Diabetic Ketoacidosis and Hyperosmolar Coma
Jack L. Leahy, Nathaniel G. Clark, William T. Cefalu in Medical Management of Diabetes Mellitus, 2000
One way to classify tissues in the body is by how they transport glucose. Accordingly, tissue may require insulin for glucose uptake and thus is insulin-sensitive, or it may not require insulin and is classed as insulin-insensitive. Figure 1 depicts the metabolism of glucose, amino acids, and fatty acids in the fed state, during fasting and during DKA in the major insulin-sensitive tissues: liver, muscle, and fat. This is compared with glucose metabolism in the nervous system (brain), which is an insulin-insensitive tissue in terms of glucose uptake. The brain's need for glucose, which is essential for mentation, remains relatively constant during feeding and in times of stress, fasting, and DKA. In contrast, insulin-sensitive tissues are deprived of glucose during times of insulin deficiency, such as fasting. Instead, they alter their intermediary metabolism from carbohydrate, which predominates in the fed state, to metabolizing fat. This alteration to fat mobilization and utilization as energy is a consequence of two hormonal shifts: one, the lack of effective levels of insulin allows lipolysis to occur; and two, the increased levels of the counterregulatory hormones—glucagon, catecholamines, and Cortisol—contribute to hyperglycemia and ketonemia. The counterregulatory hormones do this by inhibiting insulin secretion; by activating lipolysis, glycogenosis, and gluconeogenesis; and by inhibiting insulin-mediated glucose uptake by muscle (peripheral utilization).
The Endocrine Pancreas
George H. Gass, Harold M. Kaplan in Handbook of Endocrinology, 2020
Epinephrine is the other counterregulatory hormone of key importance. The contribution of adrenal activation toward correction of hypoglycemia increases with the severity of the stimulus. It turns out that the plasma glucose nadir rather than the change in level or even the rate of change is the major determinant of the peak epinephrine response.37 Physiologic increases in epinephrine that occur in response to hypoglycemia lead to both sustained increases in hepatic glucose production and suppression of peripheral glucose utilization.39 These mechanisms are mediated through both a- and p-adrenergic receptors. In addition, mobilization of certain fatty acids has been found to be an indirect effect of elevated epinephrine levels, and these fatty acids further enhance glucose production while limiting utilization.38 Although epinephrine deficiency (as would be seen after bilateral adrenalectomy or experimentally caused by both α and β blockade) does not impair glucose recovery from hypoglycemia if glucagon secretion is normal, the absence of both inevitably leads to severe hypoglycemia.
Mahvash Disease
Dongyou Liu in Handbook of Tumor Syndromes, 2020
Glucagon is a counterregulatory hormone for insulin, which lowers the extracellular glucose (usually stored in the liver as a polymer of glucose molecules or polysaccharide glycogen), and works to raise the concentration of glucose in the bloodstream through its binding to the glucagon receptor (GCGR, a G protein-coupled receptor of 485 aa) located in the plasma membranes of the liver (hepatocytes or liver cells) as well as the kidney, pancreas, heart, brain, and smooth muscle. This activates the stimulatory G protein, and then adenylate cyclase, triggering cAMP production and converting stored polysaccharide glycogen into glucose (i.e., glycogenolysis). After exhaustion of stored glycogen, glucagon promotes synthesis of additional glucose (i.e., gluconeogenesis) in the liver and kidneys. In addition, glucagon may shut off glycolysis in the liver, turning glycolytic intermediates into gluconeogenesis.
An unusual presentation of insulinoma and the serious consequences of delayed diagnosis
Published in Journal of Endocrinology, Metabolism and Diabetes of South Africa, 2020
It is well known that glucose is an obligate supplier of fuel to the brain.6 The brain contains minimal glycogen stores and therefore relies on a consistent supply of glucose for normal function. Counterregulatory hormones are in place to minimise reaching a critical glucose level; these include suppression of insulin secretion at a glucose level of about 4.5 mmol/l, increasing glucagon when glucose level falls below 3.8 mmol/l, and cortisol, growth hormone secretion and upregulation of the sympathetic nervous system function are implemented when level reaches below 3.0 mmol/l.7 Glycaemic thresholds at which these counter-regulatory mechanisms are implemented tend to be lower in diabetic patients and patients with previous hypoglycaemic episodes (see figure 3).6
In-patient outcomes of patients with diabetic ketoacidosis and concurrent protein energy malnutrition: A national database study from 2016 to 2017
Published in Postgraduate Medicine, 2021
Asim Kichloo, Hafeez Shaka, Zain El-Amir, Farah Wani, Jagmeet Singh, Genaro Romario Velazquez, Ehizogie Edigin, Dushyant Dahiya
DKA is aknown metabolic derangement of DM. Its morality rate is estimated to be 6–10% [8]. It can be a consequence of type 1 or type 2 DM [9,10]. In type 1 DM, DKA occurs as a result of decreased serum insulin secondary to β-cell destruction and decreased functional β-cells [9]. Decreased serum insulin leads to increases in counterregulatory hormones like cortisol, glucagon, growth hormone, and epinephrine [9]. This leads to increased hepatic gluconeogenesis and glycogenolysis increasing serum glucose concentrations [9]. Additionally, there is also decreased peripheral glucose uptake secondary to decreased insulin in the circulation, resulting in hyperglycemia and increased serum osmolality. Muscle proteolysis also contributes to hyperglycemia, and these processes ultimately result in osmotic diuresis [9]. Fatty acid production also occurs and is promoted by the presence of catecholamines, which results in increased redox reactions including the β-oxidation of free fatty acids. This results in ketone production [9]. Pyruvate depletion secondary to gluconeogenesis shifts fatty acids toward ketone production and away from the citric acid cycle, also resulting in excessive ketone production and ultimately ketoacidosis [9].
Glucagon receptor signalling – backwards and forwards
Published in Expert Opinion on Investigational Drugs, 2018
Tongzhi Wu, Christopher K. Rayner, Chinmay S. Marathe, Karen L. Jones, Michael Horowitz
Glucagon is well characterized as a counterregulatory hormone to insulin, acting to increase glycogenolysis and gluconeogenesis. That intravenous infusion of somatostatin delays the development of hyperglycemia and ketosis after withdrawal of insulin therapy in patients with type 1 diabetes suggests that excessive glucagon secretion or action contributes to the pathogenesis of hyperglycemia in this condition [2]. More recently, the physiological actions of glucagon signalling through the GCGr have been defined in gain- and loss-of-function studies using genetic models and highly specific GCGr antagonists. GCGr knockout mice are resistant to the development of hyperglycemia and demonstrate normal glucose tolerance even after major destruction of β-cells [9]. However, in the case of complete lack of insulin (e.g. induction of complete loss of β-cells and deletion of the insulin gene), these effects are less prominent, suggesting that some residual β-cell function is critical to maintaining the metabolic phenotype of GCGr knockout mice [10,11]. Notably, deletion of the GCGr gene or blockade of GCGr signalling is accompanied by marked changes in other metabolic regulators, including GLP-1, which complicate elucidation of the mechanisms that contribute to glucose lowering [12]. Recent clinical data relating to investigational GCGr antagonists reviewed in this issue attest to the relevance of glucagon excess to hyperglycemia in patients with type 2 diabetes.
Related Knowledge Centers
- Adrenaline
- Cortisol
- Glucose
- Norepinephrine
- Gluconeogenesis
- Insulin
- Glycogenolysis
- Glucagon
- Hormone
- Growth Hormone