Addition of exenatide twice daily to basal insulin for the treatment of type 2 diabetes: clinical studies and practical approaches to therapy.

BACKGROUND: Type 2 diabetes is a progressive disease that requires stepwise additions of non-insulin and insulin therapies to meet recommended glycaemic goals. The final stage of intensification may require prandial insulin, adding complexity and increased risks of hypoglycaemia and weight gain. AIMS: This review assesses the benefits and risks of adding exenatide twice daily, a glucagon-like peptide 1 receptor agonist, in patients with type 2 diabetes who are currently treated with basal insulin, but have failed to reach their glycaemic goals. METHODS AND RESULTS: Based on data from published studies, exenatide has a number of actions that complement basal insulin therapy. Exenatide has been shown to increase glucose-dependent insulin production, suppress abnormal plasma glucagon production, slow gastric emptying, enhance liver uptake of glucose and promote satiety. A recently published randomised clinical trial reported that the addition of exenatide twice daily to titrated basal insulin provided greater glycaemic control than titrated basal insulin alone, and did so without an increase in hypoglycaemic events and with modest weight loss. Exenatide use was associated with gastrointestinal side effects. The recent randomised trial confirmed and extended data from a number of prior observational studies that demonstrated the efficacy and safety of insulin/exenatide combination therapy. Practical considerations for adding exenatide twice daily to ongoing basal insulin are discussed.

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 (f(b), f(d), f(s), T(up), T(down) ), and insulin sensitivity (Si). RESULTS: ISR differed significantly between step-up and -down phases only in Obese-IGT individuals. Basal (f(b)) and stimulated (f(d), f(s)) beta-cell sensitivity to glucose were similar in the three groups. Delays between glucose stimulus and beta-cell response during both step-up (T(up)) and -down (T(down)) phases were higher in Obese-IGT compared to Controls and Obese-NGT individuals. The product ISR x Si (10(-5.)min(-2) x 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 f(s) x Si (10(-14.)min(-2). pmol(-1) x 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.

Oral glucose tolerance test minimal model indexes of beta-cell function and insulin sensitivity.

The simultaneous assessment of quantitative indexes of insulin secretion and action in a single individual is important when quantifying their relative role in the evolution of glucose tolerance in different physiopathological states. Available methods quantify these indexes in relatively nonphysiological conditions, e.g., during glucose clamps or intravenous glucose tolerance tests. Here, we present a method based on a physiological test applicable to large-scale genetic and epidemiologic studies-the oral glucose tolerance test (OGTT). Plasma C-peptide, insulin, and glucose data from a frequently sampled OGTT with 22 samples throughout 300 min (FSOGTT300-22) were analyzed in 11 subjects with various degrees of glucose tolerance. In each individual, two indexes of pancreatic sensitivity to glucose (phis [10(9) min(-1)] and phid [10(9)]) and the insulin sensitivity index (SI) (10(5) dl/kg per min per pmol/l) were estimated by using the minimal model of C-peptide secretion and kinetics originally proposed for intravenous graded glucose infusion and the minimal model approach recently proposed for meal/OGTTs. The indexes obtained from FSOGTT300-22 were used as a reference for internal validation of OGTT protocols with reduced sampling schedules. Our results show that 11 samples in a 300-min period (OGTT300-11) is the test of choice because the indexes it provides (phis = 36 +/- 3 [means +/- SE]; phid = 710 +/- 111; SI = 10.2 +/- 2.4) show excellent correlation and are not statistically different from those of FSOGTT300-22 (phis = 33 +/- 3; phid = 715 +/- 120; SI = 10.1 +/- 2.3). In conclusion, OGTT300-11, interpreted with C-peptide and glucose minimal models, provides a quantitative description of beta-cell function and insulin sensitivity in a single individual while preserving the important clinical classification of glucose tolerance provided by the standard 120-min OGTT.

Quantitative indexes of beta-cell function during graded up&down glucose infusion from C-peptide minimal models.

