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Localized lesions at the foot skeleton are a serious and well recognized complication of diabetes mellitus which may impair the clinical outcome of the patients remarkably. In contrast, the presence of a generalized bone disease or osteoporosis related to diabetes mellitus is less acknowledged and its clinical relevance is less obvious. This paper is a clinically focused review of the literature on osteoporosis related to diabetes mellitus. Due to the different pathogenesis of diabetes mellitus type 1 and type 2 it is not surprising that there is no uniform entity of diabetic osteopathy. The majority of clinical studies in subjects with diabetes mellitus type 1 showed a moderately decreased bone mass at the forearm, while bone mass at the femur or lumbar spine was either decreased or not different from non-diabetic controls. In patients with diabetes mellitus type 2 the risk of osteopenia is not as clear as in type 1 diabetes. Bone mineral density at the forearm in patients with type 2 diabetes mellitus was decreased, unchanged or even increased in comparison to controls, while bone mineral density at the vertebrae or femoral neck was either not significantly different or increased, but rarely decreased. The underlying mechanisms triggering changes in bone mass in patients with diabetes mellitus type 1 and type 2 are not well known. In most studies there was no consistent relationship between the metabolic control of diabetes and bone mineral density. Biochemical parameters of the calcium and bone metabolism showed no clear relationship to the bone mineral density measurements. From few bone histology studies in humans and experimental studies there is evidence that a decreased bone formation is one major mechanism leading to reduced bone mass in diabetics. Microangiopathy at the bone tissue was also discussed as a possible reason for diabetic osteopenia. It was shown that insulin and insulin like growth factors (IGF-1, IGF-2) have an influence on bone metabolism itself and other growth factors, cytokines and hormones may determine changes in diabetic bone metabolism. Recent findings suggest that leptin is involved in the regulation of osteoblast function and bone mass, which is of special interest in diabetes mellitus type 2. The clinical relevance of osteoporosis or osteopenia is determined by the increased risk for insufficiency fractures. Few studies found an increased fracture risk, especially in older women with type 1 diabetes mellitus, while others did not show an increased risk for fractures or even found a decreased rate of fractures in women with diabetes mellitus type 2. There is a need for further longitudinal studies, including the incidence and risk factors for osteoporotic fractures. In clinical routine the extent of diagnostic and therapeutic activities in patients with type 1 or type 2 diabetes mellitus in respect to generalized bone disease or diabetic osteopenia should be based on individual conditions and risk profile for osteoporosis.
Exp Clin Endocrinol Diabetes 2001
PMID:Diabetes mellitus a risk for osteoporosis? 1146 May 94

Previous studies have demonstrated that insulin and IGF-1 both increase lumbar sympathetic nerve activity (LSNA) and decrease mean arterial pressure (MAP). We hypothesized that the peripheral responses to insulin and IGF-1 are mediated, at least in part, via the central nervous system. In this study we determined the effects of the peripheral administration of both insulin and IGF-1 on cardiovascular dynamics and LSNA following removal of the area postrema (APX), a major site of blood-brain communication. Insulin infusion in normal rats decreased MAP but increased HR and LSNA. When insulin was infused in APX rats it also decreased the MAP but the MAP recovered rapidly and plateaued at a level equivalent to normals after 40 min. Insulin significantly increased the HR and LSNA in the APX rats compared to normals. However, when hypoglycemia was prevented by glucose infusion, the HR and LSNA responses to insulin in the APX rats were similar to normals. IGF-1 also decreased MAP and to a greater extent in the APX rats compared to normals but the increased LSNA in APX rats was equivalent to normals. The APX rats when compared to normals had a greater sensitivity to insulin-induced hypoglycemia while IGF-1 decreased the plasma glucose to a lesser degree in APX rats. We conclude that insulin and IGF-1 entry into the CNS at least via the area postrema does not contribute significantly to the hypotensive response and that the greater depressor response to IGF-1 is likely due to enhanced vascular sensitivity in APX rats. The increased HR and LSNA following insulin were likely mediated by an increased reflexive response to hypoglycemia.
Int J Exp Diabetes Res 2000
PMID:The effect of the removal of the area postrema on insulin and IGF-1-induced cardiovascular and sympathetic nervous responses. 1146 91

