scholarly journals Session 7: Early nutrition and later health Early developmental pathways of obesity and diabetes risk

2007 ◽  
Vol 66 (3) ◽  
pp. 451-457 ◽  
Author(s):  
D. B. Dunger ◽  
B. Salgin ◽  
K. K. Ong
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Weight Gain ◽  
Cell Mass ◽  
Disposition Index ◽  
Β Cell ◽  
Igf I ◽  
The Face

Size at birth and patterns of postnatal weight gain have been associated with adult risk for the development of type 2 diabetes in many populations, but the putative pathophysiological link remains unknown. Studies of contemporary populations indicate that rapid infancy weight gain, which may follow fetal growth restriction, is an important risk factor for the development of childhood obesity and insulin resistance. Data from the Avon Longitudinal Study of Pregnancy and Childhood shows that rapid catch-up weight gain can lead to the development of insulin resistance, as early as 1 year of age, in association with increasing accumulation of central abdominal fat mass. In contrast, the disposition index, which reflects the β-cells ability to maintain insulin secretion in the face of increasing insulin resistance, is much more closely related to ponderal index at birth than postnatal catch-up weight gain. Infants with the lowest ponderal index at birth show a reduced disposition index at aged 8 years associated with increases in fasting NEFA levels. The disposition index is also closely related to childhood height gain and insulin-like growth factor-I (IGF-I) levels; reduced insulin secretory capacity being associated with reduced statural growth, and relatively short stature with reduced IGF-I levels at age 8 years. IGF-I may have an important role in the maintenance of β-cell mass, as demonstrated by recent studies of pancreatic β-cell IGF-I receptor knock-out and adult observational studies indicating that low IGF-I levels are predictive of subsequent risk for the development of type 2 diabetes. However, as insulin secretion is an important determinant of IGF-I levels, cause and effect may be difficult to establish. In conclusion, although rapid infancy weight gain and increasing rates of childhood obesity will increase the risk for the development of insulin resistance, prenatal and postnatal determinants of β-cell mass may ultimately be the most important determinants of an individual's ability to maintain insulin secretion in the face of increasing insulin resistance, and thus risk for the development of type 2 diabetes.

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

2007 ◽  
Vol 292 (6) ◽  
pp. E1694-E1701 ◽  
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.

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.

scholarly journals Insulin: The Friend and the Foe in the Development of Type 2 Diabetes Mellitus

2020 ◽  
Vol 21 (5) ◽  
pp. 1770
Author(s):  
Nadia Rachdaoui
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Cell Mass ◽  
Β Cells ◽  
Β Cell ◽  
Peripheral Insulin Resistance

Insulin, a hormone produced by pancreatic β-cells, has a primary function of maintaining glucose homeostasis. Deficiencies in β-cell insulin secretion result in the development of type 1 and type 2 diabetes, metabolic disorders characterized by high levels of blood glucose. Type 2 diabetes mellitus (T2DM) is characterized by the presence of peripheral insulin resistance in tissues such as skeletal muscle, adipose tissue and liver and develops when β-cells fail to compensate for the peripheral insulin resistance. Insulin resistance triggers a rise in insulin demand and leads to β-cell compensation by increasing both β-cell mass and insulin secretion and leads to the development of hyperinsulinemia. In a vicious cycle, hyperinsulinemia exacerbates the metabolic dysregulations that lead to β-cell failure and the development of T2DM. Insulin and IGF-1 signaling pathways play critical roles in maintaining the differentiated phenotype of β-cells. The autocrine actions of secreted insulin on β-cells is still controversial; work by us and others has shown positive and negative actions by insulin on β-cells. We discuss findings that support the concept of an autocrine action of secreted insulin on β-cells. The hypothesis of whether, during the development of T2DM, secreted insulin initially acts as a friend and contributes to β-cell compensation and then, at a later stage, becomes a foe and contributes to β-cell decompensation will be discussed.

Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis

2005 ◽  
Vol 288 (4) ◽  
pp. E707-E714 ◽  
Author(s):  
Marcela Brissova ◽  
Michael Blaha ◽  
Cathi Spear ◽  
Wendell Nicholson ◽  
Aramandla Radhika ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Cell Mass ◽  
Glucose Disposal ◽  
Β Cell ◽  
Impaired Insulin Secretion ◽  
Impaired Insulin

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic β-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1+/−, resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4+/−, resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4+/−;PDX-1+/−). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4+/−;PDX-1+/− mice developed β-cell hyperplasia but failed to increase their β-cell insulin content. These results indicate that PDX-1 heterozygosity (∼60% of normal protein levels) abrogates the β-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.

