The mammalian heart must contract incessantly; which means the energy requirement for an optimal function is immense and this is an interesting phenomenon because there is no ATP reserve in heart muscle. Instead, energy is stored in cardiac muscle cells in three forms:.

The first is Phosphocreatine PCr , which can rapidly donate its high-energy phosphates to produce ATP from ADP [ ]. The energy available from PCr is relatively modest, used only during very rapid bursts of exercise [ ].

The second is glycogen, which forms the endogenous form of energy in the cell. However, its advantage is that it consumes much less oxygen compared to fatty acids and is readily available for use as fuel in muscle [ ].

The third form is triglycerides and FFA. Their oxidation is less efficient compared to glycogen, though it has greater energy input. It is widely accepted that FFAs are the predominant substrates used in the adult myocardium for ATP production in the mitochondrion [ ].

The levels of circulating FFAs determines largely FFA uptake in the heart [ ]. Once the FFA is absorbed, its metabolism is regulated predominantly at the transcriptional level by a family of ligand-activated transcriptional factors namely peroxisome proliferator activator receptor α PPAR-α [ ].

Depending on their availability or energy requirement feeding, fasting, and intense exercise , the cardiac metabolic network is highly flexible in using other substrates [ ].

Glucose uptake is mediated via glucose transporters. GLUT1 and GLUT4 are the major players for glucose transport in the heart. GLUT4 represents the major mechanism that regulates glucose entry in the beating heart, with GLUT1 playing a lesser role as it is primarily localized on plasma membranes and is responsible for basal cardiac glucose uptake.

GLUT4 is mostly present in the intracellular vesicles at resting stages and is translocated to the plasma membrane upon insulin stimulation [ ]. After uptake, free glucose is rapidly phosphorylated to glucose 6-phosphate G6P , which subsequently enters many metabolic pathways [ 13 ].

Glycolysis represents the major pathway in glucose and yields pyruvate for subsequent oxidation. Beside glycolysis, G6P also may be channeled into glycogen synthesis or the pentose phosphate pathway PPP. The PPP is an important source of NADPH, which plays a critical role in regulating cellular oxidative stress and is required for lipid synthesis [ ].

In response to an increased energy demand, heart muscle cells initially rely on carbohydrate oxidation. For example, under stress such as exercise, ischemia and pathological hypertrophy, the substrate preference of glucose can be changed [ ].

Under stress, a rapid increase in GLUT4 expression is an early adaptive response that suggests the physiological role of this adaptation is to enhance the replenishment of muscle glycogen stores. When glycogen content is high, the heart preferentially uses glycogen as a source, but when glycogen stores are low, it changes to fatty acid oxidation.

This induction can be prevented by a high carbohydrate diet during recovery. The control of metabolism in recovery by glycogen levels underlines its importance as the metabolic muscles reserve [ ]. In insulin resistance, the heart is embedded in a rich fatty acid and glucose environment [ , , ].

An excess of insulin promotes increased uptake of FFA in the heart due to up regulation of the cluster differentiation protein 36 CD36 [ ], which is a potent FFA transporter; this increases intracellular fatty acids levels and PPAR-α expression.

The latter, increases the gene expression in the three stages of fatty acid oxidation by increasing the synthesis of 1 FFA transporters in the cell, 2 proteins that imports FFA to the mitochondrium, and 3 enzymes in the fatty acid oxidation [ ]. On the other hand, due to the inhibition of glucose utilization, a glycolytic intermediate accumulates in the cardiomyocytes, which induces glucotoxicity.

Furthermore, when diabetes progresses or when additional stresses are posed on the heart; metabolic mal-adaptation can occur and there is a great loss of metabolic flexibility [ ]. The heart decreases its ability to use fatty acids, increasing FFA delivery, and leading to intramyocardial lipid accumulation ceramides, diacylglycerols, long-chain acyl-CoAs, and acylcarnitines [ ].

This lipid accumulation may contribute to apoptosis, impairing mitochondrial function, cardiac hypertrophy, and contractile dysfunction [ , ] Fig. For example, diacylglycerol and fatty acyl-coenzyme CoA induce activation of atypical PKC, which results in impaired insulin signal transduction [ ].

Ceramides act as key components of lipotoxic signaling pathways linking lipid-induced inflammation with insulin signaling inhibition [ ]. On other hand, high lipid contents can induce contractile dysfunction independently of insulin resistance [ ].

Therefore, the resultant defect in myocardial energy production impairs myocyte contraction and diastolic function [ 93 , ] Fig. These alterations produce functional changes that lead to cardiomyopathy and heart failure [ , , , ].

In uncontrolled diabetes, the body goes from the fed to the fasted state and the liver switches from carbohydrate or lipid utilization to ketone production in response to low insulin levels and high levels of counter-regulatory hormones [ ].

The ketone bodies generated in the liver enter in the blood stream and are used by other organs, such as the brain, kidneys, skeletal muscle, and heart. Disruptions in myocardial fuel metabolism and bioenergetics contribute to cardiovascular disease as the adult heart requires high energy for contractile function [ ].

