Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats

Objective: Diet-induced obesity promotes type 2 diabetes (T2D). Drugs that inhibit the renin-angiotensin system (RAS) have been demonstrated in clinical trials to decrease the onset of T2D. Angiotensin converting enzyme 2 (ACE2) negatively regulates the RAS by catabolizing angiotensin II (AngII). Preliminary data indicate that ACE2 deficient mice display impairments in glucose homeostasis at 8 weeks of age. We tested the hypothesis that ACE2 deficiency promotes the development of glucose intolerance and β-cell dysfunction in mice with diet-induced obesity. Methods and Results: Male Ace2 +/y or -/y mice were fed a low fat (LF, 10% kcal as fat) or high fat (HF, 60% kcal as fat) diet for 5 or 17 weeks. After 5 weeks, plasma insulin concentrations (0, 30 min) following a glucose challenge were significantly greater in HF versus ( vs) LF-fed mice. However, glucose-stimulated increases in plasma insulin concentrations were decreased in HF-fed ACE2 deficient mice compared to controls (2.96 ± 0.18 vs 4.44 ± 0.40 ng/ul, respectively; P<0.01). Surprisingly, isolated pancreatic islets from HF-fed mice of either genotype released similar concentrations of insulin in response to glucose. However, mRNA abundance of insulin was significantly reduced in islets from HF-fed Ace2 -/y compared to +/y mice (1.76 ± 0.17 vs 2.54 ± 0.18 insulin/18S ratio; P<0.05). After 17 weeks, the plasma insulin response to glucose was further reduced in the HF-fed ACE2 deficient mice compared to controls (8.07 ± 0.98 vs 13.90 ± 1.10 ng/ul; P<0.01). Further, LF-fed ACE2 deficient mice also displayed reductions in plasma glucose-stimulated insulin concentrations (1.92 ± 0.98 vs 3.09 ± 0.98 ng/ul; P<0.01). Islets from HF-fed wild type mice displayed reduced ACE2 gene expression compared to LF (0.069 ± 0.009 vs 0.169 ± 0.01, ACE2/18S ratio; P<0.001) and AngII totally suppressed islet glucose-stimulated insulin secretion compared to vehicle (-0.16 ± 0.18 vs 0.9 ± 0.26, fold change over basal; P<0.05). Conclusions: These results demonstrate that ACE2 deficiency promotes the development of T2D by regulating islet insulin content. Moreover, diet-induced obesity reduces islet ACE2 gene expression with augmented AngII-induced impairment of insulin secretion.

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Maternal Protein Malnutrition Does Not Impair Insulin Secretion from Pancreatic Islets of Offspring after Transplantation into Diabetic Rats

PLoS ONE ◽

10.1371/journal.pone.0030685 ◽

2012 ◽

Vol 7 (2) ◽

pp. e30685 ◽

Cited By ~ 6

Author(s):

Renato Chaves Souto Branco ◽

Júlio Cezar de Oliveira ◽

Sabrina Grassiolli ◽

Rosiane Aparecida Miranda ◽

Luiz Felipe Barella ◽

...

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Diabetic Rats ◽

Protein Malnutrition

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Relationship between insulin secretion, insulin content and dry weight of single rat pancreatic islets

Acta Endocrinologica ◽

10.1530/acta.0.0940365 ◽

1980 ◽

Vol 94 (3) ◽

pp. 365-370

Author(s):

G. H. J. Wolters ◽

W. Konijnendijk

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Outer Surface ◽

Basal Insulin ◽

Dry Weight ◽

Insulin Content ◽

Curvilinear Relationship ◽

Rat Pancreatic Islets ◽

Basal Insulin Secretion

Abstract. Single islets were incubated at glucose 5 mm for 60 min and subsequently at glucose 15 mm for 30 min. The insulin content of the incubated islets was proportional to the dry weight of the islets. The insulin secretion (Y) demonstrated a curvilinear relationship with the dry weight (X) of the islets, which could be described by the function Y = aX⅔ (a being a constant). On basis of this function it can be calculated that the insulin secretion of a particular islet is proportional to its outer surface. The consequence of this is that small sized islets secrete relatively much more insulin than large islets. Islets isolated with either purified or crude collagenase gave the same results except that a higher basal insulin secretion was observed with crude collagenase.

