Gluten-Free Diet in Co-Existent Celiac Disease and Type 1 Diabetes Mellitus: Is It Detrimental or Beneficial to Glycemic Control, Vascular Complications, and Quality of Life?

Celiac disease (CeD) is associated with type 1 diabetes mellitus (T1DM), and both have the same genetic background. Most patients with T1DM who develop CeD are either asymptomatic or have mild CeD-related gastrointestinal symptoms. Therefore, children affected by T1DM should undergo screening for asymptomatic CeD. The aim of this review is to highlight the influence of a gluten-free diet (GFD) on glycemic control, growth rate, microvascular complications, and quality of life in patients with T1DM and CeD. PubMed, Google Scholar, Web of Science, and Cochrane Central databases were searched. Reports reviewed were those published from 1969 to 2022 that focused on the interplay of T1DM and CeD and examined the effect of diet on glycemic control, growth rate, and quality of life. The most challenging aspect for a child with T1DM and CeD is that most GFD foods have a high glycemic index, while low glycemic index foods are recommended for T1DM. Interestingly, dietary therapy for CeD could improve the elevated HbA1c levels. Avoiding gluten added to a diabetic dietary regimen in T1DM patients might impose practical limitations and lead to important restrictions in the lifestyle of a young patient. Consequently, non-adherence to GFD in patients with T1DM and CeD is common. GFD in patients with T1DM and CeD seems to lower the incidence of micro- and macrovascular complications, but this requires further investigation. It seems that adherence to GFD in young patients with T1DM and CeD leads to regular growth and a stable body mass index without any negative effect on HbA1c or insulin requirements. Furthermore, the lipid profile and quality of life seem to have improved with the introduction of GFD.

Effects of intravenous thyrotropin-releasing hormone on 18F-fluorodeoxyglucose uptake in human brown adipose tissue: a randomized controlled trial.

OBJECTIVE: Brown adipose tissue (BAT) activity in humans is stimulated by cold and by a limited number of pharmacological agents, including ß3-adrenergic agonists and bile acids. Although thyrotropin-releasing hormone (TRH) is known to activate BAT in several mammals, this has not been reported in humans. DESIGN: A randomized, placebo-controlled, double-blind, cross-over trial. METHODS: We investigated the effects of intravenous bolus administration of 400 µg TRH or 2 mL saline on BAT activity in healthy, lean men. BAT activity was measured as standardized 18F-fluorodeoxyglucose (18F-FDG) uptake and glucose metabolic rate (MRglu) using dynamic PET/CT imaging. The first six individuals were studied at room temperature, while subsequently nine were exposed to mild cold (17°C ± 1°C) for 60 min before imaging. During the dynamic scan, blood was withdrawn for measurement of thyroid hormone and catecholamine concentrations. This trial is registered with The Netherlands National Trial Register (number NTR5512). RESULTS: Sixteen participants were recruited. Six men studied at room temperature showed no visible BAT activity during either session. After exposure to mild cold, four of nine men (44.4%) showed clear increase of 18F-FDG uptake after TRH administration compared to placebo. Maximal standardized 18F-FDG uptake showed a trend toward increase after TRH compared to placebo (P = 0.066). MRglu showed a significant increase after TRH administration (P = 0.014). The increase in 18F-FDG uptake was not paralleled by changes in plasma thyroid hormone or catecholamine concentrations. CONCLUSION: Systemic TRH administration can increase the activity of cold-stimulated BAT in adult men. These findings may assist developing pharmacological strategies for modulating BAT activity in the management of obesity.

Hormonal control of metabolism by the hypothalamus-autonomic nervous system-liver axis.

