Effects of levothyroxine substitution therapy on hunger and food intake in individuals with hypothyroidism.

Context: In individuals with hypothyroidism and overweight, levothyroxine substitution therapy is often expected to cause weight loss due to its effect on resting energy expenditure. However, despite levothyroxine-induced enhancement of resting energy expenditure, fat mass loss is rarely seen after levothyroxine substitution therapy. The mechanism behind this conundrum is unknown. Aim: The aim of the study was to assess the effect of levothyroxine therapy on hunger sensations and ad libitum food intake in individuals with hypothyroidism. Design and setting: Prospective cohort study of 18 newly diagnosed hypothyroid women (thyroid-stimulating hormone (TSH) >10 mU/L). Participants were investigated at diagnosis, after normalization of TSH (<4.0 mU/L), and after 6 months of successful treatment. Eighteen age and body mass index-matched healthy controls were also included. Intervention: Hypothyroid individuals were treated with levothyroxine according to European Thyroid Association guidelines. Main outcomes: Changes in hunger sensation were assessed using visual analog scales (cm) before and during a standardized mixed meal test, and food intake was measured during a subsequent ad libitum meal (g). Results: After 6 months of levothyroxine therapy, mean resting energy expenditure was increased by 144 kcal/day (10%) (P < 0.001). Weight loss was comprised of 0.8 kg fat-free mass while fat mass remained unchanged. Fasting hunger sensation increased from a mean of 4.5 (s.d. 2.2) cm to 5.5 (s.d. 2.2) cm (P = 0.047). The numerical increase in ad libitum meal intake did not reach statistical significance. Conclusion: Our data suggest that levothyroxine-induced hunger may be a culprit in the lack of fat mass loss from levothyroxine therapy.

Endothelial function after 10 days of bed rest in individuals at risk for type 2 diabetes and cardiovascular disease.

Physical inactivity is considered to be deleterious to vascular health, and in particular in first-degree relatives to patients with type 2 diabetes (FDR) and persons born with low birth weight (LBW), who may later in life develop cardiovascular disease. A period of imposed physical inactivity could unmask this risk. We hypothesized that the impact of physical inactivity on endothelial function would be more marked in subjects at increased risk for type 2 diabetes and cardiovascular disease (LBW and FDR) compared with a matched control group (CON), all of whom were recruited via advertisements and via the Danish Birth Registry. Twenty LBW, 20 CON and 13 FDR were studied before and after 10 days of bed rest. Forearm blood flow (FBF) was measured by venous occlusion plethysmography during brachial intra-arterial infusion of acetylcholine or adenosine at baseline and with superimposed hyperinsulinaemia. Markers of endothelial activation and inflammation were measured in plasma. Bed rest did not change the vasodilator responses to adenosine or acetylcholine alone in any group, but reduced vasodilator responses to adenosine or acetylcholine during hyperinsulinaemia in LBW. Bed rest impaired insulin-mediated vasodilatation in CON and LBW and increased endothelial activation markers in FDR and LBW but not in CON. Vasodilator responses were very low in FDR prior to bed rest, and did not decrease further during bed rest. Physical inactivity does not impair endothelium-dependent vasodilatation per se, but the vascular vasodilator effect of insulin diminished in CON and LBW after bed rest. In FDR, a further deterioration of FBF with inactivity is not possible.

Physical inactivity affects skeletal muscle insulin signaling in a birth weight-dependent manner.

AIMS: We investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects. METHODS: Twenty LBW and 20 normal birth weight (NBW) subjects were investigated using the euglycemic-hyperinsulinemic clamp with excision of skeletal muscle biopsies pre and post 9days of bed rest. Employing Western blotting, we investigated skeletal muscle Akt, AS160, GLUT4, and AMPK signaling. RESULTS: Peripheral insulin action was similar in the two groups and was decreased to the same extent post bed rest. Insulin and AMPK signaling was unaffected by bed rest in NBW individuals. LBW subjects showed decreased insulin-stimulated Akt phosphorylation and increased AMPK α1 and γ3 protein expression post bed rest. Insulin response of AS160 phosphorylation was lower in LBW subjects both pre and post bed rest. CONCLUSIONS: Bed rest-induced insulin resistance is not explained by impaired muscle insulin or AMPK signaling in subjects with or without LBW. Lower muscle insulin signaling in LBW subjects post bed rest despite similar degree of insulin resistance as seen in controls may to some extent support the idea that LBW subjects are at higher risk of developing type 2 diabetes when being physically inactive.

Muscle inflammatory signaling in response to 9 days of physical inactivity in young men with low compared with normal birth weight.

