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  • 1
    Electronic Resource
    Electronic Resource
    The effects of different plasma insulin concentrations on lipolytic and ketogenic responses to epinephrine in normal and Type 1 (insulin-dependent) diabetic humans (1992)
    Springer
    Diabetologia 35 (1992), S. 129-138 
    Details
    ISSN: 1432-0428
    Keywords: Ketone bodies ; non-esterified fatty acids ; epinephrine ; insulin ; stable isotopes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study was performed to verify: (1) the ability of different insulin concentrations to restrict the lipolytic and ketogenic responses to exogenous epinephrine administration; (2) whether the ability of insulin to suppress the lipolytic and ketogenic responses during epinephrine administration is impaired in Type 1 (insulin-dependent) diabetic patients. Each subject was infused on separate occasions with insulin at rates of 0.2, 0.4, and 0.8 mU·kg−1·min−1 while normoglycaemic. To avoid indirect adrenergic effects on endocrine pancreas secretions, the so-called “islet clamp” technique was used. Rates of appearance of palmitic acid, acetoacetate, and 3-hydroxybutyrate were simultaneously measured with an infusion of 13C-labelled homologous tracers. After a baseline observation period epinephrine was exogenously administered at a rate of 16 ng·kg−1·min−1. At low insulin levels (20 μU/ml) the lipolytic response of comparable magnitude was detected in normal and Type 1 diabetic patients. However, the ketogenic response was significantly higher in Type 1 diabetic patients. During epinephrine administration, similar plasma glucose increments were observed in the two groups (from 4.74±0.53 to 7.16±0.77 mmol/l (p〈0.05) in Type 1 diabetic patients and from 4.94±0.20 to 7.11±0.38 mmol/l (p〈0.05) in normal subjects, respectively). At intermediate insulin levels (35 μU/ml) no significant differences were found between Type 1 diabetic patients and normal subjects, whereas plasma glucose levels rose from 4.98±0.30 to 6.27±0.66 mmol/l (p〈0.05) in Type 1 diabetic patients, and from 5.05±0.13 to 6.61±0.22 mmol/l (p〈0.05) in normal subjects. At high insulin levels (70 μU/ml) the lipolytic response was detectable only in Type 1 diabetic patients; the ketogenic response was reduced in both groups. During the third clamp, a significant rise in plasma glucose concentration during epinephrine infusion was observed in both groups. In conclusion this study shows that at low insulin levels Type 1 diabetic patients show an increased ketogenic response to epinephrine, despite their normal nonesterified fatty acid response. Instead, high insulin levels are able to restrict the ketogenic response to epinephrine in both normal and Type 1 diabetic subjects, although there is a still detectable lipolytic response in the latter. In the presence of plasma free insulin levels that completely restrict the ketogenic response in the same group, there is still a distinct glycaemic response. Plasma insulin levels in Type 1 diabetic patients are a major determinant of the metabolic response to epinephrine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402544
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  • 2
    Electronic Resource
    Electronic Resource
    Partial recovery of insulin secretion and action after combined insulin-sulfonylurea treatment in Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral agents (1990)
    Springer
    Diabetologia 33 (1990), S. 688-695 
    Details
    ISSN: 1432-0428
    Keywords: insulin ; sulfonylurea ; combined therapy ; insulin action ; insulin secretion ; metabolic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Metabolic control, insulin secretion and insulin action were evaluated in seven Type 2 (non-insulin-dependent) diabetic patients with secondary failure to oral antidiabetic agents before and after two months of combined therapy with supper-time insulin (Ultratard: 0.4 U/kg body weight/day) plus premeal glibenclamide (15 mg/day). Metabolic control was assessed by 24 h plasma glucose, NEFA, and substrate (lactate, alanine, glycerol, ketone bodies) profile. