Type 2 diabetes in children: clinical aspects and risk factors

In the past, type 2 diabetes mellitus was considered a disease of adults and older individuals, not a paediatric condition. Over the last decade, however, in the USA and the rest of the world there has been a disturbing trend of increasing cases of type 2 diabetes in children, mirroring increasing rates of obesity. The risk factors for paediatric type 2 diabetes are: (1) obesity and increased body mass index; (2) family history of type 2 diabetes; (3) membership of ethnic minority; (4) puberty (mean age of diagnosis is approximately 13.5 years); (5) female gender; and (6) features of 'syndrome X'. The common link among these risk factors is insulin resistance, which plays a pivotal role in the pathophysiology of type 2 diabetes. Both insulin resistance and beta-cell failure are present in the fully established diabetes state. Data will be presented on how these risk factors impact on insulin sensitivity and insulin secretion in childhood, ultimately leading to type 2 diabetes. The clinical presentation of type 2 diabetes in children and its distinction from type 1 diabetes will be discussed.     

Attenuation of insulin-stimulated insulin receptor substrate-1 serine 307 phosphorylation in insulin resistance of type 2 diabetes

Insulin resistance is a primary characteristic of type 2 diabetes and likely causally related to the pathogenesis of the disease. It is a result of defects in signal transduction from the cell surface receptor of insulin to target effects. We found that insulin-stimulated phosphorylation of serine 307 (corresponding to serine 302 in the murine sequence) in the immediate downstream mediator protein of the insulin receptor, insulin receptor substrate-1 (IRS1), is required for efficient insulin signaling and that this phosphorylation is attenuated in adipocytes from patients with type 2 diabetes. Inhibition of serine 307 phosphorylation by rapamycin mimicked type 2 diabetes and reduced the sensitivity of IRS1 tyrosine phosphorylation in response to insulin, while stimulation of the phosphorylation by okadaic acid, in cells from patients with type 2 diabetes, rescued cells from insulin resistance. EC(50) for insulin-stimulated phosphorylation of serine 307 was about 0.2 nM with a t(1/2) of about 2 min. The amount of IRS1 was similar in cells from non-diabetic and diabetic subjects. These findings identify a molecular mechanism for insulin resistance in non-selected patients with type 2 diabetes.     

Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes

As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes.     

Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance

Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with approximately 35% of DHet males developing diabetes by 9-10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.     

Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor gamma in human skeletal muscle cells

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPARgamma induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H(2)O(2) levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulin-resistant cells, suggesting that GPx3 is required for the regulation of PPARgamma-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPARgamma is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.     

Psammomys obesus and the albino rat--two different models of nutritional insulin resistance, representing two different types of human populations.

Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 +/- 40 mg/dl), hyperinsulinaemia (194 +/- 31 microU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 +/- 4 microU/ml), hypertriglyceridaemia (170 +/- 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 +/- 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.     

Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults

Background

Previous studies have demonstrated that fetuin-A is related to insulin resistance among subjects with normal glucose tolerance but not patients with type 2 diabetes. There are limited data available concerning fetuin-A and insulin resistance in Chinese. We aimed to study the association of feuin-A with insulin resistance among participants with or without type 2 diabetes in a large sample size of adults aged 40 and older.

Methodology and Principal Findings

A community-based cross-sectional study was performed among 5,227 Chinese adults. The average age of our study was 61.5±9.9 years. Serum fetuin-A concentrations were not significantly different between male and female (296.9 vs. 292.9 mg/l, p = 0.11). Compared with the lowest quartile, the highest quartile of serum fetuin-A revealed a significant higher proportion of type 2 diabetic patients (34.8% vs. 27.3%, p<0.0001). In the multinomial logit models, the risk of type 2 diabetes was associated with each one quartile increase of serum fetuin-A concentrations when referenced not only to normal glucose tolerance (OR 1.24, 95% CI 1.07–1.43, p = 0.004) but also to impaired glucose regulation (OR 1.25, 95% CI 1.08–1.44, p = 0.003, respectively), after adjustment for age, sex, community, current smoking, and current drinking. The logistic regression analysis showed that fetuin-A were associated with elevated HOMA-IR and fasting serum insulin both among the participants with or without type 2 diabetes in the full adjusted analysis. There was no significant association between elevated serum fetuin-A concentrations and impaired glucose regulation (all p≥0.12).

