Search

Patients with type-2 diabetes (T2D) are more likely to develop severe respiratory tract infections. Such susceptibility has gained increasing attention since the global spread of Coronavirus Disease 2019 (COVID-19) in early 2020. The earliest reports marked T2D as an important risk-factor for severe forms of disease and mortality across all adult age groups. Several mechanisms have been proposed for this increased susceptibility, including pre-existing immune dysfunction, a lack of metabolic flexibility due to insulin resistance, inadequate dietary quality or adverse interactions with antidiabetic treatments or common comorbidities. Some mechanisms that predispose patients with T2D to severe COVID-19 may indeed be shared with other previously characterized respiratory tract infections. Accordingly, in this review, we give an overview of response to Influenza A virus and to Mycobacterium tuberculosis (Mtb) infections. Similar risk factors and mechanisms are discussed between the two conditions and in the case of COVID-19. Lastly, we address emerging approaches to address research needs in infection and metabolic disease, and perspectives with regards to deployment or repositioning of metabolically active therapeutics., Competing Interests: KS is a consultant for Sanofi, Roche and NovoNordisk. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Al-Sayyar, Hulme, Thibaut, Bayry, Sheedy, Short and Alzaid.)

The COVID-19 pandemic has highlighted the vulnerability of people with diabetes mellitus (DM) to respiratory viral infections. Despite the short history of COVID-19, various studies have shown that patients with DM are more likely to have increased hospitalisation and mortality rates as compared to patients without. At present, the mechanisms underlying this susceptibility are unclear. However, prior studies show that the course of COVID-19 disease is linked to the efficacy of the host's T-cell responses. Healthy individuals who can elicit a robust T-cell response are more likely to limit the severity of COVID-19. Here, we investigate the hypothesis that an impaired T-cell response in patients with type 2 diabetes mellitus (T2DM) drives the severity of COVID-19 in this patient population. While there is currently a limited amount of information that specifically addresses T-cell responses in COVID-19 patients with T2DM, there is a wealth of evidence from other infectious diseases that T-cell immunity is impaired in patients with T2DM. The reasons for this are likely multifactorial, including the presence of hyperglycaemia, glycaemic variability and metformin use. This review emphasises the need for further research into T-cell responses of COVID-19 patients with T2DM in order to better inform our response to COVID-19 and future disease outbreaks., (© 2021 Federation of European Biochemical Societies.)

Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about pre-diabetes and the relative contribution of impaired glucose tolerance vs. obesity towards susceptibility to TB. Here, we developed a preclinical model of pre-diabetes and TB. Mice fed a high fat diet (HFD) for 12 weeks presented with impaired glucose tolerance and hyperinsulinemia compared to mice fed normal chow diet (NCD). Infection with M. tuberculosis (Mtb) H 37 R v after the onset of dysglycemia was associated with significantly increased lung pathology, lower concentrations of TNF-α, IFN-γ, IFN-β and IL-10 and a trend towards higher bacterial burden at 3 weeks post infection. To determine whether the increased susceptibility of pre-diabetic mice to TB is reversible and is associated with dysglycemia or increased body fat mass, we performed a diet reversal experiment. Pre-diabetic mice were fed a NCD for 10 additional weeks (HFD/NCD) at which point glucose tolerance was restored, but body fat mass remained higher compared to control mice that consumed NCD throughout the entire experiment (NCD/NCD). Upon Mtb infection HFD/NCD mice had significantly lower bacterial burden compared to NCD/NCD mice and this was accompanied by restored IFN-γ responses. Our findings demonstrate that pre-diabetes increases susceptibility to TB, but a high body mass index without dysglycemia is protective. This murine model offers the opportunity to further study the underlying immunological, metabolic and endocrine mechanisms of this association., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sinha, Ngo, Bartlett, Bielefeldt-Ohmann, Keshvari, Hasnain, Donovan, Kling, Blumenthal, Chen, Short and Ronacher.)

People with diabetes are two times more likely to die from influenza than people with no underlying medical condition. The mechanisms underlying this susceptibility are poorly understood. In healthy individuals, small and short-lived postprandial peaks in blood glucose levels occur. In diabetes mellitus, these fluctuations become greater and more frequent. This glycemic variability is associated with oxidative stress and hyperinflammation. However, the contribution of glycemic variability to the pathogenesis of influenza A virus (IAV) has not been explored. Here, we used an in vitro model of the pulmonary epithelial-endothelial barrier and novel murine models to investigate the role of glycemic variability in influenza severity. In vitro , a history of glycemic variability significantly increased influenza-driven cell death and destruction of the epithelial-endothelial barrier. In vivo , influenza virus-infected mice with a history of glycemic variability lost significantly more body weight than mice with constant blood glucose levels. This increased disease severity was associated with markers of oxidative stress and hyperinflammation both in vitro and in vivo Together, these results provide the first indication that glycemic variability may help drive the increased risk of severe influenza in people with diabetes mellitus. IMPORTANCE Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza., (Copyright © 2020 Marshall et al.)

