Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes.

OBJECTIVE: Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analog with a prolonged duration of action compared with NPH human insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 diabetes who had been previously treated with multiple daily injections of NPH insulin and regular insulin. RESEARCH DESIGN AND METHODS: This study was a multicenter randomized parallel-group study in which subjects were randomized to receive premeal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. Dose titration of both basal insulins was based on capillary fasting whole blood glucose (FBG) levels; the goal was a premeal blood glucose concentration of 4.4-6.7 mmol/l. RESULTS: A total of 534 well-controlled type 1 diabetic subjects (mean GHb 7.7%, mean fasting plasma glucose [FPG] 11.8 mmo/l) were treated. A small decrease in GHb levels was noted with both insulin glargine (-0.16%) and NPH insulin (-0.21%; P > 0.05). Significant reductions in median FPG levels from baseline (-1.67 vs. -0.33 mmol/l with NPH insulin, P = 0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin glargine. After the 1-month titration phase, significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycemia (39.9 vs. 49.2%, P = 0.0219) or nocturnal hypoglycemia (18.2 vs. 27.1%, P = 0.0116) with a blood glucose level <2.0 mmol/l compared with subjects receiving NPH insulin. CONCLUSIONS: Lower FPG levels with fewer episodes of hypoglycemia were achieved with insulin glargine compared with once- or twice-daily NPH insulin as part of a basal-bolus regimen in patients with type 1 diabetes.

The contribution of insulin-dependent and insulin-independent glucose uptake to intravenous glucose tolerance in healthy human subjects.

Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18-44 years of age; body mass index, 19.5-52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated beta-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG - [SI x basal insulin]). Insulin-dependent glucose uptake was estimated as SI x IIR0-19, because the relationship between SI and beta-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI x IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin (auto)antibodies from human IDDM cross-react with retroviral antigen p73.

In NOD mice, endogenous retroviruses including intracisternal type A particles (IAP) are expressed in the pancreatic beta cells. Furthermore, in these mice, insulin autoantibodies (IAA) cross-react with retroviral protein p73 (the IAP gag gene product), suggesting molecular mimicry between insulin and p73. We therefore investigated whether IAA and insulin antibodies (IA) associated with human IDDM cross-reacted with p73. Fifty IAA positive sera from 30 newly diagnosed IDDM before insulin therapy and 20 non-diabetic first degree relatives of IDDM and 27 IA positive sera from insulin treated IDDM, initially defined as IAA or IA positive by radioimmunoassay, were evaluated. Binding to insulin and to p73 of these sera were analysed by ELISA. Approximately 65% of sera which bound insulin by ELISA also bound p73. Only one sample negative for insulin binding was positive for p73 binding. Preabsorption with either insulin or p73 inhibited binding to both insulin and p73. However, preabsorption with mouse hemoglobin had no effect on their binding. Repeat measurement of binding to insulin and p73 in 10 non-diabetic first degree relatives of IDDM over an average of 16.6 months showed that each individual's reactivity to insulin and to p73 was relatively stable over time. Furthermore, in different individuals, binding to p73 and to insulin was closely correlated over time. In addition, 75 healthy teenagers (IAA negative by RIA) were used as normal controls in this study. p73 binding was found in only two (2.7%) of the 75 subjects. These results indicate that approximately 65% of ELISA (+) IAA and IA subjects have antibodies which recognize both insulin and p73, suggesting that IAA and IA from some subjects recognize an epitope shared between human insulin and the murine gag gene product. This raises the possibility that for some subjects who are IAA positive, the immunizing antigen may be antigenically similar to p73, rather than insulin, and that endogenous retroviruses may be involved in human IDDM.

Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function.

To determine the relationship between insulin sensitivity and beta-cell function, we quantified the insulin sensitivity index using the minimal model in 93 relatively young, apparently healthy human subjects of varying degrees of obesity (55 male, 38 female; 18-44 yr of age; body mass index 19.5-52.2 kg/m2) and with fasting glucose levels < 6.4 mM. SI was compared with measures of body adiposity and beta-cell function. Although lean individuals showed a wide range of SI, body mass index and SI were related in a curvilinear manner (P < 0.0001) so that on average, an increase in body mass index was associated generally with a lower value for SI. The relationship between the SI and the beta-cell measures was more clearly curvilinear and reciprocal for fasting insulin (P < 0.0001), first-phase insulin response (AIRglucose; P < 0.0001), glucose potentiation slope (n = 56; P < 0.005), and beta-cell secretory capacity (AIRmax; n = 43; P < 0.0001). The curvilinear relationship between SI and the beta-cell measures could not be distinguished from a hyperbola, i.e., SI x beta-cell function = constant. This hyperbolic relationship described the data significantly better than a linear function (P < 0.05). The nature of this relationship is consistent with a regulated feedback loop control system such that for any difference in SI, a proportionate reciprocal difference occurs in insulin levels and responses in subjects with similar carbohydrate tolerance. We conclude that in human subjects with normal glucose tolerance and varying degrees of obesity, beta-cell function varies quantitatively with differences in insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Prospective evaluation of beta-cell function in insulin autoantibody-positive relatives of insulin-dependent diabetic patients.

