Mechanism of impaired glucose-potentiated insulin secretion in diabetic 90% pancreatectomy rats. Study using glucagonlike peptide-1 (7-37).

Abstract

Chronic hyperglycemia causes a near-total disappearance of glucose-induced insulin secretion. To determine if glucose potentiation of nonglucose secretagogues is impaired, insulin responses to 10 Ϫ 9 M glucagonlike peptide-1 (GLP-1) (7-37) were measured at 2.8, 8.3, and 16.7 mM glucose with the in vitro perfused pancreas in rats 4-6 wk after 90% pancreatectomy (Px) and sham-operated controls. In the controls, insulin output to GLP-1 was Ͼ 100-fold greater at 16.7 mM glucose versus 2.8 mM glucose. In contrast, the increase was less than threefold in Px, reaching an insulin response at 16.7 mM glucose that was 10 Ϯ 2% of the controls, well below the predicted 35-40% fractional ␤ -cell mass in these rats. Px and control rats then underwent a 40-h fast followed by pancreas perfusion using a protocol of 20 min at 16.7 mM glucose followed by 15 min at 16.7 mM glucose/ 10 Ϫ 9 M GLP-1. In control rats, fasting suppressed insulin release to high glucose (by 90%) and to GLP-1 (by 60%) without changing the pancreatic insulin content. In contrast, in Px the insulin response to GLP-1 tripled in association with a threefold increase of the insulin content, both now being twice normal when stratified for the fractional ␤ -cell mass. The mechanism of the increased pancreas insulin content was investigated by assessing islet glucose metabolism and proinsulin biosynthesis. In controls with fasting, both fell 30-50%. In Px, the degree of suppression with fasting was similar, but the attained levels both exceeded those of the controls because of higher baseline (nonfasted) values.In summary, chronic hyperglycemia is associated with a fasting-induced paradoxical increase in glucose-potentiated insulin secretion. In Px rats, the mechanism is an increase in the ␤ -cell insulin stores, which suggests a causative role for a lowered ␤ -cell insulin content in the im-

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…We and others have suggested that a depletion of beta cell insulin stores is a cause of the lowered insulin secretion in type 2 diabetes, these proposals being based on studies of animal models of diabetes and of human patients showing a paradoxical rise in stimulated insulin output after pharmacological [12][13][14] and fasting-induced inhibition of insulin secretion [32,33]. The current study supports this view in part, as the lowered insulin response to arginine at high glucose in the ZF-Px rats equalled or exceeded that in other groups after correcting for their relative pancreas insulin contents.…”

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

“…Similar to the individuals with T2DM, animal models like the diabetic Zucker fatty rat, the Goto Kakizaki (GK) rat, and the 90% pancreatectomized diabetic rat have perturbations in glucose and lipid handling resulting in elevated levels of glucose and fatty acids (Leahy et al 1986, Goto et al 1988, Unger 1995, Hosokawa et al 1996. When administered to the animal models, diazoxide improved plasma glucose values and oral glucose tolerance, suppressed circulating insulin levels, enhanced insulin sensitivity, and improved lipid metabolism (Leahy et al 1994, Bjorklund et al 1997, Alemzadeh & Tushaus 2005.…”

“…When administered to the animal models, diazoxide improved plasma glucose values and oral glucose tolerance, suppressed circulating insulin levels, enhanced insulin sensitivity, and improved lipid metabolism (Leahy et al 1994, Bjorklund et al 1997, Alemzadeh & Tushaus 2005. b-cells from the diabetic Zucker fatty rat, the GK rat, and the 90% pancreatectomized diabetic rat have increased apoptosis, reduced insulin content, and deranged insulin secretory patterns including reduction of the initial glucose-induced rise and loss of regular pulsatility (Leahy et al 1986, Unger 1995, Hosokawa et al 1996, Maedler et al 2001, Lupi et al 2002, Prentki et al 2002, Ostenson et al 2007. Similar derangements are also observed after exposing primary b-cells or b-cell lines to elevated levels of glucose and fatty acids, in particular the saturated fatty acid palmitate, for prolonged time periods (Sako & Grill 1990, Bollheimer et al 1998, Lupi et al 2002, El-Assaad et al 2003, Maedler et al 2003, Song et al 2003, Kharroubi et al 2004.…”

Combination of Aronia, Red Ginseng and Shiitake Mushroom Potentiated Insulin Secretion and Reduced Insulin Resistance with Improving Gut Microbiome Dysbiosis in Insulin Deficient Type 2 Diabetic Rats

“…The rats underwent a 90% pancreatectomy using the Hosokawa technique [12] or received a sham pancreatectomy (sham) under anesthesia induced by intramuscular injection of a mixture of ketamine and xylazine (100 and 10 mg/kg body weight, respectively). The pancreatectomized (Px) rats exhibited characteristics of type 2 diabetes (random glucose levels > 180 mg/dL), whereas the sham rats did not [12,13].…”

“…A hyperglycemic clamp was performed in 10 free-moving and overnight-fasted rats/group after 5-6 days of implantation to determine insulin secretion capacity, as described previously [12,16,17]. During the clamp, glucose was infused to maintain a serum glucose level of 5.5 mM above baseline, and serum insulin level was measured at designated times.…”