Dynamics of insulin sensitivity, β-cell function, and β-cell mass during the development of diabetes in fa/fa rats

2007 ◽  
Vol 293 (6) ◽  
pp. E1730-E1735 ◽  
Author(s):  
Brian G. Topp ◽  
Laura L. Atkinson ◽  
Diane T. Finegood
Keyword(s):  
Insulin Sensitivity ◽  
Cell Function ◽  
Cell Mass ◽  
Primary Role ◽  
High Fat ◽  
Β Cell ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Zdf Rats ◽  
Secretory Capacity

Both male Zucker Fatty (mZF) and lower-fat-fed female Zucker diabetic fatty (LF-fZDF) rats are obese but remain normoglycemic. Male ZDF (mZDF) and high-fat-fed female ZDF rats (HF-fZDF) are also obese but develop diabetes between 7 and 10 wk of age. Although these models have been well studied, the mechanisms governing the adaptations to obesity in the normoglycemic animals, and the failure of adaptation in the animals that develop diabetes, remain unclear. Here we use quantitative morphometry and our recently developed coupled β-cell mass (βm), insulin, and glucose model to elucidate the dynamics of insulin sensitivity (SI), β-cell secretory capacity (βsc), and βm in these four animal models. Both groups that remained normoglycemic with increasing obesity (mZF, LF-fZDF) exhibited increased βm and constant βsc in response to a falling SI. In rats that developed hyperglycemia (mZDF, HF-fZDF), there was a greater reduction in SI and slower expansion of βm, with constant βsc. βsc decreased after glucose levels rose above 20 mM. Taken together, these data suggest that excessive insulin resistance and insufficient β m adaptation play a primary role in the pathogenesis of diabetes.

scholarly journals TRPM7 is a critical regulator of pancreatic endocrine development and high-fat diet-induced β-cell proliferation

Development ◽  
2021 ◽  
Author(s):  
Molly K. Altman ◽  
Charles M. Schaub ◽  
Matthew T. Dickerson ◽  
Karolina E. Zaborska ◽  
Prasanna K. Dadi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Cell Mass ◽  
Transient Receptor Potential Channels ◽  
High Fat ◽  
Β Cell ◽  
Β Cell Function

The melastatin subfamily of the transient receptor potential channels (TRPM) are regulators of pancreatic β-cell function. TRPM7 is the most abundant islet TRPM channel; however, the role of TRPM7 in β-cell function has not been determined. Here, we utilized various spatiotemporal transgenic mouse models to investigate how TRPM7 knockout influences pancreatic endocrine development, proliferation, and function. Ablation of TRPM7 within pancreatic progenitors reduced pancreatic size, α-cell and β-cell mass. This resulted in modestly impaired glucose tolerance. However, TRPM7 ablation following endocrine specification or in adult mice did not impact endocrine expansion or glucose tolerance. As TRPM7 regulates cell proliferation, we assessed how TRPM7 influences β-cell hyperplasia under insulin resistant conditions. β-cell proliferation induced by high-fat diet was significantly decreased in TRPM7-deficient β-cells. The endocrine roles of TRPM7 may be influenced by cation flux through the channel, and indeed we find that TRPM7 ablation alters β-cell Mg2+ and reduces the magnitude of elevation in β-cell Mg2+ during proliferation. Together, these findings reveal that TRPM7 controls pancreatic development and β-cell proliferation, which is likely due to regulation of Mg2+ homeostasis.

scholarly journals Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats

2010 ◽  
Vol 45 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Riccarda Granata ◽  
Marco Volante ◽  
Fabio Settanni ◽  
Carlotta Gauna ◽  
Corrado Ghé ◽  
...  
Keyword(s):  
Islet Cell ◽  
Cell Function ◽  
Cell Mass ◽  
Newborn Rats ◽  
Β Cell ◽  
Unacylated Ghrelin ◽  
Insulin Levels ◽  
Glucose Levels ◽  
Pancreatic Insulin ◽  
Β Cell Function

