Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review.

Metformin, a widely used first-line anti-diabetic therapy for the treatment of type-2 diabetes, has been shown to lower hyperglycemia levels in the blood by enhancing insulin actions. For several decades this drug has been used globally to successfully control hyperglycemia. Lactic acidosis has been shown to be a major adverse effect of metformin in some type-2 diabetic patients, but several studies suggest that it is a typically well-tolerated and safe drug in most patients. Further, recent studies also indicate its potential to reduce the symptoms associated with various inflammatory complications and infectious diseases including coronavirus disease 2019 (COVID-19). These studies suggest that besides diabetes, metformin could be used as an adjuvant drug to control inflammatory and infectious diseases. In this article, we discuss the current understanding of the role of the anti-diabetic drug metformin in the prevention of various inflammatory complications and infectious diseases in both diabetics and non-diabetics.

Role of Innate Immune and Inflammatory Responses in the Development of Secondary Diabetic Complications.

Increased hyperglycemia due to uncontrolled diabetes is the major cause of secondary diabetic complications such as retinopathy, neuropathy, nephropathy, and cardiovascular diseases. Although it is well known that increased oxidative stress, activation of the polyol pathway, protein kinase C and increased generation of advanced glycation end products could contribute to the development of diabetic complications, recent studies implicated the role of innate immunity and its related inflammatory responses in the pathophysiology of secondary diabetic complications. Increased activation of oxidative stress signaling could regulate NLRP3 inflammasome-mediated innate immune responses as well as NF-κB signalosome-mediated pro-inflammatory responses. This review article focused on the pathogenic role of innate immune and inflammatory responses in the progression of hyperglycemia-induced secondary diabetic complications. Specifically, we discussed in depth how deregulated innate immune and inflammatory responses could lead to an aggravated release of cytokines, chemokines, and growth factors resulting in the development of various secondary complications of diabetes.

Higher fasting plasma FGF21 concentration is associated with lower ad libitum soda consumption in humans.

BACKGROUND: The hepatokine fibroblast growth factor 21 (FGF21) influences eating behavior and sugar consumption in rodent models. However, whether circulating FGF21 concentration is associated with food and soda intake in humans is still unclear. OBJECTIVE: We investigated whether fasting plasma FGF21 concentration is associated with objective measures of ad libitum food intake and soda consumption. METHODS: Healthy individuals [n = 109; 69 men, aged 34 ± 10 y; BMI (kg/m2): 30.4 ± 7.7; body fat by DXA: 30.5% ± 8.9%] with available plasma for hormonal measurements participated in an inpatient cohort study to objectively quantify ad libitum food and soda intake for 3 d using an automated and reproducible vending machine paradigm. Fasting plasma FGF21 concentration was measured by ELISA prior to ad libitum feeding. RESULTS: Fasting FGF21 concentration was inversely associated with daily soda intake (R = -0.22, P = 0.02 adjusted for demographics and anthropometrics), such that an interindividual difference of 200 pg/mL was associated with an average lower soda consumption by 68 kcal/d. Conversely, no associations were observed with total daily energy intake or macronutrient intake (all P > 0.17). CONCLUSIONS: Higher plasma fasting FGF21 concentration is associated with lower ad libitum soda intake. Although this inverse correlation does not imply causation, the present results support the putative role of FGF21 in the reward pathways regulating sugar consumption in humans. This trial was registered at www.clinicaltrials.gov as NCT00342732.

Lower insulin clearance is associated with increased risk of type 2 diabetes in Native Americans.

AIMS/HYPOTHESIS: Impaired insulin clearance is implicated in the pathogenesis of type 2 diabetes, but prospective evidence remains limited. Therefore, we sought to identify factors associated with the metabolic clearance rate of insulin (MCRI) and to investigate whether lower MCRI is associated with increased risk of incident type 2 diabetes. METHODS: From a longitudinal cohort, 570 adult Native Americans without diabetes living in the Southwestern United States were characterised at baseline and 448 participants were monitored over a median follow-up period of 7.9 years with 146 (32%) incident cases of diabetes identified (fasting plasma glucose ≥7.0 mmol/l, 2 h plasma glucose [2-h PG] ≥11.1 mmol/l, or clinical diagnosis). At baseline, participants underwent dual-energy x-ray absorptiometry or hydrodensitometry to assess body composition, a 75 g OGTT, an IVGTT to assess acute insulin response (AIR), and a hyperinsulinaemic-euglycaemic clamp to assess MCRI and insulin action (M). RESULTS: In adjusted linear models, MCRI was inversely associated with body fat percentage (r = -0.35), fasting plasma insulin (r = -0.55) and AIR (r = -0.22), and positively associated with M (r = 0.17; all p < 0.0001). In multivariable Cox proportional hazard models, lower MCRI was associated with an increased risk of diabetes after adjustment for age, sex, heritage, body fat percentage, AIR, M, fasting plasma glucose, 2-h PG, and fasting plasma insulin (HR per one-SD difference in MCRI: 0.77; 95% CI 0.61, 0.98; p = 0.03). CONCLUSIONS/INTERPRETATION: Lower MCRI is associated with an unfavourable metabolic phenotype and is associated with incident type 2 diabetes independent of established risk factors. CLINICAL TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00339482; NCT00340132.

Thigh Adipocyte Size is Inversely Related to Energy Intake and Respiratory Quotient in Healthy Women.

OBJECTIVE: The relationship between adipocyte size and ad libitum energy intake has not been previously examined. This study hypothesized an inverse relationship between adipocyte size and daily energy intake (DEI). METHODS: Seventy healthy adults (39 men and 31 women; BMI 30.0 [SD 6.3]) underwent dual-energy x-ray absorptiometry and subcutaneous fat biopsies from the abdomen and thigh. Osmium-fixed adipocytes were sized with a Coulter counter. Volunteers self-selected food from a vending machine paradigm as the only source of energy intake over 3 days as inpatients. Volunteers also had 24-hour respiratory quotient (RQ) measured in a whole-room indirect calorimeter. RESULTS: In women, the large cell peak diameter of the thigh depot was greater than that of the abdominal depot (Δ = +15.8 µm; P < 0.0001). In women, thigh peak diameter was inversely associated with DEI (ß = -264.7 kcal/d per 10-µm difference; P = 0.03) after adjusting for demographics and body composition. The thigh peak diameter in women was associated with 24-hour RQ (r = -0.47, P = 0.04) after adjusting for demographics, body composition, and 24-hour energy balance. These associations did not extend to men or the abdominal depot. CONCLUSIONS: In women, thigh adipocyte size was associated with reduced DEI and 24-hour RQ, indicating a special role for thigh fat in women. This depot-specific sexual dimorphism indicates common regulation of energy intake and adipocyte size in the thigh region of women.