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

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

scholarly journals Development of a Nongenetic Mouse Model of Type 2 Diabetes

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Elizabeth R. Gilbert ◽  
Zhuo Fu ◽  
Dongmin Liu
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Mouse Model ◽  
Serum Insulin ◽  
Cell Mass ◽  
Low Fat ◽  
Β Cell ◽  
Islet Mass ◽  
Metabolic Characteristics

Insulin resistance and loss of β-cell mass cause Type 2 diabetes (T2D). The objective of this study was to generate a nongenetic mouse model of T2D. Ninety-six 6-month-old C57BL/6N males were assigned to 1 of 12 groups including (1) low-fat diet (LFD; low-fat control; LFC), (2) LFD with 1 i.p. 40 mg/kg BW streptozotocin (STZ) injection, (3), (4), (5), (6) LFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively, (7) high-fat diet (HFD), (8) HFD with 1 STZ injection, (9), (10), (11), (12) HFD with 2, 3, 4, or 5 STZ injections on consecutive days, respectively. After 4 weeks, serum insulin levels were reduced in HFD mice administered at least 2 STZ injections as compared with HFC. Glucose tolerance was impaired in mice that consumed HFD and received 2, 3, or 4 injections of STZ. Insulin sensitivity in HFD mice was lower than that of LFD mice, regardless of STZ treatment. Islet mass was not affected by diet but was reduced by 50% in mice that received 3 STZ injections. The combination of HFD and three 40 mg/kg STZ injections induced a model with metabolic characteristics of T2D, including peripheral insulin resistance and reduced β-cell mass.

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

2009 ◽  
Vol 75 (6) ◽  
pp. 498-503 ◽  
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.

scholarly journals A Mathematical Model of the Pathogenesis, Prevention, and Reversal of Type 2 Diabetes

Endocrinology ◽  
2015 ◽  
Vol 157 (2) ◽  
pp. 624-635 ◽  
Author(s):  
Joon Ha ◽  
Leslie S. Satin ◽  
Arthur S. Sherman
Keyword(s):  
Mathematical Model ◽  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Cell Function ◽  
Cell Mass ◽  
Β Cell ◽  
Metabolic Defects ◽  
Normal Individuals ◽  
Β Cell Function

Abstract Type 2 diabetes (T2D) is generally thought to result from the combination of 2 metabolic defects, insulin resistance, which increases the level of insulin required to maintain glucose within the normal range, and failure of insulin-secreting pancreatic β-cells to compensate for the increased demand. We build on a mathematical model pioneered by Topp and colleagues to elucidate how compensation succeeds or fails. Their model added a layer of slow negative feedback to the classic insulin-glucose loop in the form of a slow, glucose-dependent birth and death law governing β-cell mass. We add to that model regulation of 2 aspects of β-cell function on intermediate time scales. The model quantifies the relative contributions of insulin action and insulin secretion defects to T2D and explains why prevention is easier than cure. The latter is a consequence of a threshold separating the normoglycemic and diabetic states (bistability), which also underlies the success of bariatric surgery and acute caloric restriction in rapidly reversing T2D. The threshold concept gives new insight into “Starling's Law of the Pancreas,” whereby insulin secretion is higher for prediabetics and early diabetics than for normal individuals.

scholarly journals β-Cell Expansion for Therapeutic Compensation of Insulin Resistance in Type 2 Diabetes

2003 ◽  
Vol 4 (1) ◽  
pp. 1-5 ◽  
Author(s):  
Shimon Efrat
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Cell Expansion ◽  
Cell Function ◽  
Cell Mass ◽  
Disease Type ◽  
Insulin Production ◽  
Β Cell ◽  
Overt Disease

Insulin resistance is the primary cause of type 2 diabetes. However, if compensated by increased insulin production, insulin resistance by itself does not lead to overt disease. Type 2 diabetes develops when this compensation is insufficient, due to defects inβ-cell function and in regulation of theβ-cell mass.β-Cell transplantation, as well as approaches that replenish or preserve the endogenousβ-cell mass, may facilitate the treatment of type 2 diabetes in patients requiring exogenous insulin.

Sign in / Sign up

Export Citation Format

Share Document