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.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases.

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Histological Manifestations of Diabetic Kidney Disease and its Relationship with Insulin Resistance.

Histological manifestations of diabetic kidney disease (DKD) include mesangiolysis, mesangial matrix expansion, mesangial cell proliferation, thickening of the glomerular basement membrane, podocyte loss, foot process effacement, and hyalinosis of the glomerular arterioles, interstitial fibrosis, and tubular atrophy. Glomerulomegaly is a typical finding. Histological features of DKD may occur in the absence of clinical manifestations, having been documented in patients with normal urinary albumin excretion and normal glomerular filtration rate. Furthermore, the histological picture progresses over time, while clinical data may remain normal. Conversely, histological lesions of DKD improve with metabolic normalization following effective pancreas transplantation. Insulin resistance has been associated with the clinical manifestations of DKD (nephromegaly, glomerular hyperfiltration, albuminuria, and kidney failure). Likewise, insulin resistance may underlie the histological manifestations of DKD. Morphological changes of DKD are absent in newly diagnosed type 1 diabetes patients (with no insulin resistance) but appear afterward when insulin resistance develops. In contrast, structural lesions of DKD are typically present before the clinical diagnosis of type 2 diabetes. Several heterogeneous conditions that share the occurrence of insulin resistance, such as aging, obesity, acromegaly, lipodystrophy, cystic fibrosis, insulin receptor dysfunction, and Alström syndrome, also share both clinical and structural manifestations of kidney disease, including glomerulomegaly and other features of DKD, focal segmental glomerulosclerosis, and C3 glomerulopathy, which might be ascribed to the reduction in the synthesis of factor H binding sites (such as heparan sulfate) that leads to uncontrolled complement activation. Alström syndrome patients show systemic interstitial fibrosis markedly similar to that present in diabetes.

Biochemical composition of the glomerular extracellular matrix in patients with diabetic kidney disease.

In the glomeruli, mesangial cells produce mesangial matrix while podocytes wrap glomerular capillaries with cellular extensions named foot processes and tether the glomerular basement membrane (GBM). The turnover of the mature GBM and the ability of adult podocytes to repair injured GBM are unclear. The actin cytoskeleton is a major cytoplasmic component of podocyte foot processes and links the cell to the GBM. Predominant components of the normal glomerular extracellular matrix (ECM) include glycosaminoglycans, proteoglycans, laminins, fibronectin-1, and several types of collagen. In patients with diabetes, multiorgan composition of extracellular tissues is anomalous, including the kidney, so that the constitution and arrangement of glomerular ECM is profoundly altered. In patients with diabetic kidney disease (DKD), the global quantity of glomerular ECM is increased. The level of sulfated proteoglycans is reduced while hyaluronic acid is augmented, compared to control subjects. The concentration of mesangial fibronectin-1 varies depending on the stage of DKD. Mesangial type III collagen is abundant in patients with DKD, unlike normal kidneys. The amount of type V and type VI collagens is higher in DKD and increases with the progression of the disease. The GBM contains lower amount of type IV collagen in DKD compared to normal tissue. Further, genetic variants in the α3 chain of type IV collagen may modulate susceptibility to DKD and end-stage kidney disease. Human cellular models of glomerular cells, analyses of human glomerular proteome, and improved microscopy procedures have been developed to investigate the molecular composition and organization of the human glomerular ECM.

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.

The differential effect of animal versus vegetable dietary protein on the clinical manifestations of diabetic kidney disease in humans.

BACKGROUND: Patients with diabetes are at a high risk for kidney disease and cardiovascular disease (CVD). Inadequate glycemic control or conventional cardiovascular risk factors do not fully explain these vascular complications. Insulin resistance has been established as a powerful and independent risk factor for both CVD and diabetic kidney disease (DKD). The source of dietary protein (animal versus vegetable) largely defines the degree of insulin sensitivity. Animal protein intake activates glucagon secretion and magnifies insulin resistance while vegetable food enhances insulin sensitivity. Reducing animal meat while augmenting vegetable protein has demonstrated definite advantages regarding insulin sensitivity. AIMS AND METHODS: A comprehensive literature search was conducted on the PubMed database up to December 2021 on the differential effect of animal versus vegetable protein on DKD. Articles written in English concerning human subjects were included. RESULTS: Animal protein is strongly associated with clinical features of DKD (glomerular hyperfiltration, albuminuria and kidney function decline) and CVD. Conversely, plant-sourced protein has a strong beneficial effect on both DKD and CVD. Plant-based diets have demonstrated to be nutritionally safe in subjects from the general population, patients with diabetes, and patients with kidney disease. Available evidence suggests that the dietary potassium load due to plant-sourced food does not usually induce hyperkalemia, although future research is required to establish the effect of meat (and subsequent insulin resistance) and vegetable food on kalemia. CONCLUSIONS: Nutritional advice to patients with diabetes should consider the strikingly different effect of animal versus vegetable protein on insulin resistance and its clinical consequences.