The hypothalamus has long been appreciated to be fundamental in the control and coordination of homeostatic activity. Historically, this has been viewed in terms of the extensive neuroendocrine control system resulting from processing of hypothalamic signals relayed to the pituitary. Through these actions, endocrine signals are integrated throughout the body, modulating a vast array of physiological processes. Our understanding of the responses to endocrine signals is crucial for the diagnosis and management of many pathological conditions. More recently, the control emanating from the hypothalamus over the autonomic nervous system has been increasingly recognized as a powerful additional modulator of peripheral tissues. However, the neuroendocrine and autonomic control pathways emanating from the hypothalamus are not separate processes. They appear to act as a single integrated regulatory system, far more subtle and complex than when each is viewed in isolation. Consequently, hypothalamic regulation should be viewed as a summation of both neuroendocrine and autonomic influences. The neural regulation is believed to be fine and rapid, whereas the hormonal regulation is more stable and widespread. In this chapter, we will focus on the hypothalamic control of hepatic glucose and lipid metabolism.

Energy Homeostasis and Body Weight before and after Cessation of Block and Replacement Therapy in Euthyroid Patients with Graves' Disease.

Patients with Graves' hyperthyroidism (GH) treated with a combination of thyrostatic drugs and T(4), that is, block and replacement therapy (BRT), often report body weight (BW) gain. We aimed to determine changes in BW and energy metabolism upon cessation of BRT in these patients, and to identify possible endocrine determinants. We analysed 22 patients with GH (i) during BRT, and (ii) 12 weeks after BRT cessation. Patients were euthyroid at both visits. There were no differences in BW or resting energy expenditure (REE) between visits. At visit 1, after 13.5 (9.5-48.0) months of BRT, serum free (F)T(4) correlated positively with REE (r = 0.433, P = 0.044) and negatively with body fat % (r = -0.450, P = 0.035). Plasma FT(3) and FT(3)/FT(4) ratio showed an increase 12 w after cessation of BRT (20%, P < 0.0001 and 16%, P = 0.007, resp.). Moreover, the relative change in FT(3)/FT(4) ratio showed a significant, positive correlation with the relative change in REE between the 2 visits (r = 0.465, P = 0.029). In conclusion, serum FT(4) determines REE in euthyroid patients with GH treated with BRT. Twelve weeks after BRT cessation, BW and energy homeostasis are unaltered. However, as serum FT(3)/FT(4) ratio increases after cessation of BRT, which is a positive determinant of changes in REE, a longer term BW decrease is likely to occur.

Novel neural pathways for metabolic effects of thyroid hormone.

The relation between thyrotoxicosis, the clinical syndrome resulting from exposure to excessive thyroid hormone concentrations, and the sympathetic nervous system remains enigmatic. Nevertheless, beta-adrenergic blockers are widely used to manage severe thyrotoxicosis. Recent experiments show that the effects of thyrotoxicosis on hepatic glucose production and insulin sensitivity can be modulated by selective hepatic sympathetic and parasympathetic denervation. Indeed, thyroid hormone stimulates hepatic glucose production via a sympathetic pathway, a novel central pathway for thyroid hormone action. Rodent studies suggest that similar neural routes exist for thyroid hormone analogues (e.g. thyronamines). Further elucidation of central effects of thyroid hormone on autonomic outflow to metabolic organs, including the thyroid and brown adipose tissue, will add to our understanding of hyperthyroidism.

Thyroid hormone effects on whole-body energy homeostasis and tissue-specific fatty acid uptake in vivo.

The effects of thyroid hormone (TH) status on energy metabolism and tissue-specific substrate supply in vivo are incompletely understood. To study the effects of TH status on energy metabolism and tissue-specific fatty acid (FA) fluxes, we used metabolic cages as well as (14)C-labeled FA and (3)H-labeled triglyceride (TG) infusion in rats treated with methimazole and either 0 (hypothyroidism), 1.5 (euthyroidism), or 16.0 (thyrotoxicosis) microg per 100 g/d T(4) for 11 d. Thyrotoxicosis increased total energy expenditure by 38% (P = 0.02), resting energy expenditure by 61% (P = 0.002), and food intake by 18% (P = 0.004). Hypothyroidism tended to decrease total energy expenditure (10%; P = 0.064) and resting energy expenditure (12%; P = 0.025) but did not affect food intake. TH status did not affect spontaneous physical activity. Thyrotoxicosis increased fat oxidation (P = 0.006), whereas hypothyroidism decreased glucose oxidation (P = 0.035). Plasma FA concentration was increased in thyrotoxic but not hypothyroid rats. Thyrotoxicosis increased albumin-bound FA uptake in muscle and white adipose tissue (WAT), whereas hypothyroidism had no effect in any tissue studied, suggesting mass-driven albumin-bound FA uptake. During thyrotoxicosis, TG-derived FA uptake was increased in muscle and heart, unaffected in WAT, and decreased in brown adipose tissue. Conversely, during hypothyroidism TG-derived FA uptake was increased in WAT in association with increased lipoprotein lipase activity but unaffected in oxidative tissues and decreased in liver. In conclusion, TH status determines energy expenditure independently of spontaneous physical activity. The changes in whole-body lipid metabolism are accompanied by tissue-specific changes in TG-derived FA uptake in accordance with hyper- and hypometabolic states induced by thyrotoxicosis and hypothyroidism, respectively.

Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver.

Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T(3)) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T(3) or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T(3) microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T(3) microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T(3) microdialysis in the PVN increased EGP by 11 +/- 4% (P = 0.020), while EGP decreased by 5 +/- 8% (ns) in vehicle-treated rats (T(3) vs. Veh, P = 0.030). Plasma glucose increased by 29 +/- 5% (P = 0.0001) after T(3) microdialysis versus 8 +/- 3% in vehicle-treated rats (T(3) vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T(3) administration. Effects of PVN T(3) microdialysis were independent of plasma T(3), insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T(3) microdialysis on EGP. We conclude that stimulation of T(3)-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.

Central effects of thyronamines on glucose metabolism in rats.

Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T(1)AM) and - to a lesser extent - thyronamine (T(0)AM), leads to acute bradycardia, hypothermia, decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines. We investigated whether a low dose i.c.v. infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following i.p. thyronamine administration. Plasma glucose, glucoregulatory hormones, and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus infusion of T(1)AM, T(0)AM, or vehicle. To identify the peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T(1)AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared with i.p.-administered T(1)AM, a 100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T(0)AM caused smaller increases in EGP, plasma glucose, and glucagon compared with T(1)AM. Neither T(1)AM nor T(0)AM influenced any of these parameters upon low dose i.v. administration. We conclude that central administration of low-dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.

Effects of thyrotoxicosis and selective hepatic autonomic denervation on hepatic glucose metabolism in rats.

Thyrotoxicosis is known to induce a broad range of changes in carbohydrate metabolism. Recent studies have identified the sympathetic and parasympathetic nervous system as major regulators of hepatic glucose metabolism. The present study aimed to investigate the pathogenesis of altered endogenous glucose production (EGP) in rats with mild thyrotoxicosis. Rats were treated with methimazole in drinking water and l-thyroxine (T(4)) from osmotic minipumps to either reinstate euthyroidism or induce thyrotoxicosis. Euthyroid and thyrotoxic rats underwent either a sham operation, a selective hepatic sympathetic denervation (Sx), or a parasympathetic denervation (Px). After 10 days of T(4) administration, all animals were submitted to a hyperinsulinemic euglycemic clamp combined with stable isotope dilution to measure EGP. Plasma triiodothyronine (T(3)) showed a fourfold increase in thyrotoxic compared with euthyroid animals. EGP was increased by 45% in thyrotoxic compared with euthyroid rats and correlated significantly with plasma T(3). In thyrotoxic rats, hepatic PEPCK mRNA expression was increased 3.5-fold. Relative suppression of EGP during hyperinsulinemia was 34% less in thyrotoxic than in euthyroid rats, indicating hepatic insulin resistance. During thyrotoxicosis, Sx attenuated the increase in EGP, whereas Px resulted in increased plasma insulin with unaltered EGP compared with intact animals, compatible with a further decrease in hepatic insulin sensitivity. We conclude that chronic, mild thyrotoxicosis in rats increases EGP, whereas it decreases hepatic insulin sensitivity. Sympathetic hepatic innervation contributes only to a limited extent to increased EGP during thyrotoxicosis, whereas parasympathetic hepatic innervation may function to restrain EGP in this condition.