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, hyperglycaemic clamp (+7 mmol/l) and 24 h free-insulin and C-peptide profiles. The repeat studies, after two months of combined therapy, were performed at least 72 h after supper-time insulin withdrawal. Combining insulin and sulfonylurea agents resulted in a reduction in fasting plasma glucose (12.9±7 vs 10.4±1.2 mmol/l; p〈0.05) and hepaic glucose production (13.9±1.1 vs 11.1±1.1 μmol·kgc-min−1; p〈0.05). Mean 24 h plasma glucose was also lower (13.7±1.2 vs 11.1±1.4 mmol/l; p〈0.05). Decrements in fasting plasma glucose and mean 24 h profile were correlated (r=0.90; p〈0.01). HbA1c also improved (11.8±0.8 vs 8.9±0.5%; p〈0.05). Twenty-four hour profile for NEFA, glycerol, and ketone bodies was lower after teatment, while no difference occurred in the blood lactate and alanine profile. Insulin secretion in response to glucagon (C-peptide =+0.53±0.07 vs +0.43±0.07 pmol/ml) and hyperglycaemia (freeinsulin = 13.1±2.0 vs 12.3±2.2 mU/l) did not change. On the contrary, mean 24 h plasma freeinsulin (13.2±2.6 vs 17.5±2.2 mU/l; p〈0.01) and C-peptide (0.76±0.10 vs 0.98±0.13 pmol/l; p〈0.02) as well as the area under the curve (19.1±4.1 vs 23.6±3.1 U/24 h;p〈0.01 and 1.16±0.14 vs 1.38±0.18 μmol/24 h; p〈0.02 respectively) were significantly increased. The ratio between glucose infusion (M) and plasma insulin concentration (I) during the hyperglycaemic clamp studies (M/I, an index of insulin sensitivity), was not statistically different (1.40±0.25 vs 1.81±0.40 μmol·kg−1· min−1/mU·l−1). These data suggest that, in Type 2 diabetic patients with secondary failure to oral antidiabetic agents, the combination of supper-time longacting insulin and premeal sulfonylurea agents can improve metabolic control. This positive effect is possibly mediated through an increased secretion of insulin in response to physiologic stimuli.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400571
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  • 3
    Electronic Resource
    Electronic Resource
    Impaired response to angiotensin II in Type 1 (insulin-dependent) diabetes mellitus. Role of prostaglandins and sodium-lithium countertransport activity (1991)
    Springer
    Diabetologia 34 (1991), S. 595-603 
    Details
    ISSN: 1432-0428
    Keywords: Prostaglandins ; angiotensin ; sodium-lithium countertransport ; hypertension ; diabetic nephropathy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The pathogenesis of diabetic nephropathy remains elusive. A role for renal prostaglandins in antagonizing the hormonal effects of renin-angiotensin II has been postulated as a putative factor leading to hyperfiltration in patients with Type 1 (insulin-dependent) diabetes mellitus. Our aim was to elucidate the effects of angiotensin II on kidney haemodynamics and on blood pressure in eight normal subjects, in nine normotensive, in nine hypertensive with normal sodium-lithium countertransport activity in erythrocytes, in seven hypertensive without and in eight hypertensive Type 1 diabetic patients with microalbuminuria and with high sodium-lithium countertransport activity in erythrocytes. Angiotensin II infusion 4ng·kg−1·min−1 for 60 min) decreased the glomerular filtration rate to a greater extent in normal subjects (−20%), than in normotensive patients (−5% p〈0.01), in hypertensive patients with normal sodium-lithium countertransport activity in erythrocytes (−8% p〈0.01) in hypertensive patients with high sodium-lithium countertransport (−6% p〈0.01) and in hypertensive microalbuminuric patients (−5% p〈0.01) with Type 1 diabetes. The urinary excretion rate of vasodilatory prostaglandins was two-three fold higher in all patients than in normal subjects. Acute indomethacin treatment restored a normal response to angiotensin II infusion in normotensive patients, but did not change the renal haemodynamic response in normal subjects. With regard to hypertensive patients with and without microalbuminuria indomethacin treatment restored a normal response to angiotensin II in some but not all patients. An inverse relation was found between angiotensin II-induced decrease in the glomerular filtration rate and the sodium-lithium countertransport activity in erythrocytes during indomethacin treatment. Hypertensive and microalbuminuric patients with a sodium-lithium countertransport activity higher than 0.41 mmol·l erythrocyte−1·h−1 (the upper limit in normal subjects) also had a greater intimal plus medial thickness of the carotid artery using an ultrasonic imaging technique. Chronic indomethacin administration (30 days) significantly decreased the baseline overnight fasting glomerular filtration rate in normotensive and in hypertensive patients with normal but not in hypertensive and microalbuminuric patients with high sodium-lithium countertransport activity. In conclusion these results demonstrate that: (1) excessive synthesis of vasodilatory prostaglandins antagonizes the regulation of renal haemodynamics by angiotensin II, at least partially accounting for hyperfiltration in Type 1 diabetes, (2) elevated sodium-lithium countertransport activity in erythrocytes identifies a subgroup of patients with Type 1 diabetes and hypertension, with and without microalbuminuria, in whom the normalization of urinary excretion rate of prostaglandins does not restore a normal response to angiotensin II.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00400280
