E. Torlone

Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial

Aims  The goal of the study was to determine whether continuous subcutaneous insulin infusion (CSII) differs from a multiple daily injection (MDI) regimen based on neutral protamine hagedorn (NPH) as basal insulin with respect to glycaemic control and quality of life in people with Type 1 diabetes.

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM.

SummaryHypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “conventional” insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n=16), or maintenance of the original “conventional” therapy (control group, CON, n=5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day; HbA1C increased from 5.83±0.18 to 6.94±0.13% (range in non-diabetic subjects 3.8–5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p<0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

ACE-inhibition increases hepatic and extrahepatic sensitivity to insulin in patients with Type 2 (non-insulin-dependent) diabetes mellitus and arterial hypertension

SummaryTo assess the effects of ACE-inhibition on insulin action in Type 2 (non-insulin-dependent) diabetes mellitus associated with essential hypertension, 12 patients with Type 2 diabetes (on diet and oral hypoglycaemic agents) and arterial hypertension were examined on two occasions, in a single blind, cross-over study, after two days of treatment with either captopril or a placebo. The study consisted of a euglycaemic-hyperinsulinaemic clamp (two sequential steps of insulin infusion at the rates of 0.25 mU·kg−1·min−1 and 1 mU·kg−1·min−1, 2 h each step), combined with an infusion of 3-3H-glucose to measure the rate of hepatic glucose production and that of peripheral glucose utilization. The results show that blood pressure was lower after captopril (sitting, systolic 148±5 mmHg, diastolic 89±2 mm Hg) compared to placebo (155±6 and 94±2 mm Hg) (p<0.05). Captopril treatment resulted in a more suppressed hepatic glucose production (2.7±0.4 vs 4.94±0.55 μmol·kg−1·min−1), and a lower plasma non-esterified fatty acid concentration (0.143±0.05 vs 0.200±0.05 mmol/l) (captopril vs placebo, p<0.05) at the end of the first step of insulin infusion (estimated portal plasma insulin concentration 305±28 pmol/l); and in a greater glucose utilization (36.5±5.1 vs 28±3.6μmol·kg−1·min−1, p<0.001) at the end of the second step of insulin infusion (arterial plasma insulin concentration of 604±33 pmol/l). We conclude that captopril improved insulin sensitivity in Type 2 diabetes associated with hypertension at the level of the liver and extrahepatic tissues, primarily muscle and adipose tissue. Thus, in contrast to other antihypertensive drugs such as diuretics and beta-blockers which may have a detrimental effect on insulin action, ACE-inhibitors appear to improve insulin action in Type 2 diabetes and essential hypertension, at least on a short-term basis.

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin

Background  Glargine is a long‐acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long‐term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH.

Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28),Pro(B29)] in IDDM

SummaryThe aim of these studies was to compare the pharmacokinetics, pharmacodynamics, counterregulatory hormone and symptom responses, as well as cognitive function during hypoglycaemia induced by s. c. injection of 0.15 IU/kg of regular human insulin (HI) and the monomeric insulin analogue [Lys(B28),Pro (B29)] (MI) in insulin-dependent-diabetic (IDDM) subjects. In these studies glucose was infused whenever needed to prevent decreases in plasma glucose below 3 mmol/l. After MI, plasma insulin increased earlier to a peak (60 vs 90 min) which was greater than after HI (294±24 vs 255±24 pmol/l), and plasma glucose decreased earlier to a 3 mmol/l plateau (60 vs 120 min) (p<0.05). The amount of glucose infused to prevent plasma glucose falling below 3 mmol/l was ∼three times greater after MI than HI (293±26 vs 90±25 μmol · kg−1 · 60–375 min−1, p<0.05). After MI, hepatic glucose production was more suppressed (0.7±1 vs 5.9±0.54 μmol · kg−1 · min−1) and glucose utilization was less suppressed than after HI (11.6±0.65 vs 9.1±0.11μmol · kg−1 · min−1) (p<0.05). Similarly, plasma NEFA, glycerol, and β-OH-butyrate were more suppressed after MI than HI (p<0.05), whereas plasma lactate increased only after MI, but not after HI. Responses of counterregulatory hormones, symptoms and deterioration in cognitive function during plasma glucose plateau of 3 mmol/l were superimposable after MI and HI (p=NS). Post-hypoglycaemia hyperglycaemia was greater after MI than HI (at 480 min 12.1±1 vs 11±1 mmol/l) because of greater hepatic glucose production during insulin waning which occurred at least 135 min earlier with MI as compared to HI (p<0.05). It is concluded that counterregulatory hormones, symptoms and deterioration in cognitive function during hypoglycaemia respond similarly after MI and HI. The biological effect of MI appears greater than that of HI for at least 4 h after the s.c. injection and appears as a good candidate for achieving optimal post-prandial glucose control in IDDM.

