Interferon Upregulation Associates with Insulin Resistance in Humans.

In humans, insulin resistance is a physiological response to infections developed to supply sufficient energy to the activated immune system. This metabolic adaptation facilitates the immune response but usually persists after the recovery period of the infection and predisposes the hosts to type 2 diabetes and vascular injury. In patients with diabetes, superimposed insulin resistance worsens metabolic control and promotes diabetic ketoacidosis. Pathogenic mechanisms underlying insulin resistance during microbial invasions remain to be fully defined. However, interferons cause insulin resistance in healthy subjects and other population groups, and their production is increased during infections, suggesting that this group of molecules may contribute to reduced insulin sensitivity. In agreement with this notion, gene expression profiles [transcriptomes] from patients with insulin resistance show a robust overexpression of interferon-stimulated genes [interferon signature]. In addition, serum levels of interferon and surrogates for interferon activity are elevated in patients with insulin resistance. Circulating levels of interferon-γ-inducible protein-10, neopterin, and apolipoprotein L1 correlate with insulin resistance manifestations, such as hypertriglyceridemia, reduced HDL-c, visceral fat, and homeostasis model assessment-insulin resistance. Furthermore, interferon downregulation improves insulin resistance. Antimalarials such as hydroxychloroquine reduce interferon production and improve insulin resistance, reducing the risk for type 2 diabetes and cardiovascular disease. In addition, diverse clinical conditions that feature interferon upregulation are associated with insulin resistance, suggesting that interferon may be a common factor promoting this adaptive response. Among these conditions are systemic lupus erythematosus, sarcoidosis, and infections with severe acute respiratory syndrome-coronavirus-2, human immunodeficiency virus, hepatitis C virus, and Mycobacterium tuberculosis.

The metabolic effects of APOL1 in humans.

Harboring apolipoprotein L1 (APOL1) variants coded by the G1 or G2 alleles of the APOL1 gene increases the risk for collapsing glomerulopathy, focal segmental glomerulosclerosis, albuminuria, chronic kidney disease, and accelerated kidney function decline towards end-stage kidney disease. However, most subjects carrying APOL1 variants do not develop the kidney phenotype unless a second clinical condition adds to the genotype, indicating that modifying factors modulate the genotype-phenotype correlation. Subjects with an APOL1 high-risk genotype are more likely to develop essential hypertension or obesity, suggesting that carriers of APOL1 risk variants experience more pronounced insulin resistance compared to noncarriers. Likewise, arterionephrosclerosis (the pathological correlate of hypertension-associated nephropathy) and glomerulomegaly take place among carriers of APOL1 risk variants, and these pathological changes are also present in conditions associated with insulin resistance, such as essential hypertension, aging, and diabetes. Insulin resistance may contribute to the clinical features associated with the APOL1 high-risk genotype. Unlike carriers of wild-type APOL1, bearers of APOL1 variants show impaired formation of lipid droplets, which may contribute to inducing insulin resistance. Nascent lipid droplets normally detach from the endoplasmic reticulum into the cytoplasm, although the proteins that enable this process remain to be fully defined. Wild-type APOL1 is located in the lipid droplet, whereas mutated APOL1 remains sited at the endoplasmic reticulum, suggesting that normal APOL1 may participate in lipid droplet biogenesis. The defective formation of lipid droplets is associated with insulin resistance, which in turn may modulate the clinical phenotype present in carriers of APOL1 risk variants.

Cardiovascular Protection Associated With Cilostazol, Colchicine, and Target of Rapamycin Inhibitors.

ABSTRACT: An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

Insulin Resistance is Associated with Clinical Manifestations of Diabetic Kidney Disease (Glomerular Hyperfiltration, Albuminuria, and Kidney Function Decline).