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  • 4
    Electronic Resource
    Electronic Resource
    Abnormal Na + /H + antiport activity in cultured fibroblasts from NIDDM patients with hypertension and microalbuminuria (1996)
    Springer
    Diabetologia 39 (1996), S. 717-724 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Non-insulin-dependent diabetes mellitus ; arterial hypertension ; microalbuminuria ; skin fibroblasts ; sodium-hydrogen exchange ; intracellular pH.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An increased activity of Na + /H + antiport has been reported in leukocytes and fibroblasts from insulin-dependent diabetic (IDDM) patients with nephropathy. To test whether a similar abnormality is present in fibroblasts from non-insulin-dependent diabetic (NIDDM) patients with microalbuminuria and hypertension, we examined intracellular pHi and Na + /H + antiport activity, using the pH sensitive dye 2 ′, 7 ′–bis (2–carboxyethyl–5(6)-carboxyfluorescein (BCECF), in cultured skin fibroblasts obtained from 34 NIDDM patients, divided into four groups based upon whether they had microalbuminuria or hypertension, or both: Group 1, nine NIDDM patients with microalbuminuria and hypertension. Group 2, nine NIDDM patients with hypertension and normal albumin excretion rate. Group 3, seven NIDDM patients with microalbuminuria and normal blood pressure. Group 4, nine NIDDM patients with normal blood pressure and normal albumin excretion rate. Nine normal subjects served as control group. Resting pHi was more alkaline in fibroblasts from Group 1 (7.22 ± 0.03; p 〈 0.05), Group 2 (7.21 ± 0.02; p 〈 0.05) and Group 3 (7.19 ± 0.02, p = 0.17) than in Group 4 and normal subjects. This was due to higher Vmax values of Na + /H + antiport activity in cultured fibroblasts from Group 1 (52.1 ± 5.3 mmol H + /min; p 〈 0.05), Group 2 (57.7 ± 8.3; p 〈 0.05) and Group 3 (60.6 ± 7.4, p 〈 0.05) than those from Group 4 (31.2 ± 3.6) or control subjects (31.3 ± 3.5). The intracellular pH for half-maximal activation, Hill coefficient and buffering power capacity was similar in all the groups. These data suggest that in vitro phenotypic abnormalities of long-term cultured fibroblasts from NIDDM patients with microalbuminuria and/or hypertension are likely to be, at least in part, independent of the degree of metabolic control in vivo and to be an intrinsic feature of these cells. [Diabetologia (1996) 39: 717–724]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00418544
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  • 5
    Electronic Resource
    Electronic Resource
    Abnormal Na+/H+ antiport activity in cultured fibroblasts from NIDDM patients with hypertension and microalbuminuria (1996)
    Springer
    Diabetologia 39 (1996), S. 717-724 
    Details
    ISSN: 1432-0428
    Keywords: Non-insulin-dependent diabetes mellitus ; arterial hypertension ; microalbuminuria ; skin fibroblasts ; sodium-hydrogen exchange ; intracellular pH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An increased activity of Na+/H+ antiport has been reported in leukocytes and fibroblasts from insulin-dependent diabetic (IDDM) patients with nephropathy. To test whether a similar abnormality is present in fibroblasts from non-insulin-dependent diabetic (NIDDM) patients with microalbuminuria and hypertension, we examined intracellular pHi and Na+/H+ antiport activity, using the pH sensitive dye 2′, 7′-bis (2-carboxyethyl-5(6)-carboxyfluorescein (BCECF), in cultured skin fibroblasts obtained from 34 NIDDM patients, divided into four groups based upon whether they had microalbuminuria or hypertension, or both: Group 1, nine NIDDM patients with microalbuminuria and hypertension. Group 2, nine NIDDM patients with hypertension and normal albumin excretion rate. Group 3, seven NIDDM patients with microalbuminuria and normal blood pressure. Group 4, nine NIDDM patients with normal blood pressure and normal albumin excretion rate. Nine normal subjects served as