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.

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.

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.

Metabolic Effects of Metformin in Humans.

BACKGROUND: Both insulin deficiency and insulin resistance due to glucagon secretion cause fasting and postprandial hyperglycemia in patients with diabetes. INTRODUCTION: Metformin enhances insulin sensitivity, being used to prevent and treat diabetes, although its mechanism of action remains elusive. RESULTS: Patients with diabetes fail to store glucose as hepatic glycogen via the direct pathway (glycogen synthesis from dietary glucose during the post-prandial period) and via the indirect pathway (glycogen synthesis from "de novo" synthesized glucose) owing to insulin deficiency and glucagoninduced insulin resistance. Depletion of the hepatic glycogen deposit activates gluconeogenesis to replenish the storage via the indirect pathway. Unlike healthy subjects, patients with diabetes experience glycogen cycling due to enhanced gluconeogenesis and failure to store glucose as glycogen. These defects raise hepatic glucose output causing both fasting and post-prandial hyperglycemia. Metformin reduces post-prandial plasma glucose, suggesting that the drug facilitates glucose storage as hepatic glycogen after meals. Replenishment of glycogen store attenuates the accelerated rate of gluconeogenesis and reduces both glycogen cycling and hepatic glucose output. Metformin also reduces fasting hyperglycemia due to declining hepatic glucose production. In addition, metformin reduces plasma insulin concentration in subjects with impaired glucose tolerance and diabetes and decreases the amount of insulin required for metabolic control in patients with diabetes, reflecting improvement of insulin activity. Accordingly, metformin preserves ß-cell function in patients with type 2 diabetes. CONCLUSION: Several mechanisms have been proposed to explain the metabolic effects of metformin, but evidence is not conclusive and the molecular basis of metformin action remains unknown.