Comparison of a Multiple Daily Insulin Injection Regimen (Basal Once-Daily Glargine Plus Mealtime Lispro) and Continuous Subcutaneous Insulin Infusion (Lispro) in Type 1 Diabetes A randomized open parallel multicenter study

OBJECTIVE Insulin pump therapy (continuous subcutaneous insulin infusion [CSII]) and multiple daily injections (MDIs) with insulin glargine as basal insulin and mealtime insulin lispro have not been prospectively compared in people naïve to either regimen in a multicenter study. We aimed to help close that deficiency. RESEARCH DESIGN AND METHODS People with type 1 diabetes on NPH-based insulin therapy were randomized to CSII or glargine-based MDI (both otherwise using lispro) and followed for 24 weeks in an equivalence design. Fifty people were correctly randomized, and 43 completed the study. RESULTS Total insulin requirement (mean ± SD) at end point was 36.2 ± 11.5 units/day on CSII and 42.6 ± 15.5 units/day on MDI. Mean A1C fell similarly in the two groups (CSII −0.7 ± 0.7%; MDI −0.6 ± 0.8%) with a baseline-adjusted difference of −0.1% (95% CI −0.5 to 0.3). Similarly, fasting blood glucose and other preprandial, postprandial, and nighttime self-monitored plasma glucose levels did not differ between the regimens, nor did measures of plasma glucose variability. On CSII, 1,152 hypoglycemia events were recorded by 23 of 28 participants (82%) and 1,022 in the MDI group by 27 of 29 patients (93%) (all hypoglycemia differences were nonsignificant). Treatment satisfaction score increased more with CSII; however, the change in score was similar for the groups. Costs were ∼3.9 times higher for CSII. CONCLUSIONS In unselected people with type 1 diabetes naïve to CSII or insulin glargine, glycemic control is no better with the more expensive CSII therapy compared with glargine-based MDI therapy.

Use of the short-acting insulin analogue lispro in intensive treatment of type 1 diabetes mellitus : Importance of appropriate replacement of basal insulin and time-interval injection-meal

To establish whether lispro may be a suitable short‐acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA1c <7.5 %) were studied with an open, cross‐over design for two periods of 3 months each (lispro or soluble). The % HbA1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I–IV). Lispro was always injected at mealtime, soluble 10–40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA1c was no different (p = NS), but frequency of hypoglycaemia was greater (p < 0.05). When NPH was given 3–4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA1c by 0.35 ± 0.25 % with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA1c increased by 0.18 ± 0.15% and hypoglycaemia was more frequent than when soluble was injected 10–40 min prior to meals (Group IV, n = 24) (p < 0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin.

Improved Insulin Action and Glycemic Control After Long Term Angiotensin-Converting Enzyme Inhibition in Subjects with Arterial Hypertension and Type II Diabetes

OBJECTIVE To determine the long-term effects of the angiotensin-converting enzyme inhibitor captopril on insulin sensitivity in subjects with type II diabetes and arterial hypertension. The chronic effects of angiotensin-converting enzyme inhibition on insulin-sensitive individuals are presently controversial. RESEARCH DESIGN AND METHODS Sixteen subjects, with type II diabetes (on diet and/or diet plus oral hypoglycemic agents) and arterial hypertension, were studied. During a 1-mo run-in period no antihypertensive drugs were administered, but oral hypoglycemic agents were continued in subjects already in therapy. The subjects were then randomly assigned to two 3-mo treatment periods, with either captopril or placebo (single blind, cross-over design). At the end of each treatment period, insulin sensitivity was assessed by means of a euglycemic-hyperinsulinemic clamp (2 sequential steps, 2-h each, insulin infusion 0.25 and 1 mU ·kg−1 ·min−1, steps 1 and 2, respectively), combined with infusion of [3-3H]glucose (for calculation of hepatic glucose output and peripheral glucose utilization, rates of glucose disappearance), and indirect calorimetry (for calculation of glucose oxidation, nonoxidative glucose metabolism, and lipid oxidation). The percentage of HbAlc was measured to assess long-term glycemic control. RESULTS Comparing data at the end of placebo and captopril treatment, captopril resulted in: lower blood pressure (systolic 154 ± 2 vs. 163 ± 3 mmHg and diastolic 93 ± 2 vs. 101 ± 2 mmHg); greater insulin sensitivity in hyperglycemic conditions (total amount of insulin infused and time of insulin infusion required to reach euglycemia, 1.73 ± 0.54 vs. 2.08 ± 0.60 U and 58 ± 8 vs. 70 ± 11 min, captopril and placebo, respectively, P < 0.05); greater insulin sensitivity in euglycemic conditions at liver level (hepatic glucose output 4.11 ± 0.55 vs. 5.2 ± 0.4 μmol · kg−1 · min−1, step 1 of the clamp), muscle level (rates of glucose disappearance 26.1 ± 2.3 vs. 23.8 ± 2.1 μmol · kg−1 · min−1, step 2 of the clamp), primarily attributable to ∼29% increase in nonoxidative glucose metabolism, and adipose tissue level (plasma free fatty acid 0.185 ± 0.03 vs. 0.24 ± 0.02 mM and lipid oxidation 1.9 ± 0.3 vs. 2.21 ± 0.04 μmol · kg−1 · min−1 in step 1); and lower HbA1c (6.7 ± 0.2 vs. 7.3 ± 0.2%, P < 0.05). CONCLUSIONS Long-term captopril administration in type II diabetic subjects improves insulin sensitivity in the postprandial state, not in the fasting state, and improves glycemic control.

