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1.
Diabetes Care ; 22(5): 795-800, 1999 May.
Article in English | MEDLINE | ID: mdl-10332684

ABSTRACT

OBJECTIVE: To quantitate the contribution of postprandial blood glucose, which improves with the short-acting insulin analog lispro [Lys(B28),Pro(B29)] in type 1 diabetes, to the overall 24-h blood glucose concentration and the long-term HbA1c concentration under conditions of different postabsorptive blood glucose. RESEARCH DESIGN AND METHODS: A total of 24 type 1 diabetic patients on long-term intensive therapy with premeal human regular insulin (Hum-R) and bedtime NPH were randomly assigned to a continuation of Hum-R (group 1, n = 8), lispro (group 2, n = 8), or lispro + NPH (in variable proportions) administered at mealtime (group 3, n = 8) for 3 months, NPH administered at bedtime was continued in all three groups. Data from home blood glucose monitoring were collected, and a 24-h plasma glucose and insulin profile was obtained during a 2-day hospital visit to calculate areas under the postprandial glucose curve (3.5 h after breakfast, 3.5 h after lunch, and 3.0 h after dinner for a total of 10.0 h) and the postabsorptive blood glucose curve (the remaining 14.0 h out of 24.0 h) (AUC). Eight nondiabetic subjects were also studied. RESULTS: The substitution of Hum-R with lispro (group 2) resulted in lower postprandial blood glucose, but greater postabsorptive blood glucose (P < 0.05 vs. group 1). The postprandial blood glucose AUC was lower (161 +/- 19 vs. 167 +/- 20 mg.100 ml-1.h-1), but the postabsorptive blood glucose AUC was greater (155 +/- 22 vs. 142 +/- 19 mg.100 ml-1.h-1) (P < 0.05). Therefore, the 24-h blood glucose AUC was no different (NS). Consequently, HbA1c was no different (NS). This occurred because in group 2, mealtime lispro resulted in normal prandial plasma insulin, but also resulted in lower interprandial concentration (P < 0.05 vs. group 1). When NPH was added to lispro (30% at breakfast, 40% at lunch, 10% at dinner) in group 3, postabsorptive plasma insulin was similar to group 1 (NS), in group 3, the postprandial blood glucose AUC (153 +/- 17 mg.100 ml-1.h-1) was lower and the postabsorptive blood glucose AUC was no different, as compared with group 1 (NS). Therefore, the 24-h blood glucose AUC was lower (147 +/- 17 vs. 155 +/- 21 and 158 +/- 20 mg.100 ml-1.h-1), and HbA1c was lower (6.41 +/- 0.12 vs. 6.84 +/- 0.2 and 6.96 +/- 0.2% (groups 3, 1, and 2 respectively, P < 0.05). Frequency of hypoglycemia was greater in group 2 (P < 0.05), but not in group 3 (NS) vs. group 1.


Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Glycated Hemoglobin/metabolism , Hypoglycemic Agents/therapeutic use , Insulin/analogs & derivatives , Adult , Circadian Rhythm , Drug Administration Schedule , Eating , Female , Humans , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Insulin/therapeutic use , Insulin Lispro , Male , Postprandial Period
2.
Diabetes Care ; 22(3): 468-77, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10097931

