Melvin J. Prince

Bed-rest-induced insulin resistance occurs primarily in muscle

Treatment of trauma victims and patients with severe illness may contribute to their metabolic derangements by severely restricting physical activity. We sought to quantitate the impact of absolute bed rest alone on insulin regulation of glucose metabolism in six healthy subjects. Six to seven days of strict bed rest resulted in moderate deterioration in oral glucose tolerance and increased both fasting plasma insulin concentration and the insulin response to an oral glucose challenge by more than 40%. Euglycemic insulin clamp studies demonstrated the development of resistance to insulins stimulation of whole-body glucose utilization. This change was characterized by a rightward shift of the insulin dose-response curve (insulin concentration at which 50% of maximal stimulation occurred was 45 +/- 3 (SE) microU/mL in the base line period and 78 +/- 8 microU/mL after seven days of bed rest, P less than .01) with little alteration in the maximal response in the rate of glucose uptake (baseline 15.4 +/- 1.4 mg/kg.min and bed rest 14.0 +/- 1.3 mg/kg.min). In contrast to the shift of sensitivity of whole-body glucose utilization to insulin, suppression of hepatic glucose output by insulin was unchanged by seven days of bed rest. Insulin binding to circulating mononuclear cells was not changed by bed rest. These studies demonstrate that the limited physical activity dictated by bed rest for as little as seven days is associated with substantial resistance to insulins effects on glucose metabolism. Further, the data suggest that these effects occur primarily in skeletal muscle with little change in insulin action on the liver.

Hyperphosphatemic Tumoral Calcinosis: Association with Elevation of Serum 1,25-Dihydroxycholecalciferol Concentrations

Seven siblings with hyperphosphatemic tumoral calcinosis were studied using metabolic measures. Serum phosphorus and 1, 25-dihydroxycholecalciferol concentrations were significantly increased and serum parathyroid hormone and 25-hydroxycholecalciferol concentrations were significantly decreased in these subjects. Metabolic balance studies done in three of the siblings showed positive calcium and phosphorus balances, reflected by increased gastrointestinal absorption and decreased renal excretion. These data suggest that a hereditary abnormality of vitamin D metabolism may be present in patients with hyperphosphatemic tumoral calcinosis. Failure of the normal feedback mechanism regulating the 25-hydroxy-1-alpha-hydroxylase enzyme is suggested as the major cause. Although this defect could lead to many of the metabolic abnormalities seen in these patients, the overall contribution of altered vitamin D metabolism to the pathogenesis of tumoral calcinosis is not fully understood.

Insulin resistance with acanthosis nigricans: The roles of obesity and androgen excess☆

The roles of hyperandrogenemia and obesity in the syndrome of severe insulin resistance with acanthosis nigricans were evaluated in studies of 11 females with this condition. Our results in these subjects were compared to evaluations of control subjects matched for degree of androgen excess or obesity. Fasting insulin levels were 3-, 5-, and 15-fold higher in the obese (OB), hyperandrogenemic (HO), and acanthosis nigricans (AN) groups, respectively, when compared to normal females. Responsiveness to a standard bolus of exogenous insulin was 78% of normal in the OB group, 40% of normal in the HO group, and 30% of normal in the AN group. Insulin binding to monocytes from both the OB group, and the HO group was modestly diminished primarily due to decreased receptor number. As a group, AN subjects when compared to either normal or weight-matched controls, demonstrated a significant decrease in monocyte insulin binding predominantly due to a decrease in receptor number. However, two patients in the AN group had normal insulin binding suggesting a postreceptor mechanism for the insulin resistance in at least some of these subjects. In vivo glucose utilization insulin dose response curves were determined in 3 acanthotic subjects using the euglycemic clamp technique. All 3 of these subjects had a right shift of the curve and diminished maximal utilization, consistent with combined receptor and postreceptor defects in insulin action. In evaluating the relationship between hyperandrogenemia, insulin resistance, and acanthosis nigricans, significant correlations among basal levels of plasma insulin, and both testosterone and androstenedione were demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Obesity, acanthosis nigricans, insulin resistance, and hyperandrogenemia: Pediatric perspective and natural history

We studied the syndrome of acanthosis nigricans, obesity, insulin resistance, and hyperandrogenemia in 22 patients. Although isolated case reports in adolescents have appeared, this syndrome has not received full recognition as a pediatric entity. Our patients (17 girls, five boys) had a mean weight 5.7 SD above the mean for age, although mean height was only 0.5 SD above the mean for age. All patients had acanthosis nigricans. Their insulin resistance was significantly greater than that in a control group with comparable obesity. Fasting insulin concentration was 5.25 microU/ml in lean controls, 19.6 microU/ml in obese controls, and 49.8 microU/ml in study patients (P less than 0.002). Mean glucose disappearance rate during an insulin tolerance test was 6.7%/min in lean controls, 5.19%/min in obese controls, and 2.35%/min in study patients (P less than 0.02). After menarche, mean plasma testosterone concentration was 106 ng/dl, compared with less than 50 ng/dl in all lean and obese control patients. Data derived from our series of patients lead us to conclude that (1) this is a genetic syndrome, although the exact mode of inheritance is unclear; (2) the natural history of the syndrome invariably begins with the onset of obesity, followed by acanthosis nigricans that worsens with progressive weight gain; (3) acanthosis nigricans is thus a marker for hyperinsulinemia, which occurs before hyperandrogenemia; (4) hyperandrogenemia occurs only after menarche. Identification of this syndrome should permit monitoring for the development of hyperandrogenemia during puberty and determination of other affected family members.