Spexin is a novel peptide that has been reported to be down regulated in obese adults and children and in normoglycemic adults following glucose ingestion. Spexin may therefore have a role in metabolic regulation. The purpose of the current study was to determine the effect of obesity and type 2 diabetes (T2DM), and the effect of glucose ingestion on circulating spexin concentration in adolescents. Boys and girls (mean age 16 years old) classified as healthy normal weight (NW, n = 22), obese (Ob, n = 10), or obese with T2DM (n = 12) completed measurements of body composition, blood pressure, cardiorespiratory fitness, and blood concentrations of glucose, insulin, and lipids. The median fasting serum spexin concentration did not differ between groups (NW: 0.35; Ob: 0.38, T2DM: 0.34 ng/mL, respectively). In 10 NW participants who completed a standard oral glucose tolerance test, spexin concentration was unchanged at 30 and 120 minutes relative to the fasting baseline. Finally, spexin was not significantly correlated with any of the body composition, fitness, or blood biochemical measurements. These data do not support the proposed role of spexin as a metabolic regulator or biomarker of glucose control in adolescents., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Pigment epithelium-derived factor (PEDF) is a member of the serpin family secreted by adipocytes. Plasma PEDF is increased in obese children and adults. Adults with type 2 diabetes mellitus (T2DM) have higher circulating PEDF but there are no reports in children with T2DM., Objective: To compare PEDF concentration in children with T2DM to normal weight and obese children without T2DM and determine associations with anthropometric or serum factors., Methods: Participants were 34 obese children with T2DM diagnosed by American Diabetes Association (ADA) criteria, 61 normal weight [body mass index (BMI) 25-75 percentile] and 63 obese (BMI ≥ 95 percentile) children of age 8-18 yr. Plasma PEDF was measured in fasting plasma samples. Anthropometric, serum, and body composition (dual-energy x-ray absorptiometry, DXA) data were obtained for each subject to identify potential predictor variables., Results: PEDF was 55% higher (p = 0.001) in the T2DM group compared with normal weight children, but did not differ from obese children. In the T2DM group, fat mass and lean mass both individually predicted PEDF (r² = 0.22 and 0.17, p = 0.02 and p < 0.01, respectively). PEDF was positively correlated with homeostatic model assessment - insulin resistance (HOMA-IR) when all groups were combined (r² = 0.15, p<0.001)., Conclusions: Plasma PEDF was similar in the T2DM and obese groups, therefore, obesity, rather than diabetes, may account for the higher PEDF in children with T2DM compared with normal weight children. PEDF was positively associated with both lean mass and fat mass both of which may contribute to the circulating level of the protein, and potentially to PEDF's association with insulin resistance in obese children with and without diabetes., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Obesity and type 2 diabetes mellitus (T2DM) are associated with oxidative stress. Oxidative damage of high-density lipoprotein (oxHDL) leads to a dysfunctional molecule, potentially a mediator and/or marker of cardiometabolic disease. We tested the hypothesis that circulating concentration of oxHDL is higher in obese (Ob) or T2DM adolescents compared to normal-weight (NW) peers., Methods: In 37 NW, 38 Ob, and 42 T2DM adolescents, ages 11-18 y, fasting concentrations of HDL and LDL cholesterol, oxHDL, oxidized low-density lipoprotein (oxLDL), and myeloperoxidase (MPO) were measured., Results: Compared to the NW group, oxHDL in the Ob group was not different, but was 65% higher (p < 0.01) in the T2DM group. Within the T2DM group oxHDL was higher in boys than in girls, but this sex difference was not evident in NW or Ob groups. OxLDL was 23% higher in Ob (p = 0.02), and 56% higher in T2DM (p < 0.01) versus NW and did not differ between boys and girls. MPO was not different between NW and Ob but was 88% (p < 0.02) higher in T2DM compared to NW. Contrary to our hypothesis MPO and insulin resistance (HOMA-IR) were not correlated with oxHDL. OxHDL was positively associated with oxLDL and lean body mass while oxLDL was positively associated with apolipoprotein B, triglycerides, HOMA-IR and trunk fat., Conclusions: The higher concentrations of oxHDL and oxLDL, along with higher MPO in children with T2DM reflect higher oxidative stress compared with obesity alone and potentially increased cardiovascular disease risk in youth with T2DM., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Offspring of women with diabetes mellitus (DM) during pregnancy have a risk of developing metabolic disease in adulthood greater than that conferred by genetics alone. The mechanisms responsible are unknown, but likely involve fetal exposure to the in utero milieu, including glucose and circulating adipokines. The purpose of this study was to assess the impact of maternal DM on fetal adipokines and anthropometry in infants of Hispanic and Native American women., Methods: We conducted a prospective study of offspring of mothers with normoglycemia (Con-O; n = 79) or type 2 or gestational DM (DM-O; n = 45) pregnancies. Infant anthropometrics were measured at birth and 1-month of age. Cord leptin, high-molecular-weight adiponectin (HMWA), pigment epithelium-derived factor (PEDF) and C-peptide were measured by ELISA. Differences between groups were assessed using the Generalized Linear Model framework. Correlations were calculated as standardized regression coefficients and adjusted for significant covariates., Results: DM-O were heavier at birth than Con-O (3.7 ± 0.6 vs. 3.4 ± 0.4 kg, p = 0.024), but sum of skinfolds (SSF) were not different. At 1-month, there was no difference in weight, SSF or % body fat or postnatal growth between groups. Leptin was higher in DM-O (20.1 ± 14.9 vs. 9.5 ± 9.9 ng/ml in Con-O, p < 0.0001). Leptin was positively associated with birth weight (p = 0.0007) and SSF (p = 0.002) in Con-O and with maternal hemoglobin A1c in both groups (Con-O, p = 0.023; DM-O, p = 0.006). PEDF was positively associated with birth weight in all infants (p = 0.004). Leptin was positively associated with PEDF in both groups, with a stronger correlation in DM-O (p = 0.009). At 1-month, HMWA was positively associated with body weight (p = 0.004), SSF (p = 0.025) and % body fat (p = 0.004) across the cohort., Conclusions: Maternal DM results in fetal hyperleptinemia independent of adiposity. HMWA appears to influence postnatal growth. Thus, in utero exposure to DM imparts hormonal differences on infants even without aberrant growth.

