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Geremia B Bolli

Publications and source records attributed to Geremia B Bolli.

17 recordsLinked to original sources
PubMed2006

Fluctuation of serum basal insulin levels following single and multiple dosing of insulin glargine.

BACKGROUND: The large fluctuations in blood concentrations and activity observed with insulin therapies such as NPH insulin or insulin ultralente may result in hyper- or hypoglycemia. METHODS: We compared the fluctuations of these insulins with the long-acting basal insulin analog insulin glargine as a re-analysis of three Phase I studies: (I) glargine with NPH or ultralente [single-dose (0.4 IU/kg), randomized study in healthy volunteers (n = 36)]; (II) glargine or NPH [single-dose (0.3 IU/kg), randomized study in patients with diabetes mellitus Type 1 (DMT1) (n = 20)]; and (III) glargine (tailor-made dose) plus insulin lispro in DMT1 (n = 15 over 11 days). Percent deviation around average serum concentration over 24 h (PF24) was used to determine within-patient fluctuation and mean fluctuation value for each treatment group. RESULTS: Mean PF24 in healthy volunteers (Study I) was significantly lower with glargine (19.8%) than with NPH and ultralente (31.9% and 47.2%, respectively; both P < 0.001 vs. glargine). Similarly, about half the fluctuation observed with NPH (PF24 25.8%) was seen with glargine (PF24 14.2%; P < 0.001) in DMT1 (Study II). In ambulatory DMT1 patients receiving multiple glargine doses, PF24 values demonstrated that the same low fluctuations (PF24 20%) were retained throughout near-maintenance treatment (Study III). CONCLUSIONS: Glargine provided less diurnal fluctuation in serum insulin levels than NPH and ultralente in healthy volunteers and patients with DMT1. This lower fluctuation of glargine over NPH or ultralente can help to reduce hyper- or hypoglycemia risks associated with insulin therapy and accordingly encourage achievement of better blood glucose control.

Adolescent↗
PubMed2005

Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations.

BACKGROUND: Growing evidence indicates that the administration of large amounts of ghrelin to humans increases circulating concentrations of several pituitary and adrenal hormones, induces hyperglycemia and reduces serum insulin concentrations. At present, it is not known whether physiological increments in plasma ghrelin concentrations affect glucose kinetics or hormone concentrations in humans. METHODS AND RESULTS: We compared the effects of two- and three-fold increments in plasma ghrelin concentrations in eight healthy subjects during a 2 h intravenous infusion of 7.5 (GHRE7.5), 15 (GHRE15) pmol kg(-1) min(-1) acylated human ghrelin or placebo (PL), in a randomized double-blind study. Compared with PL (146 +/- 24 pM) plasma ghrelin concentrations increased at 120 min (p<0.001) about two-fold after GHRE7.5 (300 +/- 35 pM) and three-fold after GHRE15 (494 +/- 30 pM). GHRE15 significantly increased circulating concentrations of NEFA, GH, ACTH, epinephrine, and prolactin (p<0.01). GHRELIN7.5 significantly (p<0.01) increased only serum GH concentrations. Neither ghrelin infusions changed glucose flux or circulating concentrations of glucose, insulin, C-peptide, glucagon, IGF-1, cortisol and norepinephrine. CONCLUSIONS: GH secretion is the only response that is stimulated by physiological increments in plasma ghrelin concentrations; about three-fold increases in plasma ghrelin concentrations are required to elicit the responses of epinephrine, prolactin, ACTH and NEFA.

Acylation↗
PubMed2003

Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus.