Acanthosis nigricans and obesity: Acquired and intrinsic defects in insulin action

Six obese, severely acanthotic females were evaluated for insulin resistance by an oral glucose tolerance test, intravenous insulin tolerance test, and insulin binding to freshly isolated monocytes, as well as studies of cultured skin fibroblasts. After baseline studies were obtained, the acanthotic subjects were maintained for 14 days on a 500 calorie diet, and the evaluations were repeated. Initial evaluation demonstrated normal glucose tolerance, but marked fasting hyperinsulinemia (57 +/- 5 microU/mL) and dramatically blunted response to exogenous insulin (KITT, 2.0%/min) when compared with five nonacanthotic weight-matched controls (insulin, 15 +/- 2 microU/mL; KITT, 5.2%/min). Monocyte insulin binding for the acanthotic group (0.251 +/- 0.050%/10(6) cells) was only 56% of the binding seen in the obese controls (0.447 +/- 0.108%). After the acanthotic females dieted for 14 days, their hyperinsulinemia and monocyte insulin binding improved, but failed to normalize. The response to exogenous insulin was unchanged and remained drastically blunted. In contrast to the normal insulin binding found in the cultured fibroblasts from the nonacanthotic obese controls, insulin binding to fibroblasts from the acanthotic group was decreased by 40%, suggesting that an intrinsic defect in insulin binding was present. Thus, we conclude that this cohort of acanthotic obese females are considerably more insulin-resistant than nonacanthotic weight-matched females. Furthermore, these studies suggest that the severe insulin resistance results from a combination of an acquired defect related to obesity and an inherent cellular defect in insulin action at, or beyond, the receptor.

Tumoral calcinosis: scintigraphic studies of an affected family

Tumoral calcinosis is a rare, familial ectopic calcification syndrome associated with hyperphosphataemia. A family in which seven of 13 siblings had demonstrable, clinical, radiological and pathological findings of tumoral calcinosis was evaluated. The purposes were to compare the efficacy of bone scintiscans with serum phosphorus determination in detecting subclinical disease early in asymptomatic siblings and to assess therapeutic results in affected family members following initiation of phosphate depletion therapy. History, physical examination, serum calcium, serum phosphorus and bone scintiscans were performed in 12 of 13 siblings. All the affected siblings had markedly elevated serum phosphorus levels and abnormal bone scintiscans while the unaffected siblings had normal serum phosphorus levels and normal bone scintiscans. All the siblings, affected and unaffected, were normocalcaemic. After initiation of phosphate depletion therapy, gross changes in the appearance of lesions were detected on bone scintiscans. Serum phosphorus levels likewise showed a modest decline, although still remaining in the hyperphosphataemic range. In conclusion, bone scintiscans and serum phosphorus determinations are equally sensitive in detecting subclinical disease. However, the scintiscans are helpful in assessing not only the extent of the disease, but also whole-body and regional changes following any therapeutic interventions.

Autophosphorylation of Cultured Skin Fibroblast Insulin Receptors From Patients With Severe Insulin Resistance and Acanthosis Nigricans

The severe insulin resistance with acanthosis nigricans seen in young women without insulin-receptor autoantibodies is characterized by hyperinsulinemia and decreased in vivo responsiveness to insulin. We evaluated the potential cellular defects in insulin-receptor binding and autophosphorylation in 12 subjects with this syndrome. When evaluated as a group, insulin binding to freshly isolated monocytes was 55% that of controls. Specific binding of insulin to skin fibroblasts in monolayer culture was 49% that of controls. Maximal insulin-stimulated receptor autophosphorylation was only 27% that of controls. Individual data demonstrated that the diminished autophosphorylation activity was out of proportion to the diminished fibroblast insulin binding in cell lines from most subjects and was <50% of the predicted activity in 6 of the 12 studied cell lines. These data are consistent with genetically determined defects leading to diminished numbers of cell surface insulin receptors with intact tyrosine kinase autophosphorylation in many of our cell lines. However, in at least half, there appeared to be an additional defect beyond insulin binding, resulting in a disproportionate decrease in insulin-sensitive phosphorylation of the insulin-receptor β-subunit.

Scintiscans of two siblings with tumoral calcinosis.

Seven of 15 siblings were affected by tumoral calcinosis, a rare ectopic calcification syndrome. Case reports and scintigraphic findings of two affected siblings are presented. Bone scintiscanning may be useful in determining both initial extent of the disease and prognosis after treatment.

Functional Characteristics of Decreased Insulin Receptors on Fibroblasts Obtained from a Subject with Severe Insulin Resistance and Acanthosis Nigricans

In a patient with severe insulin resistance and acanthosis nigricans, a decrease in the number of insulin receptors has been found on freshly isolated monocytes and cultured fibroblasts compatible with a primary or genetic decrease in cell-surface insulin receptors. To determine the functional characteristics of the remaining receptors on these cells, insulin-stimulated glucose uptake, insulin internalization, and insulin-induced receptor loss were evaluated in monolayer fibroblasts obtained from this subject. Maximal insulin stimulation of 2-deoxyglucose was markedly blunted, compatible with abnormal insulin responsiveness due to a functional impairment of the remaining receptors. In the presence of chloroquine, the acanthotic subjects fibroblasts internalized more insulin per available receptor compared with the normal cell line, suggesting an accelerated rate of insulin internalization. When the rate of insulin internalization was more directly determined by assessing the rate of appearance of acid-resistant, cell-associated radioactivity at 37°C, a similar increase in insulin internalization rate was evident. When downregulation was assessed, insulins ability to induce receptor loss in the acanthotic subjects cell line was augmented. Thus, a primary or genetic decrease in insulin receptors on cultured fibroblasts from a patient with acanthosis nigricans and insulin resistance is associated with functional impairment of the remaining receptors leading to significant alterations in ligand processing and subsequent insulin action.