Maternal low-protein diet on the last week of pregnancy contributes to insulin resistance and β-cell dysfunction in the mouse offspring

Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for β-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal β-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient β-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes.

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Visceral Adiposity Index is associated with Insulin Resistance, impaired Insulin Secretion, and β-cell dysfunction in subjects at risk for Type 2 Diabetes

Diabetes Epidemiology and Management ◽

10.1016/j.deman.2021.100013 ◽

2021 ◽

pp. 100013

Author(s):

Froylan David Martínez-Sánchez ◽

Valerie Paola Vargas-Abonce ◽

Andrea Rocha-Haro ◽

Romina Flores-Cardenas ◽

Milagros Fernández-Barrio ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

At Risk ◽

Insulin Secretion ◽

Visceral Adiposity ◽

Visceral Adiposity Index ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

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Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00430.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1694-E1701 ◽

Cited By ~ 17

Author(s):

Jane J. Kim ◽

Yoshiaki Kido ◽

Philipp E. Scherer ◽

Morris F. White ◽

Domenico Accili

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Secretion ◽

Cell Response ◽

Cell Mass ◽

Comprehensive Treatment ◽

Β Cell ◽

Cell Dysfunction ◽

Impaired Insulin

Type 2 diabetes results from impaired insulin action and β-cell dysfunction. There are at least two components to β-cell dysfunction: impaired insulin secretion and decreased β-cell mass. To analyze how these two variables contribute to the progressive deterioration of metabolic control seen in diabetes, we asked whether mice with impaired β-cell growth due to Irs2 ablation would be able to mount a compensatory response in the background of insulin resistance caused by Insr haploinsufficiency. As previously reported, ∼70% of mice with combined Insr and Irs2 mutations developed diabetes as a consequence of markedly decreased β-cell mass. In the initial phases of the disease, we observed a robust increase in circulating insulin levels, even as β-cell mass gradually declined, indicating that replication-defective β-cells compensate for insulin resistance by increasing insulin secretion. These data provide further evidence for a heterogeneous β-cell response to insulin resistance, in which compensation can be temporarily achieved by increasing function when mass is limited. The eventual failure of compensatory insulin secretion suggests that a comprehensive treatment of β-cell dysfunction in type 2 diabetes should positively affect both aspects of β-cell physiology.

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

Journal of Endocrinology ◽

10.1530/joe-15-0517 ◽

2016 ◽

Vol 229 (3) ◽

pp. 343-356 ◽

Cited By ~ 19

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.

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Aging and insulin secretion

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00366.2002 ◽

2003 ◽

Vol 284 (1) ◽

pp. E7-E12 ◽

Cited By ~ 233

Author(s):

Annette M. Chang ◽

Jeffrey B. Halter

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Older People ◽

Glucose Intolerance ◽

Therapeutic Interventions ◽

Β Cell ◽

Insulin Levels ◽

Cell Dysfunction ◽

Age Related

Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting β-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, β-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired β-cell compensation to age-related insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance.

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The role of vitamin D in the development of type 2 diabetes

Voprosy detskoj dietologii ◽

10.20953/1727-5784-2021-1-44-52 ◽

2021 ◽

Vol 19 (1) ◽

pp. 44-52

Author(s):

A.P. Shumilov ◽

◽

M.Yu. Semchenkova ◽

D.S. Mikhalik ◽

T.G. Avdeeva ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Vitamin D ◽

Inverse Relationship ◽

Biological Mechanisms ◽

Β Cell ◽

Cell Dysfunction ◽

Vitamin D Levels

Vitamin D plays an important role in decreasing the risk of developing type 2 diabetes by influencing calcium metabolism, thereby reducing β-cell dysfunction and preventing insulin resistance. The findings of research works are contradictory enough, although some of them demonstrated an inverse relationship between vitamin D levels and the incidence of type 2 diabetes. The article describes the biological mechanisms of relationships between vitamin D levels and type 2 diabetes, reviews the results of the studies conducted and summarizes the available data. Key words: vitamin D, type 2 diabetes mellitus, insulin resistance

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Insulin resistance and β-cell dysfunction as therapeutic targets in type 2 diabetes

Diabetes Obesity and Metabolism ◽

10.1046/j.1463-1326.2001.00101.x ◽

2001 ◽

Vol 3 (4) ◽

pp. 219-229 ◽

Cited By ~ 9

Author(s):

Alison J. Evans ◽

Andrew J. Krentz

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Therapeutic Targets ◽

Β Cell ◽

Cell Dysfunction

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Dual Mechanism for Type-2 Diabetes Resolution after Roux-en-Y Gastric Bypass

The American Surgeon ◽

10.1177/000313480907500608 ◽

2009 ◽

Vol 75 (6) ◽

pp. 498-503 ◽

Cited By ~ 10

Author(s):

Edward Lin ◽

S. Scott Davis ◽

Jahnavi Srinivasan ◽

John F. Sweeney ◽

Thomas R. Ziegler ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Weight Loss ◽

Gastric Bypass ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Β Cell ◽

Peripheral Insulin Resistance

Resolution of Type-2 diabetes mellitus (DM) after weight loss surgery is well documented, but the mechanism is elusive. We evaluated the glucose-insulin metabolism of patients undergoing a Roux-en-Y gastric bypass (RYGB) using the intravenous glucose tolerance test (IVGTT) and compared it with patients who underwent laparoscopic adjustable gastric band (AB) placement. Thirty-one female patients (age range, 20 to 50 years; body mass index, 47.2 kg/m2) underwent RYGB. Nine female patients underwent AB placement and served as control subjects. All patients underwent IVGTT at baseline and 1 month and 6 months after surgery. Thirteen patients undergoing RYGB and one patient undergoing AB exhibited impaired glucose tolerance or DM defined by the American Diabetes Association. By 6 months post surgery, diabetes was resolved in all but one patient undergoing RYGB but not in the patient undergoing AB. Patients with diabetes undergoing RYGB demonstrated increased insulin secretion and β-cell responsiveness 1 month after surgery and continued this trend up to 6 months, whereas none of the patients undergoing AB had changes in β-cell function. Both patients undergoing RYGB and those undergoing AB demonstrated significant weight loss (34.6 and 35.0 kg/m2, respectively) and improved insulin sensitivity at 6 months. RYGB ameliorates DM resolution in two phases: 1) early augmentation of beta cell function at 1 month; and 2) attenuation of peripheral insulin resistance at 6 months. Patients undergoing AB only exhibited reduction in peripheral insulin resistance at 6 months but no changes in insulin secretion.

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