Addition of biphasic insulin aspart 30 to optimized metformin and pioglitazone treatment of type 2 diabetes mellitus: The ACTION Study (Achieving Control Through Insulin plus Oral ageNts).

AIM: Efficacy and safety of biphasic insulin aspart (BIAsp 30, 30% short-acting and 70% intermediate-acting insulin aspart) added to an optimized treatment of metformin and pioglitazone (met/pio) were compared with treatment with optimized met/pio in type 2 diabetes patients. METHODS: This randomized, 34-week, parallel-group study enrolled insulin-naive, type 2 diabetes patients (HbA(1c) 7.5-12.0%) previously using two oral antidiabetic (OAD) agents. During an 8-week run-in period, treatment was changed to met/pio and doses were adjusted up to 2500 mg/day and 30 or 45 mg/day respectively. Subjects either continued met/pio alone or added BIAsp 30 initiated at 6 units twice daily and titrated to target plasma glucose (PG) (4.4-6.1 mmol/l). RESULTS: At end-of-study, subjects treated with BIAsp 30+met/pio (n = 93) had a mean (+/-s.d.) HbA(1c) reduction significantly greater than treatment with met/pio (n = 88) (1.5% +/- 1.1 vs. 0.2% +/- 0.9, p < 0.0001 between groups). Subjects treated with BIAsp 30+met/pio were more likely to reach The American Association of Clinical Endocrinologists and European Association for the Study of Diabetes/American Diabetes Association HbA(1c) targets of < or =6.5 and <7.0%, respectively, than with met/pio only (HbA(1c)< or =6.5%: 59 vs. 12%; HbA(1c) <7.0%: 76 vs. 24%). At end-of-study, self-monitored glucose profile values at all eight daily time points were significantly less for the BIAsp 30+met/pio group compared with the met/pio group, and minor hypoglycaemia (defined as PG < 3.1 mmol/l) was more frequent (8.3 vs. 0.1 events/year, p < 0.001). Both groups gained weight during treatment (BIAsp 30+met/pio, 4.6 +/- 4.3 kg; met/pio, 0.8 +/- 3.2 kg; p < 0.001). CONCLUSION: Addition of insulin in type 2 patients treated with met/pio is an effective way to achieve glycaemic targets. Treatment with BIAsp 30+met/pio achieved significantly greater reduction in HbA(1c), as compared with met/pio alone. In patients with type 2 diabetes poorly controlled by 2 OADs, more achieved glycaemic targets using BIAsp 30+met/pio than using met/pio alone.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization.

OBJECTIVE: The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann's syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X-linked-KS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient sample might provide new insights into the genetics of this rare disorder. Specifically, we wished to examine the following propositions. First, whether normosmic (nIHH) and anosmic (KS) forms of IHH were likely to be genetically discrete entities, on the basis of quantitative olfactory testing, analysis of autosomal pedigrees and the prevalence of developmental defects such as cryptorchidism and cleft palate. Second, whether mirror movements and/or unilateral renal agenesis were specific phenotypic markers for X-linked-KS. DESIGN AND PATIENTS: We conducted a clinical study of 170 male and 45 female IHH patients attending the endocrinology departments of three London University teaching hospitals. Approximately 80% of data were obtained from case records and 20% collected prospectively. Parameters assessed included olfaction, testicular volume, family history of hypogonadism, anosmia or pubertal delay, and history or presence of testicular maldescent, neurological, renal or craniofacial anomalies. Where possible, the clinical information was correlated with published data on genetic analysis of the KAL locus. RESULTS: Olfactory acuity was bimodally distributed with no evidence for a spectrum of olfactory deficit. Testicular volume, a marker of integrated gonadotrophin secretion, did not differ significantly between anosmic and normosmic patients, at 2.0 ml and 2.2 ml, respectively. Nevertheless, the prevalence of cryptorchidism was nearly three times greater in anosmic (70.3%, of which 75.0% bilateral) than in normosmic (23.2%, of which 43.8% bilateral) patients. Individuals with nIHH, eugonadal isolated anosmia and/or KS were observed to coexist within 6/13 autosomal IHH pedigrees. On three occasions, fertility treatment given to an IHH patient had resulted in the condition being transmitted to the resulting offspring. Mirror movements and unilateral renal agenesis were observed in 24/98 and 9/87 IHH patients, respectively, all of whom were identifiable as X-KS males on the basis of pedigree analysis and/or defective KAL coding sequence. Abnormalities of eye movement and unilateral sensorineural deafness were observed in 10/21 and 6/111 KS patients, respectively, but not in nIHH patients. DISCUSSION: Patients with IHH are almost invariably either anosmic (KS) or normosmic (nIHH), rather than exhibiting intermediate degrees of olfactory deficit. Moreover, the prevalence of cryptorchidism is nearly three times greater in KS than in nIHH despite comparable testicular volumes, suggesting a primary defect of testicular descent in KS independent of gonadotrophin deficiency. Disorders of eye movement and hearing appear only to occur in association with KS. Taken together, these findings indicate a clear phenotypic separation between KS and nIHH. However, pedigree studies suggest that autosomal KS is an heterogeneous condition, with incomplete phenotypic penetrance within pedigrees, and that some cases of autosomal KS, nIHH and even isolated anosmia are likely to have a common genetic basis. The prevalences of anosmia, mirror movements and unilateral renal agenesis among X-KS men are estimated to be 100, 85 and 31%, respectively. In sporadic IHH, mirror movements and unilateral renal agenesis are 100% specific phenotypic markers of de novo X-KS. By comparison, only 7/10 X-KS families harboured KAL coding defects. Clinical ascertainment, using mirror movements, renal agenesis and ichthyosis as X-KS-specific phenotypic markers, suggested that de novo X-KS was unlikely to comprise more than 11% of sporadic cases. The majority of sporadic KS cases are therefore presumed to have an autosomal basis and, hence, the preponderance of affected KS males over females remains unexplained, though reduced penetrance in women would be a possibility.