OBJECTIVE: The molecular mechanisms linking physical inactivity and muscle insulin resistance in humans have been suggested to include increased muscle inflammation, possibly associated with impaired oxidative metabolism. We employed a human bed rest study including 20 young males with normal birth weight (NBW) and 20 with low birth weight (LBW) and increased risk of diabetes. METHODOLOGY: The subjects were studied before and after 9 days of bed rest using the euglycemic-hyperinsulinemic clamp and muscle biopsy excision. Muscle inflammatory status was assessed as nuclear factor-κB (NF-κB) activity and mRNA expression of the pro-inflammatory MCP1 (CCL2) and IL6 and the macrophage marker CD68. Furthermore, mRNA expression of genes central to oxidative phosphorylation (OXPHOS) was measured including ATP5O, COX7A1, NDUFB6, and UQCRB. RESULTS: At baseline, muscle inflammatory status was similar in NBW and LBW individuals. After bed rest, CD68 expression was increased in LBW (P=0.03) but not in NBW individuals. Furthermore, expression levels of all OXPHOS genes were reduced after bed rest in LBW (P ≤ 0.05) but not in NBW subjects and were negatively correlated with CD68 expression in LBW subjects (P ≤ 0.03 for all correlations). MCP1 expression and NF-κB activity were unaffected by bed rest, and IL6 expression was too low for accurate measurements. None of the inflammatory markers correlated with insulin sensitivity. CONCLUSIONS: Although LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest, our data altogether do not support the notion that bed rest-induced (9 days) insulin resistance is caused by increased muscle inflammation.

Increased lipolysis but diminished gene expression of lipases in subcutaneous adipose tissue of healthy young males with intrauterine growth retardation.

Intrauterine growth retardation (IUGR) is associated with a central fat distribution and risk of developing type 2 diabetes in adults when exposed to a sedentary Western lifestyle. Increased lipolysis is an early defect of metabolism in IUGR subjects, but the sites and molecular mechanisms involved are unknown. Twenty IUGR and 20 control (CON) subjects, aged 20-30 years, were studied before and after 10 days of bed rest using the glucose clamp technique combined with measurements of in vivo metabolism by microdialysis technique and blood flow by (133)Xe washout technique in subcutaneous abdominal (SCAAT) and femoral (SCFAT) adipose tissue. Additionally, mRNA expression of lipases was evaluated in biopsies from SCAAT. Lipolysis in SCAAT was substantially higher in IUGR than in CON subjects despite markedly lower mRNA expression of lipases. Blood flow was higher in IUGR compared with CON in both SCAAT and SCFAT. Whole body insulin sensitivity did not differ between groups and decreased after bed rest. After bed rest, SCAAT lipolysis remained higher in IUGR compared with CON, and SCFAT lipolysis decreased in CON but not in IUGR. Prior to the development of whole body insulin resistance, young men with IUGR are characterized by increased in vivo adipose tissue lipolysis and blood flow with a paradoxically decreased expression of lipases compared with CON, and 10 days of physical inactivity underlined the baseline findings. Subjects with IUGR exhibit primary defects in adipose tissue metabolism.

Effect of 10 days of bedrest on metabolic and vascular insulin action: a study in individuals at risk for type 2 diabetes.

Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes [persons with low birth weight (LBW group; n = 20) and first-degree relatives to type 2 diabetic patients (FDR group; n = 13)] as well as a control (CON) group (n = 20) matched for body mass index, age, and physical activity levels before and after 10 days of bedrest. Subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. All groups responded with a decrease in whole body insulin sensitivity in response to bedrest [CON group: 6.8 +/- 0.5 to 4.3 +/- 0.3 mg x min(-1) x kg(-1) (P < 0.0001), LBW group: 6.2 +/- 0.5 to 4.3 +/- 0.3 mg x min(-1) x kg(-1) (P < 0.0001), and FDR group: 4.3 +/- 0.7 to 3.1 +/- 0.3 mg x min(-1) x kg(-1) (P = 0.068)]. The percent decrease was significantly greater in the CON group compared with the FDR group (CON group: 34 +/- 4%, LBW group: 27 +/- 4%, and FDR group: 10 +/- 13%). Forearm insulin-stimulated glucose clearance decreased significantly in the CON and LBW groups in response to bedrest; in the FDR group, clearance was very low before bedrest and no change was observed. Before bedrest, the CON and LBW groups demonstrated a significant increase in FBF during hyperinsulinemia; after bedrest, an increase in FBF was observed only in the CON group. In conclusion, bedrest induced a pronounced reduction in whole body, skeletal muscle, and vascular insulin sensitivity in the CON and LBW groups. The changes were most pronounced in the CON group. In the FDR group, insulin resistance was already present before bedrest, but even this group displayed a high sensitivity to changes in daily physical activity.

The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest.

OBJECTIVE: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS: A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance. RESULTS: The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS: Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of beta-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes.

Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes.

OBJECTIVE: The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS: A total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS: Bed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001). CONCLUSIONS: Whole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance.

Impaired endothelial function and insulin action in first-degree relatives of patients with type 2 diabetes mellitus.

