follow-up study

CONTEXT Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. OBJECTIVE The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. DESIGN This was a follow-up study using positron emission tomography imaging. MAIN OUTCOME MEASURES Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. RESULTS Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. CONCLUSIONS Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.

Isolation and characterization of the human muscle glycogen synthase gene

Background: Hypokalemic periodic paralysis as a complication of thyrotoxicosis (THypoKPP) is common in Asians but not well recognized in Western countries or pediatric patients, where most cases are due to the familial variant (FHypoKPP). Ion channel gene mutations may underlie these diseases. We describe the first pediatric and a rare adult Caucasian case of THypoKPP in Finland. Methods: Manifestation and management of two THypoKPP cases. We studied for possible mutations in KCNE3, KCNJ2, SCN4A and CACNA1S genes. Results: A 15-year-old Vietnamese boy presented with sudden-onset paralysis and severe hypokalemia, 1.8 mmol/l. The case was first regarded as FHypoKPP, but thyroid function testing revealed a suppressed TSH and highly elevated FT4. A 37-year-old Caucasian male presented with acute tetraparesis. His plasma potassium was only 1.4 mmol/l. Treatment with carbimazole had been initiated two weeks earlier, but FT4 was still elevated. No mutations in KCNE3, KCNJ2, SCN4A or CACNA1S genes were detected. Conclusions: THypoKPP is a potentially life-threatening condition which bares many similarities with FHypoKPP. THypoKPP is rare in Western countries but should be considered in sudden-onset paralysis, independently of age and especially in males. Mutations in ion channel candidate genes did not underlie the disease in the present cases.