α-Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-susceptible mice

2005 ◽  
Vol 289 (2) ◽  
pp. E218-E224 ◽  
Author(s):  
Mary E. Rabaglia ◽  
Mark P. Gray-Keller ◽  
Brian L. Frey ◽  
Michael R. Shortreed ◽  
Lloyd M. Smith ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Mouse Strains ◽  
Stimulate Insulin Secretion ◽  
Insulin Resistant ◽  
Severe Diabetes ◽  
Patients At Risk ◽  
Mouse Islets ◽  
Branched Chain ◽  
Rate Limiting

Most patients at risk for developing type 2 diabetes are hyperinsulinemic. Hyperinsulinemia may be a response to insulin resistance, but another possible abnormality is insulin hypersecretion. BTBR mice are insulin resistant and hyperinsulinemic. When the leptin ob mutation is introgressed into BTBR mice, they develop severe diabetes. We compared the responsiveness of lean B6 and BTBR mouse islets to various insulin secretagogues. The transamination product of leucine, α-ketoisocaproate (KIC), elicited a dramatic insulin secretory response in BTBR islets. The KIC response was blocked by methyl-leucine or aminooxyacetate, inhibitors of branched-chain amino transferase. When dimethylglutamate was combined with KIC, the fractional insulin secretion was identical in islets from both mouse strains, predicting that the amine donor is rate-limiting for KIC-induced insulin secretion. Consistent with this prediction, glutamate levels were higher in BTBR than in B6 islets. The transamination product of glutamate, α-ketoglutarate, elicited insulin secretion equally from B6 and BTBR islets. Thus formation of α-ketoglutarate is a requisite step in the response of mouse islets to KIC. α-Ketoglutarate can be oxidized to succinate. However, succinate does not stimulate insulin secretion in mouse islets. Our data suggest that α-ketoglutarate may directly stimulate insulin secretion and that increased formation of α-ketoglutarate leads to hyperinsulinemia.

scholarly journals Reducing Glucokinase Activity Restores Endogenous Pulsatility and Enhances Insulin Secretion in Islets From db/db Mice

Endocrinology ◽  
2018 ◽  
Vol 159 (11) ◽  
pp. 3747-3760 ◽  
Author(s):  
Ishrat Jahan ◽  
Kathryn L Corbin ◽  
Avery M Bogart ◽  
Nicholas B Whitticar ◽  
Christopher D Waters ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Release ◽  
Opposite Effect ◽  
Glucose Sensing ◽  
Β Cell ◽  
Left Shift ◽  
Low Glucose ◽  
Mouse Islets ◽  
Secretion Rates

Abstract An early sign of islet failure in type 2 diabetes (T2D) is the loss of normal patterns of pulsatile insulin release. Disruptions in pulsatility are associated with a left shift in glucose sensing that can cause excessive insulin release in low glucose (relative hyperinsulinemia, a hallmark of early T2D) and β-cell exhaustion, leading to inadequate insulin release during hyperglycemia. Our hypothesis was that reducing excessive glucokinase activity in diabetic islets would improve their function. Isolated mouse islets were exposed to glucose and varying concentrations of the glucokinase inhibitor d-mannoheptulose (MH) to examine changes in intracellular calcium ([Ca2+]i) and insulin secretion. Acutely exposing islets from control CD-1 mice to MH in high glucose (20 mM) dose dependently reduced the size of [Ca2+]i oscillations detected by fura-2 acetoxymethyl. Glucokinase activation in low glucose (3 mM) had the opposite effect. We then treated islets from male and female db/db mice (age, 4 to 8 weeks) and heterozygous controls overnight with 0 to 10 mM MH to determine that 1 mM MH produced optimal oscillations. We then used 1 mM MH overnight to measure [Ca2+]i and insulin simultaneously in db/db islets. MH restored oscillations and increased insulin secretion. Insulin secretion rates correlated with MH-induced increases in amplitude of [Ca2+]i oscillations (R2 = 0.57, P < 0.01, n = 10) but not with mean [Ca2+]i levels in islets (R2 = 0.05, not significant). Our findings show that correcting glucose sensing can restore proper pulsatility to diabetic islets and improved pulsatility correlates with enhanced insulin secretion.

Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes

2004 ◽  
Vol 82 (7) ◽  
pp. 506-514 ◽  
Author(s):  
Enoka P Wijekoon ◽  
Craig Skinner ◽  
Margaret E Brosnan ◽  
John T Brosnan
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Plasma Concentrations ◽  
Branched Chain Amino Acids ◽  
Insulin Resistant ◽  
Branched Chain

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, α-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.Key words: plasma amino acids, liver amino acids, muscle amino acids, gluconeogenesis.

scholarly journals Five stages of progressive β-cell dysfunction in the laboratory Nile rat model of type 2 diabetes

2016 ◽  
Vol 229 (3) ◽  
pp. 343-356 ◽  
Author(s):  
Kaiyuan Yang ◽  
Jonathan Gotzmann ◽  
Sharee Kuny ◽  
Hui Huang ◽  
Yves Sauvé ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Pancreatic Islet ◽  
Cell Mass ◽  
Β Cell ◽  
High Fiber ◽  
Insulin Resistant ◽  
Cell Dysfunction

We compared the evolution of insulin resistance, hyperglycemia, and pancreatic β-cell dysfunction in the Nile rat (Arvicanthis niloticus), a diurnal rodent model of spontaneous type 2 diabetes (T2D), when maintained on regular laboratory chow versus a high-fiber diet. Chow-fed Nile rats already displayed symptoms characteristic of insulin resistance at 2 months (increased fat/lean mass ratio and hyperinsulinemia). Hyperglycemia was first detected at 6 months, with increased incidence at 12 months. By this age, pancreatic islet structure was disrupted (increased α-cell area), insulin secretion was impaired (reduced insulin secretion and content) in isolated islets, insulin processing was compromised (accumulation of proinsulin and C-peptide inside islets), and endoplasmic reticulum (ER) chaperone protein ERp44 was upregulated in insulin-producing β-cells. By contrast, high-fiber-fed Nile rats had normoglycemia with compensatory increase in β-cell mass resulting in maintained pancreatic function. Fasting glucose levels were predicted by the α/β-cell ratios. Our results show that Nile rats fed chow recapitulate the five stages of progression of T2D as occurs in human disease, including insulin-resistant hyperglycemia and pancreatic islet β-cell dysfunction associated with ER stress. Modification of diet alone permits long-term β-cell compensation and prevents T2D.

Tetrahydrobiopterin and Endothelial Dysfunction in Cardiovascular Diseases

Pteridines ◽  
2006 ◽  
Vol 17 (1) ◽  
pp. 11-15
Author(s):  
Kazuya Shinozaki ◽  
Atsunori Kashiwagi ◽  
Masahiro Masada ◽  
Tomio Okamura
Keyword(s):  
Nitric Oxide ◽  
Superoxide Anion ◽  
Vascular Endothelial ◽  
Insulin Resistant ◽  
Oxidative Breakdown ◽  
Patients At Risk ◽  
Relative Deficiency ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Rate Limiting

Abstract Endothelial vasodilator dysfunction is a characteristic feature of patients at risk for coronary atheroscierosis. We have reported that insulin resistance may be a pathogenic factor for endothehal dysfunction through impaired endothelial nitric oxide synthase (eNOS) activity and increased oxidative breakdown of nitric oxide (NO) due to an enhanced fonnation of Superoxide anion, which arc caused by relative deficiency of tetrahydrobiopterin (BH4) in vascular endothelial cclls. Guanosine-triphosphate cyclohydrolase I, the rate-limiting cnzyme in the production of BH4, is decreased in the aorta of insulin-resistant rats and supplementation of BH4 restored the endothelial function and relieved oxidative tissue damage. The BH4 treatment may evoke these benefits not only by providing eNOS with cofactor to enhance NO synthesis, but also by acting as an indirect and/or direct antioxidant to decrease Superoxide anion derived from the endothelium. A further understanding of the physiological and pathological roles and their regulation may lead to new therapeutic avenues.