Availability of quantitative indexes of insulin secretion is important for definition of the alterations in beta-cell responsivity to glucose associated with different physiopathological states. This is presently possible by using the intravenous glucose tolerance test (IVGTT) in conjunction with the C-peptide minimal model. However, the secretory response to a more physiological slowly increasing/decreasing glucose stimulus may uncover novel features of beta-cell function. Therefore, plasma C-peptide and glucose data from a graded glucose infusion protocol (seven 40-min periods of 0, 4, 8, 16, 8, 4, and 0 mg. kg(-1). min(-1)) in eight normal subjects were analyzed by use of a new model of insulin secretion and kinetics. The model assumes a two-compartment description of C-peptide kinetics and describes the stimulatory effect on insulin secretion of both glucose concentration and the rate at which glucose increases. It provides in each individual the insulin secretion profile and three indexes of pancreatic sensitivity to glucose: Phi(s), Phi(d), and Phi(b), related, respectively, to the control of insulin secretion by the glucose level (static control), the rate at which glucose increases (dynamic control), and basal glucose. Indexes (means +/- SE) were Phi(s) = 18.8 +/- 1.8 (10(9) min(-1)), Phi(d) = 222 +/- 30 (10(9)), and Phi(b) = 5.2 +/- 0.4 (10(9) min(-1)). The model also allows one to quantify the beta-cell times of response to increasing and decreasing glucose stimulus, equal to 5.7 +/- 2.2 (min) and 17.8 +/- 2.0 (min), respectively. In conclusion, the graded glucose infusion protocol, interpreted with a minimal model of C-peptide secretion and kinetics, provides a quantitative assessment of pancreatic function in an individual. Its application to various physiopathological states should provide novel insights into the role of insulin secretion in the development of glucose intolerance.

Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

OBJECTIVE: NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS: A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. RESULTS: Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). CONCLUSIONS: The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.

Oncogenic osteomalacia as a harbinger of recurrent osteosarcoma.

Discussion. Oncogenic osteomalacia is a rare paraneoplastic syndrome of skeletal demineralization from renal phosphate loss. Patients with this disorder have the characteristic clinical, laboratory, and radiographic findings of hyperphosphaturic osteomalacia. Although the pathophysiology has not yet been clearly delineated, a humoral factor produced by the tumor is suspected to be the cause.Purpose. We report the first case of oncogenic osteomalacia that improved with chemotherapy, discuss this paraneoplastic syndrome, and review the medical literature regarding its etiology.

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.

Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) are characterized by defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis. We administered the insulin-sensitizing agent troglitazone to 13 obese women with PCOS and impaired glucose tolerance to determine whether attenuation of hyperinsulinemia ameliorates these defects. All subjects had oligomenorrhea, hirsutism, polycystic ovaries, and hyperandrogenemia. Before and after treatment with troglitazone (400 mg daily for 12 weeks), all had 1) a GnRH agonist (leuprolide) test, 2) a 75-g oral glucose tolerance test, 3) a frequently sampled iv glucose tolerance test to determine the insulin sensitivity index and the acute insulin response to glucose, 4) an oscillatory glucose infusion to assess the ability of the beta-cell to entrain to glucose as quantitated by the normalized spectral power for the insulin secretion rate, and 5) measures of fibrinolytic capacity [plasminogen activator inhibitor type 1 (PAI-1) and tissue plasminogen activator]. There was no change in body mass index (39.9 +/- 1.4 vs. 40.2 +/- 1.4 kg/m2) or body fat distribution after treatment. Both the fasting (91 +/- 3 vs. 103 +/- 3 mg/dL; P < 0.001) and 2 h (146 +/- 8 vs. 171 +/- 6 mg/dL; P < 0.02) plasma glucose concentrations during the oral glucose tolerance test declined significantly. There was a concordant reduction in glycosylated hemoglobin to 5.7 +/- 0.1 from a pretreatment level of 6.1 +/- 0.1% (P < 0.03). Insulin sensitivity increased from 0.58 +/- 0.14 to 0.95 +/- 0.26 10(-5) min-1/pmol.L (P < 0.01) after treatment as did the disposition index (745 +/- 135 vs. 381 +/- 96; P < 0.05). The ability of the beta-cell to appropriately detect and respond to an oscillatory glucose infusion improved significantly after troglitazone treatment; the normalized spectral power for the insulin secretion rate increased to 5.9 +/- 1.1 from 4.3 +/- 0.8 (P < 0.05). Basal levels of total testosterone (109.3 +/- 15.2 vs. 79.4 +/- 9.8 ng/dL; P < 0.05) and free testosterone (33.3 +/- 4.0 vs. 21.2 +/- 2.6 pg/mL; P < 0.01) declined significantly after troglitazone treatment. Leuprolide-stimulated levels of 17-hydroxyprogesterone, androstenedione, and total testosterone were significantly lower posttreatment compared to pretreatment. The reduction in androgen levels occurred independently of any changes in gonadotropin levels. A decreased functional activity of PAI-1 in blood (from 12.7 +/- 2.8 to 6.3 +/- 1.4 AU/mL P < 0.05) was associated with a decreased concentration of PAI-1 protein (from 64.9 +/- 9.1 to 44.8 +/- 6.1 ng/mL; P < 0.05). No change in the functional activity of tissue plasminogen activator (from 5.3 +/- 0.4 to 5.1 +/- 0.5 IU/mL) was observed despite a decrease in its concentration (from 9.6 +/- 0.9 to 8.2 +/- 0.7 ng/mL; P < 0.05). The marked reduction in PAI-1 could be expected to improve the fibrinolytic response to thrombosis in these subjects. We conclude that administration of troglitazone to women with PCOS and impaired glucose tolerance ameliorates the metabolic and hormonal derangements characteristic of the syndrome. Troglitazone holds potential as a useful primary or adjunctive treatment for women with PCOS.

Effects of metformin on insulin secretion, insulin action, and ovarian steroidogenesis in women with polycystic ovary syndrome.

Hyperinsulinemia contributes to the ovarian androgen overproduction and glucose intolerance of polycystic ovary syndrome (PCOS). We sought to determine whether metformin would reduce insulin levels in obese, nondiabetic women with PCOS during a period of weight maintenance and thus attenuate the ovarian steroidogenic response to the GnRH agonist leuprolide. All subjects (n = 14) had an oral glucose tolerance test, a GnRH agonist (leuprolide) test, a frequently sampled iv glucose tolerance test, graded and oscillatory glucose infusions, and a dual energy x-ray absorptiometry scan before and after treatment with metformin (850 mg, orally, three times daily for 12 weeks). With weight maintenance (body mass index: pretreatment, 39.0 +/- 7.7 kg/m2, posttreatment, 39.1 +/- 7.9 kg/m2), oral glucose tolerance, insulin sensitivity (Si; 0.87 +/- 0.82 vs. 0.74 +/- 0.63 x 10(-5) min-1/ pmol.L), and the relationship between Si and first phase insulin secretion (AIRg vs. Si) were not improved by metformin. The insulin secretory response to glucose, administered in both graded and oscillatory fashions, was likewise unaltered in response to metformin. Free testosterone levels remained about 2-fold elevated (pretreatment, 26.6 +/- 12.7 pg/mL; posttreatment, 22.4 +/- 9.8 pg/mL). Both basal and stimulated LH and FSH levels were unaffected by metformin. The mean responses to leuprolide of 17-hydroxyprogesterone (pretreatment, 387 +/- 158 ng/dL; posttreatment, 329 +/- 116 ng/dL) as well as those of the other ovarian secretory products (androstenedione, dehydroepiandrosterone, progesterone, and estradiol) were not attenuated by metformin. We conclude that hyperinsulinemia and androgen excess in obese nondiabetic women with PCOS are not improved by the administration of metformin.