The effects of glucagon and the target of rapamycin (TOR) on skeletal muscle protein synthesis and age-dependent sarcopenia in humans.

BACKGROUND AND AIMS: Human target of rapamycin (TOR) is a kinase that stimulates protein synthesis in the skeletal muscle in response to amino acids and physical activity. METHODS: A comprehensive literature search was conducted on the PubMed database from its inception up to May 2021 to retrieve information on the effects of TOR and glucagon on muscle function. Articles written in English regarding human subjects were included. RESULTS: l-leucine activates TOR to initiate protein synthesis in the skeletal muscle. Glucagon has a crucial role suppressing skeletal muscle protein synthesis by increasing l-leucine oxidation and the irreversible loss of this amino acid. Glucagon-induced l-leucine oxidation suppresses TOR and attenuates the ability of skeletal muscle to synthesize proteins. Conditions associated with increased glucagon secretion typically feature reduced ability to synthesize proteins in the skeletal muscle that may evolve into sarcopenia. Animal protein ingestion, unlike vegetable protein, stimulates glucagon secretion. High intake of animal protein increases l-leucine oxidation and promotes the use of amino acids as fuel. Sarcopenia and arterial stiffness characteristically occur together in conditions featuring insulin resistance, such as aging. Insulin resistance mediates the relationship between aging and sarcopenia and arterial stiffness. The loss of skeletal muscle fibers that characterizes sarcopenia is followed by collagen and lipid accumulation. Likewise, insulin resistance is associated with arterial stiffness and intima-media thickening due to adaptive accretion of collagen and lipids in the arterial wall. CONCLUSIONS: Human TOR participates in the pathogenesis of sarcopenia and arterial stiffness, although its effects remain to be fully elucidated.

Insulin Resistance is Associated with Subclinical Vascular Injury in Patients with a Kidney Disease.

Patients with kidney disease have a strikingly high cardiovascular risk in the absence of conventional cardiovascular risk factors, including smoking or elevation of cholesterol associated with low-density lipoprotein. Kidney failure remains independently associated with increased cardiovascular risk in patients with diabetes, underlining the specific adverse influence of kidney disease on cardiovascular risk. Vascular injury develops in asymptomatic patients with kidney failure early in the course of the disease. Defective arterial vasodilation, increased arterial stiffness, increased intima-media thickness, and vascular calcification develop in patients with kidney disease long before clinical evidence of cardiovascular events. Even mildly reduced kidney function is associated with a subclinical vascular disease, which is a predictor of worse cardiovascular outcome in patients with kidney failure, similar to the general population and patients with diabetes. Insulin resistance is a typical feature of kidney disease that occurs during the entire span of the disorder, from mild dysfunction to the dialysis phase. Insulin resistance (or its clinical manifestations, the metabolic syndrome or its components) is independently associated with a subclinical vascular injury in patients with kidney disease. Additionally, the risk of developing incident kidney disease and the rapid decline in kidney function is higher in patients with insulin resistance. Animal protein consumption increases dietary acid load and intensifies insulin resistance. Consistently, meat intake promotes diabetes, cardiovascular disease, and kidney failure, while the consumption of plant-based food is protective against the development of the vascular disease. Insulin resistance is a robust cardiovascular risk factor in the general population, patients with diabetes, and patients with kidney disease.

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.

Effect of diet composition on insulin sensitivity in humans.