ABSTRACT

OBJECTIVE: To establish whether the short-acting insulin analog lispro can be successfully implemented in long-term intensive insulin therapy in type 1 diabetes, and if so, what its effects are on glycemic control and frequency and awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: We randomized 56 type 1 diabetic patients to treatment with either lispro (n = 28) or human regular insulin (Hum-R; n = 28) as mealtime insulin for 1 year (open design, parallel groups). Lispro was injected at mealtime and Hum-R was given 10-40 min before meals (bedtime NPH was continued on both occasions). With lispro, NPH was added at breakfast (approximately 70/30), lunch (approximately 60/40), and supper (approximately 80/20) (mixing percentage of lispro/NPH) to optimize premeal and bedtime blood glucose. RESULTS: Total daily insulin units were no different in the two treatment groups, but with lispro approximately 30% less short-acting insulin at meals and approximately 30% more NPH was needed versus Hum-R (P < 0.05). The bedtime NPH dosage was no different. With lispro + NPH, the mean daily blood glucose was lower than with Hum-R (8.0 +/- 0.1 vs. 8.8 +/- 0.1 mmol/l; P < 0.05), HbA1c was lower (6.34 +/- 0.10 vs. 6.71 +/- 0.11%, mean value over 1 year; P < 0.002), and hypoglycemia (blood glucose < or = 3.8 mmol/l) was less frequent (7.4 +/- 0.5 vs. 11.5 +/- 0.7 episodes/patient-month) and tended to occur more within 90 min after meals than in the postabsorptive state (P < 0.05 vs. Hum-R). After 1 year, plasma adrenaline and symptom responses to experimental, stepped hypoglycemia improved with lispro and were closer to the responses of 12 nondiabetic control subjects versus Hum-R both in terms of thresholds and magnitude (P < 0.05). CONCLUSIONS: We concluded that mealtime injection of lispro + NPH improves the 24-h blood glucose and the percentage HbA1c as compared with Hum-R. The improvement can be maintained long term. Intensive therapy with lispro + NPH results in less frequent hypoglycemia and better awareness and counterregulation of hypoglycemia.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Eating/physiology , Hypoglycemic Agents/therapeutic use , Insulin, Isophane/therapeutic use , Insulin/analogs & derivatives , Adult , Diabetes Mellitus, Type 1/blood , Drug Administration Schedule , Drug Combinations , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemic Agents/administration & dosage , Insulin/administration & dosage , Insulin/therapeutic use , Insulin Lispro , Insulin, Isophane/administration & dosage , Male , Time Factors
3.
Diabet Med ; 15(7): 592-600, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9686700

ABSTRACT

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.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Food , Hypoglycemic Agents , Insulin/analogs & derivatives , Insulin/administration & dosage , Adult , Blood Glucose/metabolism , Body Weight , Cross-Over Studies , Diabetes Mellitus, Type 1/blood , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/chemically induced , Insulin/adverse effects , Insulin/therapeutic use , Insulin Lispro , Male , Solubility , Time Factors
4.
Diabetes ; 46(7): 1172-81, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9200653

ABSTRACT

To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN-]; 13 with DAN [DAN+]; of the latter, 7 had orthostatic hypotension [DAN+PH+] and 6 did not [DAN+PH-]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from approximately 20 to approximately 2 episodes/patient-month while HbA1c increased from 6.2 +/- 0.3 to 6.9 +/- 0.2% (P < 0.05). Responses of adrenaline improved more in DAN- patients (from 1.17 +/- 0.12 to 2.4 +/- 0.22 nmol/l) than in DAN+PH- (from 0.75 +/- 0.25 to 1.56 +/- 0.23 nmol/l) and DAN+PH+ patients (from 0.80 +/- 0.24 to 1.15 +/- 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 +/- 0.37 nmol/l, P < 0.05), whereas glycemic thresholds normalized only in DAN-, not DAN+. Autonomic symptoms of hypoglycemia improved but remained lower in DAN- (6.2 +/- 0.6) than in nondiabetic subjects (8.1 +/- 1.1) and lower in DAN+PH+ (4 +/- 0.8) than in DAN+PH- subjects (5.1 +/- 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN+ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.