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Attenuated Insulin Release and Storage in Fetal Sheep Pancreatic Islets with Intrauterine Growth Restriction

Endocrinology ◽

10.1210/en.2005-0900 ◽

2006 ◽

Vol 147 (3) ◽

pp. 1488-1497 ◽

Cited By ~ 129

Author(s):

Sean W. Limesand ◽

Paul J. Rozance ◽

Gary O. Zerbe ◽

John C. Hutton ◽

William W. Hay

Keyword(s):

Insulin Secretion ◽

Glucose Metabolism ◽

Pancreatic Islets ◽

Insulin Release ◽

Intrauterine Growth Restriction ◽

Glucose Oxidation ◽

Placental Insufficiency ◽

Growth Restriction ◽

Insulin Content ◽

Intrauterine Growth

We determined in vivo and in vitro pancreatic islet insulin secretion and glucose metabolism in fetuses with intrauterine growth restriction (IUGR) caused by chronic placental insufficiency to identify functional deficits in the fetal pancreas that might be caused by nutrient restriction. Plasma insulin concentrations in the IUGR fetuses were 69% lower at baseline and 76% lower after glucose-stimulated insulin secretion (GSIS). Similar deficits were observed with arginine-stimulated insulin secretion. Fetal islets, immunopositive for insulin and glucagon, secreted insulin in response to increasing glucose and KCl concentrations. Insulin release as a fraction of total insulin content was greater in glucose-stimulated IUGR islets, but the mass of insulin released per IUGR islet was lower because of their 82% lower insulin content. A deficiency in islet glucose metabolism was found in the rate of islet glucose oxidation at maximal stimulatory glucose concentrations (11 mmol/liter). Thus, pancreatic islets from nutritionally deprived IUGR fetuses caused by chronic placental insufficiency have impaired insulin secretion caused by reduced glucose-stimulated glucose oxidation rates, insulin biosynthesis, and insulin content. This impaired GSIS occurs despite an increased fractional rate of insulin release that results from a greater proportion of releasable insulin as a result of lower insulin stores. Because this animal model recapitulates the human pathology of chronic placental insufficiency and IUGR, the β-cell GSIS dysfunction in this model might indicate mechanisms that are developmentally adaptive for fetal survival but in later life might predispose offspring to adult-onset diabetes that has been previously associated with IUGR.

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Muscarinic M1, M3 receptors function in the brainstem of streptozotocin induced diabetic rats: Their role in insulin secretion from the pancreatic islets as a function of age

European Journal of Pharmacology ◽

10.1016/j.ejphar.2009.01.047 ◽

2009 ◽

Vol 608 (1-3) ◽

pp. 14-22 ◽

Cited By ~ 8

Author(s):

Savitha Balakrishnan ◽

Jobin Mathew ◽

Sherin Antony ◽

Cheramadathikudyil S. Paulose

Keyword(s):

Insulin Secretion ◽

Pancreatic Islets ◽

Diabetic Rats ◽

M3 Receptors

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Insulin secretion and islet endocrine cell content at onset and during the early stages of diabetes in the BB rat: effect of the level of glycemic control

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-180 ◽

1991 ◽

Vol 69 (8) ◽

pp. 1230-1236 ◽

Cited By ~ 3

Author(s):