Conclusions and Significance

Higher fetuin-A concentrations were associated with type 2 diabetes and insulin resistance in middle aged and elderly Chinese.     

Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling

Although insulin resistance has been traditionally associated with type 2 diabetes, recent evidence in humans and animal models indicates that insulin resistance may also develop in type 1 diabetes. A point mutation of insulin 2 gene in Ins2(Akita) mice leads to pancreatic beta-cell apoptosis and hyperglycemia, and these mice are commonly used to investigate type 1 diabetes and complications. Since insulin resistance plays an important role in diabetic complications, we performed hyperinsulinemic-euglycemic clamps in awake Ins2(Akita) and wild-type mice to measure insulin action and glucose metabolism in vivo. Nonobese Ins2(Akita) mice developed insulin resistance, as indicated by an approximately 80% reduction in glucose infusion rate during clamps. Insulin resistance was due to approximately 50% decreases in glucose uptake in skeletal muscle and brown adipose tissue as well as hepatic insulin action. Skeletal muscle insulin resistance was associated with a 40% reduction in total GLUT4 and a threefold increase in PKCepsilon levels in Ins2(Akita) mice. Chronic phloridzin treatment lowered systemic glucose levels and normalized muscle insulin action, GLUT4 and PKCepsilon levels in Ins2(Akita) mice, indicating that hyperglycemia plays a role in insulin resistance. Echocardiography showed significant cardiac remodeling with ventricular hypertrophy that was ameliorated following chronic phloridzin treatment in Ins2(Akita) mice. Overall, we report for the first time that nonobese, insulin-deficient Ins2(Akita) mice develop type 2 diabetes phenotypes including peripheral and hepatic insulin resistance and cardiac remodeling. Our findings provide important insights into the pathogenesis of metabolic abnormalities and complications affecting type 1 diabetes and lean type 2 diabetes subjects.     

Plasma Adiponectin Levels in High Risk African‐Americans with Normal Glucose Tolerance,Impaired Glucose Tolerance,and Type 2 Diabetes**

Objective: We studied plasma adiponectin, insulin sensitivity, and insulin secretion before and after oral glucose challenge in normal glucose tolerant, impaired glucose tolerant, and type 2 diabetic first degree relatives of African‐American patients with type 2 diabetes. Research Methods and Procedures: We studied 19 subjects with normal glucose tolerance (NGT), 8 with impaired glucose tolerance (IGT), and 14 with type 2 diabetes. Serum glucose, insulin, C‐peptide, and plasma adiponectin levels were measured before and 2 hours after oral glucose tolerance test. Homeostasis model assessment‐insulin resistance index (HOMA‐IR) and HOMA‐β cell function were calculated in each subject using HOMA. We empirically defined insulin sensitivity as HOMA‐IR < 2.68 and insulin resistance as HOMA‐IR > 2.68. Results: Subjects with IGT and type 2 diabetes were more insulin resistant (as assessed by HOMA‐IR) when compared with NGT subjects. Mean plasma fasting adiponectin levels were significantly lower in the type 2 diabetes group when compared with NGT and IGT groups. Plasma adiponectin levels were 2‐fold greater (11.09 ± 4.98 vs. 6.42 ± 3.3811 μg/mL) in insulin‐sensitive (HOMA‐IR, 1.74 ± 0.65) than in insulin‐resistant (HOMA‐IR, 5.12 ± 2.14) NGT subjects. Mean plasma adiponectin levels were significantly lower in the glucose tolerant, insulin‐resistant subjects than in the insulin sensitive NGT subjects and were comparable with those of the patients with newly diagnosed type 2 diabetes. We found significant inverse relationships of adiponectin with HOMA‐IR (r = ?0.502, p = 0.046) and with HOMA‐β cell function (r = ?0.498, p = 0.042) but not with the percentage body fat (r = ?0.368, p = 0.063), serum glucose, BMI, age, and glycosylated hemoglobin A1C (%A1C). Discussion: In summary, we found that plasma adiponectin levels were significantly lower in insulin‐resistant, non‐diabetic first degree relatives of African‐American patients with type 2 diabetes and in those with newly diagnosed type 2 diabetes. We conclude that a decreased plasma adiponectin and insulin resistance coexist in a genetically prone subset of first degree African‐American relatives before development of IGT and type 2 diabetes.     

