Insulin resistance in latent autoimmune diabetes of adulthood.

Insulin resistance in patients with latent autoimmune diabetes of adulthood (LADA) was determined by homeostasis model assessment (HOMA). LADA was identified by a clinical phenotype of type 2 diabetes with antibodies to GAD65 and/or IA-2/ICA512. All patients were managed with insulin therapy. Insulin resistance in LADA was lower than in antibody-negative type 2 diabetes, higher than in normal humans and in recent-onset type 1 diabetes, and similar to that in long-term type 1 diabetes. Mean values for HOMA varied linearly with mean values for BMI, which accounted for much of the insulin resistance in these forms of diabetes. LADA resembles long-term type 1 diabetes with respect to insulin resistance and BMI, but occurs at an older age.

Heterogeneity of nuclear lamin A mutations in Dunnigan-type familial partial lipodystrophy.

We previously identified a novel mutation, namely LMNA R482Q, that was found to underlie Dunnigan-type partial lipodystrophy (FPLD) and diabetes in an extended Canadian kindred. We have since sequenced LMNA in five additional Canadian FPLD probands and herein report three new rare missense mutations in LMNA: V440M, R482W, and R584H. One severely affected subject was a compound heterozygote for both V440M and R482Q. The findings indicated that 1) a spectrum of LMNA mutations underlies FPLD; 2) aberrant lamin A, and not lamin C, is likely to underlie FPLD, as R584H occurs within LMNA sequence that is specific for lamin A; 3) the V440M mutation may not cause lipodystrophy on its own; 4) compound heterozygosity for V440M and R482Q is associated with a relatively more severe FPLD phenotype, but not with complete lipodystrophy; and 5) variation in the severity of the phenotype might be related to environmental factors.

Factors affecting glucose tolerance in hereditary hemochromatosis.

OBJECTIVE: To determine insulin action and insulin secretory function in patients with hemochromatosis, and to find evidence for or against hypothesized pathogenetic mechanisms for the abnormal glucose metabolism associated with hemochromatosis. These mechanisms include decreased beta-cell secretion of insulin due to iron overload, insulin resistance and genetic factors. DESIGN: Prospective in vivo study. PARTICIPANTS: Seventeen subjects with hemochromatosis, of whom 4 had cirrhosis but not diabetes mellitus, 6 had diabetes mellitus and 7 had neither; 10 controls. INTERVENTIONS: Insulin sensitivity and insulin secretion were determined during an intravenous glucose tolerance test. Insulin secretion was measured as the acute insulin response to glucose (AIRg). Insulin sensitivity (Si) was quantified with the minimal-model method. Of the patients with hemochromatosis, 14 agreed to undergo a second metabolic study after treatment with venous phlebotomy. RESULTS: All subjects with hereditary hemochromatosis had impaired glucose tolerance as measured by K(g) (rate of glucose disappearance). Subjects who were free of both diabetes mellitus and liver cirrhosis had a normal S1 and a decreased AIRg. In these subjects, phlebotomy treatment normalized serum ferritin levels, increased AIRg by 35% and normalized glucose tolerance (K(g)). Subjects with hemochromatosis and cirrhosis had a reduced Si and maintained a normal insulin secretion. Phlebotomy treatment did not change these parameters. Subjects with hemochromatosis and diabetes mellitus had both a reduced Si and AIRg, and these parameters were unaffected by phlebotomy treatment. CONCLUSIONS: These results suggest that iron overload can impair insulin secretion and glucose tolerance early in hereditary hemochromatosis, before cirrhosis occurs. Phlebotomy treatment can reverse these defects. Impaired glucose tolerance resulting from insulin resistance in subjects with cirrhosis or diabetes mellitus is not affected by phlebotomy treatment.

Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM.