Raymond A. Pederson ◽

Susan B. Curtis ◽

Connie B. Chisholm ◽

Neil R. A. Gaba ◽

Robert V. Campos ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Therapy ◽

Endocrine Cell ◽

Diabetic Rats ◽

Insulin Content ◽

Bb Rat ◽

Β Cell ◽

Cell Content ◽

Autoimmune Destruction ◽

Onset Of Diabetes

Although it is agreed that autoimmune destruction of pancreatic islets in diabetic BB rats is rapid, reports of endocrine cell content of islets from BB diabetic rats at the time of onset of diabetes vary considerably. Because of the rapid onset of the disease (hours) and the attendant changes in islet morphology and insulin secretion, it was the aim of this study to compare islet β-cell numbers to other islet endocrine cells as close to the time of onset of hyperglycemia as possible (within 12 h). As it has been reported that hyperglycemia renders the β cell insensitive to glucose, the early effects of different levels of insulin therapy (well-controlled vs. poorly controlled glycemia) on islet morphology and insulin secretion were examined. When measured within 12 h of onset, insulin content of BB diabetic islets, measured by morphometric analysis or pancreatic extraction, was 60% of insulin content of control islets. Despite significant amounts of insulin remaining in the pancreas, 1-day diabetic rats exhibited fasting hyperglycemia and were glucose intolerant. The insulin response from the isolated perfused pancreas to glucose and the glucose-dependent insulinotropic hormone, gastric inhibitory polypeptide (GIP), was reduced by 95%. Islet content of other endocrine peptides, glucagon, somatostatin, and pancreatic polypeptide, was normal at onset and at 2 weeks post onset. A group of diabetic animals, maintained in a hyperglycemic state for 7 days with low doses of insulin, were compared with a group kept normoglycemic by appropriate insulin therapy. No insulin could be detected in islets of poorly controlled diabetics, while well-controlled animals had 30% of the normal islet insulin content. Well-controlled diabetic animals were more glucose tolerant and exhibited greater in vivo and in vitro insulin responses to glucose and GIP than poorly controlled animals. These studies indicate that at the onset of diabetes in the BB rat, significant amounts of insulin remain in the islet, although secretion in response to glucose and GIP is severely blunted. Adjusting insulin dosage to achieve normoglycemia has a significant β-cell sparing effect in diabetic animals, which is reflected in only a small increase in glucose-stimulated insulin secretion. These data suggest that impaired glucose recognition by the BB diabetic β cell occurs prior to autoimmune destruction of the islet and may contribute to the onset and severity of the diabetic state in these animals.Key words: diabetes, BB rat, islet endocrine cell content, insulin secretion.

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Metabolic Disturbances and Defects in Insulin Secretion in Rats With Streptozotocin-Nicotinamide-Induced Diabetes

Physiological Research ◽

10.33549/physiolres.932509 ◽

2013 ◽

pp. 663-670 ◽

Cited By ~ 7

Author(s):

T. SZKUDELSKI ◽

A. ZYWERT ◽

K. SZKUDELSKA

Keyword(s):

Body Weight ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Animal Studies ◽

Diabetic Rats ◽

Significant Rise ◽

Metabolic Disturbances ◽

Mild Diabetes ◽

Insulin Secretory Response

Rats with diabetes induced by streptozotocin (STZ) and nicotinamide (NA) are often used in animal studies concerning various aspects of diabetes. In this experimental model, the severity of diabetes is different depending on doses of STZ and NA. Moreover, diabetic changes in rats with STZ-NA-induced diabetes are not fully characterized. In our present study, metabolic changes and insulin secretion were investigated in rats with diabetes induced by administration of 60 mg of STZ and 90 mg of NA per kg body weight. Four to six weeks after diabetes induction, insulin, glucagon and some metabolic parameters were determined to evaluate the severity of diabetes. Moreover, insulin secretory capacity of pancreatic islets isolated from control and diabetic rats was compared. It was demonstrated that administration of 60 mg of STZ and 90 mg of NA per kg body weight induced relatively mild diabetes, since insulin, glucagon and other analyzed parameters were only slightly affected in diabetic rats compared with control animals. In vitro studies revealed that insulin secretory response was preserved in pancreatic islets of diabetic rats, however, was lower than in islets of control animals. This effect was observed in the presence of different stimuli. Insulin secretion induced by 6.7 and 16.7 mmol/l glucose was moderately reduced in islets of diabetic rats compared with control islets. In the presence of leucine with glutamine, insulin secretion appeared to be also decreased in islets of rats with STZ-NA-induced diabetes. Insulinotropic action of 6.7 mmol/l glucose with forskolin was also deteriorated in diabetic islets. Moreover, it was demonstrated that at a non-stimulatory glucose, pharmacological depolarization of plasma membrane with a concomitant activation of protein kinase C evoked significant rise in insulin release in islets of control and diabetic rats. However, in diabetic islets, this effect was attenuated. These results indicate that impairment in insulin secretion in pancreatic islets of rats with mild diabetes induced by STZ and NA results from both metabolic and nonmetabolic disturbances in these islets.

