Diabetes-inducing effects of bronchial asthma

Table 1 The effect of bronchial asthma medications on blood glucose and diabetes mellitus

Drug	Effect	Mechanism
Beta-agonists	Beta2-agonists can improve insulin sensitivity[83]. Improved glucose tolerance and homeostasis[84]. No clinically significant increase in blood glucose in patients with DM[85]	Stimulating glucose uptake in the skeletal muscle, improving whole-body insulin sensitivity, and reducing hepatic lipids and glycogen[84]
Anticholinergic	There are no recorded harmful effects of inhaled anticholinergic drugs on the glucose level or insulin resistance. Oral anticholinergics can attenuate the late-phase insulin activity in varying degrees of glycemic status[86]	Insulin secretion is influenced by the cholinergic system[86]
Xanthine derivatives (phosphodiesterase inhibitors)	Aminophylline inhibits the endogenous glucose production in T2DM by stimulating insulin secretion[87]. A single dose of theophylline can improve hypoglycemia unawareness in patients with T1DM; however, prolonged theophylline use is associated with tolerance of that effect, causing a sustained effect on different responses to hypoglycemia (cardiovascular, metabolic, and symptom responses)[88]	Paracrine factors, such as adenosine, may be involved in regulating basal insulin secretion[87]
Systemic corticosteroids	High risk of developing DM and progression to insulin therapy in persons using long-term systemic steroids[90-93]. Patients with asthma without a diagnosis of DM who used corticosteroids developed hyperglycemia[94]. Risk factors for developing DM in subjects using systemic glucocorticoids include older age, higher fasting blood glucose levels and HbA1c, lower glomerular filtration rate, presence of pregnancy, visceral obesity, insulin resistance, and family history of DM[97]	Increased hepatic gluconeogenesis. The peripheral glucose uptake by the skeletal muscle, adipose tissue, liver, and bone is reduced. Insulin resistance and its effect on glycemic control. Inhibition of insulin secretion by pancreatic β cells. Steroids favor the systemic release of triglycerides and fatty acids that negatively affect β cells' function[96,97]
ICS	Systemic bioavailability of ICS increases the risk of systemic adverse effects, especially with higher doses of ICS, increasing the risk of DM and hyperglycemia. Other factors that determine ICS's potential for systemic adverse effects include the dose of the drug, the patient's age, and the presence of other co-morbidities. Newer ICS preparations have essentially zero oral bioavailability and exhibit 98%–99% binding to serum proteins, making them unable to reach the glucocorticoid receptors. Efforts to improve the delivery devices to choose the best form of the ICS are ongoing[101,102]	The same mechanisms as with systemic steroids when the drug reaches the circulation
Leukotriene receptor antagonists	No recorded evidence of their effect on DM control or insulin resistance exists. Montelukast has a protective effect against diabetic retinopathy[104]	Leukotriene receptor antagonism by montelukast resulted in a significant decrease in early, diabetes-induced retinal capillary leakage, leukocyte adherence, and superoxide generation[104]
Biologic agents	Few case reports show elevation of blood glucose following administration of omalizumab, an anti-IgE antibody. That was not noticed after administering mepolizumab, a monoclonal antibody against IL-5[105-107]	Each vial of omalizumab (150 mg) contains 145.5 mg sucrose. However, because of the infrequent use of omalizumab (every two or four weeks), sucrose included in the omalizumab vial did not seem to influence glycaemic control[105-107]

T2DM: Type 2 diabetes mellitus; T1DM: Type 1 diabetes mellitus; ICS: Inhaled corticosteroids; IL: Interleukin.

Table 2 The effect of diabetes mellitus medications on bronchial asthma

Drug	Effect	Mechanism
Metformin	It reduces the airway inflammation[109,111,112]. It is linked to a lower incidence of asthma[110]. Metformin reduced asthma exacerbation, asthma-related hospitalization, and emergency department visits[109,114,115]	Its anti-inflammatory effect is mediated through the activation of 5 adenosine monophosphate-activated protein kinase[112], which decreases oxidative stress via the regulation of cellular proliferation and protein synthesis with subsequent effects on nicotinamide adenine dinucleotide phosphate-oxidases[113]. Activation of adenosine monophosphate-activated protein kinase also inhibits glycolysis and cytokine production in immune cells with subsequent reduction of airway inflammation, collagen deposition, fibrosis, and airway remodeling[117]. Metformin inhibits tumor necrosis factor-α-induced inflammatory signaling and nuclear factor-kappa B-mediated inducible nitric oxide synthase expression[111]. Activation of lipopolysaccharide evoked Toll-like receptor-4[116]
Thiazolidinediones	Thiazolidinediones decrease bronchial hyper-responsiveness[118]. Thiazolidinediones reduce the risk of asthma exacerbation and oral steroid prescription[119]. The use of pioglitazone improves the level of asthma control[120]. Other studies showed no changes in the amount of exhaled nitric oxide, level of asthma control, and lung function parameters using pioglitazone[121,122]	Thiazolidinediones decrease airway inflammation and levels of Th2 cytokines[118]. Thiazolidinediones ameliorate the epithelial function[120]
Dipeptidyl peptidase 4 inhibitors	The use of the dipeptidyl peptidase 4 inhibitors did not significantly affect the rate of asthma hospitalization, lower respiratory tract infections, oral glucocorticoid prescriptions, total asthma control, and the number of severe exacerbations[123]	Anti-inflammatory effect
GLP1R agonists	GLP1R agonists use results in relaxation of airway smooth muscle cells, lowering of airway eosinophilia, and improvement of airway hyperresponsiveness[126]. GLP1R agonists reduce rates of asthma exacerbations and frequencies of asthma symptoms[128]. GLP1R agonists can improve baseline pulmonary function[126]	GLP1R agonists activate cyclic AMP-dependent protein kinase A in the human airway[126]. GLP1R agonists decrease the expression of IL-5 and IL-13, the lung protein expression of type-2 cytokines and chemokines, the number of perivascular eosinophils, the mucus production, and the airway responsiveness[125]. Liraglutide reduces the number of lung epithelial cells expressing IL-33, the level of IL-33 expression by individual cells, and the level of IL33 in broncho-alveolar lavage fluid
Insulin	Increased insulin level increases airway hyperresponsiveness[47,63]. The use of insulin therapy in patients with DM was associated with a higher occurrence of asthma[110]. Other insulin-resistance medications, such as sulfonylureas, improve asthma control[115]	Insulin increases bronchial smooth muscle proliferation[47,63]
SGLT2I	SGLT2I use was associated with a reduced risk of incident obstructive airway diseases and a lower rate of obstructive airway diseases exacerbations in comparison with placebo or dipeptidyl peptidase 4[134-136]	The potential anti-inflammatory effect of SGLT2Is was noticed in both animal and human cohort studies[137,138]. SGLT2Is also inhibit NLRP3 inflammasome activation in multiple tissues, including the lung[139]. NLRP3 inflammasome activation has been implicated in asthmatic airway inflammation[140]
PDE inhibitors	Nonselective PDE inhibitors such as aminophylline and theophylline increase cAMP and cyclic guanosine monophosphate levels, leading to bronchodilation and reduced airway inflammation. PDE4 Inhibitors such as roflumilast increase cAMP levels in bronchial smooth muscle cells, leading to muscle relaxation and bronchodilation. PDE inhibitors reduce inflammation in the airways. PDE inhibitors can decrease the hyperresponsiveness of airways to allergens and irritants, a key feature of asthma[87,88,141]. PDE inhibitors improve the control of DM and reduce its related complications[142,143]	Modulating cyclic nucleotide signaling pathways that are critical for various cellular functions, including metabolism and smooth muscle relaxation[141,142]. PDE inhibitors have effects on bronchial asthma including bronchodilation, anti-inflammatory effects and reduction of airway hyperresponsiveness. PDE inhibitors reduce inflammation in the airways by inhibiting the breakdown of cAMP, which decreases the release of pro-inflammatory cytokines and reduces the activity of inflammatory cells like eosinophils and neutrophils[87,88,141]. PDE inhibitors have effects on DM, including improved insulin sensitivity and glucose homeostasis, reduction of inflammation, cardiovascular benefits, and potential weight management effects[142,143]

DM: Diabetes mellitus; GLP1R: Glucagon-like peptide 1 receptor; cAMP: Cyclic adenosine monophosphate; SGLT2I: Sodium/glucose cotransporter 2 inhibitors; PDE: Phosphodiesterase.