Fausto Santeusanio

Acute Antihyperglycemic Mechanisms of Metformin in NIDDM: Evidence for Suppression of Lipid Oxidation and Hepatic Glucose Production

To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus (NIDDM) independently of the long-term, aspecific effects of removal of glucotoxicity, 21 NIDDM subjects (14 obese, 7 nonobese) were studied on two separate occasions, with an isoglycemic (plasma glucose ∼9 mM) hyperinsulinemic (two-step insulin infusion, 2 h each, at the rate of 4 and 40 mU · m−2 · min−1) clamp combined with [3−3H]glucose infusion and indirect calorimetry, after administration of either metformin (500 mg per os, at –5 and –1 h before the clamp) or placebo. Compared with placebo, hepatic glucose production (HGP) decreased ∼30% more after metformin (from 469 ± 50 to 330 ± 54 μmol/min), but glucose uptake did not increase. Metformin suppressed free fatty acids (FFAs) by ∼17% (from 0.42 ± 0.04 to 0.35 ± 0.04 mM) and lipid oxidation by ∼25% (from 4.5 ± 0.4 to 3.4 ± 0.4 μmol · kg−1 · min−1) and increased glucose oxidation by ∼ 16% (from 16.2 ± 1.4 to 19.3 ± 1.3 μmol.kg−1 · min−1) compared with placebo (P < 0.05), but did not affect nonoxidative glucose metabolism, protein oxidation, or total energy expenditure. Suppression of FFA and lipid oxidation after metformin correlated with suppression of HGP (r = 0.70 and r = 0.51, P < 0.001). The effects of metformin in obese and nonobese subjects were no different. We conclude that the specific, antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP, not stimulation of glucose uptake, and are mediated, at least in part, by suppression of FFA and lipid oxidation.

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

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

A Multicenter Study on the Prevalence of Diabetic Neuropathy in Italy

OBJECTIVE The prevalence of neuropathy, a common complication of diabetes, was determined in diabetic patients recruited from 109 outpatient diabetes clinics in Italy. RESEARCH DESIGN AND METHODS Neuropathy was diagnosed using the Diabetic Neuropathy Index (DNI), a standardized examination developed for use in the outpatient setting. A total of 8,757 diabetic patients were studied, 51.2% men and 48.8% women, with average and median ages of 56 and 58 years, respectively. RESULTS Of the 8,757 patients, 32.3% had neuropathy, defined as a positive score of > 2 points on the DNI. A total of 2,033 (49.6% men and 50.4% women) were administered the Diabetic Neuropathy Score (DNS), the second component of the screening program, by a neurologist. This component consists of a quantitative neurological examination and nerve conduction studies that together provide a summated score. A total of 335 patients (16.5%) were not neuropathic, and 395 (19.4%) had borderline, 453 (22.3%) mild, 592 (29.1%) moderate, and 258 (12.7%) severe neuropathy. The concordance between a positive score on the DNI and a DNS indicating neuropathy was 83.5%. The severity of neuropathy increased with both age and disease duration. Of patients with neuropathy, 64.1% had an average age between 58 and 59 years with a disease duration between 12.4 ± 8.4 years (mild neuropathy) and 15.6 ± 9.7 years (severe neuropathy). CONCLUSIONS Neuropathy is a common complication of diabetes and, in this study, was present in 32.3% of all patients. An increased awareness of the high prevalence of neuropathy can lead to early therapeutic intervention and possible prevention of later neuropathic complications, such as infection and foot ulcers.

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

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

Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes?