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Pancreatic Thyrotropin Releasing Hormone and Mechanism of Insulin Secretion

Cellular Physiology and Biochemistry ◽

10.1159/000494013 ◽

2018 ◽

Vol 50 (1) ◽

pp. 378-384 ◽

Cited By ~ 3

Author(s):

Vladimír Štrbák

Keyword(s):

Insulin Resistance ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Basal Insulin ◽

Thyrotropin Releasing Hormone ◽

Insulin Content ◽

Β Cells ◽

Releasing Hormone ◽

Rat Pancreatic Islets ◽

Basal Insulin Secretion

Thyrotropin releasing hormone (TRH; pGlu-His-ProNH2) is expressed also in pancreatic β cells where it is colocalized in secretory granules with insulin. High perinatal changes of the TRH gene expression and TRH concentrations in rat pancreatic islets coincide with the perinatal maturation of the adequate insulin secretory responsiveness to glucose and other nutrient secretagogues. TRH secretion from pancreatic islets is stimulated by glucose and inhibited by insulin. Disruption of the TRH gene in knockout mice results in hyperglycemia accompanied by impaired insulin secretory response to glucose. Progress in understanding TRH - insulin relations may be substantial for improving knowledge of pathophysiological mechanisms included in changes of insulin secretion with possible clinical impact. Block of the last step of biosynthesis of α-amidated peptides, including TRH by disulfiram (DS) treatment of adult male rats subcutaneously with 200 mg/kg for five days in our experiments resulted in barely detectable levels of peptidyl-glycine α-amidating monooxygenase (PAM) in their pancreatic islets. TRH in physiological concentration (1 nM) does not affect basal insulin secretion from intact rat pancreatic islets. In contrast, basal insulin secretion from islets of DS-treated rats is four times higher compared to controls and could not be further stimulated by high-glucose. The addition of 1 nM TRH into medium decreased immediately basal insulin secretion in DS (TRH lacking) islets to control level and normalized also their response to glucose. Interestingly, absence of the secretory response to glucose in islets from TRH depleted rats was connected with their increase of insulin content during stimulation. Glucose stimulation together with 1 nM TRH normalized also insulin content in DS islets. Apparently, high insulin content in islets from TRH depleted animals is a result of block of regulatory secretion pathway redirected to constitutional secretion which was corrected by the addition of TRH. Type 2 diabetes mellitus is a disease characterized by various range from predominant insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance. These symptoms suggest a possible role of TRH dysregulation. In conclusion, presence of TRH in β cells ensures appropriate low basal (constitutive) insulin secretion. Release of TRH induced by glucose and possibly by other secretagogues has autocrine effect resulting in directing insulin secretion to regulatory pathway reacting to stimulation. If some defects of insulin secretion could be treated by TRH, various ways of applications (also oral and nasal) could be utilized. Moreover, positive side effects shown in animal experiments may accompany the treatment: TRH has the potential to prevent apoptosis and promotes insulin-producing cell proliferation and has also aging-reversing properties.

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