Changes in insulin sensitivity over time and associated factors in HIV-infected adolescents

OBJECTIVE: To compare prevalence of insulin resistance between perinatally HIV-infected (PHIV+) and perinatally HIV-exposed, but uninfected adolescents (PHEU), determine incidence of and contributory factors to new and resolved cases of insulin resistance in PHIV+, and evaluate glucose metabolism. DESIGN: Cross-sectional design for comparison of prevalence among PHIV+ and PHEU. Longitudinal design for incidence and resolution of insulin resistance among PHIV+ at risk for these outcomes. METHODS: The source population was adolescents from pediatric HIV clinics in the United States and Puerto Rico participating in the Pediatric HIV/AIDS Cohort Study, an ongoing prospective cohort study designed to evaluate impact of HIV infection and its treatment on multiple domains in preadolescents and adolescents. Insulin resistance was assessed by homeostatic model assessment of insulin resistance. Those with incident insulin resistance underwent 2-h oral glucose tolerance test and HbA1c. Baseline demographic, metabolic, and HIV-specific variables were evaluated for association with incident or resolved insulin resistance. RESULTS: Unadjusted prevalence of insulin resistance in PHIV+ was 27.3 versus 34.1% in PHEU. After adjustment for Tanner stage, age, sex, and race/ethnicity, there was no significant difference between groups. Factors positively associated with developing insulin resistance included female sex, higher BMI z score, and higher waist circumference; those associated with resolving insulin resistance included male sex and lower BMI z score. CONCLUSION: Prevalence of insulin resistance in PHIV+ and PHEU was substantially higher than that reported in HIV-uninfected nonoverweight youth, but similar to that in HIV-uninfected obese youth. Factors associated with incident or resolved insulin resistance among PHIV+ were similar to those reported in HIV-negative obese youth. However, a contributory role of HIV infection and/or its treatment to the incident risk of insulin resistance cannot be excluded

Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1.

Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pM/kg) or high (100 pM/kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early and late fasted seals; however the timing of the signaling response was blunted in adipose of late fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation

Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study

Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to determine whether their insulin resistance was reversible. Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03), lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by the Helsinki heart study). Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk

Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, p = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation

Helicobacter pylori infection and insulin resistance in diabetic and nondiabetic population

Helicobacter pylori (HP) is a common worldwide infection with known gastrointestinal and nongastrointestinal complications. One of the gastrointestinal side effects posed for this organism is its role in diabetes and increased insulin resistance. The aim of this study was to evaluate the association between HP and insulin resistance in type 2 diabetic patients and nondiabetics. This cross-sectional study was carried out from May to December 2013 on 211 diabetic patients referred to diabetes clinic of Shahid Beheshti Hospital of Qom and 218 patients without diabetes. HP was evaluated using serology method and insulin resistance was calculated using HOMA-IR. The prevalence of H. pylori infection was 55.8% and 44.2% in diabetics and nondiabetics (P=0.001). The study population was divided into two HP positive and negative groups. Among nondiabetics, insulin resistance degree was 3.01±2.12 and 2.74±2.18 in HP+ and HP- patients, respectively P=0.704. Oppositely, insulin resistance was significantly higher in diabetic HP+ patients rather than seronegative ones (4.484±2.781 versus 3.160±2.327, P=0.013). In diabetic patients, in addition to higher prevalence of HP, it causes a higher degree of insulin resistance. © 2014 Jamshid Vafaeimanesh et al

The novel adiponectin-resistin (AR) and insulin resistance (IR~AR~) indexes

Serum hypoadiponectinemia and hyperrestinemia independently links insulin resistance to type 2 diabetes (T2DM) and metabolic syndrome (MS). Thus, the aim of this study was propose a novel adiponectin-resistin (AR) index by unifying the effect of adiponectin and resistin. Then, a novel insulin resistance (IR~AR~) index was proposed by taking into account the AR index. Serum adiponectin and resistin levels as well as other insulin resistance, T2DM and MS risk factors were tested. Experimental results showed the AR index was more stronger correlated with insulin resistance risk factors and had stronger association (df=5; F=51.154; P<0.001) with T2DM and MS susceptibility rather than the serum adiponectin (df=5; F=15.680; P<0.001) and resistin (df=5; F=40.648; P<0.001) levels alone. Therefore, the AR index looks very strongly links insulin resistance to T2DM and MS. Meanwhile, the IR~AR~ index (df=5; F=78.396; P<0.001) is a potent useful index of insulin sensitivity in subjects with T2DM and MS

Insulin Resistance: From Theory To Practice

Insulin resistance is at the core of the well recognised metabolic syndrome and possibly many other ailments commonly seen in the modern society. While the quantification of insulin resistance remains a difficult task, the problems associated with it are increasing in epidemic proportions. Need of the hour therefore is to develop concise dietary and pharmacotherapeutic guidelines for prevention and management of insulin resistanc

Deficiency of the bone mineralization inhibitor NPP1 protects against obesity and diabetes

The emergence of bone as an endocrine regulator has prompted a re-evaluation of the role of bone mineralization factors in the development of metabolic disease. Ectonucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) controls bone mineralization through the generation of pyrophosphate, and levels of NPP1 are elevated both in dermal fibroblast cultures and muscle of individuals with insulin resistance. We investigated the metabolic phenotype associated with impaired bone metabolism in mice lacking the gene that encodes NPP1 (Enpp1−/− mice). Enpp1−/− mice exhibited mildly improved glucose homeostasis on a normal diet but showed a pronounced resistance to obesity and insulin resistance in response to chronic high-fat feeding. Enpp1−/− mice had increased levels of the insulin-sensitizing bone-derived hormone osteocalcin but unchanged insulin signalling within osteoblasts. A fuller understanding of the pathways of NPP1 could inform the development of novel therapeutic strategies for treating insulin resistance

Hyperinsulinemia and insulin resistance : What comes first ?