scholarly journals Metformin Inhibits Mouse Islet Insulin Secretion and Alters Intracellular Calcium in a Concentration-Dependent and Duration-Dependent Manner near the Circulating Range

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Lindor Gelin ◽  
Jiewen Li ◽  
Kathryn L. Corbin ◽  
Ishrat Jahan ◽  
Craig S. Nunemaker
Keyword(s):  
Insulin Secretion ◽  
Day Treatment ◽  
Unintended Consequences ◽  
Calcium Handling ◽  
Dependent Manner ◽  
Direct Effects ◽  
Beneficial Effects ◽  
Cellular Processes ◽  
Mouse Islets

Metformin is considered the first-line treatment for type 2 diabetes. While metformin primarily increases insulin sensitivity, evidence also suggests that metformin affects the activity of insulin-secreting pancreatic islets. This study was designed to systematically examine the direct effects of metformin by measuring insulin secretion and the kinetics of the calcium response to glucose stimulation in isolated mouse islets using varying concentrations (20 μM, 200 μM, and 1 mM) and durations (~1, 2, and 3 days) of metformin exposure. We observed both concentration- and duration-dependent inhibitory effects of metformin. Concentrations as little as 20 μM (nearing circulating therapeutic levels) were sufficient to reduce insulin secretion following 3-day treatment. Concentrations of 200 μM and 1 mM produced more pronounced effects more rapidly. With 1 mM metformin, islets showed severe impairments in calcium handling, inhibition of insulin secretion, and increased cell death. No stimulatory effects of metformin were observed for any experimental endpoint. We conclude that the direct effects of metformin on islets are inhibitory at near-physiological concentrations. Beneficial effects of metformin observed on islets under various stressors may occur by “resting” fatigued cellular processes. However, metformin may have unintended consequences on normally functioning islets within the circulating range that require further evaluation.

769-P: Short-Term Dietary Reduction of Branched-Chain Amino Acids Reduces Meal-Induced Insulin Secretion and Modifies Microbiome Composition in Overweight Patients with Type 2 Diabetes

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 769-P
Author(s):  
YANISLAVA KARUSHEVA ◽  
THERESA VAN GEMERT ◽  
KLAUS STRASSBURGER ◽  
DANIEL F. MARKGRAF ◽  
TOMAS JELENIK ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Insulin Secretion ◽  
Branched Chain Amino Acids ◽  
Short Term ◽  
Microbiome Composition ◽  
Branched Chain

scholarly journals Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial

2019 ◽  
Vol 110 (5) ◽  
pp. 1098-1107 ◽  
Author(s):  
Yanislava Karusheva ◽  
Theresa Koessler ◽  
Klaus Strassburger ◽  
Daniel Markgraf ◽  
Lucia Mastrototaro ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Crossover Trial ◽  
Branched Chain Amino Acids ◽  
Short Term ◽  
Microbiome Composition ◽  
Branched Chain

ABSTRACT Background Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits. Objective We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity. Methods This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling. Results After the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes. Conclusions Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients. This trial was registered at clinicaltrials.gov as NCT03261362.

scholarly journals SUMO downregulates GLP-1-stimulated cAMP generation and insulin secretion

2012 ◽  
Vol 302 (6) ◽  
pp. E714-E723 ◽  
Author(s):  
Sindhu Rajan ◽  
Jacqueline Torres ◽  
Michael S. Thompson ◽  
Louis H. Philipson
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
High Glucose ◽  
Hormone Receptors ◽  
Intracellular Camp ◽  
Camp Generation ◽  
Primary Mouse ◽  
Mouse Islets ◽  
Conjugating Enzyme

