OBJECTIVE -To compare the efficacy and safety of adding once-daily basal insulin versus switching to twice-daily premixed insulin in type 2 diabetic patients insufficiently controlled by oral antidiabetic agents (OADs). RESEARCH DESIGN AND METHODS-In a 24-week, multinational, multicenter, open, parallel group clinical trial, 371 insulin-naïve patients with poor glycemic control (fasting blood glucose [FBG] Ն120 mg/dl, HbA 1c 7.5-10.5%) on OADs (sulfonylurea plus metformin) were randomized to once-daily morning insulin glargine plus glimepiride and metformin (glargine plus OAD) or to 30% regular/70% human NPH insulin (70/30) twice daily without OADs. Insulin dosage was titrated to target FBG Յ100 mg/dl (both insulins) and predinner blood glucose Յ100 mg/dl (70/30 only) using a weekly forced-titration algorithm.RESULTS -Mean HbA 1c decrease from baseline was significantly more pronounced (Ϫ1.64 vs. Ϫ1.31%, P ϭ 0.0003), and more patients reached HbA 1c Յ7.0% without confirmed nocturnal hypoglycemia (45.5 vs. 28.6%, P ϭ 0.0013) with glargine plus OAD than with 70/30. Similarly, FBG decrease was greater with glargine plus OAD (adjusted mean difference Ϫ17 mg/dl [-0.9 mmol/l], P Ͻ 0.0001), and more patients reached target FBG Յ100 mg/dl with glargine plus OAD than with 70/30 (31.6 vs. 15.0%, P ϭ 0.0001). Glargine plus OAD patients had fewer confirmed hypoglycemic episodes than 70/30 patients (mean 4.07 vs. 9.87/patient-year, P Ͻ 0.0001).CONCLUSIONS -Initiating insulin treatment by adding basal insulin glargine once daily to glimepiride plus metformin treatment was safer and more effective than beginning twice-daily injections of 70/30 and discontinuing OADs in type 2 diabetic patients inadequately controlled with OADs. Diabetes Care 28:254 -259, 2005T he association between poor glycemic control and the occurrence of micro-and macrovascular complications has been demonstrated in patients with type 1 and type 2 diabetes (1-3); however, achieving glycemic control, preferably with HbA 1c values Ͻ7%, can markedly reduce the risk of such complications (4) and is now recommended clinical practice (5,6). In many patients, insulin treatment is required to achieve good glycemic control (1).Consensus opinion on how or when to initiate insulin treatment in type 2 diabetic patients is lacking, and treatment regimens are known to vary between countries. Since most patients with type 2 diabetes are older and physicians' time is limited, the insulin regimen should be easy to apply. However, few studies have directly compared the leading methods. We studied two commonly used, simple regimens for initiating insulin therapy. One approach consists of stopping oral antidiabetic agent (OAD) therapy and initiating two injections of insulin, often premixed insulin containing a fixed ratio of regular and intermediateacting insulin (NPH), administered twice daily. The European Diabetes Policy Group (5) recommended that, in the majority of patients with type 2 diabetes, insulin therapy should be initiated using premixed insulin twice daily. N...

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To elucidate the acute metabolic actions of insulin-like growth factor I (IGF-I), we administered a primed (250 ,ug/kg), continuous (5 gg/kg. min) infusion of human recombinant (Thr 59) IGF-I or saline to awake, chronically catheterized 24-h fasted rats for 90 min. IGF-I was also infused while maintaining euglycemia (glucose clamp technique) and its effects were compared to those of insulin. IGF-I infusion caused a twofold rise in IGF-I levels and a 75-85% decrease in plasma insulin. When IGF-I alone was given, plasma glucose fell by 30-40 mg/dl (P < 0.005) due to a transient twofold increase (P < 0.05) in glucose uptake; hepatic glucose production and plasma FFA levels remained unchanged. IGF-I infusion with maintenance of euglycemia produced a sustained rise in glucose uptake and a marked stimulation of 13-3Hjglucose incorporation into tissue glycogen, but still failed to suppress glucose production and FFA levels. IGF-I also produced a generalized 30-40% reduction in plasma amino acids, regardless of whether or not hypoglycemia was prevented. This was associated with a decrease in leucine flux and a decline in the incorporation of i1-'4Clleucine into muscle and liver protein (P < 0.05). When insulin was infused in a dosage that mimicked the rise in glucose uptake seen with IGF-I, nearly identical changes in amino acid metabolism occurred. However, insulin suppressed glucose production by 65% and FFA levels by 40% (P < 0.001). Furthermore, insulin was less effective than IGF-I in promoting glycogen synthesis.We conclude that (a) IGF-I produces hypoglycemia by selectively enhancing glucose uptake; (b) IGF-I is relatively ineffective in suppressing hepatic glucose production or FFA levels; and (c) IGF-I, like insulin, lowers circulating amino acids by reducing protein breakdown rather than by stimulating protein synthesis. Thus, IGF-I's metabolic actions in fasted rats are readily distinguished from insulin.

To examine mechanisms underlying the development of insulin resistance during normal puberty, sequential 8 and 40 mU/m2.min euglycemic insulin clamp and hyperglycemic clamp studies were performed in 14 healthy prepubertal and 19 pubertal children. Both groups had comparable rates of glucose turnover and plasma levels of branched chain amino acids and FFA at baseline. The low as well as the high insulin dose stimulated peripheral glucose uptake much more effectively in prepubertal children (P less than 0.05). In contrast, suppression of hepatic glucose production (60% at low dose in both groups, pNS) and lowering of substrates in response to insulin was not affected by puberty at either dose. During the hyperglycemic clamp pubertal children showed enhanced insulin responses and in turn a sharper fall in amino acids (P less than 0.05 vs. prepubertals). Our data suggest that insulin resistance during puberty is restricted to peripheral glucose metabolism. Selective insulin resistance leading to compensatory hyperinsulinemia may serve to amplify insulin's effect on amino acid metabolism, thereby facilitating protein anabolism during this period of rapid growth.