control group. Resting pHi was more alkaline in fibroblasts from Group 1 (7.22±0.03; p〈0.05), Group 2 (7.21±0.02; p〈0.05) and Group 3 (7.19±0.02, p=0.17) than in Group 4 and normal subjects. This was due to higher Vmax values of Na+/H+ antiport activity in cultured fibroblasts from Group 1 (52.1±5.3 mmol H+/min; p〈0.05), Group 2 (57.7±8.3; p〈0.05) and Group 3 (60.6±7.4, p〈0.05) than those from Group 4 (31.2±3.6) or control subjects (31.3±3.5). The intracellular pH for half-maximal activation, Hill coefficient and buffering power capacity was similar in all the groups. These data suggest that in vitro phenotypic abnormalities of long-term cultured fibroblasts from NIDDM patients with microalbuminuria and/or hypertension are likely to be, at least in part, independent of the degree of metabolic control in vivo and to be an intrinsic feature of these cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00418544
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  • 6
    Electronic Resource
    Electronic Resource
    Hyperaminoacidaemia reduces insulin-mediated glucose disposal in healthy man (1985)
    Springer
    Diabetologia 28 (1985), S. 870-872 
    Details
    ISSN: 1432-0428
    Keywords: Hyperaminoacidaemia ; euglycaemic hyperinsulinaemic clamp ; glucose disposal
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine whether hyperaminoacidaemia may modify insulin-mediated glucose disposal, normal subjects were studied with the euglycaemic glucose-clamp technique, with or without an amino acid infusion, at a rate sufficient to duplicate the plasma concentration of most amino acids. Steady-state glucose infusion rates to maintain euglycaemia were 36% lower during hyperaminoacidaemia (7.3±1.0 versus 11.4±0.8mg· kg−1· min−1, p〈0.01) at comparable insulin concentrations (92±6 versus 93±7 mU/l respectively). Thus, under conditions of hyperinsulinaemia, amino acids could compete with glucose as metabolic fuels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00291080
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  • 7
    Electronic Resource
    Electronic Resource
    Hyperalaninaemia is an early feature of diabetes secondary to total pancreatectomy (1985)
    Springer
    Diabetologia 28 (1985), S. 277-281 
    Details
    ISSN: 1432-0428
    Keywords: pancreatogenic diabetes ; pancreatectomy ; glucagon ; alanine ; lactate ; pyruvate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary High levels of gluconeogenic precursors have been reported in patients with long-term diabetes secondary to total pancreatectomy. In the present study, blood concentrations of alanine, lactate and pyruvate were measured in six patients undergoing total pancreatectomy and in nine control subjects undergoing major abdominal surgery. To exclude the simple effect of lack of insulin and hyperglycaemia in the development of hyperalaninaemia following total pancreatectomy, three pancreatectomized patients and five control subjects underwent surgical operation while connected to an artificial pancreas. Blood concentration of alanine was constant in the control subjects during surgery (182±20 and 243±31 μmol/l with and without the artificial pancreas, respectively). In pancreatectomized patients basal blood alanine levels were similar to those in control subjects. Blood alanine level rose quickly after removal of the pancreas from 182±24 to 285±15 μmol/l (p〈0.05) in the patients connected to the artificial pancreas, and from 198±17 to 395±47 μmol/l (p〈0.05) in patients undergoing total pancreatectomy without artificial pancreas. These values were higher than those observed in the control subjects at the end of the operation (192±22 and 230±45 μmol/l with and without artificial pancreas, respectively.) Basal and intraoperative blood concentrations of lactate and pyruvate were similar in pancreatectomized patients and control subjects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271685
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  • 8
    Electronic Resource
    Electronic Resource
    On the estimation of absorption of subcutaneous injected insulin from plasma concentrations using mathematical models (1984)
    Springer
    Diabetologia 26 (1984), S. 314-316 
    Details
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00283657
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  • 9
    Electronic Resource
    Electronic Resource
    Ketone bodies increase glomerular filtration rate in normal man and in patients with Type 1 (insulin-dependent) diabetes mellitus (1987)