OBJECTIVES: The aim of our study was to assess whether acute, short-term hyperglycemia affects platelet reactivity in patients with Type II diabetes mellitus (T2DM). BACKGROUND: Hyperglycemic spikes are thought to precipitate ischemic events in T2DM. Previous studies have shown in vivo platelet activation in diabetes; however, no studies have assessed whether acute in vivo hyperglycemia induces further activation of platelets. METHODS: In a cross-over, randomized, double-blind study, 12 patients with T2DM underwent 4 h of either acute hyperglycemia (13.9 mmol/l, 250 mg/dl) or euglycemia (5.5 mmol/l, 100 mg/dl). Shear stress-induced platelet activation, P-selectin and lysosomal integral membrane protein (LIMP) expression on platelets in the bleeding-time blood, urinary 11-dehydro-thromboxane B(2) (TxB(2)) excretion, von Willebrand factor:antigen (vWF:Ag), and von Willebrand factor:activity (vWF:activity) were measured before and after hyperglycemia or euglycemia. RESULTS: Shear stress-induced platelet activation, P-selectin and LIMP expression on platelets in the bleeding-time blood, and urinary 11-dehydro-TxB(2) excretion increased significantly after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. Plasma vWF:Ag and vWF:activity increased strikingly in parallel fashion after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. CONCLUSIONS: Our data demonstrate that acute, short-term hyperglycemia induces an increased activation of platelets exposed to high shear stress conditions in vitro (filtration method) or in vivo (bleeding time). In vivo platelet activation is reflected by an increased urinary excretion of 11-dehydro-TxB(2). The increased levels of vWF in the circulation correlate with the increase in platelet activation markers and may indicate some degree of causation. Acute, short-term hyperglycemia in T2DM may precipitate vascular occlusions by facilitating platelet activation.

Acute Disease↗
PubMed2003

Insulin- and exercise-stimulated skeletal muscle blood flow and glucose uptake in obese men.

OBJECTIVE: Insulin resistance in obese subjects results in the impaired use of glucose by insulin-sensitive tissues, e.g., skeletal muscle. In the present study, we determined whether insulin resistance in obesity is associated with an impaired ability of exercise to stimulate muscle blood flow, oxygen delivery, or glucose uptake. RESEARCH METHODS AND PROCEDURES: Nine obese (body mass index = 36 +/- 2 kg/m(2)) and 11 age-matched nonobese men (body mass index = 22 +/- 1 kg/m(2)) performed one-legged isometric exercise during hyperinsulinemia. Rates of femoral muscle blood flow, oxygen consumption, and glucose uptake were measured simultaneously in both legs using [(15)O]H(2)O, [(15)O]O(2), [(18)F]fluoro-deoxy-glucose, and positron emission tomography. RESULTS: The obese subjects exhibited resistance to insulin stimulation of glucose uptake in resting muscle, regardless of whether glucose uptake was expressed per kilogram of femoral muscle mass (p = 0.001) or per the total mass of quadriceps femoris muscle. At similar workloads, oxygen consumption, blood flow, and glucose uptake were lower in the obese than the nonobese subjects when expressed per kilogram of muscle, but similar when expressed per quadriceps femoris muscle mass. DISCUSSION: We conclude that obesity is characterized by insulin resistance of glucose uptake in resting skeletal muscle regardless of how glucose uptake is expressed. When compared with nonobese individuals at similar absolute workloads and under identical hyperinsulinemic conditions, the ability of exercise to increase muscle oxygen uptake, blood flow, and glucose uptake per muscle mass is blunted in obese insulin-resistant subjects. However, these defects are compensated for by an increase in muscle mass.

Adult↗
PubMed2003

Counterregulatory hormone and symptom responses to insulin-induced hypoglycemia in the postprandial state in humans.

Plasma counterregulatory hormones and symptoms were measured during hypoglycemia in the postprandial and in the fasting state in humans to establish differences in physiological responses. We studied 8 nondiabetic subjects and 10 subjects with type 1 diabetes on two different occasions during clamped insulin-induced hypoglycemia (2.4 mmol/l) in the sitting position. On one occasion, subjects ate a standard mixed meal, and on the other they remained fasting. In response to postprandial as compared with fasting hypoglycemia, nondiabetic subjects exhibited lower total symptom scores (6.6 +/- 0.4 vs. 11.5 +/- 0.8, P = 0.001), which was due to less hunger (1.1 +/- 0.1 vs. 4.2 +/- 0.2), lower suppression of plasma C-peptide (0.23 +/- 0.1 vs. 0.08 +/- 0.07 nmol/l, P = 0.032), and greater responses of plasma glucagon (248 +/- 29 vs. 163 +/- 25 ng x l(-1) x min(-1), P = 0.018), plasma adrenaline (4.5 +/- 0.6 vs. 3.1 +/- 0.4 nmol x l(-1) x min(-1), P = 0.037), norepinephrine (3.8 +/- 0.3 vs. 3.2 +/- 0.2 nmol x l(-1) x min(-1), P = 0.037), and pancreatic polypeptide (217 +/- 12 vs. 159 +/- 22 pmol x l(-1) x min(-1), P = 0.08). Except for plasma C-peptide, responses in diabetic subjects were similarly affected. Notably, in diabetic subjects responses of glucagon, which were absent in the fasting state, nearly normalized after a meal. In conclusion, in the postprandial compared with the fasting hypoglycemic state, total symptoms are less, but counterregulatory hormones are greater and responses of glucagon nearly normalize in type 1 diabetic subjects.