This study investigated whether alterations in bone mineral content (BMC) and/or in the phosphate-calcium metabolism exist in non-insulin-dependent diabetes mellitus (NIDDM); whether they are linked to glycaemic control and whether antidiabetic therapy--oral agents or insulin--influences BMC and mineral metabolism. A cross-section assessment compared BMC and mineral metabolism in 60 well-controlled and 50 poorly controlled diabetic patients under oral hypoglycaemic therapy with 50 healthy controls. A longitudinal assessment improved the high glucose levels of the poorly controlled diabetic group either by increasing oral treatment or by adding a bedtime NPH insulin. Glycaemic control, BMC and mineral metabolism were followed-up for 1 year. In NIDDM patients BMC is reduced. This reduction is more marked in poorly controlled diabetic patients. In well-controlled diabetes osteocalcin levels are low. In poorly controlled patients glycosuria, hypercalcuria and parathyroid hyperactivity are present. In both groups vitamins 25(OH)-D, 1,25(OH)2-D and calcitonin levels are normal. Improving metabolic control increased BMC, normalized urinary calcium excretion and parathyroid activity and reduced osteocalcin levels. The type of anti-diabetic therapy does not have any significant effect upon BMC or upon phosphate-calcium metabolism. In conclusion, in NIDDM a hard-to-define osteoblast deficit appears to exist. In poorly controlled diabetes the loss of BMC is aggravated by the negative calcium balance caused by the renal calcium leak. This is due to glucosuric-induced osmotic diuresis and is maintained by parathyroid activation.

Physiological Increments in Plasma Insulin Concentrations Have Selective and Different Effects on Synthesis of Hepatic Proteins in Normal Humans

These studies tested the hypothesis that physiological increments in plasma insulin concentrations have selective effects on the synthesis of hepatic proteins in humans. Leucine kinetics and fractional synthetic rates of albumin, fibrinogen, antithrombin III, and apoB-100 were determined in 6 normal subjects, on two different occasions during either the infusion of saline (control study) or a euglycemic-hyperinsulinemic (0.4 mU.kg−1 · min−1 for 240 min) clamp, by a primed-constant infusion of [1-14C]Leu. The insulin infusion significantly decreased the rates of nonoxidative Leu disposal (1.70 ± 0.10 vs. control 2.06 ± 0.09 mol.kg−1 · min−1), increased the albumin (7.2 ± 0.4 vs. 6.2 ± 0.6%/day), decreased the fibrinogen (18 ± 1 vs. 23 ± 2%/day), and antithrombin III (28 ± 3 vs. 40 ± 4%/day) fractional synthetic rate, whereas it did not affect the total apoB-100 (49 ± 5 vs. 52 ± 6%/day) fractional synthetic rate. Thus, the insulin-induced decrement in the estimates of whole-body protein synthesis (nonoxidative Leu disposal) represents the mean result of opposite effects of hyperinsulinemia on the synthesis of proteins with different functions. The positive effect of insulin on albumin synthesis may play an important anabolic role during nutrient absorption by promoting the capture of a relevant amount of dietary essential amino acids into the protein, whereas the negative effect of insulin on fibrinogen synthesis might, at least partially, account for the increased plasma fibrinogen concentrations previously reported in poorly controlled diabetic patients.

Effects of whole-body vibration exercise on the endocrine system of healthy men.

Whole-body vibration is reported to increase muscle performance, bone mineral density and stimulate the secretion of lipolytic and protein anabolic hormones, such as GH and testosterone, that might be used for the treatment of obesity. To date, as no controlled trial has examined the effects of vibration exercise on the human endocrine system, we performed a randomized controlled study, to establish whether the circulating concentrations of glucose and hormones (insulin, glucagon, cortisol, epinephrine, norepinephrine, GH, IGF-1, free and total testosterone) are affected by vibration in 10 healthy men [age 39±3, body mass index (BMI) of 23.5±0.5 kg/m2, mean±SEM]. Volunteers were studied on two occasions before and after standing for 25 min on a ground plate in the absence (control) or in the presence (vibration) of 30 Hz whole body vibration. Vibration slightly reduced plasma glucose (30 min: vibration 4.59±0.21, control 4.74±0.22 mM, p=0.049) and increased plasma norepinephrine concentrations (60 min: vibration 1.29±0.18, control 1.01±0.07 nM, p=0.038), but did not change the circulating concentrations of other hormones. These results demonstrate that vibration exercise transiently reduces plasma glucose, possibly by increasing glucose utilization by contracting muscles. Since hormonal responses, with the exception of norepinephrine, are not affected by acute vibration exposure, this type of exercise is not expected to reduce fat mass in obese subjects.