Clinical features of diabetic kidney disease include glomerular hyperfiltration, albuminuria, and kidney function decline towards End-Stage Kidney Disease (ESKD). There are presently neither specific markers of kidney involvement in patients with diabetes nor strong predictors of rapid progression to ESKD. Serum-creatinine-based equations used to estimate glomerular filtration rate are notoriously unreliable in patients with diabetes. Early kidney function decline, reduced glomerular filtration rate, and proteinuria contribute to identifying diabetic patients at higher risk for rapid kidney function decline. Unlike proteinuria, the elevation of urinary albumin excretion in the range of microalbuminuria is frequently transient in patients with diabetes and does not always predict progression towards ESKD. Although the rate of progression of kidney function decline is usually accelerated in the presence of proteinuria, histological lesions of diabetes and ESKD may occur with normal urinary albumin excretion. No substantial reduction in the rate of ESKD associated with diabetes has been observed during the last decades despite intensified glycemic control and reno-protective strategies, indicating that existing therapies do not target underlying pathogenic mechanisms of kidney function decline. Very long-term effects of sodium-glucose transporters- 2 inhibitors and glucagon-like peptide-1 analogs remain to be defined. In patients with diabetes, glucagon secretion is typically elevated and induces insulin resistance. Insulin resistance is consistently and strongly associated with clinical manifestations of diabetic kidney disease, suggesting that reduced insulin sensitivity participates in the pathogenesis of the disease and may represent a therapeutic objective. Amelioration of insulin sensitivity in patients with diabetes is associated with cardioprotective and kidney-protective effects.

Insulin resistance underlies the elevated cardiovascular risk associated with kidney disease and glomerular hyperfiltration.

The curve that describes the relationship between glomerular filtration rate (GFR) and cardiovascular risk is U-shaped, indicating that both reduced GFR (kidney failure) and elevated GFR (glomerular hyperfiltration) are equivalent cardiovascular risk factors. The elevated cardiovascular risk associated with abnormal GFR is not explained by standard cardiovascular risk factors. The relationship between GFR and all-cause mortality follows a similar pattern, so that altered GFR (either low or high) increases the risk for overall mortality. Glomerular hyperfiltration is an adaptive process that arises under conditions that demand improved kidney excretory capacity, such as animal protein ingestion and kidney failure. Unlike vegetable protein, animal protein consumption increases dietary acid load and requires an elevation of the GFR to restore acid-base balance. The loss of functioning nephrons in diseased kidneys requires a compensatory increase of the GFR in the nephrons that remain working to enhance whole-kidney GFR. A major factor that raises GFR is the pancreatic hormone glucagon. Glucagon infusion and endogenous glucagon release increase GFR in healthy subjects and patients with kidney failure. In addition to its kidney hemodynamic effect, glucagon causes insulin resistance. Like hyperglucagonemia, insulin resistance develops across the entire spectrum of abnormal GFR, from glomerular hyperfiltration to advanced kidney disease. Insulin resistance is associated with subclinical vascular injury in the general population and patients with diabetes and kidney failure, being a strong cardiovascular risk factor in these population groups. Animal protein consumption activates glucagon secretion and promotes insulin resistance, having a detrimental effect on cardiovascular disease and renal outcomes.

Dietary habits contribute to define the risk of type 2 diabetes in humans.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) is a frequent disorder largely preventable. The aim of this review was to summarize information on the association between dietary habits and the risk of developing T2D. METHODS: We conducted a comprehensive literature search using the PubMed database from its inception to June, 2019. Articles were restricted to those written in English and concerning human subjects. Relevant manuscripts found in the list of references of the retrieved articles were also used in preparation for the review. RESULTS: Animal protein consumption increases the risk of T2D independently of body mass index. Intake of both unprocessed meat and processed meat is strongly and consistently associated with increased risk of developing T2D. In contrast, consumption of high-quality vegetable foods prevents the disease. High-quality plant foods include whole grains, nuts, legumes, fruits, and vegetables. Among less healthy plant-based foods are fruit juices, sweetened beverages, refined grains, potatoes, sweets, and desserts. Carbohydrate-restricted diets that encourage consumption of animal products promote T2D. Low intake of animal products is linked to high educational level so that well-informed individuals tend to consume diets with elevated content of vegetable food. According to the American Dietetic Association, "appropriately planned vegetarian diets including vegan diets are healthful, nutritionally adequate, and may provide health benefits in the prevention and treatment of certain diseases". CONCLUSIONS: restricting animal products while increasing healthy plant-based foods intake facilitates T2D prevention. To neutralize worldwide the burden of T2D and its devastating complications, animal products consumption should be limited or discontinued.

Insulin resistance is a cardiovascular risk factor in humans.