Adult↗
PubMed2003

Insulin is required for prandial ghrelin suppression in humans.

Accumulating evidence indicates that ghrelin plays a role in regulating food intake and energy homeostasis. In normal subjects, circulating ghrelin concentrations decrease after meal ingestion and increase progressively before meals. At present, it is not clear whether nutrients suppress the plasma ghrelin concentration directly or indirectly by stimulating insulin secretion. To test the hypothesis that insulin regulates postprandial plasma ghrelin concentrations in humans, we compared the effects of meal ingestion on plasma ghrelin levels in six C-peptide-negative subjects with type 1 diabetes and in six healthy subjects matched for age, sex, and BMI. Diabetic subjects were studied during absence of insulin (insulin withdrawal study), with intravenous infusion of basal insulin (basal insulin study) and subcutaneous administration of a prandial insulin dose (prandial insulin study). Meal intake suppressed plasma ghrelin concentrations (nadir at 105 min) by 32 +/- 4% in normal control subjects, 57 +/- 3% in diabetic patients during the prandial insulin study (P < 0.002 vs. control subjects), and 38 +/- 8% during basal insulin study (P = 0.0016 vs. hyperinsulinemia; P = NS vs. control subjects) but did not have any effect in the insulin withdrawal study (P < 0.001 vs. other studies). In conclusion, 1). insulin is essential for meal-induced plasma ghrelin suppression, 2). basal insulin availability is sufficient for postprandial ghrelin suppression in type 1 diabetic subjects, and 3). lack of meal-induced ghrelin suppression caused by severe insulin deficiency may explain hyperphagia of uncontrolled type 1 diabetic subjects.

Adult↗
PubMed2003

Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime.

OBJECTIVE: To establish differences in blood glucose between different regimens of optimized basal insulin substitution in type 1 diabetic patients given lispro insulin at meals, i.e., NPH injected four times a day versus glargine insulin once daily at dinner or at bedtime. RESEARCH DESIGN AND METHODS: A total of 51 patients with type 1 diabetes on intensive therapy (NPH four times/day and lispro insulin at each meal) were randomized to three different regimens of basal insulin substitution while continuing lispro insulin at meals: continuation of NPH four times/day (n = 17), once daily glargine at dinnertime (n = 17), and once daily glargine at bedtime (n = 17) for 3 months. Blood glucose targets were fasting, preprandial, and bedtime concentrations at 6.4-7.2 mmol/l and 2 h after meals at 8.0-9.2 mmol/l. The primary end point was HbA(1c). RESULTS: Mean daily blood glucose was lower with dinnertime glargine (7.5 +/- 0.2 mmol/l) or bedtime glargine (7.4 +/- 0.2 mmol/l) versus NPH (8.3 +/- 0.2 mmol/l) (P < 0.05). A greater percentage of blood glucose values were at the target value with glargine at dinner and bedtime versus those with NPH (P < 0.05). HbA(1c) at 3 months did not change with NPH but decreased with glargine at dinnertime (from 6.8 +/- 0.2 to 6.4 +/- 0.1%) and glargine at bedtime (from 7.0 +/- 0.2 to 6.6 +/- 0.1%) (P < 0.04 vs. NPH). Total daily insulin doses were similar with the three treatments, but with glargine there was an increase in basal and a decrease in mealtime insulin requirements (P < 0.05). Frequency of mild hypoglycemia (self-assisted episodes, blood glucose < or =4.0 mmol/l) was lower with glargine (dinnertime 8.1 +/- 0.8 mmol/l, bedtime 7.7 +/- 0.9 mmol/l) than with NPH (12.2 +/- 1.3 mmol/l) (episodes/patient-month, P < 0.04). In-hospital profiles confirmed outpatient blood glucose data and indicated more steady plasma insulin concentrations at night and before meals with glargine versus NPH (P < 0.05). There were no differences between glargine given at dinnertime and at bedtime. CONCLUSIONS: Regimens of basal insulin with either NPH four times/day or glargine once/day in type 1 diabetic patients both result in good glycemic control. However, the simpler glargine regimen decreases the HbA(1c) level and frequency of hypoglycemia versus NPH. In contrast to NPH, which should be given at bedtime, insulin glargine can be administered at dinnertime without deteriorating blood glucose control.