Effects of human glucagon-like peptide I (GLP-I)(7-36)amide were examined in volunteers having insulin-dependent diabetes mellitus (IDDM) with residual C-peptide (CP) secretion (n = 8, 7 men and 1 woman; age, 31 +/- 1.4 years; body mass index, 24.7 +/- 0.7 kg/m2; duration of diabetes, 3.2 +/- 0.8 years; insulin dose, 0.41 +/- 0.05 U.kg-1.day-1; meal-stimulated CP, 1.0 +/- 0.2 nmol/l [means +/- SE]). After a mixed meal (Sustacal, 30 kJ/kg body wt), intravenous injection of GLP-I, 1.2 pmol.kg-1.min-1 through 120 min, virtually abolished increments of plasma glucose, CP, pancreatic polypeptide (PP), and glucagon concentrations, with no significant effect on plasma gastrin levels during the infusions. At reduced dosage (0.75 pmol.kg-1.min-1), GLP-I had lesser effects on plasma glucose and CP levels. On cessation of intravenous GLP-I infusions after the meals, plasma glucose, CP, PP, and glucagon concentrations rebounded toward control levels by 180 min, and the response of plasma gastrin was prolonged. These rebound responses are consistent with intestinal delivery of food retained in the stomach on escape from inhibition of gastric emptying by GLP-I. Infusion of 1.2 pmol.kg-1.min-1 GLP-I with 20 g glucose (10% dextrose in water) injected intravenously over 60 min enhanced plasma responses of immunoreactive CP; the mean incremental areas under concentration curves (0-60 min) increased sixfold, but the glycemic excursion was not affected. Thus, in CP-positive IDDM, pharmacological doses of GLP-I reduce glycemic excursions after meals by a mechanism(s) not dependent on stimulation of insulin secretion, presumably involving delayed gastric emptying.(ABSTRACT TRUNCATED AT 250 WORDS)

Parallel regulation of the local vascular and systemic metabolic effects of insulin.

Recent studies have focused on the link between the development of disordered vascular regulation (e.g. hypertension) and alteration in the effects of insulin to mediate glucose uptake. We and others have recently demonstrated that insulin is a potent vasodilator. Further, it has been suggested that impairment of insulin-mediated vasodilation may be an important contributing factor in the development of increased peripheral resistance. However, whether the local vascular effects of insulin correlate with its systemic glucose regulatory effects remains unclear. Therefore, we assessed both vascular sensitivity to insulin (using dorsal hand vein linear variable differential transformer techniques) and glucoregulatory sensitivity to insulin (using the minimal model technique applied to a frequently sampled iv glucose tolerance test) in 12 normotensive nondiabetic volunteers. In these subjects, metabolic sensitivity to insulin and venous sensitivity to insulin were highly correlated (r2 = 0.42; P = 0.02). Additionally, vascular sensitivity to insulin was inversely correlated with fasting C-peptide levels (r2 = 0.49; P = 0.02). Both systemic and vascular sensitivities to insulin were also highly correlated with body mass index. These studies demonstrate that the glucoregulatory effects of insulin are paralleled by its local vasodilating effects and continue to support this linkage as an important factor in the correlation between alterations in systemic sensitivity to insulin and the development of elevated peripheral resistance in hypertension and obesity.

Hepatic extraction of insulin after stimulation of secretion with oral glucose or parenteral nutrients.

To determine whether hepatic extraction of insulin differs when glucose is administered by parenteral and physiological routes, we studied responses to oral glucose and to intravenous (IV) infusion of glucose or glucose plus arginine in normal volunteers. As in earlier studies, when IV glucose infusions were empirically programmed to to produce isoglycemic responses with 50 or 75 g oral glucose, ratios of integrated areas under concentration curves for immunoreactive C-peptide (CP) to insulin in the plasma were higher with IV than with oral glucose. Mean values +/- standard errors for these ratios in paired experiments with 50 g oral glucose were 5.6 +/- 0.66 compared with 8.3 +/- 1.4 with IV glucose (P < .03). With 75 g oral glucose, the corresponding values were 4.3 +/- 0.38 and 7.8 +/- 0.50 (P < .001). These results suggest that hepatic extraction of insulin is diminished when insulin secretion is potentiated by enteroinsular mechanisms after oral glucose administration. To determine whether this phenomenon is related to the route of administration of glucose or to the enhancement of insulin secretion with oral glucose, programmed IV infusions of glucose were used to elicit excursions of plasma CP similar to those obtained after 50 g oral glucose, and programmed infusions of glucose plus arginine were used to elicit excursions of plasma CP similar to those obtained after 75 g oral glucose. Plasma levels of immunoreactive gastric inhibitory polypeptide (GIP) increased substantially after ingestion of 75 g glucose, but did not change during isoglycemic IV glucose infusions or during IV infusions of glucose plus arginine.(ABSTRACT TRUNCATED AT 250 WORDS)