The ghrelin gene products, namely acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob), were shown to prevent pancreatic β-cell death and to improve β-cell function under treatment with cytokines, which are major cause of β-cell destruction in diabetes. Moreover, AG had been described previously to prevent streptozotocin (STZ)-induced diabetes in rats; however, the effect of either UAG or Ob has never been examined in this context. In the present study, we investigated the potential of UAG and Ob to increase islet β-cell mass and to reduce diabetes at adult age in STZ-treated neonatal rats. One-day-old rats were injected with STZ and subsequently administered with either AG, UAG or Ob for 7 days. On day 70, plasma glucose levels, plasma and pancreatic insulin levels, pancreatic islet area and number, insulin and pancreatic/duodenal homeobox-1 (Pdx1) gene expression, and antiapoptotic BCL2 protein expression were determined. Similarly to AG, both UAG and Ob counteracted STZ-induced high glucose levels and improved plasma and pancreatic insulin levels, which were reduced by the diabetogenic compound. UAG and Ob increased islet area, islet number, and β-cell mass with respect to STZ treatment alone. Finally, in STZ-treated animals, UAG and Ob up-regulated insulin and Pdx1 mRNA and increased the expression of BCL2 similarly to AG. Taken together, our results suggest that in STZ-treated newborn rats, UAG and Ob improve glucose metabolism and preserve islet cell mass, granting a therapeutic potential in medical conditions associated with impaired β-cell function.

Exercise improves glucose homeostasis that has been impaired by a high-fat diet by potentiating pancreatic β-cell function and mass through IRS2 in diabetic rats

2007 ◽  
Vol 103 (5) ◽  
pp. 1764-1771 ◽  
Author(s):  
Sunmin Park ◽  
Sang Mee Hong ◽  
Ji Eun Lee ◽  
So Ra Sung
Keyword(s):  
Cell Proliferation ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
Diabetic Rats ◽  
Pancreatic Β Cell ◽  
High Fat ◽  
Β Cell ◽  
Igf I ◽  
Β Cell Function

In this study, we investigated the effects of a high-fat diet and exercise on pancreatic β-cell function and mass and its molecular mechanism in 90% pancreatectomized male rats. The pancreatectomized diabetic rats were given control diets (20% energy) or a high-fat (HF) diet (45% energy) for 12 wk. Half of each group was given regular exercise on an uphill treadmill at 20 m/min for 30 min 5 days/wk. HF diet lowered first-phase insulin secretion with glucose loading, whereas exercise training reversed this decrease. However, second-phase insulin secretion did not differ among the groups. Exercise increased pancreatic β-cell mass. This resulted from stimulated β-cell proliferation and reduced apoptosis, which is associated with potentiated insulin or IGF-I signaling through insulin receptor substrate-2 (IRS2) induction. Although the HF diet resulted in decreased proliferation and accelerated apoptosis by weakened insulin and IGF-I signaling from reduction of IRS2 protein, β-cell mass was maintained in HF rats just as much as in control rats via increased individual β-cell size and neogenesis from precursor cells. Consistent with the results of β-cell proliferation, pancreas duodenal homeobox-1 expression increased in the islets of rats in the exercise groups, and it was reduced the most in rats fed the HF diet. In conclusion, exercise combined with a moderate fat diet is a good way to maximize β-cell function and mass through IRS2 induction to alleviate the diabetic condition. This study suggests that dietary fat contents and exercise modulate β-cell function and mass to overcome insulin resistance in two different pathways.

scholarly journals Systemic benefits of Gc inhibition to preserve insulin sensitivity

2020 ◽  
Author(s):  
Taiyi Kuo ◽  
Domenico Accili
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Cell Function ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
High Fat ◽  
Β Cell ◽  
Hepatic Glucose ◽  
Β Cell Function

ABSTRACTType 2 diabetes is caused by an imbalanced supply and demand of insulin. Insulin resistance and impaired β-cell function contribute to the onset of hyperglycemia. No single treatment modality can affect both aspects of diabetes pathophysiology. Thus, current treatments focus either on increasing insulin secretion (incretin mimetics, sulfonylureas) or insulin sensitivity (metformin and TZD), or reducing hyperglycemia (insulin, sglt2i). Previously, we reported that ablation of Gc, encoding a secreted protein with a primary role in vitamin D transport, improves pancreatic β-cell function in models of diet-induced insulin resistance. Here, we show that Gc ablation has systemic insulin-sensitizing effects to prevent weight gain, hyperglycemia, glucose intolerance, and lower NEFA and triglyceride in mice fed a high-fat diet. Hyperinsulinemic-euglycemic clamps show that Gc ablation protects insulin’s ability to reduce hepatic glucose production, and increases glucose uptake in skeletal muscle and adipose tissue. Moreover, acute Gc inhibition by way of adeno-associated virus encoding a short hairpin RNA to promote Gc mRNA degradation, prevents glucose intolerance caused by high fat feeding. The data suggest that Gc inhibition can provide an approach to increase insulin production in β-cells, and insulin action in peripheral tissues.RESEARCH IN CONTEXT▪ The goal was to find a therapeutic target that can improve insulin sensitivity and β-cell function simultaneously.▪ Gc ablation preserves β-cell insulin secretion ex vivo and in vivo.▪ Deletion of Gc prevents weight gain, reduces fat mass, lowers fasting glycemia, improves glucose tolerance, reduces hepatic glucose production after feeding, and increased glucose uptake in muscle and adipose.▪ Acute Gc inhibition improves glucose tolerance, which suggests that targeting Gc could provide an alternative way to treat type 2 diabetes.