First-degree relatives (FDR) of patients with type 2 diabetes mellitus are at increased risk of developing type 2 diabetes mellitus. We studied if endothelial dysfunction of the resistance vessels is present and may coexist with metabolic insulin resistance in FDR. Male FDR (n = 13; 26 +/- 1 years; body mass index, 25 +/- 1 kg m(2) [mean +/- SEM]) and matched control subjects (CON) (n = 22; 25 +/- 1 years; body mass index, 24 +/- 1 kg m(2)) were studied by hyperinsulinemic (40 mU min(-1)m(-2)) isoglycemic clamp combined with brachial arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography upon stimulation with systemic hyperinsulinemia (291 +/- 11 pmol/L, pooled data from both groups) and upon intraarterial infusion of adenosine (ADN) and acetylcholine (ACH) +/- hyperinsulinemia. Forearm blood flow response to ADN and ACH was less in FDR vs CON (P < .05); systemic hyperinsulinemia added to the FBF effect of ADN in CON (P < .05) but not in FDR. In addition, FDR demonstrated impaired FBF to hyperinsulinemia (2.1 +/- 0.2 vs 4.0 +/- 0.6 mL 100 mL(-1) min(-1)) in FDR and CON, respectively (P < .05). Both M-value (5.0 +/- 0.7 vs 7.0 +/- 0.5 mg min(-1) kg(-1)) and forearm glucose clearance (0.6 +/- 0.1 vs 1.4 +/- 0.4 mL 100 mL(-1)min(-1)) were diminished in FDR compared with CON (all P < .05). FDR demonstrated endothelial dysfunction of the resistance vessels in addition to impaired insulin-stimulated increase in bulk flow. Moreover, FDR demonstrated whole-body insulin resistance as well as decreased basal and insulin-stimulated forearm glucose uptake. It remains to be established whether FDR also demonstrate impaired insulin-stimulated microvascular function.

Interstitial concentrations of adipokines in subcutaneous abdominal and femoral adipose tissue.

Adipokines play important regulatory roles in the pathophysiology of obesity and insulin resistance. We measured plasma and interstitial concentrations of the adipokines adiponectin, resistin, leptin, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in subcutaneous, abdominal and femoral adipose tissue using calibrated, large-pore microdialysis technique in 8 healthy, lean men on 2 experimental days. The interstitial leptin concentration was 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue (P<0.05), but no regional differences were found for the remaining adipokines (P>0.05). Adiponectin and leptin concentrations were higher in plasma than subcutaneous adipose tissue (approximately 25-fold and approximately 2-fold, respectively, P<0.05), whereas MCP-1, IL-6 and IL-8 concentrations were higher in subcutaneous adipose tissue than plasma (approximately 100-fold, approximately 200-fold and approximately 1000-fold, respectively, P<0.05). Resistin concentrations did not differ significantly between compartments. Adipose tissue blood flow (ATBF) showed no regional difference (P>0.05). The intra- and inter-subject variations of all investigated adipokines as well as of ATBF were substantial (coefficient of variation: 4-177%). In conclusion, interstitial leptin concentrations are approximately 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue, which might be a potential mechanism behind the health-benefits of "pear-shape". Furthermore, subcutaneous adipose tissue has a marked production of pro-inflammatory adipokines.

Increased risk of type 2 diabetes in elderly twins.

OBJECTIVE: Genetic susceptibility, low birth weight (LBW), and aging are key etiological factors in the development of type 2 diabetes. LBW is common among twins. It is unknown whether twin status per se is associated with risk of type 2 diabetes, and valid concordance rates of type 2 diabetes in twins on a lifetime perspective are lacking. RESEARCH DESIGN AND METHODS: A clinical study was done on a population-based cohort of same-sex elderly monozygotic (MZ) and dizygotic (DZ) twins (n = 297) and singleton control subjects (C) (n = 71) including measures of anthropometry and glucose tolerance. In addition, type 2 diabetes incidence cases in twins (n = 626) and singletons (n = 553) were identified through the National Diabetes Register. RESULTS: Twins were more abdominally obese, insulin resistant, and glucose intolerant, as evidenced by a higher A1C (%) (means +/- SD) (MZ: 6.0 +/- 1.0, DZ: 5.8 +/- 0.7, C: 5.6 +/- 0.3, P = 0.004) and 120-min post-oral glucose tolerance test plasma glucose levels (in mmol/l) (MZ: 8.6 +/- 4.6, DZ: 8.4 +/- 3.9, C: 6.8 +/- 2.4, P = 0.003) compared with singletons. Importantly, twins had a higher prevalence of type 2 diabetes (MZ: 17.5% [95% CI 14.4-20.6], DZ: 15.7% [13.1-18.3], C: 5.6% [3.0-8.2], P = 0.03) together with a 60% higher incidence rate of type 2 diabetes compared with singletons. Cumulative concordance rates of type 2 diabetes to the age of 84 years were similar among elderly MZ (0.76 [0.68-0.84]) and DZ (0.71 [0.63-0.78]) twins. CONCLUSIONS: Twin status per se is associated with abdominal obesity, insulin resistance, and increased prevalence of type 2 diabetes in elderly twins. The data support a quantitatively significant impact of the fetal environment as opposed to genetics on risk of type 2 diabetes.