Clustering of albumin excretion rate abnormalities in Caucasian patients with NIDDM

Summary Proteinuria and nephropathy have been found to cluster in families of non-insulin-dependent diabetic (NIDDM) Pima Indian, and in Caucasian insulin-dependent diabetic (IDDM) patients. No information is at present available for Caucasian NIDDM patients. The aim of the present study was to determine whether micro-macroalbuminuria (AER + ) is associated with albumin excretion rate abnormalities in diabetic and non-diabetic siblings of probands with NIDDM and AER + . We identified 169 Caucasian families with one NIDDM proband (the patient with longest known NIDDM duration) (101 families with only NIDDM siblings, 33 families with both NIDDM and non-NIDDM siblings and 35 families with only non-NIDDM siblings). Of the probands 56 had AER + [Prob-NIDDM-(AER + )], 78 had AER– [Prob-NIDDM-(AER–)], 74 siblings of Prob-NIDDM-(AER + ), and 113 siblings of Prob-NIDDM-(AER–) also had NIDDM. Data on albuminuria and retinopathy from multiple sibling pairs when the size of the sibship was more than two was adjusted according to a weighting factor. The odds ratio for AER + , in siblings of Prob-NIDDM-(AER + ) adjusted for age, hypertension, glycated haemoglobin A1 c and other confounding variables was 3.94 (95 % confidence intervals: 1.93–9.01) as compared to siblings of Prob-NIDDM-(AER–). The 74 siblings of Prob-NIDDM-(AER + ) had higher prevalence of proliferative retinopathy than siblings of Prob-NIDDM-(AER–) (14 vs 2 %; p < 0.01). We also identified 66 non-diabetic siblings of 41 NIDDM probands with AER + and 36 non-diabetic siblings of 27 NIDDM probands with AER–. Albumin excretion was two times higher, although still within the normal range, in the non-diabetic siblings of Prob-NIDDM-(AER + ) than in siblings of Prob-NIDDM-(AER–) [median = 13.5 (range 0.5–148) vs 6.6 (range 1–17) μg/min (p < 0.05)]. In conclusion higher rates of albumin excretion aggregate in Caucasian families with NIDDM. Proliferative retinopathy is more frequently observed in families showing a clustering of AER + and NIDDM. These findings suggest that familial factors play a role in the pathogenesis of renal and retinal complications in NIDDM. [Diabetologia (1997) 40: 816–823]

Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies

Glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) in type 2 diabetic subjects with secondary failure to sulphonylurea treatment identify the so‐called latent autoimmune diabetes of the adult (LADA). The aim of our study was to estimate the risk for endocrine autoimmunity in type 2 diabetic subjects with GAD65Ab.

Nocturnal spikes of growth hormone secretion cause the dawn phenomenon in Type 1 (insulin-dependent) diabetes mellitus by decreasing hepatic (and extrahepatic) sensitivity to insulin in the absence of insulin waning

SummaryThe aim of the present studies was to test the hypothesis that the dawn phenomenon in Type 1 (insulin-de-pendent) diabetes mellitus is due to a decrease in insulin sensitivity caused by nocturnal spikes of growth hormone. Twelve subjects with Type 1 diabetes were studied on two different occasions, from 24.00 to 02.00 hours, and from 06.00 to 08.00 hours with the euglycaemic clamp technique at two plasma free insulin levels (≈25 mU/l,n=7; ≈80 mU/l,n=5). To eliminate the confounding factor of insulin waning of previous Biostator studies, prior to clamp experiments the diabetic subjects were infused with i.v. insulin by means of a syringe pump according to their minute-to-minute insulin requirements. Insulin sensitivity decreased at dawn as compared to the early night hours (≈30% increase in the rate of hepatic glucose production, ≈25% decrease in the rate of peripheral glucose utilisation). Plasma insulin clearance did not change overnight. In seven Type 1 diabetic subjects, suppression of nocturnal spikes of growth hormone secretion by somatostatin during basal glucagon and growth hormone replacement resulted in complete abolition of the increased rate of hepatic glucose production at dawn. Replacement of nocturnal spikes of growth hormone faithfully reproduced the increase in hepatic glucose production at dawn of the control study. It is concluded that the dawn phenomenon in Type 1 diabetes mellitus examined during optimal insulin replacement, first, is due solely to a decrease in insulin sensitivity and not to an increase in insulin clearance; second, that the decrease in insulin sensitivity at dawn takes place both in the liver and peripheral tissues; third, that the decrease in hepatic (and most likely extrahepatic) insulin sensitivity at dawn is caused by nocturnal spikes of growth hormone secretion.