Glucagon-like peptide-1 (GLP-1)-based incretin therapy is becoming central to the treatment of type 2 diabetes. Activation of incretin hormone receptors results in rapid elevation of cAMP followed by enhanced insulin secretion. However, the incretin effect may be significantly impaired in diabetes. The objective of this study is to investigate downregulation of GLP-1 signaling by small ubiquitin-related modifier protein (SUMO). Mouse islets exposed to high glucose showed increased expression of endogenous SUMO transcripts and its conjugating enzyme Ubc-9. Overexpression of SUMO-1 in mouse insulinoma 6 (MIN6) cells and primary mouse β-cells resulted in reduced static and real-time estimates of intracellular cAMP upon receptor stimulation with exendin-4, a GLP-1 receptor (GLP-1R) agonist. GLP1-R was covalently modified by SUMO. Overexpression of SUMO-1 attenuated cell surface trafficking of GLP-1R, which resulted in significantly reduced insulin secretion when stimulated by exendin-4. Partial knock down of SUMO-conjugating enzyme Ubc-9 resulted in enhanced exendin-4-stimulated insulin secretion in mouse islets exposed to high glucose. Thus, SUMO modification of the GLP-1R could be a contributing factor to reduced incretin responsiveness. Elucidating mechanisms of GLP-1R regulation by sumoylation will help improve our understanding of incretin biology and of GLP-1-based treatment of type 2 diabetes.

Dual mechanism of the potentiation by glucose of insulin secretion induced by arginine and tolbutamide in mouse islets

2006 ◽  
Vol 290 (3) ◽  
pp. E540-E549 ◽  
Author(s):  
Nobuyoshi Ishiyama ◽  
Magalie A. Ravier ◽  
Jean-Claude Henquin
Keyword(s):  
Insulin Secretion ◽  
Diabetic Patients ◽  
Cellular Mechanisms ◽  
Type 2 Diabetic Patients ◽  
Mouse Islets ◽  
Dual Mechanism ◽  
Relative Change ◽  
Arginine Concentration ◽  
Type 2 Diabetic

Glucose induces insulin secretion (IS) and also potentiates the insulin-releasing action of secretagogues such as arginine and sulfonylureas. This potentiating effect is known to be impaired in type 2 diabetic patients, but its cellular mechanisms are unclear. IS and cytosolic Ca2+ concentration ([Ca2+]i) were measured in mouse islets during perifusion with 3–15 mmol/l glucose (G3–G15, respectively) and pulse or stepwise stimulation with 1–10 mmol/l arginine or 5–250 μmol/l tolbutamide. In G3, arginine induced small increases in [Ca2+]i but no IS. G7 alone only slightly increased [Ca2+]i and IS but markedly potentiated arginine effects on [Ca2+]i, which resulted in significant IS (already at 1 mmol/l). For each arginine concentration, both responses further increased at G10 and G15, but the relative change was distinctly larger for IS than [Ca2+]i. At all glucose concentrations, tolbutamide dose dependently increased [Ca2+]i and IS with thresholds of 25 μmol/l for [Ca2+]i and 100 μmol/l for IS at G3 and of 5 μmol/l for both at G7 and above. Between G7 and G15, the effect of tolbutamide on [Ca2+]i increased only slightly, whereas that on IS was strongly potentiated. The linear relationship between IS and [Ca2+]i at increasing arginine or tolbutamide concentrations became steeper as the glucose concentration was raised. Thus glucose augmented more the effect of each agent on IS than that on [Ca2+]i. In conclusion, glucose potentiation of arginine- or tolbutamide-induced IS involves increases in both the rise of [Ca2+]i and the action of Ca2+ on exocytosis. This dual mechanism must be borne in mind to interpret the alterations of the potentiating action of glucose in type 2 diabetic patients.

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