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Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Leptin is known primarily for its adipostatic role, but it is also essential for the regulation of glucose homeostasis. The loss of leptin action leads to hyperglycaemia, hyperinsulinemia and glucose intolerance (72). The leptin receptor-deficient Lepdb/db mouse is named after its diabetic phenotype (73). Leptin therapy in leptin-deficient rodents and humans ameliorates all aspects of dysregulated glucose homeostasis. Initially, these effects were thought to be secondary effects following a reduction in body weight. However, it has been firmly established that leptin regulates glucose homeostasis independent of its adipostatic effects by acting on various central and peripheral cells.
Energy balance and its regulation
Published in Geoffrey P. Webb, Nutrition, 2019
Leptin administration to ob/ob mice causes weight loss, normalisation of body composition and corrects all of the other metabolic and hormonal abnormalities of these mice. Leptin also causes reduced food intake when it is administered to normal mice. Leptin administration has no effect in the db/db mouse, an observation that is entirely consistent with the earlier suggestion of Coleman that the genetic defect in these mice was in a gene that codes for satiety factor (i.e. leptin) receptor. In 1995, Tartaglia et al. were able to identify and characterise the leptin receptor. They confirmed that the mutation in db/db mice leads to abnormalities in the leptin receptor. The leptin receptor can be detected in all the areas of the hypothalamus known to be involved in the control of energy balance and in the vascular region where leptin is conducted across the blood–brain barrier (the choroid plexus).
Myocardial Metabolism During Diabetes Mellitus
Published in Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla, Heart Dysfunction in Diabetes, 2019
Grant N. Pierce, Robert E. Beamish, Naranjan S. Dhalla
Several investigators have reported a decrease in carnitine content of the heart during diabetes.75,99–104 This alteration in carnitine content in hearts during diabetes is dependent upon several factors. The more severe the diabetic condition is, the faster the changes in serum and myocardial carnitine concentration occur.103 In mild, alloxan diabetes, as the duration of diabetes increases, the magnitude of the decrease in tissue levels of carnitine in the heart is greater.101 In the genetically diabetic (db/db) mouse, this tendency is also generally observed (Figure 10). The time-dependency of this change and the direction of the alteration in carnitine concentration in the heart during diabetes is also dependent upon the type of carnitine moiety under examination. As shown in Figure 10, alterations in free carnitine and short-chain carnitine esters occur later in the progression of the disease than do changes in long-chain carnitine esters and total carnitine. In addition, although all other carnitine moieties demonstrate a decrease in myocardial content during diabetes in comparison to control, long-chain acyl-carnitine is elevated at 18 weeks of age in the db/db mouse (Figure 10). The elevation in long-chain acyl-carnitine has been reported by other investigators in a model of chemically induced diabetes.101,102,104
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
Ten years later, Coleman’s first parabiosis experiments coupled a db/db mouse to a wild type C57Bl/KsJ mouse in search of a factor that might sensitize the db/db animals to insulin and normalize their blood sugar [22]. These conventional parabiosis studies measured the effect of shared circulation on the mice during parabiosis. Instead of rescuing the diabetic phenotype, parabiosis between db/db and wild type mice lead to the starvation and swift death (median survival time 23 days) of the wild type animals. Similar results had been found in a parabiosis study 10 years earlier, where rats with hypothalamic lesions had been surgically fused with uninjured rats [23]. Rats with bilateral ventromedial hypothalamic lesions overeat, gain weight, and become obese. Healthy, lesion-less rats coupled to obese, lesioned rats suffered the same fate as the wild type mice coupled to db/db mice: anorexia and eventual death. These studies led to the hypothesis that db/db and lesioned mice overproduced a satiety factor to which they were somehow unable to respond. The hypothalamic lesioning experiments implied that receptors for the satiety response were located in the ventromedial hypothalamus.
PPAR-δ Activation Ameliorates Diabetes-Induced Cognitive Dysfunction by Modulating Integrin-linked Kinase and AMPA Receptor Function
Published in Journal of the American College of Nutrition, 2019
Engy A. Abdel-Rahman, Subhrajit Bhattacharya, Manal Buabeid, Mohammed Majrashi, Jenna Bloemer, Ya-Xiong Tao, Muralikrishnan Dhanasekaran, Martha Escobar, Rajesh Amin, Vishnu Suppiramaniam
Due to the body condition of db/db mice (i.e., increased body weight and reduced mobility), the possibility that the extent to which exploratory behavior may be compromised due to decreased general activity or increased anxiety in a novel environment was determined by analyzing the number of alternations animals made within the maze. Number of alternations analyzed with one-way ANOVA showed that vehicle-treated wild-type mice produced more alternations than vehicle-treated db/db mice (F(2,10) = 26.79, MSE = 29.87, p < 0.001, Figure 1C; all F(1,10) = 48.21, n = 5, p < 0.001). However, the vehicle-treated and GW0742-treated db/db mice did not differ in this measure (F(1,10) < 0.10). Thus, although non-diabetic wild-type mice showed more activity and general exploratory behavior than vehicle-treated and GW0742-treated db/db mice, mobility was not a concern when comparing the two db/db mouse groups.
Perinatal exposure to high dietary advanced glycation end products in transgenic NOD8.3 mice leads to pancreatic beta cell dysfunction
Published in Islets, 2018
Danielle J. Borg, Felicia Y. T. Yap, Sahar Keshvari, David G. Simmons, Linda A. Gallo, Amelia K. Fotheringham, Aowen Zhuang, Robyn M. Slattery, Sumaira Z. Hasnain, Melinda T. Coughlan, Phillip Kantharidis, Josephine M. Forbes
Protein modifications termed advanced glycation end products (AGEs) are environmental factors which, together with modifications in their receptor, RAGE, associate with risk for islet autoimmunity and type 1 diabetes development.19–21 AGEs are made endogenously22 and may be absorbed from dietary sources.23,24 Circulating levels of AGEs appear to correlate between mother and baby,25 suggesting maternal transmission of AGEs to the fetus. Previous studies have identified that decreasing dietary AGE intake can improve glucose homeostasis in individuals with type 2 diabetes26 and in healthy, but overweight, adults.27 In type 1 diabetes, dietary reduction in AGE intake across generations of NOD/ShiLt mice suppressed diabetes incidence and improved glucose tolerance,28 confirming previously described effects of AGEs on murine islet function,29,30 islet infiltration,29 and glucose homeostasis29,31,32 in the NOD/ShiLt mouse and the type 2 diabetic db/db mouse. Together, these data highlight the importance of excessive AGEs as risk factors that impact on metabolic health in diabetes.