Subject(s)
Autonomic Nervous System Diseases/physiopathology , Diabetes Mellitus, Type 1/complications , Diabetic Neuropathies/physiopathology , Hypoglycemia/blood , Adult , Autonomic Nervous System Diseases/drug therapy , Blood Glucose/analysis , Blood Glucose/metabolism , Cohort Studies , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/physiopathology , Diabetic Neuropathies/drug therapy , Epinephrine/blood , Epinephrine/metabolism , Fatty Acids, Nonesterified/blood , Fatty Acids, Nonesterified/metabolism , Female , Glucagon/blood , Glucagon/metabolism , Glucose Clamp Technique , Human Growth Hormone/blood , Human Growth Hormone/metabolism , Humans , Hydrocortisone/blood , Hydrocortisone/metabolism , Hydroxybutyrates/blood , Hydroxybutyrates/metabolism , Hypoglycemia/chemically induced , Hypoglycemia/psychology , Hypoglycemic Agents/blood , Hypoglycemic Agents/therapeutic use , Insulin/blood , Insulin/metabolism , Insulin/therapeutic use , Lactic Acid/blood , Lactic Acid/metabolism , Male , Middle Aged , Norepinephrine/blood , Norepinephrine/metabolism , Pancreatic Polypeptide/blood , Pancreatic Polypeptide/metabolism , Perception , Time Factors
5.
Diabetes ; 46(6): 1010-6, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9166673

ABSTRACT

To assess the mechanisms of fasting hyperglycemia in NIDDM patients with mild elevation of fasting plasma glucose (FPG) compared with NIDDM patients with overt hyperglycemia, we studied 29 patients with NIDDM, who were divided in two groups according to their fasting plasma glucose (<7.8 and > or =7.8 mmol/l for groups A and B, respectively), and 16 control subjects who were matched with NIDDM patients for age, sex, and body mass index. All subjects were infused with [3-3H]glucose between 10:00 P.M. and 10:00 A.M. during overnight fasting to determine glucose fluxes. In 27 subjects (17 diabetic and 10 control), [U-14C]alanine was simultaneously infused between 4:00 A.M. and 10:00 A.M. to measure gluconeogenesis (GNG) from alanine. Arterialized-venous plasma samples were collected every 30 min for measurement of glucose fluxes, GNG, and glucoregulatory hormones. In group A, plasma glucose, rate of systemic glucose production (SGP), and GNG were greater than in control subjects (7.2 +/- 0.2 vs. 4.9 +/- 0.1 mmol/l, 10.9 +/- 0.2 vs. 9.5 +/- 0.3 micromol x kg(-1) x min(-1), and 0.58 +/- 0.04 vs. 0.37 +/- 0.02 micromol x kg(-1) x min(-1), respectively, for group A and control subjects; mean value 8:00 A.M.-10:00 A.M., all P < 0.05). Both increased SGP and GNG correlated with plasma glucose in all subjects (r = 0.77 and r = 0.75, respectively, P < 0.005). Plasma counterregulatory hormones did not differ in NIDDM patients compared to control subjects. The present studies demonstrate that SGP and GNG are increased in NIDDM patients without overt fasting hyperglycemia. Thus these metabolic abnormalities primarily contribute to early development of overnight and fasting hyperglycemia in NIDDM.


Subject(s)
Alanine/metabolism , Diabetes Mellitus, Type 2/metabolism , Gluconeogenesis/physiology , Glucose/metabolism , Hyperglycemia/blood , Alanine/analysis , Blood Glucose/analysis , Blood Glucose/metabolism , Carbon Radioisotopes , Cohort Studies , Diabetes Mellitus, Type 2/blood , Epinephrine/blood , Epinephrine/metabolism , Fasting , Female , Glucagon/blood , Glucagon/metabolism , Glucose/analysis , Human Growth Hormone/blood , Human Growth Hormone/metabolism , Humans , Hydrocortisone/blood , Hydrocortisone/metabolism , Hyperglycemia/metabolism , Insulin/blood , Insulin/metabolism , Male , Middle Aged , Reference Values , Tritium
6.
Diabetes ; 46(5): 814-23, 1997 May.
Article in English | MEDLINE | ID: mdl-9133549