Effects of pioglitazone and metformin on β-cell function in nondiabetic subjects at high risk for type 2 diabetes

2007 ◽  
Vol 292 (1) ◽  
pp. E359-E365 ◽  
Author(s):  
Neda Rasouli ◽  
Philip A Kern ◽  
E. Albert Reece ◽  
Steven C. Elbein
Keyword(s):  
At Risk ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Glucose Disposal ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Glucose Levels ◽  
Β Cell Function

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved β-cell function is not clear. In vitro studies showed improved β-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on β-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect β-cell function. We evaluated β-cell function and insulin sensitivity (SI) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved SI, glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (SG)]. Neither pioglitazone nor metformin significantly improved β-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline SI. Insulin secretion in response to arginine at maximally potentiating glucose levels (AIRmax) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for SI, the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving SI and SG. We did not find any evidence that either pioglitazone or metformin improved β-cell function. Improved β-cell compensation was observed primarily in the subgroup of subjects that had the lowest SI at baseline.

scholarly journals A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1593
Author(s):  
Phyu-Phyu Khin ◽  
Jong-Han Lee ◽  
Hee-Sook Jun
Keyword(s):  
Type 2 Diabetes ◽  
Cell Function ◽  
Cell Mass ◽  
Cell Loss ◽  
Β Cell ◽  
Cell Dedifferentiation ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Dedifferentiation Process

Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

Identifying glucose thresholds for incident diabetes by physiological analysis: a mathematical solution

2015 ◽  
Vol 308 (7) ◽  
pp. R590-R596 ◽  
Author(s):  
Ele Ferrannini ◽  
Maria Laura Manca
Keyword(s):  
Insulin Sensitivity ◽  
Confidence Interval ◽  
Glucose Tolerance ◽  
Odds Ratio ◽  
Cell Function ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Β Cell ◽  
Glucose Levels ◽  
Β Cell Function

Plasma glucose thresholds for diagnosis of type 2 diabetes are currently based on outcome data (risk of retinopathy), an inherently ill-conditioned approach. A radically different approach is to consider the mechanisms that control plasma glucose, rather than its relation to an outcome. We developed a constraint optimization algorithm to find the minimal glucose levels associated with the maximized combination of insulin sensitivity and β-cell function, the two main mechanisms of glucose homeostasis. We used a training cohort of 1,474 subjects (22% prediabetic, 7.7% diabetic) in whom insulin sensitivity was measured by the clamp technique and β-cell function was determined by mathematical modeling of an oral glucose tolerance test. Optimized fasting glucose levels were ≤87 and ≤89 mg/dl in ≤45-yr-old women and men, respectively, and ≤92 and ≤95 mg/dl in >45-yr-old women and men, respectively; the corresponding optimized 2-h glucose levels were ≤96, ≤98, ≤103, and ≤105 mg/dl. These thresholds were validated in three prospective cohorts of nondiabetic subjects (Relationship Between Insulin Sensitivity and Cardiovascular Disease Study, Botnia Study, and Mexico City Diabetes Study) with baseline and follow-up oral glucose tolerance tests. Of 5,593 participants, 452 progressed to diabetes. Similarly, in the three cohorts, subjects with glucose levels above the estimated thresholds had an odds ratio of 3.74 (95% confidence interval = 2.64–5.48) of progressing, substantially higher than the risk carried by baseline conventionally defined prediabetes [odds ratio = 2.32 (95% confidence interval = 1.91–2.81)]. The concept that optimization of glucose concentrations by direct measures of insulin sensitivity and β-cell function identifies gender- and age-specific thresholds that bear on disease progression is proven in a physiologically sound, quantifiable manner.