Diabetes is a common metabolic disorder associated to elevated cardiovascular morbidity and mortality that is not explained by hyperglycemia or traditional cardiovascular risk factors such as smoking or hypercholesterolemia. Intensive glycemic control with insulin that achieves near-normal glycemia does not reduce significantly macrovascular complications compared with conventional glycemic control. Cardiovascular disease continues to develop in patients with diabetes despite adequate glycemic control. In contrast, intensive control with metformin (leading to insulin resistance improvement) reduces diabetes complications, including cardiovascular events, suggesting that enhancement of insulin sensitivity rather than plasma glucose level has a major role improving diabetes outcomes. Accordingly, insulin resistance estimated by glucose tolerance tests is better predictor of future cardiovascular events than fasting glucose level in nondiabetic individuals. Insulin resistance precedes for decades the clinical onset of type 2 diabetes and deteriorates metabolic control of type 1 diabetes. Numerous investigations including cross-sectional and prospective studies, meta-analyses, and systematic reviews provide compelling evidence that insulin resistance by itself is a cardiovascular risk factor in a variety of population groups, including the general population and patients with diabetes. Several estimations of insulin resistance have been consistently associated with elevated rate of cardiovascular events independently of other cardiovascular risk factors and diabetes status. The clinical expression of insulin resistance (the metabolic syndrome or any of its components including obesity, hyperinsulinemia, hypertension, and dyslipemia) has been related to cardiovascular disease as well. An estimation conducted by the Archimedes model confirms that insulin resistance is the most important single cause of coronary artery disease.

Metabolic effects of glucagon in humans.

Diabetes is a common metabolic disorder that involves glucose, amino acids, and fatty acids. Either insulin deficiency or insulin resistance may cause diabetes. Insulin deficiency causes type 1 diabetes and diabetes associated with total pancreatectomy. Glucagon produces insulin resistance. Glucagon-induced insulin resistance promotes type 2 diabetes and diabetes associated with glucagonoma. Further, glucagon-induced insulin resistance aggravates the metabolic consequences of the insulin-deficient state. A major metabolic effect of insulin is the accumulation of glucose as glycogen in the liver. Glucagon opposes hepatic insulin action and enhances the rate of gluconeogenesis, increasing hepatic glucose output. In order to support gluconeogenesis, glucagon promotes skeletal muscle wasting to supply amino acids as gluconeogenic precursors. Glucagon promotes hepatic fatty acid oxidation to supply energy required to sustain gluconeogenesis. Hepatic fatty acid oxidation generates ß-hydroxybutyrate and acetoacetate (ketogenesis). Prospective studies reveal that elevated glucagon secretion at baseline occurs in healthy subjects who develop impaired glucose tolerance at follow-up compared with subjects who maintain normal glucose tolerance, suggesting a relationship between elevated glucagon secretion and development of impaired glucose tolerance. Prospective studies have identified animal protein consumption as an independent risk factor for type 2 diabetes and cardiovascular disease. Animal protein intake activates glucagon secretion inducing sustained elevations in plasma glucagon. Glucagon is a major hormone that causes insulin resistance. Insulin resistance is an established cardiovascular risk factor additionally to its pathogenic role in diabetes. Glucagon may be a potential link between animal protein intake and the risk of developing type 2 diabetes and cardiovascular disease.

Sodium bicarbonate therapy in patients with metabolic acidosis.

Metabolic acidosis occurs when a relative accumulation of plasma anions in excess of cations reduces plasma pH. Replacement of sodium bicarbonate to patients with sodium bicarbonate loss due to diarrhea or renal proximal tubular acidosis is useful, but there is no definite evidence that sodium bicarbonate administration to patients with acute metabolic acidosis, including diabetic ketoacidosis, lactic acidosis, septic shock, intraoperative metabolic acidosis, or cardiac arrest, is beneficial regarding clinical outcomes or mortality rate. Patients with advanced chronic kidney disease usually show metabolic acidosis due to increased unmeasured anions and hyperchloremia. It has been suggested that metabolic acidosis might have a negative impact on progression of kidney dysfunction and that sodium bicarbonate administration might attenuate this effect, but further evaluation is required to validate such a renoprotective strategy. Sodium bicarbonate is the predominant buffer used in dialysis fluids and patients on maintenance dialysis are subjected to a load of sodium bicarbonate during the sessions, suffering a transient metabolic alkalosis of variable severity. Side effects associated with sodium bicarbonate therapy include hypercapnia, hypokalemia, ionized hypocalcemia, and QTc interval prolongation. The potential impact of regular sodium bicarbonate therapy on worsening vascular calcifications in patients with chronic kidney disease has been insufficiently investigated.