Insulin resistance in human adipocytes occurs downstream of IRS1 after surgical cell isolation but at the level of phosphorylation of IRS1 in type 2 diabetes

Insulin resistance is a cardinal feature of type 2 diabetes and also a consequence of trauma such as surgery. Directly after surgery and cell isolation, adipocytes were insulin resistant, but this was reversed after overnight incubation in 10% CO(2) at 37 degrees C. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1 was insulin sensitive, but protein kinase B (PKB) and downstream metabolic effects exhibited insulin resistance that was reversed by overnight incubation. MAP-kinases ERK1/2 and p38 were strongly phosphorylated after surgery, but was dephosphorylated during reversal of insulin resistance. Phosphorylation of MAP-kinase was not caused by collagenase treatment during cell isolation and was present also in tissue pieces that were not subjected to cell isolation procedures. The insulin resistance directly after surgery and cell isolation was different from insulin resistance of type 2 diabetes; adipocytes from patients with type 2 diabetes remained insulin resistant after overnight incubation. IRS1, PKB, and downstream metabolic effects, but not insulin-stimulated tyrosine phosphorylation of insulin receptor, exhibited insulin resistance. These findings suggest a new approach in the study of surgery-induced insulin resistance and indicate that human adipocytes should recover after surgical procedures for analysis of insulin signalling. Moreover, we pinpoint the signalling dysregulation in type 2 diabetes to be the insulin-stimulated phosphorylation of IRS1 in human adipocytes.     

Regulation of Adipose Tissue Inflammation and Insulin Resistance by MAPK Phosphatase 5

Obesity and metabolic disorders such as insulin resistance and type 2 diabetes have become a major threat to public health globally. The mechanisms that lead to insulin resistance in type 2 diabetes have not been well understood. In this study, we show that mice deficient in MAPK phosphatase 5 (MKP5) develop insulin resistance spontaneously at an early stage of life and glucose intolerance at a later age. Increased macrophage infiltration in white adipose tissue of young MKP5-deficient mice correlates with the development of insulin resistance. Glucose intolerance in MKP5-deficient mice is accompanied by significantly increased visceral adipose weight, reduced AKT activation, enhanced p38 activity, and increased inflammation in visceral adipose tissue when compared with wild-type (WT) mice. Deficiency of MKP5 resulted in increased inflammatory activation in macrophages. These findings thus demonstrate that MKP5 critically controls inflammation in white adipose tissue and the development of metabolic disorders.     

For debate: Starling's curve of the pancreas--overuse of a concept?

It is commonly accepted that insulin secretion follows the pattern of an inverted U, also termed 'Starling's curve of the pancreas' during the natural history of hyperglycemia in glucose intolerance and type 2 diabetes. This concept is based on the cross-sectional observation that insulin concentrations initially increase when insulin sensitivity declines (as a consequence of obesity, for example) and decrease when glucose tolerance deteriorates (impaired glucose tolerance or overt type 2 diabetes). The initial increase in insulin concentrations has been viewed as 'hypersecretion' of insulin, thought to indicate that beta cell dysfunction is not etiological but secondary in nature. However, this view is oblivious to the now well-established fact that assessment of insulin secretion must account for individual insulin sensitivity. Here, we revisit the concept of Starling's curve of the pancreas based on first-phase C-peptide concentrations (hyperglycemic clamp) from subjects with normal glucose tolerance (n=66), impaired glucose tolerance (n=19) and mild type 2 diabetes (n=9). In absolute terms, first-phase C-peptide concentrations plotted against increasing fasting glucose concentrations indeed followed an inverted U. However, adjusted for direct and indirect measures of insulin sensitivity (insulin sensitivity index from the hyperglycemic clamp, body mass index, age and sex), first-phase C-peptide concentrations of the same individuals tended to decrease steadily. In conclusion, while the Starling curve exists for insulin concentrations, and perhaps also for insulin secretion, it does not hold for beta-cell function if that term were to imply appropriateness of insulin secretion (based on a formal test of glucose-stimulated insulin secretion) for the degree of insulin resistance, as it should.     

