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The present studies were designed to assess the percentage of HbA1c, frequency, and awareness of hypoglycaemia (H) during long-term intensive therapy (IT) of insulin-dependent diabetes mellitus (IDDM). From 1981 to 1994, 112 IDDM patients were on IT. HbA1cwas 7.17±0.16% (non-diabetic subjects 3.8–5.5%), the frequency of severe H 0.01±0.009 episodes/patient-year, frequency of mild symptomatic H 35.6±2.9 episodes/patient-year. IDDM patients with HbA1c≤ 5.5% (Group I, n=10), between 6.1–7.0% (Group II, n=12), and ≥ 7.6% (Group III, n=11) were studied to assess responses of counterregulatory hormones, symptoms and cognitive function during experimental, stepped H. Compared to 18 non-diabetic subjects, Group I exhibited high thresholds (plasma glucose had to decrease more than normal to evoke responses), and impaired responses of adrenaline, unawareness of H and delayed onset of cognitive dysfunction at the lowest glycaemic plateau (2.3 mmol/l). Group II had normal thresholds and responses, whereas Group III had low thresholds. Frequency of mild H was higher in Group I (54.5±1.9 episodes/patient-year) than in Group II and III (33.7±3.5 and 20.4±2.5 episodes/ patient-year, respectively, p<0.001) and correlated with percentage of HbA1c(r=−0.82). In conclusion: IT can maintain near-normal HbA1cand is compatible with low frequency of severe H. However, if HbA1cis less than 6.0%, mild, symptomatic H is excessively frequent and causes impaired counterregulation and H unawareness. Efforts should be made not only to maintain HbA1c≤ 7.0%, but also to prevent, recognize and reverse iatrogenic H unawarenes during long-term IT of IDDM by maintaining HbA1c>6.0%.

Hypoglycaemia 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; HbA1Cincreased 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 increasesthe 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.

To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n=8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU·kg−1·min−1(n=22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU· kg−1·min−1(n=9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (∼20%) and pancreatic polypeptide (∼30%), whereas it increased plasma noradrenaline (∼R10%, p<0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44±0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (∼3.8-3.6 mmol/l); noradrenaline (3.1±0.0 mmol/l), autonomic (3.05±0.06 mmol/l) and neuroglycopenic (3.05±0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45±0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89±0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15±1 min) and growth hormone (14±3 min) was shorter than adrenaline (19±3 min) and cortisol (39±4 min) (p<0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitve function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.

The 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.

To 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−1and 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.