Aims: Prior studies have reported that elevated concentrations of several plasma amino acids (AA), particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes., Methods: We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI ~30kg/m(2)) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45mg per day) plus metformin (1000mg twice per day, N=12 participants) or placebo (N=13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention., Results: Insulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/α-aminoadipic acid., Conclusions: Reductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Recent work showed that arterial compliance may be elevated unexpectedly in obese children, attributable to accelerated growth and maturation. We hypothesize that children with obesity or Type 2 diabetes may reach peak arterial maturation earlier in life and then experience an earlier, and potentially more rapid, decline in arterial compliance, leading toward earlier cardiovascular disease development.

Background: We reported that obesity was associated with increased arterial compliance in children, possibly due to accelerated vascular maturation. Here, we explored the additional burden of type 2 diabetes (T2DM) on vascular function in children., Methods: Fifty normal weight [body mass index (BMI) 25-75%], 58 obese (BMI ≥ 95%), and 34 children with T2DM diagnosed by American Diabetes Association (ADA) criteria ages 10-18 yr were studied. Large and small artery elasticity (LAEI and SAEI, respectively) were measured by diastolic pulse-wave contour analysis., Results: SAEI was 27% higher in children with T2DM compared to normal weight children (p = 0.005). Mean LAEI for those with T2DM not different from either group. In the group with T2DM, both SAEI and LAEI increased with age up to 16 yr, but declined thereafter. The strongest multivariable model predicting SAEI in children with T2DM combined lean mass, systolic blood pressure (SBP), and glucose (r2  = 0.59); for predicting LAEI, the strongest model included height, SBP, and low-density lipid-cholesterol (r2  = 0.61)., Conclusion: The lower arterial compliance in older adolescents with T2DM compared to that of their peers without diabetes may indicate a premature maturation of the vascular system; however, follow-up will clarify whether these vascular changes portend an early increase in diabetes-associated cardiovascular disease risk., (© 2013 John Wiley & Sons A/S.)