Aging and insulin secretion

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 beta-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, beta-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired beta-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.     

Accelerated endothelial dysfunction in mild prediabetic insulin resistance: the early role of reactive oxygen species

Insulin resistance is well established as an independent risk factor for the development of type 2 diabetes and cardiovascular atherosclerosis. Most studies have examined atherogenesis in models of severe insulin resistance or diabetes. However, by the time of diagnosis, individuals with type 2 diabetes already demonstrate a significant atheroma burden. Furthermore, recent studies suggest that, even in adolescence, insulin resistance is a progressive disorder that increases cardiovascular risk. In the present report, we studied early mechanisms of reduction in the bioavailability of the antiatheroscerotic molecule nitric oxide (NO) in very mild insulin resistance. Mice with haploinsufficiency for the insulin receptor (IRKO) are a model of mild insulin resistance with preserved glycemic control. We previously demonstrated that 2-mo-old (Young) IRKO mice have preserved vasorelaxation responses to ACh. This remained the case at 4 mo of age. However, by 6 mo, despite no significant deterioration in glucose homeostasis (Adult), IRKO mice had marked blunting of ACh-mediated vasorelaxation [IRKO maximum contraction response (E(max)) 66 +/- 5% vs. wild type 87 +/- 4%, P < 0.01]. Despite the endothelial dysfunction demonstrated, aortic endothelial nitric oxide synthase (eNOS) mRNA levels were similar in Adult IRKO and wild-type mice, and, interestingly, aortic eNOS protein levels were increased, suggesting a compensatory upregulation in the IRKO. We then examined the potential role of reactive oxygen species in mediating early endothelial dysfunction. The superoxide dismutase mimetic Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) restored ACh relaxation responses in the Adult IRKO (E(max) to ACh with MnTMPyP 85 +/- 5%). Dihydroethidium fluorescence of aortas and isolated coronary microvascular endothelial cells confirmed a substantial increase in endothelium-derived reactive oxygen species in IRKO mice. These data demonstrate that mild insulin resistance is a potent substrate for accelerated endothelial dysfunction and support a role for endothelial cell superoxide production as a mechanism underlying the early reduction in NO bioavailability.     

Lipocalin-13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms

Insulin sensitivity is impaired in obesity, and insulin resistance is the primary risk factor for type 2 diabetes. Here we show that lipocalin-13 (LCN13), a lipocalin superfamily member, is a novel insulin sensitizer. LCN13 was secreted by multiple cell types. Circulating LCN13 was markedly reduced in mice with obesity and type 2 diabetes. Three distinct approaches were used to increase LCN13 levels: LCN13 transgenic mice, LCN13 adenoviral infection, and recombinant LCN13 administration. Restoration of LCN13 significantly ameliorated hyperglycemia, insulin resistance, and glucose intolerance in mice with obesity. LCN13 enhanced insulin signaling not only in animals but also in cultured adipocytes. Recombinant LCN13 increased the ability of insulin to stimulate glucose uptake in adipocytes and to suppress hepatic glucose production (HGP) in primary hepatocyte cultures. Additionally, LCN13 alone was able to suppress HGP, whereas neutralization of LCN13 increased HGP in primary hepatocyte cultures. These data suggest that LCN13 regulates glucose metabolism by both insulin-dependent and insulin-independent mechanisms. LCN13 and LCN13-related molecules may be used to treat insulin resistance and type 2 diabetes.     

Association of the -112A>C polymorphism of the uncoupling protein 1 gene with insulin resistance in Japanese individuals with type 2 diabetes

The -112A>C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) has been associated with type 2 diabetes mellitus in Japanese individuals. The aim of the present study was to investigate the effects of this polymorphism, as well as the well-known -3826A>G polymorphism (rs1800592), on clinical characteristics of type 2 diabetes. We determined the genotypes of the two polymorphisms in 93 Japanese patients with type 2 diabetes. Intramyocellular lipid content and hepatic lipid content (HLC) were measured by magnetic resonance spectroscopy. No significant differences in age, sex, BMI, or HbA1c level were detected between type 2 diabetic patients with the -112C allele and those without it. However, homeostasis model assessment for insulin resistance (p=0.0089) and HLC (p=0.012) was significantly greater in patients with the -112C allele. We did not detect an association of the -3826A>G polymorphism (rs1800592) of UCP1 gene with any measured parameters. These results suggest that insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes.     

Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions

Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.     

Effect of Family History of Type 2 Diabetes on White Blood Cell Count in Adult Women

Objective: To evaluate the effect of a first‐degree family history of type 2 diabetes on white blood cell (WBC) count, a risk factor for atherosclerotic vascular disease, in glucose‐tolerant adult women Research Methods and Procedures: WBC count was measured in 174 normal weight, overweight, and obese female offspring of type 2 diabetic patients (FH⁺) and 174 age‐ and BMI‐matched female controls with no family history of type 2 diabetes (FH^?). Other measurements included fat mass (FM), measured by body impedance analysis; central fat accumulation, evaluated by waist circumference; insulin resistance, estimated by homeostatic model assessment for insulin resistance (HOMA_IR); systolic and diastolic blood pressure; and fasting concentrations of glucose, insulin, and lipids. Results: WBC count, waist circumference, systolic blood pressure, and fasting levels of glucose, insulin, and triglycerides were significantly higher in FH⁺ than in FH^? subjects. In FH⁺ individuals, WBC count was positively associated with BMI, FM, waist circumference, HOMA_IR, and triglyceride and insulin concentrations, and negatively correlated with age and high‐density lipoprotein‐cholesterol. In FH^? subjects, WBC count was directly associated with BMI, FM, waist circumference, and triglyceride and insulin concentrations, and inversely correlated with age and high‐density lipoprotein‐cholesterol. After multivariate analyses, WBC count maintained a significant association with age, systolic blood pressure, and HOMA_IR in FH⁺ subjects and with age, BMI, FM, and triglycerides in FH^? individuals. Discussion: This study indicates that WBC count is increased in adult women with genetic predisposition to type 2 diabetes, and its main correlates are insulin resistance in FH⁺ and adiposity in FH^? individuals.     

Type 2 diabetes in childhood: the American perspective

The incidence of type 2 diabetes mellitus is steadily escalating throughout the world in people from a wide range of ethnic groups and all social and economic levels. Type 2 diabetes is no longer a disease only of adults: parallel with the global epidemic of type 2 diabetes in adults, an 'emerging epidemic' of type 2 diabetes has been observed in youth over the last decade. Research and clinical experience in adults have established that insulin resistance is a major risk factor for type 2 diabetes. However, insulin resistance alone is not sufficient to cause diabetes, which will develop only when insulin secretion by the beta-cells fails. This review discusses the recent emergence of type 2 diabetes in children and adolescents, its risk factors, pathophysiologic mechanisms and treatment modalities.     

Accumulation of autophagosomes contributes to enhanced amyloidogenic APP processing under insulin-resistant conditions

Alzheimer disease (AD) is sometimes referred to as type III diabetes because of the shared risk factors for the two disorders. Insulin resistance, one of the major components of type II diabetes mellitus (T2DM), is a known risk factor for AD. Insulin resistance increases amyloid-β peptide (Aβ) generation, but the exact mechanism underlying the linkage of insulin resistance to increased Aβ generation in the brain is unknown. In this study, we investigated the effect of insulin resistance on amyloid β (A4) precursor protein (APP) processing in mice fed a high-fat diet (HFD), and diabetic db/db mice. We found that insulin resistance promotes Aβ generation in the brain via altered insulin signal transduction, increased BACE1/β-secretase and γ-secretase activities, and accumulation of autophagosomes. Using an in vitro model of insulin resistance, we found that defects in insulin signal transduction affect autophagic flux by inhibiting the mechanistic target of rapamycin (MTOR) pathway. The insulin resistance-induced autophagosome accumulation resulted in alteration of APP processing through enrichment of secretase proteins in autophagosomes. We speculate that the insulin resistance that underlies the pathogenesis of T2DM might alter APP processing through autophagy activation, which might be involved in the pathogenesis of AD. Therefore, we propose that insulin resistance-induced autophagosome accumulation becomes a potential linker between AD and T2DM.