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.
Nutritional Support in the Diabetic Patient
Jack L. Leahy, Nathaniel G. Clark, William T. Cefalu in Medical Management of Diabetes Mellitus, 2000
Severe stress can cause hyperglycemia in patients without an antecedent diagnosis of diabetes mellitus. Severe stress (as during a serious illness) is accompanied by significant increases in the plasma concentration of counterregulatory hormones (i.e., glucagon, epinephrine, Cortisol, and growth hormone) that increase hepatic glucose release and decrease peripheral glucose uptake (2). Stress causes an even greater derangement in glucose metabolism in patients with diabetes because they cannot increase insulin secretion as a compensatory response. The exaggerated glucose response following a stress dose counterregulatory hormone infusion in healthy subjects with diabetes, in comparison with nondiabetic subjects, is one explanation for the deterioration in glucose control that occurs in stressed diabetic patients. Cytokines may also profoundly affect carbohydrate metabolism. Typically, the interleukins cause hyperglycemia. Endotoxin can cause hyperglycemia or hypoglycemia.
Pathophysiology and Management of Type 1 Diabetes
Emmanuel C. Opara, Sam Dagogo-Jack in Nutrition and Diabetes, 2019
Many factors can contribute to the development of hypoglycemia in insulin-treated individuals. These include changes in insulin sensitivity (e.g., weight loss, exercise), mismatches between insulin dosing and carbohydrate/caloric intake (e.g., excessive insulin, poor insulin timing, skipped or delayed meals, gastroparesis, errors in carbohydrate counting or estimation), and comorbid medical conditions (e.g., liver disease, renal failure, adrenal insufficiency, and critical illness) (59). Other risk factors include lower A1c, elderly age, longer duration of diabetes, and prior history of severe hypoglycemia (60). Patients who have experienced recurrent hypoglycemia may develop impaired counterregulatory hormone activity and a reduced autonomic response to low blood glucose, known as hypoglycemia-associated autonomic failure. This leads to hypoglycemia unawareness (the attenuation or absence of adrenergic symptoms during hypoglycemia) and increases the risk for subsequent hypoglycemia (58).
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.
Profile of tirzepatide in the management of type 2 diabetes mellitus: design, development, and place in therapy
Published in Expert Opinion on Pharmacotherapy, 2023
Lina Naseralallah, Bodoor Aboujabal
In the MAD study, all tirzepatide doses, as well as dulaglutide, significantly improved glucose response compared with placebo as assessed by the glucose AUC(0–2 h) during the OGTT at Day 23, while only the 4.5 mg tirzepatide yielded a significant reduction in FBG at study end (Day 29). This reduction in FBG is undesirable as it is in healthy subjects and incretin hormones are supposed to have glucose lowering effect only in hyperglycemic conditions. This finding aligns with a previous study where patients with T2DM who are taking semaglutide showed reduction in FBG [19]. In semaglutide, this reduction was viewed as an initial short-term response to the administration of medication. After this, the counterregulatory hormone (homeostatic mechanism) will be activated and subsequently normoglycemia will be achieved. Hence, as subjects in this study were followed for 29 days only, longer follow-up duration may mask this finding. In addition to the fact that normal individuals have impairment of processes underpinning glycemic control; therefore restitution of normoglycemia is likely to occur faster following exposure to these agents than patients with T2DM. This data is only available for semaglutide; it is thus needed to confirm in future studies if this justification also applies to tirzepatide. Moreover, dose-dependent body weight reductions were only seen at doses higher than 0.5 mg.
Impact of heart-specific disruption of the circadian clock on systemic glucose metabolism in mice
Published in Chronobiology International, 2018
Tomomi Nakao, Akira Kohsaka, Tsuyoshi Otsuka, Zaw Lin Thein, Hue Thi Le, Hidefumi Waki, Sabine S Gouraud, Hayato Ihara, Masako Nakanishi, Fuyuki Sato, Yasuteru Muragaki, Masanobu Maeda
As mentioned above, clinical evidence has indicated a close association between heart function and systemic glucose metabolism (Demant et al. 2014; From et al. 2006; Tenenbaum et al. 2003); however, it remains unclear how decreased heart function alters systemic glucose metabolism. Activation of the sympathetic nervous system has been proposed as the cause of insulin resistance when heart function is decreased (Riehle and Abel 2016). However, we did not identify an increase in urinary noradrenaline excretion in H-Bmal1−/− mice. One plausible explanation for this observation is that the alteration in sympathetic nerve activity of H-Bmal1−/− mice might have been too small to detect at the urinary noradrenaline level. Because the autonomic nervous system occasionally controls certain tissues (Watson et al. 2006), sympathetic efferent neurons to only a small number of tissues (i.e., liver) might be activated in H-Bmal1−/− mice; therefore, we did not detect changes in noradrenaline at the systemic level. On the other hand, inflammation in metabolic tissues, which can cause insulin resistance, is also known to be induced under heart failure conditions (Jahng et al. 2016). However, no inflammation was observed in the liver, WAT, and skeletal muscle of 12-week-old H-Bmal1−/− mice. Finally, heart failure may also increase the blood level of corticosterone, a major insulin counterregulatory hormone in rodents, but we did not observe an increase in plasma corticosterone levels in H-Bmal1−/− mice.