Context: Type 2 diabetes (T2D) is characterized by insulin resistance to glucose metabolism. Most studies suggest that protein metabolism is unaffected by T2D, but regional protein metabolism and response to multiple doses of insulin have not been examined., Objective: Our objective was to determine whether insulin regulation of splanchnic and leg protein metabolism are affected by T2D during hyperglycemia and graded insulin levels., Design and Setting: We conducted a cross-sectional study at an academic medical center., Participants: T2D and non-T2D adults were matched for age (62 yr) and body mass index (30 kg/m(2))., Interventions: Glucose was maintained at approximately 9 mmol/liter while insulin was infused at three progressively higher rates, achieving circulating concentrations of approximately 150, 350, and 700 pmol/liter, respectively., Main Outcome Measures: Protein kinetics were measured using labeled phenylalanine (Phe) and tyrosine (Tyr)., Results: Whole-body protein breakdown and synthesis rates were higher in T2D but declined with increasing insulin in both groups. Leg Phe and Tyr appearance and disappearance and estimates of protein breakdown and synthesis, respectively, were higher in T2D but did not decline significantly with insulin, resulting in similar net balance between groups. Splanchnic response to insulin was blunted in T2D, shown by a smaller reduction in rates of disappearance and net balance of Phe and Tyr as insulin increased. Splanchnic conversion of Phe to Tyr was lower in T2D and less sensitive to insulin, whereas nonsplanchnic Phe to Tyr tended to be higher in T2D., Conclusions: T2D results in higher whole-body, splanchnic, and leg protein turnover and blunts the insulin-mediated suppression of splanchnic protein anabolism under hyperglycemic, hyperinsulinemic conditions.

Context: A close association between insulin resistance and reduced skeletal muscle oxidative capacity has been reported in adult offspring of people with type 2 diabetes (T2D), prompting a hypothesis that insulin resistance may result from mitochondrial dysfunction or vice versa., Objective: We determined whether 9 d of intensive exercise training ameliorates the mitochondrial dysfunction and insulin resistance in offspring of T2D., Methods: We compared the response to 9 d of intensive exercise training in eight (seven females, one male) healthy adult offspring of mothers with T2D with eight (six females, two males) nondiabetic controls. Skeletal muscle mitochondrial ATP production was assessed using a luciferase-based assay, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamps., Results: Short-term intensive training increased skeletal muscle mitochondrial ATP production and citrate synthase activity similarly in both groups (P < 0.01). In contrast, whereas short-term intensive training reduced the fasting glucose (~5%, P = 0.035) and insulin levels (~40%, P = 0.011) as well as increased the glucose infusion rate during the hyperinsulinemic-euglycemic clamp (~50%, P = 0.028) among controls, no changes in these parameters were observed among offspring except for an increase in fasting glucose (~7%, P = 0.004)., Conclusion: A short-term intensive exercise training program was equally effective at increasing skeletal muscle oxidative capacity in nondiabetic people and in the offspring of mothers with diabetes. In contrast, the exercise improved insulin sensitivity only in nondiabetic people but not in the offspring of T2D mothers, revealing dissociation between improvements in skeletal muscle mitochondrial function and insulin sensitivity. The exercise effect on mitochondrial function and insulin sensitivity seems to be mediated by different regulatory pathways.

The foundations for cardiovascular disease in adults are laid in childhood and accelerated by the presence of comorbid conditions, such as obesity, diabetes, hypertension, and dyslipidemia. Early detection of vascular dysfunction is an important clinical objective to identify those at risk for subsequent cardiovascular morbidity and events, and to initiate behavioral and medical interventions to reduce risk. Typically, cardiovascular screening is recommended for young adults, especially in people with a family history of cardiovascular conditions. Children and adolescents were once considered to be at low risk, but with the growing health concerns related to sedentary lifestyle, poor diet and obesity, cardiovascular screening may be needed earlier so that interventions to improve cardiovascular health can be initiated. This review describes comorbid conditions that increase cardiovascular risk in youth, namely obesity and diabetes, and describes noninvasive methods to objectively detect vascular disease and quantify vascular function and structure through measurements of endothelial function, arterial compliance, and intima-media thickness. Additionally, current strategies directed toward prevention of vascular disease in these populations, including exercise, dietary interventions and pharmacological therapy are described.

