Insulin resistance occurs frequently in metabolic syndrome components, obesity, and the polycystic ovary syndrome, and is partly due to impaired glucose transport into skeletal muscle, but underlying mechanisms are uncertain. Atypical protein kinase C and protein kinase B, operating downstream of phosphatidylinositol 3-kinase, mediate insulin effects on glucose transport, but their importance in these syndromes is poorly understood. Presently, we examined these signaling factors in muscle biopsies obtained during euglycemic/hyperinsulinemic clamp studies. In lean subjects, insulin provoked approximately twofold increases in muscle atypical protein kinase C activity. In obese subjects and obese subjects who had evidence of the polycystic ovary syndrome, insulin-stimulated glucose disposal and atypical protein kinase C activation were diminished, whereas activation of insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase and protein kinase B trended lower, but not significantly. Interestingly, direct activation of atypical protein kinase C by phosphatidylinositol-3,4,5-(PO(4))(3), the lipid product of phosphatidylinositol 3-kinase, was readily apparent in immunoprecipitates prepared from muscles of lean subjects, but to a lesser degree or poorly if at all in subjects who were obese or had the obesity/polycystic ovary syndrome. Our findings suggest that activation of muscle atypical protein kinase C by insulin and phosphatidylinositol-3,4,5-(PO(4))(3) is defective and may contribute to skeletal muscle insulin resistance in women who are obese, or have obesity associated with the polycystic ovary syndrome.

Insulin resistance in type 2 diabetes is partly due to impaired glucose transport in skeletal muscle. Atypical protein kinase C (aPKC) and protein kinase B (PKB), operating downstream of phosphatidylinositol (PI) 3-kinase and its lipid product, PI-3,4,5-(PO(4))(3) (PIP(3)), apparently mediate insulin effects on glucose transport. We examined these signaling factors during hyperinsulinemic-euglycemic clamp studies in nondiabetic subjects, subjects with impaired glucose tolerance (IGT), and type 2 diabetic subjects. In nondiabetic control subjects, insulin provoked twofold increases in muscle aPKC activity. In both IGT and diabetes, aPKC activation was markedly (70-80%) diminished, most likely reflecting impaired activation of insulin receptor substrate (IRS)-1-dependent PI 3-kinase and decreased ability of PIP(3) to directly activate aPKCs; additionally, muscle PKC-zeta levels were diminished by 40%. PKB activation was diminished in patients with IGT but not significantly in diabetic patients. The insulin sensitizer rosiglitazone improved insulin-stimulated IRS-1-dependent PI 3-kinase and aPKC activation, as well as glucose disposal rates. Bicycle exercise, which activates aPKCs and stimulates glucose transport independently of PI 3-kinase, activated aPKCs comparably to insulin in nondiabetic subjects and better than insulin in diabetic patients. Defective aPKC activation contributes to skeletal muscle insulin resistance in IGT and type 2 diabetes, rosiglitazone improves insulin-stimulated aPKC activation, and exercise directly activates aPKCs in diabetic muscle.

A 41-year-old woman who had undergone transfrontal craniotomy for a pituitary tumor 4 months before presentation was admitted with confusion and orientation only to self. She had a fever of 40 degrees C. Serum sodium and chloride levels on admission were 180 and 139 mEq/L, respectively. Measured serum osmolality was 380 mOsmol/L with a urine osmolality of 360 mOsmol/L. Magnetic resonance imaging revealed a 1.5-cm mass in the sella turcica, which was nonfunctioning on endocrine evaluation. The "bright spot" of a normal posterior pituitary was absent. Central diabetes insipidus was confirmed by a 300% increase in urine osmolality with desmopressin. The patient survived her severe hypernatremia, which has 70% mortality with a serum sodium level of 160 mEq/L or above. However, she developed permanent (6 months) disorientation to time and place even when hypernatremia was corrected, which has not been described previously.

A 67-year old man with a 3-month history of left hip pain had a history of Graves disease, treated with 131I 20 years before admission, and papillary thyroid carcinoma, treated with cervical lymphadenopathy 9 years before admission. Removal of a 3.5- x 5-cm mass from the left femur revealed it to be a tall cell variant of papillary thyroid carcinoma. Removal of this mass resulted in his thyrotropin level increasing from 2 (presurgery) to 23 mIU/mL, whereas his thyroxine level simultaneously decreased from 5.79 (presurgery) to 2.29 microg/dL 12 days after surgery despite continuation of levothyroxine of 0.137 mg/day. On histological examination, the tall cell variant in the femur was producing abundant thyroglobulin. This first case of a metastatic papillary thyroid carcinoma in bone producing thyroid hormone to the extent that the patient became hypothyroid after removal of this metastasis illustrates that metastatic thyroid lesion(s) may produce significant amounts of thyroid hormone.