Determinants of clinical remission in recent-onset IDDM.

OBJECTIVE: To assess the relationship of SI and insulin secretion (C-peptide levels) to remission status in recent-onset IDDM. RESEARCH DESIGN AND METHODS: We followed 22 newly diagnosed patients, of whom 16 received immunomodulatory treatment with low-dose (5 mg.kg-1 x day-1) CsA and/or short-term (72 h) methylprednisolone and 6 received standard insulin treatment, at 3-mo intervals for 12 mo. Insulin secretion was assessed by C-peptide levels and AIRglu, which was determined as the area under the insulin response curve, above the fasting level, from 0-10 min after a 0.3 g.kg-1 x i.v. glucose bolus. SI was assessed by the minimal model technique applied to a frequently sampled IVGTT. Clinical remission was defined in those patients who maintained normal range GHb and capillary blood glucose levels < 7.8 mM premeal without insulin therapy for a minimum of 14 days. RESULTS: The rate of clinical remission was not different with immunomodulatory treatment; nor were the metabolic parameters of plasma C-peptide levels, AIRglu, and SI different in the treatment groups. The mean plasma C-peptide level improved significantly at 3 mo and was maintained to 12 mo. AIRglu was grossly subnormal throughout, but a significant improvement was seen at 3 and 6 mo. Mean SI was normalized at 3 and 6 mo but not maintained beyond 9 mo. The maximum rate of clinical remission was seen at 6 mo. CONCLUSIONS: Clinical remission in recent-onset IDDM patients is associated with improvement in both insulin secretion and SI. Although the improvement in basal C-peptide persisted, AIRglu increased only transiently and declined as loss of remission occurred in most patients. Loss of remission to an insulin-requiring state is associated with a decrease in SI.

A modified protocol for estimation of insulin sensitivity with the minimal model of glucose kinetics in patients with insulin-dependent diabetes.

An exogenous insulin administration-modified, frequently sampled iv glucose tolerance test (FSIGT) for application in insulin-dependent diabetic patients (IDDM) to allow for estimation of insulin sensitivity (SI) and glucose effectiveness (SG) with Bergman's minimal model of glucose kinetics was investigated. An insulin infusion protocol (either 4 or 8 mU/min.kg from 20-25 min) was compared to the standard tolbutamide-modified (300 mg at 20 min) FSIGT in normal control subjects. SI and SG were not different for the insulin infusion- and tolbutamide-modified protocols [SI, 2.8 +/- 0.4, 3.6 +/- 0.6, and 2.5 +/- 0.5 X 10(4) min1/(microU/mL), respectively]. SI and SG were quantified in insulin-requiring newly diagnosed IDDM and in noninsulin-requiring IDDM in clinical remission with the exogenous insulin administration protocol. Both SI and SG were reduced in newly diagnosed IDDM compared to normal controls (by 64% and 40%, respectively). SI was normalized in IDDM in clinical remission despite a continued poor insulin secretory response to both glucose and tolbutamide. Although SI was normal in patients in clinical remission, SG remained reduced (by 65%) compared to that in normal controls. In conclusion, our results demonstrate that modification of the FSIGT with the exogenous administration of insulin allows for estimation of insulin sensitivity and glucose effectiveness in IDDM patients. Comparison to the standard protocol in normal subjects suggests that this results in valid measurements of insulin sensitivity and glucose effectiveness. Results of the application of this protocol in IDDM were consistent with previous observations that insulin sensitivity is reduced in poorly controlled IDDM and normalized in well controlled patients. Glucose effectiveness was found to be reduced in all IDDM subjects regardless of the degree of control.