We investigated whether previously reported muscle mitochondrial dysfunction and altered gene transcript levels in type 2 diabetes might be secondary to abnormal blood glucose and insulin levels rather than an intrinsic defect of type 2 diabetes. A total of 13 type 2 diabetic and 17 nondiabetic subjects were studied on two separate occasions while maintaining similar insulin and glucose levels in both groups by 7-h infusions of somatostatin, low- or high-dose insulin (0.25 and 1.5 mU/kg of fat-free mass per min, respectively), and glucose. Muscle mitochondrial DNA abundance was not different between type 2 diabetic and nondiabetic subjects at both insulin levels, but the majority of transcripts in muscle that are involved mitochondrial functions were expressed at lower levels in type 2 diabetes at low levels of insulin. However, several gene transcripts that are specifically involved in the electron transport chain were expressed at higher levels in type 2 diabetic patients. After the low-dose insulin infusion, which achieved postabsorptive insulin levels, the muscle mitochondrial ATP production rate (MAPR) was not different between type 2 diabetic and nondiabetic subjects. However, increasing insulin to postprandial levels increased the MAPR in nondiabetic subjects but not in type 2 diabetic patients. The lack of MAPR increment in response to high-dose insulin in type 2 diabetic patients occurred in association with reduced glucose disposal and expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha, citrate synthase, and cytochrome c oxidase I. In conclusion, the current data supports that muscle mitochondrial dysfunction in type 2 diabetes is not an intrinsic defect, but instead a functional defect related to impaired response to insulin.

Diabetes in the elderly is emerging as one of the most important public health problems of the 21st century. In developing countries, the majority of people with diabetes are in the age range of 45-64 years. A better understanding on the pathogenesis of diabetes in the aging population is required to successfully treat and prevent its devastating complications. Changes in body composition with accumulation of fat in the abdomen is a key factor in the causation of diabetes in the aging population. The size and strength of skeletal muscle, a major tissue involved in glucose metabolism, also declines leading to muscle weakness and a reduction in physical activity. These changes lead to marked reduction in energy expenditure and abdominal fat accumulation causing insulin resistance. Recent evidence suggests that four months of aerobic exercise can improve muscle oxidative capacity similarly in younger and older people, but that insulin sensitivity is less likely to improve in older people. It appears that older people need to exercise more frequently to improve their insulin sensitivity. Diagnosis and management of diabetes in the elderly requires special attention since age, genetics, body composition and lifestyle factors all interact. Increasing evidence suggests that postprandial hyperglycemia is more sensitive to diagnose diabetes in elderly people than in the young. Age related changes in body function and cognition demand special caution in the selection of hypoglycemic drugs in the elderly. Targets of diabetes therapy in the elderly have to be individualized, considering the age of the patient, remaining life-expectancy and severity of co-morbid conditions. Short acting insulin secretogogues are preferred to avoid prolonged and frequent hypoglycemia. Judicious choice of insulin sensitizers, timely introduction of insulin, meticulous control of hypertension and hyperlipidemia are critical to prevent complications.

Improvement of glycemic status by insulin is associated with profound changes in amino acid metabolism in type 1 diabetes. In contrast, a dissociation of insulin effect on glucose and amino acid metabolism has been reported in type 2 diabetes. Type 2 diabetic patients are reported to have reduced muscle oxidative enzymes and VO(2max). We investigated the effect of 11 days of intensive insulin treatment (T(2)D+) on whole-body amino acid kinetics, muscle protein synthesis rates, and muscle functions in eight type 2 diabetic subjects after withdrawing all treatments for 2 weeks (T(2)D-) and compared the results with those of weight-matched lean control subjects using stable isotopes of the amino acids. Whole-body leucine, phenylalanine and tyrosine fluxes, leucine oxidation, and plasma amino acid levels were similar in all groups, although plasma glucose levels were significantly higher in T(2)D-. Insulin treatment reduced leucine nitrogen flux and transamination rates in subjects with type 2 diabetes. Synthesis rates of muscle mitochondrial, sarcoplasmic, and mixed muscle proteins were not affected by glycemic status or insulin treatment in subjects with type 2 diabetes. Muscle strength was also unaffected by diabetes or glycemic status. In contrast, the diabetic patients showed increased tendency for muscle fatigability. Insulin treatment also failed to stimulate muscle cytochrome C oxidase activity in the diabetic patients, although it modestly elevated citrate synthase. In conclusion, improvement of glycemic status by insulin treatment did not alter whole-body amino acid turnover in type 2 diabetic subjects, but leucine nitrogen flux, transamination rates, and plasma ketoisocaproate level were decreased. Insulin treatments in subjects with type 2 diabetes had no effect on muscle mitochondrial protein synthesis and cytochrome C oxidase, a key enzyme for ATP production.