In this situation, the heart uses alternative pathways such as ketone bodies as fuel for oxidative ATP production [ ]. However, there is still controversy around whether this fuel shift is adaptive or maladaptive.

The ketogenic diet effect can be mediated by suppressing longevity-related insulin signaling and mTOR pathway, and activation of peroxisome proliferator activated receptor α PPARα , the master regulator that switches on genes involved in ketogenesis [ ].

Several reports suggest that ketogenic diet may be associated with a decreased incidence of risk factors of cardiovascular disease such obesity, diabetes, arterial blood pressure and cholesterol levels, but these effects are usually limited in time [ ].

However other reports indicated that cardiac risk factor reductions corresponded with weight loss regardless of a type of diet used [ ]. Excessive production of ROS leads to protein, DNA, and membrane damage. In addition, ROS exerts deleterious effects on the endoplasmic reticulum.

This also contributes to diabetic cardiomyopathy pathogenesis [ , ]. Insulin essentially provides an integrated set of signals allowing the balance between nutrient demand and availability. Impaired nutrition contributes to hyperlipidemia and insulin resistance causing hyperglycemia.

This condition alters cellular metabolism and intracellular signaling that negatively impact cells. In the cardiomyocyte, this damage can be summarized into three actions: 1 alteration in insulin signaling. All these effects induce cellular events including: 1 gene expression modifications, 2 hyperglycemia and dyslipidemia, 3 activation of oxidative stress and inflammatory response, 4 endothelial dysfunction, and 5 ectopic lipid accumulation, which, favored by obesity, perpetuates the metabolic deregulation.

Overall, insulin resistance contributes to generate CVD via two independent pathways: 1 atheroma plaque formation and 2 ventricular hypertrophy and diastolic abnormality. Both effects lead to heart failure. Future research is needed to understand the precise mechanism between insulin resistance and its progression to heart failure with a focus on new therapy development.

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Implications for the insulin-resistant state. Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin. Trends Endocrinol Metab. Verges B. Differential Diagnosis Lipodystrophy acquired, localized or generalized : Loss of adipose tissue that results from either genetic or acquired causation and can result in the ectopic deposition of fat in either hepatic or muscular tissue [56].

Obesity: Excess body weight is categorized as overweight BMI of 25 to Other forms of glucose intolerance impaired fasting glucose, impaired glucose tolerance, and gestational diabetes. Prognosis The prognosis of insulin resistance depends on the subset of the disease, the severity of the disease, underlying pancreatic beta-cell function, the heritable susceptibility of the patient to the secondary complications from insulin resistance, and individual response to appropriate therapy.

Complications Most of the complications from insulin resistance are related to the development of vascular complications. Deterrence and Patient Education Primary, secondary, and tertiary prevention have distinct roles in managing insulin resistance.

Pearls and Other Issues Intensive lifestyle intervention should be the first line of therapy for patients with metabolic syndrome or insulin resistance syndrome. Enhancing Healthcare Team Outcomes Over the past few decades, the incidence of insulin resistance has skyrocketed primarily due to our lifestyle and the rising incidence of obesity.

The consultations and coordination of care most indicated for the treatment of insulin resistance include: Obesity medicine specialist: medical management for obesity treatment. Bariatric surgeon: bariatric surgery is effective for obesity treatment in individuals who satisfy the criteria for surgery.

Cardiology and cardiac surgery: management of the cardiovascular complications of insulin resistance. Neurology: management of the cerebrovascular and peripheral neurologic complications of insulin resistance. Pharmacist: educates the patient on the importance of medication adherence, instructing the patient on the proper use of medications, potential drug-drug interactions, and side effects.

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Acute modulation of toll-like receptors by insulin. Download references. AHA is supported by grant F32 DK from the National Institutes of Diabetes and Digestive and Kidney Diseases.

AW has received funding from Novo Nordisk and research support from United Health Group and Eli Lilly. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, IL, Chicago, USA. You can also search for this author in PubMed Google Scholar.

AHA drafted the manuscript. AHA and RYG were involved in the care of at least one of the patients described; all authors reviewed and edited the manuscript; and have approved the final version of the article.

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Clin Diabetes Endocrinol 7 , 8 Download citation. Received : 18 January Accepted : 27 April Published : 15 May Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative.

Skip to main content. Search all BMC articles Search. Download PDF. Case report Open access Published: 15 May Severe hyperglycemia and insulin resistance in patients with SARS-CoV-2 infection: a report of two cases Alison H.

Gianchandani 1 Clinical Diabetes and Endocrinology volume 7 , Article number: 8 Cite this article Accesses 17 Citations 11 Altmetric Metrics details.

Abstract Background Severe insulin resistance is an uncommon finding in patients with type 2 diabetes but is often associated with difficult to managing blood glucose. Conclusions The association between critical illness and hyperglycemia is well documented in the literature, however severe insulin resistance is not commonly identified and may represent a unique clinical feature of the interaction between SARS-CoV-2 infection and type 2 diabetes.

Introduction SARS-CoV-2 infection is associated with severe hyperglycemia, which has been associated with poor patient outcomes [ 1 , 2 , 3 , 4 ].