Adult↗
PubMed2003

Rational use of insulin analogues in the treatment of type 1 diabetes mellitus.

Long-term near-normoglycaemia in Type 1 diabetes protects against the onset and/or progression of microangiopathic complications. To successfully reach the goal while avoiding the risk of hypoglycaemia and hypoglycaemia unawareness, insulin therapy has to be physiological. Mealtime insulin should be given as a bolus injection before, or both before and after, a meal. In addition, basal insulin between meals should be replaced by an insulin preparation with a square wave action profile. Rapid-acting insulin analogues are the mealtime insulin preparations of choice. Either continuous subcutaneous insulin infusion (CSII), or once day injection of the long-acting insulin analogue glargine is required to optimally replace basal insulin. In Type 1 diabetes the benefits of mealtime treatment with rapid-acting insulin analogues become apparent only to the extent to which replacement of basal insulin is optimised at the same time. This has been difficult in the past with the peak insulin NPH, but it is nowdays easier with the nearly peakless long-acting insulin analogue glargine. As compared to NPH, glargine reduces the risk for nocturnal hypoglycaemia, and at the same time improves HbA1c similarly to CSII.

Diabetes Mellitus, Type 1↗
PubMed2002

Administration of neutral protamine Hagedorn insulin at bedtime versus with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia and improve control. A randomized, controlled trial.

BACKGROUND: Intensive insulin treatment of type 1 diabetes mellitus increases the risk for nocturnal hypoglycemia. OBJECTIVE: To demonstrate that splitting the evening insulin regimen reduces the risk for nocturnal hypoglycemia in intensive treatment of type 1 diabetes mellitus. DESIGN: Randomized, open, two-treatment crossover trial in two 4-month periods. SETTING: University research center in Italy. PATIENTS: 22 C-peptide-negative persons with type 1 diabetes mellitus (mean age [+/-SD], 29 +/- 3 years). INTERVENTIONS: Each patient was randomly assigned to one of two insulin regimens for 4 months and then switched to the other regimen for another 4 months. The two treatment regimens were 1) mixed treatment--a mixture of human regular and neutral protamine Hagedorn (NPH) insulin administered before dinner and 2) split treatment--human regular insulin administered at dinner and NPH insulin administered at bedtime. MEASUREMENTS: Frequency of nocturnal hypoglycemia. Secondary end points were levels of fasting blood glucose and hemoglobin A1c and responses to experimental hypoglycemia. RESULTS: During the split-regimen treatment period, patients had fewer episodes of nocturnal hypoglycemia (mean [+/-SE], 0.10 +/- 0.02 episode/patient-day vs. 0.28 +/- 0.04 episode/patient-day; P = 0.002), a lower fasting blood glucose level (mean [+/-SE], 7.6 +/- 0.2 mmol/L vs. 8.3 +/- 0.5 mmol/L [137 +/- 4 mg/dL vs. 160 +/- 8 mg/dL]; P = 0.030), less variable fasting blood glucose levels (SD range, 2.0 +/- 0.4 vs. 3.5 +/- 0.6; P = 0.001), and lower hemoglobin A1c value (mean [+/-SE], 7.0% +/- 0.11% vs. 7.5% +/- 0.15%; P = 0.004) than during the mixed regimen. Responses to experimental hypoglycemia were better preserved with the split regimen than with the mixed regimen. CONCLUSION: When the goal of insulin therapy in type 1 diabetes mellitus is near-normoglycemia, splitting the evening insulin treatment regimen into short-acting insulin at dinner and NPH insulin at bedtime reduces the risks for nocturnal hypoglycemia and hypoglycemia unawareness and decreases the hemoglobin A1c value compared with mixing short-acting insulin and NPH insulin at dinner.