The etiology of non-insulin-dependent diabetes mellitus (NIDDM) is complex and development is manifested by initial insulin resistance coupled with elevated insulin levels in the early diabetic state with concomitant increases in circulating levels of glucose and triglycerides. This is followed by a decline in insulin levels due to pancreatic exhaustion. Our results show that administration of DHEA-PC, a phosphocholine conjugate of dehydroepiandrosterone (DHEA), delayed the development of NIDDM symptoms and the onset of type 2 diabetes in the ZDF/Gmi-fa/fa rat model. The treatment consisted of weekly implantation of subdermal osmotic infusion pumps in the rats starting at 6 weeks of age (n = 5 animals per group). For the first three weeks the pumps delivered 6 mg/day/rat followed by 12 mg/day/rat for 1 week (control group pumps delivered only carrier vehicle) after which the pumps were removed. Plasma was collected weekly from day 0 through day 58, and glucose, triglycerides, cholesterol, insulin, IGF-1, and IGF-BP3 levels were measured. Data were analyzed by two-way ANOVA. Following 3 weeks of treatment with DHEA-PC, plasma glucose levels in the treated group remained low, 150+/-9 mg/dL, while the levels in the control animals steadily increased to 320+/-100 mg/dL (p < 0.05). After the DHEA-PC treatment ended, plasma glucose plateaued for 10 days and then took 25 days to reach the level in the control animals (p < 0.05). After 2 weeks of DHEA-PC treatment, plasma triglyceride levels in the treated group remained low, 85+/-24 mg/dL, while the level in the control rats increased to 180+/-35 mg/dL (p < 0.05). After the treatment was terminated triglyceride levels in the treated group increased to control levels within 2 days. Insulin, IGF-1, IGF-BP3, cholesterol, body weight, and food consumption were not changed by DHEA-PC treatment (p < 0.05). Therefore, the delay of increases in plasma glucose and triglycerides, caused by DHEA-PC, was not the result of differences in caloric intake, increased insulin, or increased IGF-1 levels. The data suggest that DHEA-PC delayed the onset of the two most important parameters of NIDDM, namely hyperglycemia and hypertriglyceridemia. (ZDF/Gmi-fa/fa rats and their care was supplied by contract with Genetic Models Inc., Indianapolis, IN.).
Diabetes Technol Ther 2001
PMID:DHEA-PC slows the progression of type 2 diabetes (non-insulin-dependent diabetes mellitus) in the ZDF/Gmi-fa/fa rat. 1147 28

Insulin is known to regulate pancreatic beta-cell function through the activation of cell surface insulin receptors, phosphorylation of insulin receptor substrate (IRS)-1 and -2, and activation of phosphatidylinositol (PI) 3-kinase. However, an acute effect of insulin in modulating beta-cell electrical activity and its underlying ionic currents has not been reported. Using the perforated patch clamp technique, we found that insulin (1-600 nmol/l) but not IGF-1 (100 nmol/l) reversibly hyperpolarized single mouse beta-cells and inhibited their electrical activity. The dose-response relationship for insulin yielded a maximal change (mean +/- SE) in membrane potential of -13.6 +/- 2.0 mV (P < 0.001) and a 50% effective dose of 25.9 +/- 0.1 nmol/l (n = 63). Exposing patched beta-cells within intact islets to 200 nmol/l insulin produced similar results, hyperpolarizing islets from -47.7 +/- 3.3 to -65.6 +/- 3.7 mV (P < 0.0001, n = 11). In single cells, insulin-induced hyperpolarization was associated with a threefold increase in whole-cell conductance from 0.6 +/- 0.1 to 1.7 +/- 0.2 nS (P < 0.001, n = 10) and a shift in the current reversal potential from -25.7 +/- 2.5 to -63.7 +/- 1.0 mV (P < 0.001 vs. control, n = 9; calculated K(+) equilibrium potential = -90 mV). The effects of insulin were reversed by tolbutamide, which decreased cell conductance to 0.5 +/- 0.1 nS and shifted the current reversal potential to -25.2 +/- 2.3 mV. Insulin-induced beta-cell hyperpolarization was sufficient to abolish intracellular calcium concentration ([Ca(2+)](i)) oscillations measured in pancreatic islets exposed to 10 mmol/l glucose. The application of 100 nmol/l wortmannin to inactivate PI 3-kinase, a key enzyme in insulin signaling, was found to reverse the effects of 100 nmol/l insulin. In cell-attached patches, single ATP-sensitive K(+) (K(ATP)) channels were activated by bath-applied insulin and subsequently inhibited by wortmannin. Our data thus demonstrate that insulin activates the K(ATP) channels of single mouse pancreatic beta-cells and islets, resulting in membrane hyperpolarization, an inhibition of electrical activity, and the abolition of [Ca(2+)](i) oscillations. We thus propose that locally released insulin might serve as a negative feedback signal within the islet under physiological conditions.
Diabetes 2001 Oct
PMID:Insulin activates ATP-sensitive K(+) channels in pancreatic beta-cells through a phosphatidylinositol 3-kinase-dependent pathway. 1157 97

