[Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the effect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynamics. In addition, we compared the pharmacokinetics and pharmacodynamics of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A), zinc-containing LYSPRO given subcutaneously (B), human Regular insulin given subcutaneously (C), and human Regular insulin given intravenously (D). We gave a 10-U dose of each treatment to 10 healthy (nondiabetic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [Cmax], 698 vs. 308 pM, A vs. C) and in less than half the time (time to Cmax [Tmax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-free LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TRmax], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maximum glucose infusion rate [Rmax], 3.1 vs. 2.2 mmol/min, A vs. C) than that of human Regular insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

[Lys(B28), Pro(B29)]-Human Insulin: A Rapidly Absorbed Analogue of Human Insulin

In the first of a two part series, Ahn and colleagues discuss the reductionist approach pervading medicine and explain how a systems approach (as advocated by systems biology) may complement reductionism.

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The Limits of Reductionism in Medicine: Could Systems Biology Offer an Alternative?

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)

Monomeric insulins and their experimental and clinical implications.

(D) Routes of delivery: Case studies

Background. Insulin is widely used to improve metabolic control in patients with non-insulindependent diabetes mellitus (NIDDM), but there is no consensus about the optimal regimen of insulin treatment. Methods. We treated 153 patients with NIDDM for three months with five regimens: (1) oral hypoglycemic drug therapy plus NPH insulin given at 7 a.m. (the morning-NPH group), (2) oral hypoglycemic drug therapy plus NPH insulin given at 9 p.m. (the evening-NPH group), (3) NPH and regular insulin (ratio, 70 units to 30 units) given before breakfast and dinner (the two-insulin-injection group), (4) NPH insulin at 9 p.m. and regular insulin before meals (the multiple-insulin-injection group), and (5) continued oral hypoglycemic drug therapy (the control group). Results. The mean (±SE) value for glycosylated hemoglobin decreased similarly in all four insulin-treatment groups (1.7±0.3, 1.9±0.2, 1.8±0.3, and 1.6±0.3 percent, respectively). The decrease was significantly greater in these four groups than i...

https://www.nejm.org/doi/pdf/10.1056/NEJM199211123272005

Comparison of Insulin Regimens in Patients with Non-Insulin-Dependent Diabetes Mellitus

This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20-30 yr). Five experimental protocols were used: effect of changing injection site, effect of temperature change and local massage, effect of aprotinin and human serum, effect of mixing regular insulin with long-acting insulin preparations, and effect of temperature change, muscular exercise, and local massage on the absorption of long-acting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.

Absorption Kinetics and Biologic Effects of Subcutaneously Injected Insulin Preparations

To investigate whether leg exercise accelerates the absorption of exogenous insulin from Its subcutaneous depot in insulin-treated diabetics, and whether the glycemie response to exercise in these patients is related to alterations in the insulin absorption process, we studied nine insulin-dependent diabetics and four normal subjects during rest and exercise. The diabetics received the regular dose of intermediate-acting insulin, reduced by 20 U, and their morning breakfast. One hour after the meal, 20 U regular insulin (Actrapid, labeled with 125I or unlabeled) was injected into the arm or the leg. Exercise (90 ± 10 W) was initiated 35 min later for three consecutive 10-min periods. In controls, no insulin was injected. Plasma glucagon and C-peptide levels were not changed during exercise, but blood ketone bodies and lactate levels increased significantly. Whether the insulin was injected into the moving or resting limb, external counting over the injection site demonstrated no exercise-induced alteration of the disappearance of 125I-radiation during the exercise period, but revealed a small postexercise enhancement of 125I disappearance only after leg injection. Determination of plasma insulin levels in four diabetics with newly insulin-treated diabetes revealed that circulating insulin had increased by 70% 30 min after the subcutaneous administration of regular insulin and had then plateaued for 45 min. Leg exercise had no additional effect on plasma insulin levels during the physical activity. In normals, exercise lowered circulating plasma insulin to a level approximately one-fifth that in diabetics. Regardless of the insulin injection site, there was an identical glycemie response to exercise, i.e., a pronounced fall of glycemia by 15% immediately and by 50% 30 min after the onset of exercise. In normals glucose homeostasis was not disturbed by exercise. This study demonstrates that moderate leg exercise does not necessarily accelerate the absorption of exogenous insulin; however, it can induce an acute and profound fall in glycemia, which presumably is due to the presence of a fixed hyperinsulinemic state in these patients rather than an alteration of the mobilization of insulin from its subcutaneous depot. Although this study investigated only a specific situation, the results indicate the possibility that exercise-induced hypoglycemia in insulin-treated diabetics is not necessarily prevented by changing the insulin injection site to nonmoving parts Of the body.

Exercise-induced Fall of Blood Glucose in Insulin-treated Diabetics Unrelated to Alteration of Insulin Mobilization

Circulating levels of insulin, proinsulin-like component, glucagon, growth hormone, and pancreatic polypeptide were measured in 12 patients with functioning insulinomas, and the suppressibility of serum insulin by somatostatin and diazoxide was assessed before surgical removal of the tumors. The hormone content of the tumors was evaluated by radioimmunoassay and by immunofluorescence and the structure of the tumor cells by electron microscopy. Based on these findings, we propose a new classification of insulinomas in two groups: group A is characterized morphologically by abundant well-granulated typical B-cells, trabecular arrangement of tumor cells, and uniform insulin immumofluorescence; functionally, these tumors are associated with a moderate elevation of proinsulin-like component and with an almost complete suppressibility of serum insulin by somatostatin and diazoxide. In contrast, tumors of group B are characterized by scarce well-granulated typical B-cells, a medullary-type histologie structure, and irregular insulin immunofluorescence; functionally these tumors show elevated circulating levels of proinsulin-like component and a marked resistance of insulin secretion to somatostatin and diazoxide inhibition. This way of separating human insulinomas in groups A and B represents a simplification of existing classifications and emphasizes the quantitative ultrastructure in relationship to suppressibility of insulin secretion. The proposed classification of human insulinomas in groups A and B, however, does not allow the assessment of the clinical or histopathologic malignancy of the tumors.

Functional and Morphologic Characterization of Human Insulinomas

There is a close epidemiological association between obesity and blood pressure for all age groups, although not every obese individual becomes hypertensive. In populations without age-related increases in body weight, an elevation of blood pressure with age is not seen. Treatment of obesity by weight loss decreases blood pressure substantially; however, in a minority of patients blood pressure does not fall with weight loss. Blood pressure generally decreases before normal weight is achieved. Blood pressure after weight loss remains reduced as long as there is no marked regain of body weight. Salt intake reduction does not appear to explain why weight reduction lowers blood pressure. Reduced levels of plasma renin activity, serum aldosterone levels, catecholamine levels, and serum insulin levels may be involved in the blood pressure lowering associated with weight loss. Since the risk to the hypertensive patient is not only determined by the blood pressure, an overall treatment that aims at reduction of all risk factors is advocated. Some risk factors, e.g., glucose intolerance, may be normalized only when desirable weight is achieved. Thus, in any obese hypertensive patient with other risk factors, normalization of excess body weight appears to be the first the most important step of any rational therapeutic strategy.

P Berchtold

Papers

Absorption Kinetics and Biologic Effects of Subcutaneously Injected Insulin Preparations

Exercise-induced Fall of Blood Glucose in Insulin-treated Diabetics Unrelated to Alteration of Insulin Mobilization

Functional and Morphologic Characterization of Human Insulinomas

Obesity and hypertension: cardiovascular response of weight reduction.