Effects of galanin on insulin responses to hormonal, neuropeptidal, and pharmacological stimuli in conscious dogs.

Galanin, a recently characterized neuropeptide, lowers basal plasma canine insulin levels and inhibits plasma canine insulin responses to parenteral administration or oral ingestion of nutrients. This study determined the effect of galanin on the recognized insulin secretagogue effects of selected hormonal, neuropeptidal, and pharmacological agents in five conscious dogs. Bolus injections of cholecystokinin, the glucose-dependent insulinotropic polypeptide, and glucagon during saline infusions resulted in prompt elevation of plasma insulin levels (peak values, respectively: 57.8 +/- 14.6 microU/ml, 39.0 +/- 9.8 microU/ml, 60.8 +/- 14.4 microU/ml) but insulin responses after administration of these hormones during galanin infusions were statistically significantly blunted (peak values, respectively: 10.8 +/- 3.5 microU/ml, 3.0 +/- 2.8 microU/ml, 8.8 +/- 2.8 microU/ml). Bolus injection of the gastrin-releasing polypeptide, a neuropeptide, during saline infusions resulted in a peak plasma insulin level of 28.2 +/- 8.6 microU/ml but, during galanin infusions, the maximum level attained was significantly lower at 3.4 +/- 2.0 microU/ml. Similarly, tolbutamide administration during saline infusions elevated plasma insulin levels to a peak value of 28.6 +/- 6.2 microU/ml but during galanin infusions, the peak value seen after tolbutamide administration was 4.8 +/- 1.6 microU/ml. Hence, in the conscious dog, galanin effectively inhibits insulin secretion induced by hormones (cholecystokinin, glucose-dependent insulinotropic polypeptide, glucagon), a neuropeptide (gastrin-releasing polypeptide), and a pharmacological agent (tolbutamide). The results from the present and previous studies demonstrate that galanin has a broad spectrum of inhibitory activity on the beta-cell and suggest that it acts on a fundamental step in the insulin secretory process.

The effect of gastrin-releasing peptide on the endocrine pancreas.

Infusion of GRP into conscious sheep and dogs produced elevations of systemic plasma levels of insulin, glucagon, and pancreatic polypeptide (PP). In the dog, infusions of GRP produced dose-dependent decreases in plasma glucose levels, whereas, in the sheep, dose-dependent increases in plasma glucose levels occurred. Glucose turnover studies demonstrated that infusions of GRP produce prompt increases in the rate of appearance of glucose in sheep, but previous studies demonstrated a transient decrease in the rate of appearance of glucose in dogs, suggesting that sheep and dogs differ in hepatic responses to the elevated levels of insulin and glucagon. GRP was a potent PP secretagogue in the sheep, whereas, in contrast to results in the dog, infusions of GRP did not result in elevations of plasma levels of gastrin in sheep. GRP has multiple complex stimulatory effects on the endocrine pancreas, and there exist species-dependent differences in responses, which affect the potency and spectrum of the hormone-releasing activity of GRP. Further studies are required to determine the precise anatomical relation of GRP-containing nerve fibers to islet cells and to elucidate the pathways by which GRP activates endocrine pancreatic hormone release.

Decreased serum reverse triiodothyronine levels with major weight loss in obese women.

Anorexia nervosa is accompanied by increased serum reverse triiodothyronine levels and decreased serum triiodothyronine levels. We observed 28 women undergoing gastric plication for morbid obesity and found serum reverse triiodothyronine levels to be significantly decreased (p = 0.018) from a preoperative mean (+/- SD) of 0.30 (+/- 0.17) to 0.21 (+/- 0.06) ng/ml after weight loss. As all of our subjects were on semistarvation diets and had a significant weight loss (p less than 0.001), the observed decrease in reverse triiodothyronine rather than increase (as reported in anorexia nervosa) suggests factors other than weight loss or a semistarvation diet are important in the reverse triiodothyronine increase observed in anorexia nervosa.