During the preclinical period of insulin-dependent diabetes mellitus (IDDM), progression to clinical IDDM is characterized by declining beta-cell function. Although the presence of insulin autoantibodies (IAA) improves the ability of islet cell antibodies (ICA) to predict subsequent clinical IDDM, few studies have examined the risk of developing IDDM in subjects positive for IAA but negative for both ICA and antibodies to glutamic acid decarboxylase (64kA). To investigate this question, detailed beta-cell function tests (acute insulin response to glucose [AIRgluc] and slope of glucose potentiation) were performed on eight IAA-positive first-degree relatives of insulin-dependent diabetics. All eight subjects were negative for ICA, and seven were tested for 64kA and were negative. Five subjects were studied prospectively for 22.4 +/- 9.4 months, while three subjects had only initial studies. Initial beta-cell function tests were normal in each subject. AIRgluc was 122.2% +/- 19.0% of the expected normal response, while slope was 168.6% +/- 20.6% of expected normal response. beta-cell function remained normal and remarkably stable in the five subjects followed prospectively. AIRgluc did not significantly change from an initial value of 147.9% +/- 23.1% of expected to 153.2% +/- 22.4% (NS). The slope of glucose potentiation varied little from 165.5% +/- 39.4% initially to 159.5% +/- 27.3% (NS) at the most recent determination. We conclude that among nondiabetic first-degree relatives of IDDM subjects, the presence of IAA in the absence of ICA and 64kA is not usually associated with and therefore does not reliably predict beta-cell dysfunction or progressive deterioration in beta-cell function.

Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies.

First-degree relatives of Type 1 (insulin-dependent) diabetic patients are at increased risk for developing clinical diabetes. The presence of islet cell or insulin autoantibodies further identifies relatives at greater risk, but not all immunologic-marker-positive relatives progress to disease. Beta-cell dysfunction, however, seems to be more prevalent than clinical Type 1 diabetes, since stable subclinical pancreatic Beta-cell dysfunction may occur. Antibodies against a Mr 64,000 (64K) islet Beta-cell protein, identified as glutamic acid decarboxylase, have been reported both at and several years prior to the clinical onset of Type 1 diabetes. We measured 64K antibodies in first-degree relatives with varying degrees of Beta-cell dysfunction and risk for subsequent Type 1 diabetes to determine whether 64K antibodies improve the predictive power of islet cell antibodies and/or insulin autoantibodies. In the Seattle Family Study first-degree relatives of Type 1 diabetic patients are followed prospectively using detailed Beta-cell function tests, insulin sensitivity, quantitative evaluation of islet cell antibodies and fluid phase assay insulin autoantibodies. 64K antibodies were measured using dog islets. Relatives were selected, based on Beta-cell function to represent individuals at high (n = 6) and low (n = 30) risk for subsequent Type 1 diabetes. The 30 low-risk individuals followed-up for 78 months, had stable Beta-cell function, and six (20%) were negative for all autoantibodies, ten (33%) were positive for insulin autoantibodies, 16 (53%) were islet cell antibody positive while six (20%) were positive for 64K antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic state of the pancreas affects end-point titre in the islet cell antibody assay.

Quantification of islet cell antibodies is used increasingly to evaluate pre-clinical Type 1 (insulin-dependent) diabetes mellitus. If expression of the antigen(s) reacting with islet cell antibodies varies depending upon the functional state of the pancreatic islets, this may partly explain differences in assay sensitivity between laboratories. To address this question we altered Beta-cell function in Osborn-Mendel rats, by dietary manipulation prior to killing. Rats were fed chow (n = 7) or a high sucrose/high fat "cafeteria" diet (n = 8) or were fasted for 18 h (n = 6) until immediately prior to killing. Using frozen sections of these rat pancreata in the indirect immunofluorescent test for islet cell antibodies, we determined the end-point titre for 18 sera in which islet cell antibodies had been previously quantified in our standard human pancreas assay. These sera included ten positive sera and eight normal negative control sera. The four most strongly positive sera gave significantly higher end-point titres on "cafeteria" diet-fed pancreata and lower titres on fasted pancreata (p less than 0.04 to 0.002). None of non-diabetic control sera were positive on any substrate. These data suggest that islet antigen expression is increased when Beta-cell function is increased by dietary manipulation. Improved sensitivity in the islet cell antibody assay might be possible by altering Beta-cell function before or immediately after pancreas collection.