The Need for Faster Insulin

Considerable progress in treatment of diabetes has been made in the nearly 100 years following the discovery of insulin, and advances in insulin therapy have improved convenience, quality of life, overall glycemic control (A1C), and risk of hypoglycemia. An unmet need remains for a mealtime insulin that can faithfully reproduce the metabolic profile that ensues following meal ingestion in healthy persons. A number of “ultra-fast” insulin programs have been initiated, and Afrezza® (insulin human; Inhalation Powder, MannKind Corporation, Danbury, CT) stands as the first such product to be approved by the US FDA. Afrezza is unique as an “ultra-ultra” fast insulin, faster than any other entrant except IV insulin. The benefits and limitations of the Afrezza profile are discussed in this analysis.

Intraperitoneal insulin infusion: on the way to the artificial pancreas

Creating an "artificial pancreas" (a "closed loop" insulin pump, with self-adjusting insulin abilities, based on real time continuous glucose monitoring data) – is one of the most actual medical challenges of modern engineering and cybernetics.Artificial pancreas (AP) prototypes based on wearable insulin pump with subcutaneous insulin delivery are still problematic, mainly because of slow insulin pharmacokinetics. Intravenous insulin infusion via AP allows effectively maintain euglycaemia for inpatients, due to insulin pharmacokinetics and pharmacodynamics advantages. Unfortunately, it can’t be used for outpatients. Intraperitoneal insulin infusion is still relatively infrequently used in the world, but it is a promising alternative, compared to both previous methods due to a physiological action profile, fast insulin pharmacokinetics, relatively better safety and availability for outpatient usage.The purpose of this review is to describe the intraperitoneal insulin infusion features for diabetes patients at a point of AP creation perspectives.

Effects of fasting on insulin action and glucose kinetics in lean and obese men and women

The development of insulin resistance in the obese individual could impair the ability to appropriately adjust metabolism to perturbations in energy balance. We investigated a 12- vs. 48-h fast on hepatic glucose production (Ra), peripheral glucose uptake (Rd), and skeletal muscle insulin signaling in lean and obese subjects. Healthy lean [ n = 14; age = 28.0 ± 1.4 yr; body mass index (BMI) = 22.8 ± 0.42] and nondiabetic obese ( n = 11; age = 34.6 ± 2.3 yr; BMI = 36.1 ± 1.5) subjects were studied following a 12- and 48-h fast during 2 h of rest and a 3-h 40 mU·m−2·min−1hyperinsulinemic-euglycemic clamp (HEC). Basal glucose Radecreased significantly from the 12- to 48-h fast (lean 1.96 ± 0.23 to 1.63 ± 0.15; obese 1.23 ± 0.07 to 1.07 ± 0.07 mg·kg−1·min−1; P = 0.004) and was equally suppressed during the HEC after both fasts. The increase in glucose Rdduring the HEC after the 12-h fast was significantly decreased in lean and obese subjects after the 48-h fast (lean 9.03 ± 1.17 to 4.16 ± 0.34, obese 6.10 ± 0.77 to 3.56 ± 0.30 mg·kg FFM−1·min−1; P < 0.001). After the 12- but not the 48-h fast, insulin-stimulated AKT Ser473phosphorylation was greater in lean than obese subjects. We conclude that 1) 48 h of fasting produces a marked decline in peripheral insulin action, while suppression of hepatic glucose production is maintained in lean and obese men and women; and 2) the magnitude of this decline is greater in lean vs. obese subjects.

The influence of plasma concentrations of tri-iodothyronine on the acute increases in insulin and muscle protein synthesis in the refed fasted rat

ABSTRACT To examine whether the low plasma levels of triiodothyronine (T3) in fasted rats might limit the recovery of muscle protein synthesis on refeeding, rats were fasted for either 3 or 4 days and refed with or without pretreatment with thyroid hormones. Fasting suppressed T3 levels, plasma insulin and the rate of the translational phase of muscle protein synthesis (KRNA; the rate per unit RNA), especially after the 4-day fast. On refeeding, plasma T3 levels remained low for more than 3 h after the 3-day fast and for more than 8 h after the 4-day fast. Insulin concentrations increased within the first hour of refeeding, eventually achieving supranormal concentrations after the 3-day fast. The KRNA increased within the first hour of refeeding, achieving well-fed control values by 3 h after the 3-day fast or 24 h after the 4-day fast. The increases in KRNA were significantly correlated with the increases in insulin at low insulin concentrations, achieving a plateau value at 150 pmol/l, so that further increases in insulin were not associated with any further increases in protein synthesis. Pretreatment with thyroid hormone induced increased T3 levels which were maintained for up to 8 h of refeeding. This had no effect on the responses of either insulin or protein synthesis to refeeding after the 3-day fast, but did result in an acceleration of the recovery in the KRNA and plasma insulin levels in the rats fasted for 4 days. Analysis of the insulin–KRNA relationship showed no evidence for any increase in the insulin sensitivity of muscle protein synthesis with thyroid pretreatment, the initial stimulation of protein synthesis on refeeding the rats fasted for 4 days reflecting increased insulin secretion. Since in the untreated animals, insulin secretion on refeeding was also correlated with T3 levels, these results are consistent with the previously reported thyroidal dependence of insulin secretion. J. Endocr. (1988) 118, 417–422

Effect of fasting on insulin removal by liver of perfused liver-pancreas.

Using in situ perfused rat liver-pancreas preparations, the hepatic clearance of biphasically released endogenous insulin was studied using livers of fed and fasted rats. Hepatic insulin extraction was determined by subtracting the mean endogenous insulin output found in the posthepatic vena cava effluent of liver pancreas preparations from the amount of insulin found in the prehepatic portal effluent of perfused pancreas preparations. All pancreas perfusions and liver-pancreas perfusions were subjected to the same plasma glucose stimulus (250 mg/dl) for 40 min. In the fed state, no significant hepatic extraction of insulin occurred. The biphasic pattern of insulin appearance in the posthepatic vena cava effluent, which ranged from less than 1 to 21 ng/ml, was unaffected by passage through the liver. In contrast, when rats were fasted for 24 h, approximately 50% of the insulin released into the portal vein was removed by their livers during one transhepatic passage. After a 48-h fast, insulin extraction capacity decreased relative to the capacity observed for livers of 24-h fasted rats.