To determine causes of interindividual variation in insulin requirements, we recruited 20 type 2 diabetic patients with stable glucose control and insulin doses for >1 year on combination therapy with bedtime NPH insulin and metformin. Insulin absorption (increase in free and total insulin over 8 h after a subcutaneous dose of regular insulin) and actions of intravenous (6-h 0.3 mU · kg -1 · min -1 euglycemic insulin clamp combined with [3-3 H]glucose) and subcutaneous (glucose infusion rate required to maintain isoglycemia and suppression of free fatty acids [FFAs]) insulin, liver fat content (proton spectroscopy), visceral fat (magnetic resonance imaging), weight, and body composition were determined. We found the following variation in parameters: insulin dose range 10-176 U (mean 42 U, fold variation 17.6؋) or 0.13-1.39 U/kg (0.44 U/kg, 10.7؋), absorbed insulin 10.6؋, action of subcutaneous insulin to suppress FFAs 7.5؋ and to stimulate glucose metabolism (M value) 11.5؋, body weight 67-127 kg (91 kg, 1.9؋), liver fat 2-28% (12%, 14؋), and visceral fat 179-2,053 ml (1,114 ml, 11.5؋). The amount of insulin absorbed, measured as either free or total insulin, was significantly correlated with its ability to suppress FFAs and stimulate glucose metabolism but not with the insulin dose per se. The actions of absorbed insulin were, on the other hand, significantly correlated with the daily insulin dose (r = 0.70 for action on FFAs, P < 0.001, and r = -0.61 for M value, P < 0.005). Actions of subcutaneous and intravenous insulin to suppress FFAs were significantly correlated (r = 0.82, P < 0.001, R 2 = 67%). Of the measures of adiposity, the percent hepatic fat was the parameter best correlated with the daily insulin dose (r = 0.76, P < 0.001). The percent hepatic fat was also significantly correlated with the ability of intravenous insulin to suppress endogenous glucose production (r = 0.72, P < 0.005). We conclude that the major reason for interindividual variation in insulin requirements in type 2 diabetes is the variation in insulin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitivity of endogenous glucose production to insulin. Diabetes 49:749-758, 2000

We determined whether interindividual variation in hepatic insulin sensitivity could be attributed to variation in liver fat content (LFAT) independent of obesity. We recruited 30 healthy nondiabetic men whose LFAT (determined by proton spectroscopy); intraabdominal, sc, and total (determined by magnetic resonance imaging) fat; and insulin sensitivity of endogenous glucose rate of production (R(a)) and suppression of serum FFA [euglycemic insulin clamp combined with [3-(3)H]glucose (0-300 min); insulin infusion rate, 0.3 mU/kg.min, 120-300 min] were measured. The men were divided into groups of low (mean +/- SD, 1.7 +/- 0.2%) and high (10.5 +/- 2.0%) LFAT based on their median fat content. The low and high LFAT groups were comparable with respect to age (44 +/- 2 vs. 42 +/- 2 yr), body mass index (25 +/- 1 vs. 26 +/- 1 kg/m(2) ), waist to hip ratio (0.953 +/- 0.013 vs. 0.953 +/- 0.013), maximal oxygen uptake (35.6 +/- 1.5 vs. 33.5 +/- 1.5 ml/kg.min), and intraabdominal, sc, and total fat. The high compared with the low LFAT group had several features of insulin resistance, including fasting hyperinsulinemia (7.3 +/- 0.6 vs. 5.3 +/- 0.6 mU/liter; P< 0.02, high vs. low LFAT) hypertriglyceridemia (1.4 +/- 0.2 vs. 0.9 +/- 0.1 mmol/liter; P < 0.02), a low high density lipoprotein (HDL) cholesterol concentration (1.4 +/- 0.1 vs. 1.6 +/- 0.1 mmol/liter; P < 0.05), and a higher ambulatory 24-h systolic blood pressure (130 +/- 3 vs. 122 +/- 3 mm Hg; P < 0.05). Basal glucose R(a) and serum FFA were comparable between the groups, whereas insulin suppression of glucose R(a) [51 +/- 8 vs. 20 +/- 12 mg/m(2).min during 240-300 min (P < 0.05) or -55 +/- 7 vs. -85 +/- 12% below basal (P < 0.05, high vs. low LFAT)] and of serum FFA (299 +/- 33 vs. 212 +/- 13 micromol/liter; 240-300 min; P < 0.02) were impaired in the high compared with the low LFAT group. Insulin stimulation of glucose Rd were comparable in the men with high LFAT (141 +/- 12 mg/m(2).min) and those with low LFAT (156 +/- 14 mg/m(2).min; P = NS). Fat accumulation in the liver is, independent of body mass index and intraabdominal and overall obesity, characterized by several features of insulin resistance in normal weight and moderately overweight subjects.