ABSTRACT

To determine the contribution of clinically overt diabetic autonomic neuropathy (DAN) to reduced plasma adrenaline responses to hypoglycemia in IDDM and to establish its selectivity for hypoglycemia, we studied 17 IDDM patients (7 without DAN [DAN-] and 10 with DAN [DAN+]), of whom 5 had and 5 did not have postural hypotension (DAN+PH+ and DAN+PH-, respectively), and 8 nondiabetic subjects on 2 different occasions, i.e., clamped hypoglycemia (steps from 5.0 to 2.2 mmol/l plasma glucose) and 30-min steady-state exercise at 55% V(O[2max]). Recent antecedent hypoglycemia was meticulously prevented before the studies to exclude hypoglycemia as a cause of reduced responses of adrenaline to hypoglycemia. In DAN- patients, maximal responses of adrenaline to hypoglycemia were reduced (2.44 +/- 0.58 nmol/l vs. 4.9 +/- 0.54 nmol/l in nondiabetic patients) (P < 0.05). In DAN+, adrenaline responses initiated at a lower plasma glucose and were lower than in DAN- (DAN+PH-, 1.06 +/- 0.38 nmol/l; DAN+PH+, 0.84 +/- 0.27 nmol/l; P < 0.001, but NS between PH- and PH+). In response to exercise, adrenaline increased less in DAN- (0.89 +/- 0.11 nmol/l) patients than in nondiabetic subjects (1.19 +/- 0.14 nmol/l; NS) and only to 0.36 +/- 0.07 nmol/l in DAN+PH- and 0.23 +/- 0.09 nmol/l in DAN+PH+ (P < 0.001 vs. DAN- and nondiabetic subjects). These results were confirmed when nondiabetic and DAN- subjects repeated the exercise at 60 watts (35 and 41% of V(O[2max]), respectively), i.e., at the same absolute workload of DAN+ patients. Thus, DAN (both PH+ and PH-) contributes to reduced responses of adrenaline to hypoglycemia independently of recent antecedent hypoglycemia. The adrenaline defect in DAN is not selective for hypoglycemia.


Subject(s)
Autonomic Nervous System Diseases/physiopathology , Diabetes Mellitus, Type 1/blood , Diabetic Neuropathies/physiopathology , Epinephrine/blood , Hypoglycemia/blood , 3-Hydroxybutyric Acid , Blood Glucose/analysis , Carbon Dioxide/metabolism , Diabetes Mellitus, Type 1/physiopathology , Exercise/physiology , Fatty Acids, Nonesterified/blood , Glucagon/blood , Glucose/administration & dosage , Growth Hormone/blood , Humans , Hydrocortisone/blood , Hydroxybutyrates/blood , Hypoglycemia/complications , Hypoglycemia/physiopathology , Infusions, Intravenous , Insulin/analysis , Lactates/blood , Norepinephrine/blood , Oxygen/pharmacokinetics , Pancreatic Polypeptide/blood , Pulmonary Ventilation
7.
Diabetologia ; 39(6): 677-86, 1996 Jun.
Article in English | MEDLINE | ID: mdl-8781763

ABSTRACT

UNLABELLED: 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. HbA1c was 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 < or = 5.5% (Group I, n = 10), between 6.1-7.0% (Group II, n = 12), and > or = 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 HbA1c and is compatible with low frequency of severe H. However, if HbA1c is 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 < or = 7.0%, but also to prevent, recognize and reverse iatrogenic H unawareness during long-term IT of IDDM by maintaining HbA1c > 6.0%.


Subject(s)
Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/physiopathology , Glycated Hemoglobin/metabolism , Hypoglycemia/drug therapy , Hypoglycemia/physiopathology , Insulin/therapeutic use , 3-Hydroxybutyric Acid , Adult , Alanine/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Epinephrine/blood , Fatty Acids, Nonesterified/blood , Female , Glucagon/blood , Glycated Hemoglobin/analysis , Glycerol/blood , Human Growth Hormone/blood , Humans , Hydrocortisone/blood , Hydroxybutyrates/blood , Hypoglycemia/diagnosis , Insulin/blood , Insulin/metabolism , Lactic Acid/blood , Male , Norepinephrine/blood , Pancreatic Polypeptide/blood , Perception , Risk Factors
8.
Diabetes Care ; 18(11): 1452-9, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8722069

ABSTRACT

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 beta-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 beta-cell function (fasting plasma C-peptide 0.19 +/- 0.02 nmol/l) were studied on three different occasions. Postbreakfast plasma glucose was maintained at approximately 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 approximately 27 mmol glucose infused between 90 and 240 min; Hum-R approximately 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 greater than 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 beta-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.


