Background: Diabetes mellitus is a significant comorbidity of interstitial lung disease (ILD). Objectives: The aim of this study was to investigate the incidence of restrictive lung disease (RLD) and ILD in patients with prediabetes and type 2 diabetes (T2D). Methods: Forty-eight nondiabetics, 68 patients with prediabetes, 29 newly diagnosed T2D, and 110 patients with long-term T2D were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. Five participants with T2D, breathlessness, and RLD underwent multidetector computed tomography (MDCT) and a Six-Minute Walk Test (6MWT). Lung tissue from 4 patients without diabetes and from 3 patients with T2D was histologically examined for presence of pulmonary fibrosis. Results: Breathlessness in combination with RLD was significantly increased in patients with prediabetes and T2D (p < 0.01). RLD was found in 9% of patients with prediabetes, in 20% of patients with newly diagnosed T2D, and in 27% of patients with long-term T2D. Thus, patients with long-term T2D had an increased risk of RLD (OR 5.82 [95% CI 1.71–20.5], p < 0.01). RLD was significantly associated with glucose metabolism and albuminuria (p < 0.01); furthermore, presence of nephropathy increased the risk of RLD (OR 8.57 [95% CI 3.4–21.9], p < 0.01) compared to nondiabetics. MDCT revealed ILD in 4 patients, the 6MWT correlated with the extent of ILD, and histological analysis showed fibrosing ILD in patients with T2D. Conclusions: This study demonstrates increased breathlessness and a high prevalence of RLD in patients with T2D, indicating an association between diabetes and fibrosing ILD.

Human insulin and its analogues prevent the reduction in lifespan and neuronal damage caused by HG conditions. The effect of human insulin is mediated by a daf-2/insulin receptor and daf-16/FOXO-dependent pathway and is mediated by upregulation of detoxifying mechanisms.

Under high glucose conditions mitochondria-mediated oxidative stress and glycation are downstream targets of ins-7. This impairs the neuronal system and longevity via a non-neuronal/neuronal crosstalk by affecting sod-3 and glod-4, thus giving further insight into the pathophysiology of diabetic complications.

The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de-novo synthesis. It metabolizes AICAR, which is an AMP analogue, leading to activation of AMPK. It was investigated whether the AICAR-ATIC pathway plays a role in the high glucose (HG) mediated DNA damage response and AICAR mediated AMPK activation, explaining the detrimental effects of glucose on neuronal damages and shortening of lifespan. HG upregulated the expression and activity of Caenorhabditis elegans homologue of ATIC, C55F2.1 (atic-1), as well as increased the levels of reactive oxygen species (ROS) and methylglyoxalderived advanced glycation endproducts (MGAGEs). Overexpression of atic-1 decreased lifespan and head motility and increased neuronal damage under both standard (S) and high glucose (HG) conditions. Inhibition of atic-1 expression, by RNAi, under HG was associated with increased lifespan and head motility and reduced neuronal damage, ROS and MG-AGE accumulation. This effect was independent of an effect on DNA damage or antioxidant defense pathways, such as superoxide dismutase (sod-3) or glyoxalase-1 (glod-4), but was dependent upon AMPK and an accumulation of AICAR. Through AMPK, AICAR treatment also reduced the negative effects of HG. The Protective Effect of AICAR under High Glucose 2 mitochondrial inhibitor rotenone abolished the AICAR/AMPK-induced amelioration of HG effects, pointing to mitochondria as a prime target of the glucotoxic effects in C. elegans. We conclude that atic-1 is involved in glucotoxic effects under HG conditions, either by blocked atic-1 expression or via AICAR and AMPK induction.The enzyme AICAR-transformylase/IMP cyclohydrolase (ATIC) catalyzes the last two steps of purine de-novo synthesis. ATIC metabolites 5-Aminoimidazole-4-carboxamide-riboside (AICAR) to N-formyl-5-aminoimidazol-4-carboxamide-ribonucleotide (FAICAR) and then to inosine monophosphate (IMP), analog of adenosine monophosphate (AMP). IMP can then be phosphorylated by adenosine kinase to become ZMP, which can bind to the cystathionine-betasynthase (CBS) domains of the -subunit of AMPactivated protein kinase (AMPK), leading to an allosteric change [(1)]. This change makes AMPK a better substrate for its upstream kinases to phosphorylate it at Thr172 and inhibits dephosphorylation at this site by the protein phosphatases, PP2A and PP2C [(2); (3)]. This combined effect significantly increases the activity of AMPK ex vivo [(4)].Treatment with AICAR has been shown to prevent and/or reverse metabolic syndrome in animal models. In ob/ob mice, fa/fa rats, as well as rats fed on a high-fat diet, AICAR treatment has been shown to improve glucose tolerance, whole-body glucose disposal, as well as reduce hepatic glucose output and plasma triglycerides and free fatty acids levels [(5); (6); (7); (8)]. In streptozotocin (STZ)-induced diabetic mice, treatment with AICAR increased AMPK activity within the kidney and was linked with reduction in glomerular matrix and albuminuria [(9)]. Exogenous AICAR can...