A man with a swollen leg and abnormal globulins.

A 72-year-old man presented with a two-week history of exertional dyspnea and nonclaudicatory pain and swelling in the right lower leg. Elevating the leg for short periods had not helped. The symptoms had begun soon after he took a nonsteroidal anti-inflammatory drug for right shoulder pain but persisted after he stopped taking the drug. His history included two-pillow orthopnea, but that had not worsened in the last year. He had not experienced chest discomfort.

Complication after arterial bypass grafting.

A 57-year-old man experienced sudden onset of pleuritic chest pain and respiratory distress 10 days after undergoing four-vessel coronary artery bypass grafting (CABG). The surgery was performed after cardiac catheterization had shown right coronary artery dominance and the presence of lesions occluding 40% of the mid right coronary artery, 20% of the left main coronary artery, and 99% of the lower left anterior descending artery and its first diagonal branch. The patient had initially presented with acute dyspnea following an episode of crushing, nonradiating pain in the left chest and was diagnosed as having a non-Q-wave myocardial infarction after cardiac enzyme testing. His hospital course before and immediately after CABG was uneventful. The first sign of difficulty was detected one week after surgery, on day 17. An echocardiogram showed a small pericardial effusion, moderate to severe concentric thickening of the left ventricle, a left ventricular ejection fraction of 0.60 (normal, 0.67 +/- 0.08), normal valves, and normal segmental wall motion. The pleural chest pains began two days later, on day 19.

A man with vague rheumatic complaints.

A 52-year-old man presented with a four-month history of malaise, low-grade fever, decreased appetite, and a 20-pound weight loss. He complained of joint pain and swelling, proximal muscle weakness, exertional dyspnea, and a dry cough. He also noted that his fingers had turned white and then blue when chilled and red when rewarmed. He had not had pleuritic chest pain, dysphagia, dry eyes or mouth, rash, or skin photosensitivity.

An uncommon cause of oral ulcers.

A 25-year-old Hispanic woman presented with painful oral ulcers, a sore throat, and dysphagia of two weeks' duration. She was treated empirically with acyclovir for presumed herpes simplex stomatitis and esophagitis and sent home. A week later, she returned with complaints of worsening sore throat, fever (as high as 38.9 degrees C), and cough producing yellow-green sputum. She had not had chills, shortness of breath, burning on urination, or a change in bowel habits.

Arthralgias following dilation and curettage.

A 36-year-old woman presented to the emergency department with right hip pain of one week's duration. An x-ray of the hip was unremarkable. She was diagnosed with trochanteric bursitis, given ibuprofen (800 mg tid) and crutches, and sent home. The next day, continual pain and progressive functional impairment prompted her to see an orthopedist. He concurred with the initial diagnosis and administered a corticosteroid injection into the right trochanteric bursa. Propoxyphene (65 mg q4h prn) was added to her medical regimen, and she was again sent home. Pain developed in the right sacroiliac area the next day. Within 24 hours, the right shoulder and right sternoclavicular joint were also involved, and the patient began having subjective fever and chilliness. She returned to the orthopedist and was immediately referred to a rheumatologist who ordered blood cultures and admitted her to the hospital.

An inflamed elbow after an insect sting.

A 63-year-old man presented with fever and a painfully swollen right elbow and forearm. He had been stung by a yellow jacket two weeks earlier and had since found it increasingly difficult to bend his arm.

A confused man with rapid respiration.

A 71-year-old man presented with incoherent, slurred speech, auditory hallucinations, and tachypnea. According to the neighbor who called for emergency medical service, the man had appeared to be in good health the day before. On admission, his blood pressure was normal.

A woman with sudden paralysis.

A 37-year-old Hispanic woman complained of having awakened with a tingling sensation, followed by sudden weakness, in both legs. A month earlier, she had experienced heart palpitations but had not had chest pain or dyspnea. She had lost 10 lb in the last two months despite an increased appetite and no polyuria, polydipsia, vomiting, or diarrhea.

A woman with abdominal pain and a history of thromboses.

A 39-year-old woman presented with progressively severe, sharp abdominal pain of three days' duration. The pain originated in the right lower quadrant of the abdomen and radiated to the back and suprapubic area. It worsened on ambulation and was associated with nausea and loose stools.

Massive hemoptysis in a woman with seizures.

A 53-year-old woman presented with a productive cough, fever, chills, and night sweats of one month's duration. She reported having had lightly blood-streaked sputum initially but then experiencing massive hemoptysis (> 200 mL/2 hr). Since the onset of symptoms, she had had malaise, body aches, and a 27-lb weight loss. For the last two weeks, she had also had increasing shortness of breath and pleuritic chest pain.