scholarly journals Neprilysin Deficiency Is Associated With Expansion of Islet β-Cell Mass in High Fat-Fed Mice

2018 ◽  
Vol 66 (7) ◽  
pp. 523-530 ◽  
Author(s):  
Jacqueline H. Parilla ◽  
Rebecca L. Hull ◽  
Sakeneh Zraika
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Cell Function ◽  
Cell Mass ◽  
Regulatory Peptides ◽  
Wild Type ◽  
High Fat ◽  
Β Cell ◽  
Beneficial Effects ◽  
Β Cell Function

Neprilysin (NEP) is an endopeptidase known to modulate nervous, cardiovascular, and immune systems via inactivation of regulatory peptides. In addition, it may also contribute to impaired glucose homeostasis as observed in type 2 diabetes (T2D). Specifically, we and others have shown that NEP is upregulated under conditions associated with T2D, whereas NEP deficiency and/or inhibition improves glucose homeostasis via enhanced glucose tolerance, insulin sensitivity, and pancreatic β-cell function. Whether increased β-cell mass also occurs with lack of NEP activity is unknown. We sought to determine whether NEP deficiency confers beneficial effects on β- and α-cell mass in a mouse model of impaired glucose homeostasis. Wild-type and NEP−/− mice were fed low- or high-fat diet for 16 weeks, after which pancreatic β- and α-cell mass were assessed by immunostaining for insulin and glucagon, respectively. Following low-fat feeding, NEP−/− mice exhibited lower β- and α-cell mass compared with wild-type controls. A high-fat diet had no effect on these parameters in wild-type mice, but in NEP−/− mice, it resulted in the expansion of β-cell mass. Our findings support a role for NEP in modulating β-cell mass, making it an attractive T2D drug target that acts via multiple mechanisms to affect glucose homeostasis.

Swim training prevents hyperglycemia in ZDF rats: mechanisms involved in the partial maintenance of β-cell function

2008 ◽  
Vol 294 (2) ◽  
pp. E271-E283 ◽  
Author(s):  
Michael A. Király ◽  
Holly E. Bates ◽  
Natalia A. Kaniuk ◽  
Jessica T. Y. Yue ◽  
John H. Brumell ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cell Function ◽  
Cell Mass ◽  
Area Under The Curve ◽  
Tolerance Test ◽  
Β Cell ◽  
Β Cell Function ◽  
Old Rats ◽  
Zdf Rats ◽  
Mass Expansion

Exercise improves glucose tolerance in obese rodent models and humans; however, effects with respect to mechanisms of β-cell compensation remain unexplained. We examined exercise's effects during the progression of hyperglycemia in male Zucker diabetic fatty (ZDF) rats until 19 wk of age. At 6 wk old, rats were assigned to 1) basal-euthanized for baseline values; 2) exercise-swam individually for 1 h/day, 5 days/wk; and 3) controls ( n = 8–10/group). Exercise (13 wk) resulted in maintenance of fasted hyperinsulinemia and prevented increases in fed and fasted glucose ( P < 0.05) compared with sham-exercised and sedentary controls ( P < 0.05). β-Cell function calculations indicate prolonged β-cell adaptation in exercised animals alone. During an intraperitoneal glucose tolerance test (IPGTT), exercised rats had lower 2-h glucose ( P < 0.05) vs. controls. Area-under-the-curve analyses from baseline for IPGTT glucose and insulin indicate improved glucose tolerance with exercise was associated with increased insulin production and/or secretion. β-Cell mass increased in exercised vs. basal animals; however, mass expansion was absent at 19 wk in controls ( P < 0.05). Hypertrophy and replication contributed to expansion of β-cell mass; exercised animals had increased β-cell size and bromodeoxyuridine incorporation rates vs. controls ( P < 0.05). The relative area of GLUT2 and protein kinase B was significantly elevated in exercised vs. sedentary controls ( P < 0.05). Last, we show formation of ubiquitinated protein aggregates, a response to cellular/oxidative stress, occurred in nonexercised 19 wk-old ZDF rats but not in lean, 6 wk-old basal, or exercised rats. In conclusion, improved β-cell compensation through increased β-cell function and mass occurs in exercised but not sedentary ZDF rats and may be in part responsible for improved glucoregulation.

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