To examine whether and how intramyocellular lipid (IMCL) content contributes to interindividual variation in insulin action, we studied 20 healthy men with no family history of type 2 diabetes. IMCL was measured as the resonance of intramyocellular CH 2 protons in lipids/ resonance of CH 3 protons of total creatine (IMCL/Cr T ), using proton magnetic resonance spectroscopy in vastus lateralis muscle. Whole-body insulin sensitivity was measured using a 120-min euglycemic-hyperinsulinemic (insulin infusion rate 40 mU/m 2 ⅐ min) clamp. Muscle biopsies of the vastus lateralis muscle were taken before and 30 min after initiation of the insulin infusion to assess insulin signaling. The subjects were divided into groups with high IMCL (HiIMCL; 9.5 ؎ 0.9 IMCL/Cr T , n ‫؍‬ 10) and low IMCL (LoIMCL; 3.0 ؎ 0.5 IMCL/Cr T , n ‫؍‬ 10), the cut point being median IMCL (6.1 IMCL/Cr T ). The groups were comparable with respect to age (43 ؎ 3 vs. 40 ؎ 3 years, NS, HiIMCL versus LoIMCL), BMI (26 ؎ 1 vs. 26 ؎ 1 kg/m 2 , NS), and maximal oxygen consumption (33 ؎ 2 vs. 36 ؎ 3 ml ⅐ kg ؊1 ⅐ min ؊1 , NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 ؎ 0.4 mg ⅐ kg ؊1 ⅐ min ؊1 ) than the LoIMCL group (5.1 ؎ 0.5 mg ⅐ kg ؊1 ⅐ min ؊1 , P < 0.05). Serum free fatty acid concentrations were comparable basally, but during hyperinsulinemia, they were 35% higher in the HiIMCL group than the LoIMCL group (P < 0.01). Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. IR substrate-1-associated phosphatidylinositol (PI) 3-kinase activation by insulin was also lower in the HiIMCL group than in the LoIMCL group (49 ؎ 23 vs. 84 ؎ 27% above basal, A bnormal lipid metabolism is a feature of the insulin resistance syndrome (1). In addition to an increase in the total amount of fat, the lipid disturbances include elevated circulating concentrations of triglycerides and free fatty acids (FFAs) (2) and an increase in visceral fat (3). Recently, several studies have shown an association between lipid accumulation in skeletal muscle and insulin resistance (4 -10). In four of these studies, this relation was shown to be caused by intramyocellular rather than extramyocellular lipids, as measured by proton spectroscopy (5-7,11).The causes for intramyocellular lipid (IMCL) accumulation are poorly understood. The first possibility is that IMCL is an innocent bystander and simply reflects overall adiposity. This is not supported by recent experiments in mice lacking subcutaneous fat, the A-ZIP/F-1 mice (12,13). These mice deposit fat intramyocellularly and exhibit severe insulin resistance, which is reversible by fat transplantation and rechanneling of IMCL back to subcutaneous depots. In humans, however, it is less clear whether IMCL is associated with insulin resistance independent of obesity. In 20 Europeans, Forouhi et al. (6) found the rela...

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No abstract

Our findings suggest that the development of liver fibrosis is associated with insulin resistance in HCV-infected patients.

Non-alcoholic steatohepatitis (NASH) is a term used to describe a spectrum of conditions characterized by histological findings of hepatic macrovesicular steatosis with inflammation in individuals who consume little or no alcohol. The NASH patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice (PTEN-deficient mice), which the authors had generated previously, showed massive hepatomegaly and steatohepatitis with triglyceride accumulation followed by liver fibrosis and HCC, a phenotype similar to human NASH. Therefore, it was shown that PTEN deficiency in hepatocytes could induce hepatic steatosis, inflammation, fibrosis and tumors and that PTEN-deficient mice were a useful animal model for not only the understanding of the pathogenesis of NASH but also the development of treatment for NASH.

A 57-year-old woman in Japan, the first recipient of part of a liver from a 58-year-old man with familial amyloidotic polyneuropathy (FAP) amyloidogenic transthyretin Val30Met who had had sensorimotor polyneuropathy in the lower limbs for 3 years, started to develop sensory neuropathy 7 years after transplantation. Before the July 1998 sequential transplantation, she had been in a hepatic coma at the terminal stage of primary biliary cirrhosis and waiting for deceased donor liver transplantation. In September 2004, biopsy samples of her duodenum first showed amyloid deposition. Although biopsy materials in 2005 and 2006 showed no changes in amyloid deposition, decreased temperature sensation and pain in fingertips and toes were detected at a neurologic examination in March 2006. Thus, clinical symptoms of FAP appeared about 2 years after amyloid deposition started. Nerve conduction velocity studies revealed mild to moderate axonal sensory polyneuropathy without demyelination. Our findings confirmed iatrogenic sensory neuropathy induced by amyloid deposition 7 years after sequential liver transplantation.