Effects of the Short-Acting Insulin Analog [Lys(B28),Pro(B29)] on Postprandial Blood Glucose Control in IDDM

OBJECTIVE To establish the effects of the short-acting insulin analog Lispro versus human regular insulin (Hum-R) on postprandial metabolic control in IDDM. RESEARCH DESIGN AND METHODS Four studies were performed in 10 C-peptide-negative IDDM patients. Lispro or Hum-R (0.15 U/kg) or Lispro + NPH (0.07 U/kg) or Hum-R + NPH were injected subcutaneously 30 min (Hum-R) or 5 min (Lispro) before lunch. Preprandial plasma glucose (PG) was maintained on all four occasions at ∼ 7.3 mmol/l by intravenous insulin. RESULTS After subcutaneous Lispro injection, plasma free insulin (FIRI) was greater between 0 and 2 h (233 ± 22 pmol/l) than after Hum-R (197 ± 25 pmol/l) but lower between 2.25 and 7 h (81 ± 10 vs. 104 ± 13 pmol/l, P < 0.05). After Lispro, PG was lower versus Hum-R for 3 h (7.4 ± 0.6 vs. 8.3 ± 0.9 mmol/l) but subsequently increased more than after Hum-R (3.25-7h, 11.3 ± 1 vs. 9.6 ± 1.2 mmol/l), resulting in a 7-h postprandial PG greater than Hum-R (9.4 ± 0.5 vs. 8.8 ± 0.6 mmol/l) (all P < 0.05). Addition of NPH to Lispro increased the 2.5-to 7-h FIRI to 110 ± 11 pmol/l and decreased the 3.25- to 7-h PG to 7.7 ± 0.8 pmol/l, resulting in 0- to 7-h PG (7.3 ± 0.3 mmol/l) lower than after Hum-R + NPH (7.9 ± 0.5 pmol/l) (P < 0.05). CONCLUSIONS At meals, in order for Lispro to improve postprandial blood glucose not only at 2-h, but also over a 7-h period in C-peptide–negative IDDM, basal insulin must be optimally replaced.

Improved Postprandial Metabolic Control After Subcutaneous Injection of a Short-Acting Insulin Analog in IDDM of Short Duration With Residual Pancreatic β-Cell Function

OBJECTIVE To compare postprandial metabolic control after subcutaneous injection of a short-acting insulin analog [Lys(B289),Pro(B29)] (Lispro) or human regular insulin (Humulin R U-100 [Hum-R]) in insulin-dependent diabetes mellitus (IDDM) of short duration with residual β-cell function. RESEARCH DESIGN AND METHODS Six IDDM patients (age 25 ± 2 years, diabetes duration 14 ± 2 months, HbA1c 6.4 ± 0.5%) with residual pancreatic β-cell function (fasting plasma C-peptide 0.19 ± 0.02 nmol/l) were studied on three different occasions. Postbreakfast plasma glucose was maintained at ∼ 7.1 mmol/l by means of intravenous insulin until either 1200 when 0.1 U/kg Hum-R was injected or until 1225 when 0.1 U/kg of either Hum-R or Lispro was injected subcutaneously. Lunch (mixed meal, 692 Kcal) was served at 1230 (0 min). Six nondiabetic control subjects were also studied. RESULTS After Lispro administration, the 120-min plasma glucose decreased more (6.1 ± 0.3 mmol/l) than after injection of Hum-R at −30 min (7.7 ± 0.3 mmol/l) or −5 min (9.9 ± 0.2 mmol/l). By the end of the study, plasma glucose was still lower after Lispro was injected (6.7 ± 0.3 mmol/l) than after Hum-R was injected at −30 min (7.6 ± 0.3 mmol/l) or −5 min (7.3 ± 0.2 mmol/l) (P < 0.05). Two IDDM patients required glucose to prevent hypoglycemia after being injected with Lispro, but four required glucose after being injected with Hum-R at −5 min (Lispro ∼ 27 mmol glucose infused between 90 and 240 min; Hum-R ∼ 80 mmol between 240 and 390 min). After Lispro, plasma insulin peaked earlier (at 30 min, 342 ± 29 pmol/l) than after Hum-R injection at −30 min (at 90 min, 198 ± 28 pmol/l) and was superimposable on that of nondiabetic subjects. In Hum-R injected at −5 min, plasma insulin peaked later (at 120 min) and subsequently remained > in the two other studies. CONCLUSIONS Despite the lack of a time interval between injection and meal, Lispro controls postprandial plasma glucose concentration better than Hum-R given 30 min before meals and, to an even greater extent, better than Hum-R given 5 min before meals. In addition, Lispro minimizes the risk of postprandial hypoglycemia, thus closely mimicking the postprandial glucose homeostasis of nondiabetic subjects. IDDM patients with residual pancreatic β-cell function are the ideal candidates for prandial use of Lispro because they can maintain near-normoglycemia longer after subcutaneous analog injection because of residual endogenous insulin secretion.