To compare the pharmacokinetics/dynamics of the long-acting insulin analog glargine with NPH, ultralente, and continuous subcutaneous (SC) infusion of insulin lispro (continuous subcutaneous insulin infusion [CSII]), 20 C-peptide-negative type 1 diabetic patients were studied on four occasions during an isoglycemic 24-h clamp. Patients received SC injection of either 0.3 U/kg glargine or NPH insulin (random sequence, crossover design). On two subsequent occasions, they received either an SC injection of ultralente (0.3 U/kg) or CSII (0.3 U x kg(-1) x 24 h(-1)) (random sequence, crossover design). After SC insulin injection or CSII, intravenous (IV) insulin was tapered, and glucose was infused to clamp plasma glucose at 130 mg/dl for 24 h. Onset of action (defined as reduction of IV insulin >50%) was earlier with NPH (0.8 +/- 0.2 h), CSII (0.5 +/- 0.1 h), and ultralente (1 +/- 0.2 h) versus glargine (1.5 +/- 0.3 h) (P 150 mg/dl) occurred later with glargine (22 +/- 4 h) than with NPH (14 +/- 3 h) (P < 0.05) but was similar with ultralente (20 +/- 6 h). NPH and ultralente exhibited a peak concentration and action (at 4.5 +/- 0.5 and 10.1 +/- 1 h, respectively) followed by waning, whereas glargine had no peak but had a flat concentration/action profile mimicking CSII. Interindividual variability (calculated as differences in SD of plasma insulin concentrations and glucose infusion rates in different treatments) was lower with glargine than with NPH and ultralente (P < 0.05) but was similar with glargine and CSII (NS). In conclusion, NPH and ultralente are both peak insulins. Duration of action of ultralente is greater, but intersubject variability is also greater than that of NPH. Glargine is a peakless insulin, it lasts nearly 24 h, it has lower intersubject variability than NPH and ultralente, and it closely mimics CSII, the gold standard of basal insulin replacement.

https://diabetes.diabetesjournals.org/content/diabetes/49/12/2142.full.pdf

Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro.

I. Introduction II. Characteristics and Causal Mechanisms of 24-h Rhythms of Glucose Regulation in Normal Young Subjects A. 24-h variations in glucose tolerance B. Causal mechanisms III. Alterations of 24-h Rhythms of Glucose Regulation in Normal Aging A. Daytime variations in glucose tolerance B. Nighttime variations in glucose tolerance C. Respective roles of sleep and time of day D. Significance and clinical implications IV. Diurnal Variations of Glucose Regulation in Obesity A. Daytime variations in glucose tolerance B. Nighttime variations in glucose tolerance C. Significance and clinical implications V. Alterations in 24-h Rhythmicity of Glucose Regulation in Non-Insulin-Dependent Diabetes Mellitus (NIDDM) A. Alterations in daytime variations in glucose tolerance B. Alterations in nighttime variations in glucose levels during fasting C. Significance and clinical implications VI. Alterations in 24-h Rhythmicity of Glucose Regulation in Insulin-Dependent Diabetes Mellitus (IDDM) A. Alterations in dayt...

Roles of circadian rhythmicity and sleep in human glucose regulation

Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis.

https://www.physiology.org/doi/pdf/10.1152/physrev.00016.2012

Metabolism and the circadian clock converge.

The incidence of the metabolic syndrome represents a spectrum of disorders that continue to increase across the industrialized world. Both genetic and environmental factors contribute to metabolic syndrome and recent evidence has emerged to suggest that alterations in circadian systems and sleep participate in the pathogenesis of the disease. In this review, we highlight studies at the intersection of clinical medicine and experimental genetics that pinpoint how perturbations of the internal clock system, and sleep, constitute risk factors for disorders including obesity, diabetes mellitus, cardiovascular disease, thrombosis and even inflammation. An exciting aspect of the field has been the integration of behavioral and physiological approaches, and the emerging insight into both neural and peripheral tissues in disease pathogenesis. Consideration of the cell and molecular links between disorders of circadian rhythms and sleep with metabolic syndrome has begun to open new opportunities for mechanism-based therapeutics.

https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.109.208355

Circadian Rhythms and Metabolic Syndrome: From Experimental Genetics to Human Disease