Diet composition has a marked impact on the risk of developing type 2 diabetes and cardiovascular disease. Prospective studies show that dietary patterns with elevated amount of animal products and low quantity of vegetable food items raise the risk of these diseases. In healthy subjects, animal protein intake intensifies insulin resistance whereas plant-based foods enhance insulin sensitivity. Similar effects have been documented in patients with diabetes. Accordingly, pre-pregnancy intake of meat (processed and unprocessed) has been strongly associated with a higher risk of gestational diabetes whereas greater pre-pregnancy vegetable protein consumption is associated with a lower risk of gestational diabetes. Population groups that modify their traditional dietary habit increasing the amount of animal products while reducing plant-based foods experience a remarkable rise in the frequency of type 2 diabetes. The association of animal protein intake with insulin resistance is independent of body mass index. In obese individuals that consume high animal protein diets, insulin sensitivity does not improve following weight loss. Diets aimed to lose weight that encourage restriction of carbohydrates and elevated consumption of animal protein intensify insulin resistance increasing the risk of developing type 2 diabetes and cardiovascular disease. The effect of dietary components on insulin sensitivity may contribute to explain the striking impact of eating habits on the risk of type 2 diabetes and cardiovascular disease. Insulin resistance predisposes to type 2 diabetes in healthy subjects and deteriorates metabolic control in patients with diabetes. In nondiabetic and diabetic individuals, insulin resistance is a major cardiovascular risk factor.

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.

Mitochondrial ß-oxidation of saturated fatty acids in humans.

Mitochondrial ß-oxidation of fatty acids generates acetyl-coA, NADH and FADH2. Acyl-coA synthetases catalyze the binding of fatty acids to coenzyme A to form fatty acyl-coA thioesters, the first step in the intracellular metabolism of fatty acids. l-carnitine system facilitates the transport of fatty acyl-coA esters across the mitochondrial membrane. Carnitine palmitoyltransferase-1 transfers acyl groups from coenzyme A to l-carnitine, forming acyl-carnitine esters at the outer mitochondrial membrane. Carnitine acyl-carnitine translocase exchanges acyl-carnitine esters that enter the mitochondria, by free l-carnitine. Carnitine palmitoyltransferase-2 converts acyl-carnitine esters back to acyl-coA esters at the inner mitochondrial membrane. The ß-oxidation pathway of fatty acyl-coA esters includes four reactions. Fatty acyl-coA dehydrogenases catalyze the introduction of a double bond at the C2 position, producing 2-enoyl-coA esters and reducing equivalents that are transferred to the respiratory chain via electron transferring flavoprotein. Enoyl-coA hydratase catalyzes the hydration of the double bond to generate a 3-l-hydroxyacyl-coA derivative. 3-l-hydroxyacyl-coA dehydrogenase catalyzes the formation of a 3-ketoacyl-coA intermediate. Finally, 3-ketoacyl-coA thiolase catalyzes the cleavage of the chain, generating acetyl-coA and a fatty acyl-coA ester two carbons shorter. Mitochondrial trifunctional protein catalyzes the three last steps in the ß-oxidation of long-chain and medium-chain fatty acyl-coA esters while individual enzymes catalyze the ß-oxidation of short-chain fatty acyl-coA esters. Clinical phenotype of fatty acid oxidation disorders usually includes hypoketotic hypoglycemia triggered by fasting or infections, skeletal muscle weakness, cardiomyopathy, hepatopathy, and neurological manifestations. Accumulation of non-oxidized fatty acids promotes their conjugation with glycine and l-carnitine and alternate ways of oxidation, such as ω-oxidation.

The importance of the ionic product for water to understand the physiology of the acid-base balance in humans.

Human plasma is an aqueous solution that has to abide by chemical rules such as the principle of electrical neutrality and the constancy of the ionic product for water. These rules define the acid-base balance in the human body. According to the electroneutrality principle, plasma has to be electrically neutral and the sum of its cations equals the sum of its anions. In addition, the ionic product for water has to be constant. Therefore, the plasma concentration of hydrogen ions depends on the plasma ionic composition. Variations in the concentration of plasma ions that alter the relative proportion of anions and cations predictably lead to a change in the plasma concentration of hydrogen ions by driving adaptive adjustments in water ionization that allow plasma electroneutrality while maintaining constant the ionic product for water. The accumulation of plasma anions out of proportion of cations induces an electrical imbalance compensated by a fall of hydroxide ions that brings about a rise in hydrogen ions (acidosis). By contrast, the deficiency of chloride relative to sodium generates plasma alkalosis by increasing hydroxide ions. The adjustment of plasma bicarbonate concentration to these changes is an important compensatory mechanism that protects plasma pH from severe deviations.