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Objective: To determine if the International Hypoglycaemia Study Group (IHSG) level 2 low glucose definition can identify clinically relevant hypoglycemia in clinical trials and offer value as an end point for future trials., Research Design and Methods: A post hoc analysis was performed of the SWITCH (SWITCH 1: n = 501, type 1 diabetes; SWITCH 2: n = 721, type 2 diabetes) and DEVOTE ( n = 7,637, type 2 diabetes) trials utilizing the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec or insulin glargine 100 units/mL. In the main analysis, the following definitions were compared: 1 ) American Diabetes Association (ADA) 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); and 2 ) IHSG level 2 (PG confirmed <3.0 mmol/L, independent of symptoms)., Results: In SWITCH 2, the estimated rate ratios of hypoglycemic events indicated increasing differences between treatments with decreasing PG levels until 3.0 mmol/L, following which no additional treatment differences were observed. Similar results were observed for the SWITCH 1 trial. In SWITCH 2, the IHSG level 2 definition produced a rate ratio that was lower than the ADA 2005 definition., Conclusions: The IHSG level 2 definition was validated in a series of clinical trials, demonstrating its ability to discriminate between basal insulins. This definition is therefore recommended to be uniformly adopted by regulatory bodies and used in future clinical trials., (© 2019 by the American Diabetes Association.)

Insulin resistance is a major factor in the pathophysiology of type II diabetes and a major impediment to successful therapy. The identification of treatments that specifically target insulin resistance could improve diabetes management significantly. Since IGFs exert insulin-like actions and increase insulin sensitivity when administered at supraphysiological doses, we determined the effect of 6 weeks of recombinant human IGF-I (rhIGF-I) administration on insulin resistance and glycemic control in obese insulin-resistant patients with type II diabetes. A total of 12 patients with type II diabetes were recruited for the study. Subcutaneous administration of rhIGF-I (100 micrograms/kg b.i.d.) significantly lowered blood glucose. Fructosamine declined from 369 to 299 mumol/l by 3 weeks of administration and then declined further to 271 at the end of 5 weeks. Glycosylated hemoglobin, which was 10.4% pretreatment, declined to 8.1% at the end of therapy. Mean 24-h blood glucose during a modal day was 14.71 +/- 4.5 mmol/l pretreatment and declined to 9.1 +/- 3.21 mmol/l by the end of treatment. These improvements in glycemia were associated with a decrease in serum insulin levels. Mean insulin concentrations declined from 108.0 to 57.0 pmol/l during the modal day measurements and from 97.2 to 72.0 pmol/l during the mixed-meal tolerance test. Changes in glycemia were accompanied by a marked increase in insulin sensitivity. The insulin sensitivity index (SI) calculated from a frequently sampled intravenous glucose tolerance test (FSIVGTT) after the method of Bergman et al. (Bergman RN, Finegold DT, Ader M: Assessment of insulin sensitivity in vivo. Endocr Rev 6:45-86, 1985) increased 3.4-fold. Furthermore, the improvement in glycemic control was accompanied by a change in body composition with a 2.1% loss in body fat as calculated by dual energy x-ray absorptiometry without change in total body weight. Significant side effects were present in some subjects, although nine subjects were able to complete at least 4.5 weeks of the protocol and six subjects completed the entire 6 weeks. Supraphysiological IGF-I concentrations were maintained throughout the study, increasing from 206 micrograms/l in the control period to 849 micrograms/l at the end of 6 weeks of rhIGF-I treatment. The increase in IGF-I levels was accompanied by a significant increase in IGF binding protein-2 levels, a slight reduction in IGF binding protein-3 levels, and an increase in levels of IGF binding protein-1. In summary, IGF-I significantly lowered blood glucose as reflected by short-term and long-term indexes of glycemic control and increased insulin sensitivity. It remains to be determined whether a dosage can be administered that avoids significant side effects and still achieves reasonable glycemic control.

Mutations of the insulin receptor gene are a cause of the type A syndrome of extreme insulin resistance. This study assessed the prevalence of such mutations in women with clinical features of the type A syndrome including ovarian hyperandrogenism, moderate-to-severe degrees of insulin resistance, and acanthosis nigricans. We studied 22 unrelated women with insulin resistance (fasting insulin > 300 pM [50 microU/ml] and/or peak during an oral glucose tolerance test (OGTT) > 1,800 pM [300 microU/ml]), acanthosis nigricans, and the polycystic ovary syndrome (hyperandrogenemia, oligoamenorrhea, and hirsutism). Two insulin-resistant probands with congenital generalized lipodystrophy and one male proband with severe insulin resistance also were included in the study. Southern blotting experiments were performed to exclude gross gene deletions, insertions, or rearrangements. Exons 2-22 of the insulin receptor gene were polymerase chain reaction (PCR) amplified from genomic DNA and screened for nucleotide variation using single-strand conformation polymorphism (SSCP). No nucleotide variation between study subjects was detected in exons 4-6, 10-12, 15, 16, 18, 19, or 21. Sequencing of amplified DNA revealed that SSCP variants in exons 2, 3, 8, 9, and 17 corresponded to known silent polymorphisms within the coding region. Variants in exons 2, 9, 13, and 14 were caused by novel silent polymorphisms; variants in exons 7 and 22 were caused by nucleotide substitutions in flanking introns. One proband was found to have a heterozygous point mutation in exon 20 (CGG-->CAG, Arg1174-->Gln) that involves the intracellular receptor beta-subunit.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy and reproducibility of insulin administered intranasally as an insulin-deoxycholate 1% (w/v) aerosol to normal and diabetic subjects were assessed by measurements of blood glucose and serum insulin levels. Following administration of 0.5 U insulin/kg with the unconjugated bile salt to fasting volunteers (N = 29), peak serum insulin levels of 103 +/- 49 microU/ml above baseline were observed at 10 min. Blood glucose concentration began to fall by 10 min, reaching 54 +/- 14% of control levels by 30 min, and returning to baseline by 60-80 min. Blood glucose response and peak serum insulin levels were reproducible when the same aerosol dose was repeatedly administered to the same subjects; however, intersubject variations were noted. By comparing serum insulin levels after i.v. and nasal routes of administration, nasal insulin absorption was approximately 10% as efficient as intravenous insulin. Dose response studies revealed that peak serum insulin concentrations were a linear function of the administered dose. In subjects with type I and type II diabetes mellitus, serum insulin levels increased in a manner similar to controls, and resulted in a prompt reduction of blood glucose concentration. However, in contrast to normal subjects, the duration of the glucose response was more prolonged, lasting as long as 5 h. Nasal administration of insulin as an aerosol with bile salts or bile salt analogs should be further evaluated as a possible nonparenteral approach to insulin therapy.