Melissa K. Cavaghan

Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

Subjects who develop type 2 diabetes have a complex phenotype with defects in insulin secretion, increased hepatic glucose production, and resistance to the action of insulin, all of which contribute to the development of overt hyperglycemia. Although the precise mechanisms whereby these three factors interact to produce glucose intolerance and diabetes are uncertain, it has been suggested that the final common pathway responsible for the development of type 2 diabetes is the failure of the pancreatic β cell to compensate for insulin resistance (1). Here, we review evidence for this model from both human and animal studies, and we consider the effects of specific drug treatments and of heightened FFA levels on insulin sensitivity and insulin secretion in individuals at risk for type 2 diabetes. Coleman and coworkers (2), drawing on their work with the ob/ob mouse, first proposed that a failure of β-cell compensation for insulin resistance is responsible for the development of type 2 diabetes. When insulin-resistant ob/ob mice, which provide a genetic model of obesity, were bred with mice of different strains, the phenotypes of the progeny differed depending on their genetic background. Mice carrying the ob mutation in the C57BL/6 background had relatively normal blood glucose levels, whereas in the C57Ks background the animals developed overt hyperglycemia. The major difference between these two mouse strains lay in their β-cell responses. The nondiabetic C57BL/6 mice underwent a marked expansion of β-cell mass, whereas C57Ks animals showed histologic evidence of islet degeneration, degranulation, and progressive atrophy. The C57Ks animals accordingly had insulin levels about one-tenth those of the C57BL/6 animals, and these levels declined progressively with age. These data indicated that the genetic background on which insulin resistance develops influences the adequacy of pancreatic β-cell compensation for insulin resistance, and hence the predisposition to diabetes.

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.

Insulin secretory responses to rising and falling glucose concentrations are delayed in subjects with impaired glucose tolerance.

Aims/hypothesis. We hypothesized that beta-cell responses to changes in glucose would not be normal in subjects with impaired glucose tolerance (IGT). Methods. Three groups of 6 subjects were studied: normal weight with normal glucose tolerance (control subjects); obese with normal glucose tolerance (Obese-NGT); and obese with IGT (Obese-IGT). All subjects had a graded glucose infusion protocol to increase (step-up) and then decrease (step-down) plasma glucose. We obtained average insulin-secretion rates (ISR) over the glucose range common to all three groups during step-up and step-down phases, minimal model indices of beta-cell function (fb, fd, fs, Tup, Tdown ), and insulin sensitivity (Si). Results. ISR differed significantly between step-up and -down phases only in Obese-IGT individuals. Basal (fb) and stimulated (fd, fs) beta-cell sensitivity to glucose were similar in the three groups. Delays between glucose stimulus and beta-cell response during both step-up (Tup) and -down (Tdown) phases were higher in Obese-IGT compared to Controls and Obese-NGT individuals. The product ISR × Si (10–5·min–2× l) was lower in Obese-IGT compared to Controls, both during step-up (919 ± 851 vs 3192 ± 1185, p < 0.05) and step-down (1455 ± 1203 vs 3625 ± 691, p < 0.05) phases. Consistently, the product fs× Si (10–14·min–2· pmol–1× l) was lower in Obese-IGT than in control subjects (27.6 ± 25.4 vs 103.1 ± 20.2, p < 0.05). Conclusion/interpretation. Subjects with IGT are not able to secrete insulin to compensate adequately for insulin resistance. They also show delays in the timing of the beta-cell response to glucose when glucose levels are either rising or falling. [Diabetologia (2002) 45: ▪–▪]

PITuITARy MACROADENOMA IN A PATIENT WITH POEMS SyNDROME IN CONJuNCTION WITH CASTlEMAN DISEASE: FIRST REPORT OF A CASE AND REVIEW OF RElATED lITERATuRE

OBJECTIVE To describe the first reported case of a patient with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) in conjunction with the endocrinologic manifestation of panhypopituitarism due to a large clinically nonfunctioning pituitary adenoma. METHODS We present the clinical, laboratory, and radiologic details of the case and review the relevant updated literature. RESULTS A 48-year-old man with hypopituitarism and progressive polyneuropathy presented to an outside hospital with confusion and diaphoresis. He also had diffuse lymphadenopathy, monoclonal gammopathy, and skin lesions consistent with a diagnosis of POEMS syndrome. Cytopathologic study of a lymph node showed findings consistent with Castleman disease. A large suprasellar mass was found to be the cause of the hypopituitarism. CONCLUSION POEMS syndrome is a rare paraneoplastic condition, commonly associated with Castleman disease, that manifests with progressive distal polyneuropathy and a monoclonal plasma cell disorder, often accompanied by endocrinopathy, organomegaly, skin changes, sclerotic bone lesions, ascites, erythrocytosis, and thrombocytosis. Our current patient had all 5 classic features of POEMS syndrome along with some diagnostic elements of Castleman disease, sclerotic bone lesions, and thrombocytosis. To our knowledge, this is the first known reported case of a patient whose endocrinologic manifestation of POEMS syndrome was panhypopituitarism attributable to a large clinically nonfunctioning pituitary adenoma.