Adult↗
PubMed2002

Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia.

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia. To answer this question, we compared plasma ghrelin concentrations after a short-term insulin infusion that was allowed or not (euglycemic clamp) to cause hypoglycemia (2.7 +/- 0.2 mmol/l at 30 min) in five healthy volunteers. In both studies, plasma ghrelin concentrations decreased (P < 0.01) after insulin infusion (hypoglycemia by 14%, euglycemia by 22%), reached a nadir at 30 min, and returned to baseline at 60 min, without differences between the hypoglycemia and the euglycemia studies. Glucagon, cortisol, and GH increased in response to hypoglycemia despite the decreased ghrelin. There was a strong correlation (R(2) = 0.91, P < 0.002) between the insulin sensitivity of the subjects and the percentage suppression of ghrelin from baseline. These data demonstrate that ghrelin is not required for the hormonal defenses against insulin-induced hypoglycemia and that insulin can suppress ghrelin levels in healthy humans. These results raise the possibility that postprandial hyperinsulinemia is responsible for the reduction of plasma ghrelin that occurs during meal intake.

Adult↗
PubMed2002

Clinical strategies for controlling peaks and valleys: type 1 diabetes.

The DCCT and UKPDS have established that in type 1 and in type 2 diabetes respectively, long-term near-normoglycaemia protects against the onset and/or progression of microangiopathic complications. Therefore, insulin strategies to maintain long-term near-normoglycaemia are of key importance in the management of diabetes. To successfully achieve near-normoglycaemia, insulin therapy must mimic nature by providing a bolus of insulin at meal ingestion and by replacing basal insulin between meals and overnight Mealtime insulin needs can be best met by subcutaneous (s.c.) injection of a rapid-acting insulin analogue such as insulin lispro or insulin aspart. Rapid-acting insulin analogues are preferred to human regular insulin for three reasons: convenience (meal-time injection, better adaptation of insulin dose to carbohydrate content of the meal); lower blood glucose 2 hours after meals; and less risk for late postprandial hypoglycaemia. However, in type 1 diabetes the benefits of mealtime treatment with rapid-acting insulin analogues become apparent only to the extent that replacement of basal insulin is optimised. The interprandial need for basal insulin can be best met by continuous s.c. insulin infusion (CSII). CSII is very good for basal insulin replacement because it uses a rapid-acting insulin analogue with low variability in s.c. absorption, resulting in a flat and peakless action profile. A second option for basal insulin replacement is s.c. injection of an insulin preparation with retarded action. The two most commonly used are NPH and insulin glargine. NPH exhibits an action profile with a peak 4 to 5 hours after injection and duration of action of 10 to 15 hours. Insulin glargine has a peakless action profile and lasts approximately 24 hours. To optimise replacement of basal insulin with NPH, a few units of NPH must be combined with rapid-acting analogues at meals and also given at bedtime (0.2 U/kg). With insulin glargine, 0.2 to 0.4 U/kg should be injected once or, in some patients, twice daily. Modern insulin strategies for intensive therapy should include use of a rapid-acting insulin analogue at meal-time, and use of CSII to replace basal insulin. Insulin glargine reproduces closely the pharmacokinetics and pharmacodynamics of CSII and should be considered for substitution of basal insulin, especially in type 1 diabetes.

Diabetes Mellitus, Type 1↗
PubMedDate not supplied

Insulin therapy and hypoglycaemia: the size of the problem.