Subject(s)
Blood Glucose/drug effects , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Eating , Insulin/analogs & derivatives , Islets of Langerhans/metabolism , 3-Hydroxybutyric Acid , Adult , Alanine/blood , Blood Glucose/metabolism , C-Peptide/blood , Diabetes Mellitus, Type 1/physiopathology , Drug Administration Schedule , Fatty Acids, Nonesterified/blood , Female , Glucagon/blood , Glucagon/metabolism , Glycerol/blood , Humans , Hydroxybutyrates/blood , Hypoglycemia/chemically induced , Injections, Subcutaneous , Insulin/administration & dosage , Insulin/blood , Insulin/pharmacology , Insulin/therapeutic use , Insulin Lispro , Lactates/blood , Male , Recombinant Proteins/therapeutic use , Reference Values , Time Factors
9.
Diabetologia ; 37(12): 1265-76, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7895957

ABSTRACT

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; 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.


Subject(s)
Awareness , Cognition , Diabetes Mellitus, Type 1/drug therapy , Hypoglycemia/physiopathology , Hypoglycemia/psychology , Insulin/adverse effects , Adult , Blood Glucose/metabolism , Body Mass Index , Diabetes Mellitus, Type 1/physiopathology , Diabetes Mellitus, Type 1/psychology , Epinephrine/blood , Female , Glucagon/blood , Glucose Clamp Technique , Glycated Hemoglobin/analysis , Growth Hormone/blood , Humans , Hydrocortisone/blood , Hypoglycemia/chemically induced , Insulin/pharmacology , Insulin/therapeutic use , Male , Norepinephrine/blood , Pancreatic Polypeptide/blood , Reference Values , Time Factors
10.
Diabetologia ; 37(8): 797-807, 1994 Aug.
Article in English | MEDLINE | ID: mdl-7988782

ABSTRACT

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 (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, 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 (approximately 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 cognitive 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.


Subject(s)
Autonomic Nervous System/physiology , Cognition , Hormones/metabolism , Hypoglycemia/physiopathology , Hypoglycemia/psychology , Adult , Blood Glucose/metabolism , C-Peptide/blood , C-Peptide/metabolism , Cognition Disorders/etiology , Epinephrine/blood , Epinephrine/metabolism , Female , Glucagon/blood , Glucagon/metabolism , Glucose Clamp Technique , Growth Hormone/blood , Growth Hormone/metabolism , Hormones/blood , Humans , Hydrocortisone/blood , Hydrocortisone/metabolism , Insulin/blood , Insulin/metabolism , Insulin Secretion , Male , Norepinephrine/blood , Norepinephrine/metabolism , Pancreatic Polypeptide/blood , Pancreatic Polypeptide/metabolism , Reference Values , Sex Factors , Time Factors
11.
Diabetologia ; 37(7): 713-20, 1994 Jul.
Article in English | MEDLINE | ID: mdl-7958544

ABSTRACT

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 approximately three times greater after MI than HI (293 +/- 26 vs 90 +/- 25 mumol.kg-1 x 60-375 min-1, p < 0.05). After MI, hepatic glucose production was more suppressed (0.7 +/- 1 vs 5.9 +/- 0.54 mumol.kg-1.min-1) and glucose utilization was less suppressed than after HI (11.6 +/- 0.65 vs 9.1 +/- 0.11 mumol.kg-1.min-1) (p < 0.05). Similarly, plasma NEFA, glycerol, and beta-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).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Diabetes Mellitus, Type 1/metabolism , Glucose/metabolism , Hypoglycemic Agents/pharmacology , Insulin/analogs & derivatives , Adult , Blood Glucose/analysis , Cognition/physiology , Diabetes Mellitus, Type 1/complications , Female , Humans , Hypoglycemia/chemically induced , Hypoglycemia/metabolism , Hypoglycemic Agents/pharmacokinetics , Infusions, Intravenous , Injections, Subcutaneous , Insulin/blood , Insulin/pharmacokinetics , Insulin/pharmacology , Insulin Lispro , Liver/metabolism , Male
12.
Diabetologia ; 36(11): 1191-7, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8270135

ABSTRACT

It is controversial as to whether ketone bodies are utilized by the human brain as a fuel alternative to glucose during hypoglycaemia. To clarify the issue, we studied 10 normal volunteers during an experimental hypoglycaemia closely mimicking the clinical hypoglycaemia of patients with Type 1 (insulin-dependent) diabetes mellitus or insulinoma. Hypoglycaemia was induced by a continuous infusion of insulin (0.40 mU.kg-1.min-1 for 8 h, plasma insulin approximately 180 pmol/l) which decreased the plasma glucose concentration to approximately 3.1 mmol/l during the last 3 h of the studies. Subjects were studied on two occasions, i.e. spontaneous, counterregulatory-induced post-hypoglycaemic increase in 3-beta-hydroxybutyrate (from approximately 0.2 to approximately 1.1 mmol/l at 8 h), or prevention of post-hypoglycaemic hyperketonaemia (plasma beta-hydroxybutyrate approximately 0.1 mmol/l throughout the study) after administration of acipimox, a potent inhibitor of lipolysis. In the latter study, glucose was infused to match the hypoglycaemia observed in the former study. The glycaemic thresholds and overall responses of counterregulatory hormones, symptoms (both autonomic and neuroglycopenic), and deterioration of cognitive function (psychomotor tests) were superimposable in the control study in which ketones increased spontaneously after onset of hypoglycaemic counterregulation, as compared to the study in which ketones were suppressed (p = NS). The fact that responses of counterregulatory hormones, symptoms and deterioration in cognitive function were not exaggerated when posthypoglycaemic hyperketonaemia was prevented, indicate that during hypoglycaemia, the counterregulatory-induced endogenous hyperketonaemia does not provide the human brain with an alternative substrate to glucose. Thus, it is concluded that during hypoglycaemia, endogenous hyperketonaemia does not contribute to brain metabolism and function.


Subject(s)
Brain/metabolism , Cognition/drug effects , Hypoglycemia/metabolism , Insulin/pharmacology , Ketone Bodies/blood , 3-Hydroxybutyric Acid , Adult , Alanine/blood , Brain/drug effects , Diabetes Mellitus, Type 1/blood , Female , Glycerol/blood , Homeostasis , Hormones/blood , Humans , Hydroxybutyrates/blood , Hypoglycemia/blood , Hypoglycemia/chemically induced , Hypolipidemic Agents/pharmacology , Insulinoma/blood , Lactates/blood , Lipolysis/drug effects , Male , Pancreatic Neoplasms/blood , Pyrazines/pharmacology , Reaction Time/drug effects
13.
Diabetes ; 42(11): 1683-9, 1993 Nov.
Article in English | MEDLINE | ID: mdl-8405713

ABSTRACT

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 < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.


Subject(s)
Blood Glucose/analysis , Cognition/physiology , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Epinephrine/blood , Hypoglycemia , Norepinephrine/blood , Adult , Awareness/physiology , Diabetes Mellitus, Type 1/physiopathology , Female , Glucagon/blood , Glycated Hemoglobin/analysis , Humans , Hyperinsulinism/blood , Hypoglycemia/blood , Hypoglycemia/physiopathology , Hypoglycemia/prevention & control , Insulin/blood , Insulin/therapeutic use , Male , Time Factors
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