    Springer
    Diabetologia 30 (1987), S. 214-221 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; glomerular filtration rate ; ketone bodies ; albumin excretion rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The purpose of this study was to investigate whether the administration of acetoacetic and hydrochloric acids in a group of control and Type 1 (insulin-dependent) diabetic patients influenced renal haemodynamics. Renal plasma flow increased from 657±88 to 762±81 ml·min−1. 1.73 m−2 in diabetic patients (p〈0.01) and from 590±71 to 691±135 in control subjects (p〈0.01). Glomerular filtration rate increased from 135±9 to 180±8 ml·min−1·1.73 m−2 in diabetic patients (p〈 0.001) and from 117±8 to 145±7 in control subjects (p〈0.01). Similar effects on renal haemodynamics, even if less pronounced, were observed with low dose acetoacetic but not with hydrochloric acid infusion. Total protein, β2-microglobulin but not albumin excretion rates were increased by acetoacetic acid. We conclude that an acute increase in blood concentration of ketone bodies within the range found in diabetic patients with poor metabolic control (1) increases renal plasma flow and glomerular filtration rate both in control subjects and diabetic patients and (2) causes a tubular proteinuria.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00270418
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  • 10
    Electronic Resource
    Electronic Resource
    Effect of insulin replacement on intermediary metabolism in diabetes secondary to pancreatectomy (1983)
    Springer
    Diabetologia 25 (1983), S. 252-259 
    Details
    ISSN: 1432-0428
    Keywords: Pancreatogenic diabetes ; total pancreatectomy ; partial pancreatectomy ; glucagon ; free insulin ; gluconeogenesis ; intermediary metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Patients with diabetes due to pancreatectomy have metabolic features different from Type 1 (insulin-dependent) diabetes after insulin withdrawal. Whether or not glucagon by itself or combined glucagon-insulin absence are responsible for this metabolic behaviour is unknown. This study was carried out to evaluate the ability of insulin replacement to abolish differences between patients with Type 1 diabetes and patients with diabetes due to pancreatectomy. We studied the diurnal patterns of intermediary metabolites, free insulin, and glucagon using the Biostator (glucose-controlled insulin infusion system) and intensive subcutaneous insulin therapy in five patients after total pancreatectomy, five after partial pancreatectomy and seven patients with Type 1 diabetes. All were studied for 24 h after an overnight period of normoglycaemia. Insulin requirement was lower in the patients with total pancreatectomy than in patients with partial pancreatectomy or Type 1 diabetes during both types of insulin treatment (p〈 0.05). Blood glucose and free insulin were similar in all the groups in both conditions. Immunoreactive glucagon was higher in the patients with diabetes secondary to pancreatectomy than in Type 1 diabetic patients. However, glucagon levels did not increase after arginine infusion in the patients with total pancreatectomy, and column chromatography of blood samples from two totally pancreatectomized patients showed no significant levels of immunoreactive pancreatic glucagon. Non-esterified fatty acids and ketone bodies were similar during Biostator and intensive subcutaneous insulin therapy. By contrast, gluconeogenic precursors (lactate, pyruvate, alanine and glycerol) were higher in patients with total pancreatectomy than in patients with partial pancreatectomy and Type 1 diabetes. In particular, alanine was significantly higher in the patients with total pancreatectomy (400±50 μmol/l during Biostator; 437±62 μmol/l during intensive subcutaneous insulin therapy) than in patients with partial pancreatectomy (207±13 μmol/l, p〈0.005 and 226±14 μmol/l, p〈0.005) and in Type 1 diabetic patients (191±11 μmol/l, p〈0.005 and 216±10 μmol/l, p〈0.005). Our data show that the high levels of gluconeogenic precursors, already reported in patients with diabetes due to total pancreatectomy after insulin withdrawal, do not become normal even in the presence of insulin. This finding shows that gluconeogenesis is primarily dependent on pancreatic glucagon and confirms the role of glucagon in the development of diabetic hyperglycaemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279939
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