We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are involved in the synthesis of a putative hormone referred to as hepatic insulin-sensitizing substance HISS. Insulin action was assessed in Wistar rats using the rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)-nitro-l-arginine methyl ester (l-NAME, 1.0 mg/kg intraportal) decreased insulin sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3 +/- 10.1 mg glucose/kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/- 44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not after intraportal sodium nitroprusside (20 nmol x kg(-1) x min(-1)), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor l-buthionine-[S,R]-sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by 39.1%. Insulin sensitivity after l-NAME was not significantly different between BSO- and sham-treated animals. SIN-1 did not reverse the insulin resistance induced by l-NAME in the BSO-treated group. These results support our hypothesis that NO and GSH are essential for insulin action.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most prevalent cause of liver disease worldwide and afflicts adults and children as currently associated with obesity and insulin resistance. Even though lately some advances have been made to elucidate the mechanism and causes of the disease much remains unknown about NAFLD. The aim of this paper is to discuss the present knowledge regarding the pathogenesis of the disease aiming at the initial steps of NAFLD development, when inflammation impinges on fat liver deposition. At this stage, the Kupffer cells attain a prominent role. This knowledge becomes subsequently relevant for the development of future diagnostic, prevention, and therapeutic options for the management of NAFLD.

Obesity is a major risk factor for developing nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common form of chronic liver disease and is closely associated with insulin resistance, ultimately leading to cirrhosis and hepatocellular carcinoma. However, knowledge of the intracellular regulators of obesity-linked fatty liver disease remains incomplete. Here we showed that hepatic Rho-kinase 1 (ROCK1) drives obesity-induced steatosis in mice through stimulation of de novo lipogenesis. Mice lacking ROCK1 in the liver were resistant to diet-induced obesity owing to increased energy expenditure and thermogenic gene expression. Constitutive expression of hepatic ROCK1 was sufficient to promote adiposity, insulin resistance, and hepatic lipid accumulation in mice fed a high-fat diet. Correspondingly, liver-specific ROCK1 deletion prevented the development of severe hepatic steatosis and reduced hyperglycemia in obese diabetic (ob/ob) mice. Of pathophysiological significance, hepatic ROCK1 was markedly upregulated in humans with fatty liver disease and correlated with risk factors clustering around NAFLD and insulin resistance. Mechanistically, we found that hepatic ROCK1 suppresses AMPK activity and a ROCK1/AMPK pathway is necessary to mediate cannabinoid-induced lipogenesis in the liver. Furthermore, treatment with metformin, the most widely used antidiabetes drug, reduced hepatic lipid accumulation by inactivating ROCK1, resulting in activation of AMPK downstream signaling. Taken together, our findings establish a ROCK1/AMPK signaling axis that regulates de novo lipogenesis, providing a unique target for treating obesity-related metabolic disorders such as NAFLD.

Highlights A 1-hour plasma glucose (1-h PG) threshold >155 mg/dl (8.6 mmol/L) during an oral glucose tolerance test (OGTT) may be a suitable biomarker for identifying normal glucose tolerant (NGT) individuals at risk for future type 2 diabetes (T2D). A one-hour, non-fasting, 50g Glucose Challenge Test (GCT) performed during a routine health care visit has potential for practical screening of glucose disorders. The shape of the glucose curve reflects the cumulative effect of insulin sensitivity and response on glucose concentrations with prospective studies warranted to evaluate its prognostic utility. The continuous glucose monitor (CGM) has facilitated insight into the pathophysiology of prediabetes and phenotypes of T2D and holds promise for detecting glycemic disorders. Metabolomic profiling including amino acids, lipids, carbohydrates and other metabolites may be useful for early diagnosis of glycemic disorders. Non-classical markers for assessing glycemic disorders including fructosamine, glycated albumin, and 1,5-anhydroglucitol that evaluate shorter periods of glucose exposure than HbA1c have potential use as adjunctive tools.

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A rapid insulin sensitivity test (RIST) was recently introduced to assess insulin action in vivo (H. Xie, L. Zhu, Y.L. Zhang, D.J. Legare, and W.W. Lautt. J. Pharmacol. Toxicol. Methods, 35: 77-82. 1996). This technical report describes the current recommended standard operating procedure for the use of the RIST in rats based upon additional experience with approximately 100 tests. We describe the manufacture and use of an arterial-venous shunt that allows rapid multiple arterial samples and intravenous administration of drugs. The RIST procedure involves determination of a stable arterial glucose baseline to define the ideal euglycemic level to be maintained following a 5-min infusion of insulin, with the RIST index being the amount of glucose required to be infused to maintain euglycemia over the test period. Insulin administration by a 5-min infusion is preferable to a 30-s bolus administration. No significant difference was determined between the use of Toronto pork-beef or human insulin. Four consecutive RISTs were carried out in the same animal over 4-5 h with no tendency for change with time. The RIST index is sufficiently sensitive and reproducible to permit establishment of insulin dose-response curves and interference of insulin action by elimination of hepatic parasympathetic nerves, using atropine. This technical report provides the current recommended standard operating procedure for the RIST.

Diabetes mellitus is the most common metabolic disease, and its prevalence is increasing. A growing body of evidence, both in animal models and epidemiological studies, has demonstrated that metabolic diseases like obesity, insulin resistance, and diabetes are associated with alterations in the central nervous system (CNS), being linked with development of cognitive and memory impairments and presenting a higher risk for dementia and Alzheimer's disease. The rising prevalence of diabetes together with its increasing earlier onset suggests that diabetes-related cognitive dysfunction will increase in the near future, causing substantial socioeconomic impact. Decreased insulin secretion or action, dysregulation of glucose homeostasis, impairment in the hypothalamic-pituitary-adrenal axis, obesity, hyperleptinemia, and inflammation may act independently or synergistically to disrupt neuronal homeostasis and cause diabetes-associated cognitive decline. However, the crosstalk between those factors and the mechanisms underlying the diabetes-related CNS complications is still elusive. During the past few years, different strategies (neuroprotective and antioxidant drugs) have emerged as promising therapies for this complication, which still remains to be preventable or treatable. This Review summarizes fundamental past and ongoing research on diabetes-associated cognitive decline, highlighting potential contributors, mechanistic mediators, and new pharmacological approaches to prevent and/or delay this complication.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two age-related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidence on brain structural and functional abnormalities arising from brain insulin resistance and deficiency, ultimately highlighting the need for new approaches capable of preventing the development of AD in type 2 diabetic patients. This review provides an update on overlapping pathophysiological mechanisms and pathways in T2D and AD, such as amyloidogenic events, oxidative stress, endothelial dysfunction, aberrant enzymatic activity, and even shared genetic background. These events will be presented as puzzle pieces put together, thus establishing potential therapeutic targets for drug discovery and development against T2D and diabetes-induced cognitive decline-a heavyweight contributor to the increasing incidence of dementia in developed countries. Hoping to pave the way in this direction, we will present some of the most promising and well-studied drug leads with potential against both pathologies, including their respective bioactivity reports, mechanisms of action, and structure-activity relationships.