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 ± 0.05 to 0.045 ± 0.03 episodes/patient-day) and an increase in HbA1c (5.8 ± 0.3 to 6.9 ± 0.2%) ( P

https://diabetes.diabetesjournals.org/content/diabetes/42/11/1683.full.pdf

Meticulous Prevention of Hypoglycemia Normalizes the Glycemic Thresholds and Magnitude of Most of Neuroendocrine Responses to, Symptoms of, and Cognitive Function During Hypoglycemia in Intensively Treated Patients With Short-Term IDDM

To ascertain whether the dawn phenomenon occurs in nondiabetic individuals and, if so, whether it is due to an increase in glucose production or a decrease in glucose utilization, we determined plasma concentrations of glucose, insulin, C-peptide, and counterregulatory hormones, as well as rates of glucose production, glucose utilization, and insulin secretion at one-half-hourly intervals between 1:00 and 9:00 a.m. in eight normal volunteers. After 5:30 a.m., plasma glucose, insulin, and C-peptide concentrations all increased significantly; rates of glucose production, glucose utilization, and insulin secretion also increased (all P less than 0.05). Plasma cortisol, epinephrine, and norepinephrine increased significantly from nocturnal nadirs between 4:00 and 6:30 a.m. Plasma growth hormone, which had increased episodically between 1:00 and 4:30 a.m., decreased thereafter nearly 50% (P less than 0.05). Plasma glucagon did not change significantly throughout the period of observation. These results indicate that a dawn-like phenomenon, initiated by an increase in glucose production, occurs in nondiabetic individuals. Thus, early morning increases in plasma glucose concentrations and insulin requirements observed in IDDM and NIDDM may be an exaggeration of a physiologic circadian variation in hepatic insulin sensitivity induced by antecedent changes in catecholamine and/or growth hormone secretion.

Demonstration of a Dawn Phenomenon in Normal Human Volunteers

In order to assess whether the metabolic clearance of insulin changes overnight, 11 patients with Type 1 (insulin-dependent) diabetes and low insulin antibody titre, and 6 nondiabetic subjects were studied. In these studies insulin was always infused by a Harvard pump. Initially, the nocturnal insulin requirements were assessed in the diabetic patients by an overnight feedback insulin infusion to maintain euglycaemia. The insulin requirements decreased continuously after midnight to a nadir of 0.115 ± 0.014 mU · kg−1 · min−1 at 04.30 hours, but after 05.00 hours the insulin requirements increased nearly 40 percent to a maximum of 0.16 ±0.012 mU · kg−1 · min−1 at 07.00 hours. To assess whether plasma insulin clearance changes overnight, the diabetic patients were studied on two different occasions, from 22.00–02.30 hours and from 04.00–08.30 hours. During each of these two studies insulin was infused in sequential steps of 90 min each at the rate of 0.13, 0.40 and 0.20 mU · kg−1 · min−1. Despite changes in plasma free insulin concentration, the metabolic clearance of insulin in the interval 22.00–02.30 hours (12.6±0.17 ml · kg−1 · min−1) was no different from that of the interval 04.00–08.30 hours (12.5 ± 0.19 ml · kg−1 · min−1). The nondiabetic subjects were studied on two different occasions to assess whether the metabolic clearance of insulin changes overnight. Somatostatin (0.25 mg/h) and insulin (0.3 mU kg−1 · min−1) were infused from 22.00–02.30 hours on one occasion, and from 04.00–08.30 hours on the other. The metabolic clearance of plasma free insulin in the interval 22.00–02.30 hours was no different from that of the interval 04.00–08.30 hours (12.6 ± 0.20 vs 12.9 ± 0.25 ml · kg−1 · min−1 nor was it different from that of the diabetic patients. It is concluded that, first, the metabolic clearance rate of insulin does not change overnight either in diabetic or in nondiabetic subjects; second, that it is independent of plasma insulin concentration; and third, that its value is comparable in nondiabetic subjects and in diabetic patients with a low titre of insulin antibodies. Thus, changes in insulin sensitivity rather than changes in insulin clearance are implicated in the pathogenesis of the dawn phenomenon.

/pdf/studies-on-overnight-insulin-requirements-and-metabolic-1v5ga81e1x.pdf

Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon.

C. Lolli

Papers

Demonstration of a Dawn Phenomenon in Normal Human Volunteers

Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon.