II- Impact of insulin resistance on β-cell function

1. Clinical Studies

a. Islet function in obese adolescents

T2D is affecting more and more adolescents. Excess adiposity is one of the major risk factors–along with puberty and ethnicity—for development of T2D in youth as these patients have a 10.4% prevalence of excess weight and a 79.4% prevalence of obesity. Data from autopsy showed a decrease in β-cell mass mainly because of an increase in β-cell apoptosis, but it is not completely clear whether this can be applied to all T2D patients and notably to adolescents especially because of the lack of safe and noninvasive methods to measure this parameter in vivo. However, it was reported that obese adult individuals with impaired fasting glucose had a roughly 50% deficit in β-cell fractional area compared with obese nondiabetics. Regulation of β-cell replication
during infancy plays a major role in β-cell mass in adult humans. Indeed, β-cell mass expands by several fold from birth to adulthood, by growing in size rather than in number with a gradual decline thereafter to adulthood. Thus, β-cell function in adulthood strongly depends on β-cell development during childhood. Recently, Caprio’s group studied the progression of glucose tolerance in obese adolescents with normal glucose tolerance (NGT) and in those with impaired glucose tolerance (IGT) over two years. Obese adolescents with IGT are characterized by a progressive loss of β-cell glucose sensitivity during the first phase of insulin secretion, while obese T2D youth have both first and second phases impaired, accompanied by alterations in proinsulin-to-insulin processing. They showed that the adolescents with the highest 2-h glucose values during a hyperinsulinemic clamp procedure in the NGT group had similar changes to the adolescents of the IGT group, characterized by decreased insulin sensitivity and first-phase insulin secretion. This suggests that β-cell function and insulin sensitivity are impaired even in youth classified as NGT and reflects a short transition time between NGT, IGT, and diabetes, illustrating that the progression of the disease is rather fast, unlike what is usually described in adults (Sonia Caprio, Lecture).8

b. The role of genetics

As mentioned, many factors can explain the development of β-cell failure observed in T2D and among them the genetic component has a main role. Identification of relevant susceptibility genes has been difficult, mainly because the diabetes risk has been attributed to the interaction of multiple variant genes with the environment, where each of these genes only makes a small contribution to overall heritability. Studies reported that both insulin sensitivity (30%-40%) and the insulin response (38%) are heritable, and the disposition index (a quantitative measure that describes the relationship between β-cell sensitivity and insulin sensitivity) is heritable to a greater extent (67%). With the continual development of the genome-wide association study (GWAS), approximately 40 genes with single nucleotide polymorphisms (SNPs) associated with T2D have been identified (Figure 3).9

2. Experimental Studies

a. Effect of diet on islet gene expression in mice

As introduced in chapter I2, Metabolic programming of insulin secretion and action, parental diets, in particular maternal protein restriction and paternal high-fat diet (HFD) can lead to a reprogramming of gene expression in the islets of the offspring, implicating an important role of epigenetic control in islet function. HFD is the most common intervention in experimental animal models for the study of obesity and T2D. However, many mouse strains show a genetic diversity that is comparable to that of the human population and thus differ widely in their physiological response to HFD as well as in their development of obesity, their insulin sensitivity, insulin secretion, and susceptibility for diabetes-related traits. For example, expression of either the leptin gene (ob/ob) or the leptin receptor gene (db/db) mutation on the C57BL/6 back-ground resulted in a phenotype of massive obesity accompanied by insulin resistance with only transient diabetes, while the same mutations produced initial obesity and insulin resistance followed by life-shortening diabetes when present in the C57BL/KsJ
strain.
■ C57BL/6J mice are usually used for studies on diet-induced obesity and diabetes, although they have a high propensity to increase β-cell proliferation in response to insulin resistance. Interestingly, C57BL/6J mice fed a 16-week HFD are characterized by a 2-fold decreased expression of glutathione peroxidase 1 (Gpx1), a protein involved in the antioxidant defenses of β cells.13 This suggests that downregulation of Gpx1 in pancreatic islets in response to a diabetogenic HFD may constitute an important factor contributing to the pathogenesis and progression of the disease. Although no significant associations were found with genetic variants of GPX1 in the recent large-scale GWAS in diabetes, several studies have reported genetic association of GPX1 variants with diabetes-associated complications.
■ New Zealand obese (NZO) mice develop a polygenic disease pattern of obesity, hyperglycemia, hyperinsulinemia, hypercholesterolemia, and hypertension which in many ways resembles the human metabolic syndrome, and the prevalence for T2D is greatly increased in animals receiving a HFD. However, animals fed with a carbohydrate-free high-fat diet (CHFD) are protected from developing diabetes. Using laser capture microdissection and genome-wide transcriptome analyses, numerous transcripts involved in growth and development, protein processing and secretion, metabolism, and signaling were shown to be differentially regulated between HF and CHFD. Oxidative phosphorylation (OXPHOS) is the predominant gene set that was significantly upregulated in response to a HFD, demonstrating that a HF or high-carbohydrate diet enhanced islet
oxidative metabolism. As a consequence, there was increased reactive oxygen species (ROS) production, including superoxide anions, hydrogen peroxide, and hydroxyl radicals, which led to increased expression of regulators of the cellular redox state, including catalase (CAT), Gpx1, peroxiredoxins, and thioredoxin-interacting protein, strongly implicating ROS and increased oxidative stress in the early state of β-cell failure (Hadi Al-Hasani, Lecture).14