Background

1)	Classical explanation :
Classical explanation of diabetic pathophysiology states that obesity induced insulin resistance develops first and is followed by compensatory hyperinsulinnemia. Further insulin resistance leads to prolonged, increased secretary demand on beta cells leading to subsequent secondary beta cell failure, giving rise to hyperglycaemia and diabetes^2^.

2)	 Neurobehavioral origin hypothesis :
The Neurobehavioral origin hypothesis suggests that insulin resistance mediates a shift from muscle dependent (soldier) to brain dependent (diplomat) strategies of making a livelihood. If nutrient limitation affects intrauterine development, brain development is the least affected among all the organs^4,5^. As a result, in IUGR babies muscle weight is poor but the brain is relatively well developed. Such a person is more likely to be a successful diplomat rather than a soldier and insulin resistance is adaptive for such an individual^3^. Since insulin is involved in brain development and cognitive functions, higher levels of insulin are needed. As insulin is having strong anti-lipolytic effect, hyperinsulinnemia is followed by subsequent excess fat accumulation. Also compensatory insulin resistance is needed to avoid hypoglycemia. This hypothesis predicts a reverse order of pathophysiology i.e. primary hyperinsulinnemia followed by compensatory insulin resistance^3^

Objective-
To determine in diabetes whether hyperinsulinnemia develops first or insulin resistance develops first.

Methods :
We searched literature for studies that investigated directly or indirectly the sequence of development of hyperinsulinnemia and insulin resistance in humans and animal models from an early stage. Meta-analysis was conducted on published data.

Results-
1)	In low birth weight neonates in humans as well as in rat models, hyperinsulinnemia is found at very early stage.^6^
2)	Development of insulin resistance is preceded by hyperinsulinnemia in mice, rats as well as in humans.^7, 8^
3)	In normoglycaemic hyperinsulinemia state if insulin production is suppressed insulin sensitivity increases rapidly maintaining the normoglycaemic state.^9,10^
4)	Beta cell expansion beginning in intrauterine life is independent of glucose, Insulin and Insulin receptors.^6^


Conclusion-
All the four lines of evidence indicate that hyperinsulinnemia precedes insulin resistance supporting the predictions of neurobehavioral origin hypothesis over the orthodox view.



References :
1)	DeFronzo RA, Ferrannini E (1991). Diabetes Care 14:173-194
2)	Kruszynska YT, Olefsky JM (1996). J Investig Med 44: 413-428.
3)	Watve MG, Yajnik CY (2007). BMC Evolutionary Biology.7: 61-74.
 4) Winick M, Rosso P, Waterlow JC (1970). Exp Neurol, 26:393-400.
 5) Winick M. (1969) J Pediatr,74:667-679.
 6) Chakravarthy MV et.al. (2008) Diabetes, 57:2698-2707.
 7) Ramin A et. al. (1998) J Clin Endo and Met, 83 :1911-1915.
 8) Hansen BC (1990) Am J Physiol Regul Integr Comp Physiol 259: 612-617.
 9) Stanley L (1981) Life Sciences, 28: 1829-1840.
 10) Ratzmann KP et. al. (1983) Int J Obes, 7 : 453-458

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Adipocyte JAK2 Regulates Hepatic Insulin Sensitivity Independently of Body Composition, Liver Lipid Content, and Hepatic Insulin Signaling.

Disruption of hepatocyte growth hormone (GH) signaling through disruption of Jak2 (JAK2L) leads to fatty liver. Previously, we demonstrated that development of fatty liver depends on adipocyte GH signaling. We sought to determine the individual roles of hepatocyte and adipocyte Jak2 on whole-body and tissue insulin sensitivity and liver metabolism. On chow, JAK2L mice had hepatic steatosis and severe whole-body and hepatic insulin resistance. However, concomitant deletion of Jak2 in hepatocytes and adipocytes (JAK2LA) completely normalized insulin sensitivity while reducing liver lipid content. On high-fat diet, JAK2L mice had hepatic steatosis and insulin resistance despite protection from diet-induced obesity. JAK2LA mice had higher liver lipid content and no protection from obesity but retained exquisite hepatic insulin sensitivity. AKT activity was selectively attenuated in JAK2L adipose tissue, whereas hepatic insulin signaling remained intact despite profound hepatic insulin resistance. Therefore, JAK2 in adipose tissue is epistatic to liver with regard to insulin sensitivity and responsiveness, despite fatty liver and obesity. However, hepatocyte autonomous JAK2 signaling regulates liver lipid deposition under conditions of excess dietary fat. This work demonstrates how various tissues integrate JAK2 signals to regulate insulin/glucose and lipid metabolism