BACKGROUND AND METHODS: Hypoglycaemia is a fact of life for people with diabetes mellitus. Mild, asymptomatic episodes occur once or twice a week in insulin-treated diabetic subjects. Asymptomatic hypoglycaemia, including nocturnal hypoglycaemia, occurs in about 25% of diabetic subjects treated with insulin therapy. Mild hypoglycaemia, if recurrent, induces unawareness of hypoglycaemia and impairs glucose counterregulation, which in turn predisposes to severe hypoglycaemia. Even brief hypoglycaemia can cause profound dysfunction of the brain. Prolonged, severe hypoglycaemia can cause permanent neurological sequels. In addition, it is possible that hypoglycaemia may accelerate the vascular complications of diabetes by increasing platelet aggregation and/or fibrinogen formation. Finally, hypoglycaemia may be fatal. Hypoglycaemia induced by insulin as treatment of type 1 diabetes mellitus (T1 DM) is not the consequence of diabetes, but invariably of the non-physiological replacement of insulin. RESULTS: A number of studies have demonstrated that by moving from non-physiological to more physiological models of insulin therapy, most of the hypoglycaemia problems may be overcome, the percentage of glycated hemoglobin (A1c) decreased, and the quality of life improved. Interestingly, in T1 DM with hypoglycaemia unawareness, prevention of hypoglycaemia reverses not only unawareness but also improves glucose counterregulation, primarily the responses of adrenaline. CONCLUSIONS: In order to best prevent hypoglycaemia, insulin should preferably be given as continuous subcutaneous infusion via a minipump (the 'golden standard') or multiple daily insulin administrations with insulin analogues (basal insulin glargine, meal insulin rapid-acting insulin analogues) in T1 DM.

Awareness↗
PubMedDate not supplied

Insulin treatment in type 1 diabetes.

OBJECTIVE: To present key aspects and strategies for use of insulin therapy in patients with type 1 diabetes mellitus. METHODS: Limitations and advantages of various insulin regimens are discussed, and issues pertaining to insulin analogues are reviewed. RESULTS: Rapid-acting insulin analogues provide better and safer postprandial glucose coverage than does human regular insulin. Premixed insulin preparations do not provide the flexibility to address the individual needs of patients adequately to control postprandial glucose excursions. Because of its peak, short duration, and high variability, NPH insulin is inappropriate for patients with type 1 diabetes and patients with type 2 diabetes who require continuous basal coverage. Continuous infusion of soluble insulin by means of an insulin pump is currently the most physiologic approach available for treatment of type 1 diabetes. Use of insulin glargine or insulin detemir with a rapid-acting insulin analogue at meals is an effective and reasonable alternative to insulin pump therapy. CONCLUSION: Both rapid-acting and long-acting insulin analogues improve glycemic control. This improvement involves controlling hemoglobin A1c levels, reducing glucose excursions, and decreasing hypoglycemia, particularly during the night. Clinicians should prescribe insulin regimens that yield physiologic results in patients with type 1 diabetes.

Blood Glucose↗
PubMedDate not supplied

Long-term intervention studies using insulin in patients with type 1 diabetes.

OBJECTIVE: To discuss data from long-term intervention studies regarding therapy in type 1 diabetes and review strategies for preventing hypoglycemia and safely achieving glycemic goals in this patient population. METHODS: The shortcomings of traditional models of insulin therapy are elucidated, and the need for physiologic insulin replacement is emphasized. RESULTS: An estimated more than 10 million patients will have type 1 diabetes worldwide within the next 20 years. Twice-daily injection of premixed or self-mixed insulin is the most common insulin regimen; however, this therapeutic strategy is also a major contributor to hypoglycemia and, eventually, hypoglycemia unawareness. Hypoglycemia unawareness in patients with type 1 diabetes has been found to be largely reversible. Moreover, intensive insulin therapy may prevent hypoglycemia and maintain glycemic targets. The most physiologic regimen of insulin available is continuous subcutaneous insulin infusion with an insulin pump; however, insulin glargine is a useful alternative to pump therapy. CONCLUSION: Use of today's rapid- and long-acting insulin analogues in intensive management protocols not only improves glycemic control but also reduces the risk of hypoglycemia. Therefore, safe achievement and maintenance of target glycemic goals are possible.

Blood Glucose↗