b. Identification of a novel diabetes susceptibility gene

To identify a diabetes susceptibility quantitative trait loci (QTL), Leibel and colleagues studied the F2 progeny of the intercross of obese Lepob/ob, diabetes-resistant C57BL/6J and diabetes-prone DBA/2J mouse strains. They cloned a candidate gene accounting for the QTL, that was designated “Lisch-like” (Ll), encoding multiple tissue-specific transcripts in brain, liver, and islets, and predicted to encode a transmembrane protein that could mediate cholesterol transport and/or convey signals related to cell division. Using mice with reduced Ll expression, they showed that Lisch-like is novel in structure among diabetes susceptibility genes, as it appears to alter β-cell development and glucose metabolism. Interestingly, the human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with T2D (Rudolph Leibel, Lecture).15

c. IAPP and -cell dysfunction

Low-grade systemic and localized islet inflammation have been suggested to contribute as causative factors in the development of T2D. One actor of inflammation involved in decreased β-cell mass is islet amyloid deposits that contain as their unique component the β-cell peptide islet amyloid polypeptide (IAPP, or amylin). IAPP is released from β cells in response to glucose and other stimuli that also trigger insulin secretion. Small aggregates or fibrils formed from amyloidogenic human IAPP (hIAPP) are toxic to β cells in culture and increase β-cell apoptosis and decrease β-cell mass in hIAPP transgenic mice. Moreover, hIAPP was recently shown to induce islet chemokine secretion (mainly interleukin 1[IL-1]), which promotes macrophage recruitment and activation leading to islet inflammation. Islet transplantation is a promising treatment for diabetes, but long-term success is limited by progressive graft loss and many studies raise the possibility that rapid amyloid formation in transplanted islets may be detrimental to graft function and mass, thus contributing to islet graft failure. Xenotransplantation of pancreatic islets, using pigs or other animals as islet donors, has received increasing interest in recent years, given the limited number of human islets available for clinical transplantation; interestingly, porcine islets have demonstrated long-term graft survival. Verchere’s group reported that the survival of transplanted porcine islets could be due, at least in part, to the fact that the porcine IAPP sequence differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity.16 These data suggest that islet amyloid–induced inflammation contributes to β-cell dysfunction observed in T2D and after islet transplantation (Bruce Verchere, Lecture).17

d. Signaling from insulin resistant muscle to the cell

T2D and obesity are characterized by dramatically increased circulating levels of tumor necrosis factor α (TNF-α). Although there is little evidence for elevated TNF-α in the skeletal muscle of individuals with T2D, its contribution toward skeletal muscle insulin resistance is well established. TNF-α is also believed to be a major cytokine involved in “conversation” between adipose tissue and muscle. In both rat and human primary β cells, the secretome from normally-insulin-sensitive muscle cells was reported to increase rat primary β-cell proliferation as well as GIIS. On the contrary, these parameters were decreased by incubation with conditioned medium from insulin resistant, TNF-α–treated skeletal muscle cells, while β-cell apoptosis was increased. This suggests that the insulin-resistant human skeletal muscle secretes myokines in response to TNF-α that impact negatively on β-cell proliferation and survival. Silencing of the mitogen-activated protein 4 kinase 4 (MAP4K4) gene prevents these β-cell impairments. These data reveal a possible new route of communication between skeletal muscle and β cells that may contribute to maintenance of β-cell functional mass in healthy subjects, as well as to the decrease seen in T2D (Karim Bouzakri, Lecture).18

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The hyperstimulated β cell: prelude to diabetes?
I- What is the role of epigenetics in insulin gene expression and insulin secretion and action
II- Impact of insulin resistance on β-cell function
III- Intrinsic hyperstimulation of β-cells
IV- Modulation of β-cell function by secretory products
V- Conclusion
Lectures during IGIS meeting
References