To study the role that immediate early gene responses may play in impaired nerve fiber regeneration in diabetes, diabetic male BB/Wor rats were subjected to sciatic nerve crush at 6 wk of diabetes. Sciatic nerve mRNA expression of IGF-I, IGF-1-receptor, NGF, and p75 (low affinity NGF receptor), as well as protein expression of C-FOS, were examined at various time points following crush injury and compared with age- and sex-matched nondiabetic BB/Wor rats. Diabetic rats showed a delay in the early peak expression of IGF-1, C-FOS, NGF, and p75. The earliest immediate gene responses were those of IGF-I and IGF-1-receptor, which peaked at 0.5 h post-crush in control rats. In diabetic rats, IGF-1 peaked at 24 h whereas IGF-1-receptor mRNA revealed no early peak. The early NGF mRNA expression showed a maximum response at 6 h and of p75 at 4 days post-crush in control rats, whereas in diabetic rats they occurred at 2 days and 6 days, respectively. C-FOS protein expression showed a maximum at 6 h in control rats and in diabetic animals an attenuated peak was present at 2 days. These data provide the first evidence that immediate early gene responses are delayed in diabetes following sciatic nerve crush injury. The delayed IGF-1 expression may affect C-FOS induction and may be responsible for the delay in the NGF response in diabetic rats. The delayed immediate early gene responses precede the previously described perturbed macrophage recruitment and delayed Wallerian degeneration in this type I model and provide a possible explanation for impaired nerve regeneration in diabetes.
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PMID:Altered immediate early gene expression in injured diabetic nerve: implications in regeneration. 1158 28

Insulin and insulin-like growth factor (IGF) axes are major determinants of proliferation and apoptosis and thus may influence carcinogenesis. In various animal models, modulation of insulin and IGF-1 levels through various means, including direct infusion, energy excess or restriction, genetically induced obesity, dietary quality including fatty acid and sucrose content, inhibition of normal insulin secretion and pharmacologic inhibition of IGF-1, influences colonic carcinogenesis. Human evidence also associates high levels of insulin and IGF-1 with increased risk of colon cancer. Clinical conditions associated with high levels of insulin (noninsulin-dependent diabetes mellitus and hypertriglyceridemia) and IGF-1 (acromegaly) are related to increased risk of colon cancer, and increased circulating concentrations of insulin and IGF-1 are related to a higher risk of colonic neoplasia. Determinants and markers of hyperinsulinemia (physical inactivity, high body mass index, central adiposity) and high IGF-1 levels (tall stature) are also related to higher risk. Many studies indicate that dietary patterns that stimulate insulin resistance or secretion, including high consumption of sucrose, various sources of starch, a high glycemic index and high saturated fatty acid intake, are associated with a higher risk of colon cancer. Although additional environmental and genetic factors affect colon cancer, the incidence of this malignancy was invariably low before the technological advances that rendered sedentary lifestyles and obesity common, and increased availability of highly processed carbohydrates and saturated fatty acids. Efforts to counter these patterns are likely to have the most potential to reduce colon cancer incidence, as well as cardiovascular disease and diabetes mellitus.
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PMID:Insulin, insulin-like growth factors and colon cancer: a review of the evidence. 1216 83

A mesenchymal factor(s) is believed to modulate the development of the embryonic pancreas. However, the identity of this factor(s) remains elusive. Its importance in the development of the endocrine cells of the pancreas, particularly insulin cells, is considered. Our studies seek to identify factors that may influence insulin cell proliferation and differentiation, and hence may have positive implications for patients suffering from diabetes. Our experiments are based on the in vitro model which utilised the 5-day dorsal pancreatic bud of the chick embryo. These buds, devoid of most of their mesenchyme, are cultured on Matrigel in a serum-free medium for 7 days. We have investigated the effects of retinoic acid, retinoic acid in combination with IGF-1, nicotinamide and activin in this system. While most of these factors increased the proportion of insulin cells over that of their respective controls, as yet none have matched or exceeded the proportion of insulin cells demonstrated in vivo.
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PMID:The quest for factors regulating the development of chick embryonic insulin cells in vitro. 1172 89

Puberty is characterised by important physiological and hormonal changes. In type 1 diabetes, abnormalities in the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis play a important role. Spontaneous hyper-GH secretion arises, with reduced circulating IGF-1 levels, both leading to a reduction in insulin sensitivity. From a clinical point of view, these abnormalities are linked to a deterioration glycaemic control, often more marked in females (in whom the degree of insulin resistance during puberty seems to be higher). These abnormalities in the GH/IGF-1 axis in may constitute a risk for the development of microangiopathic complications. Optimisation of insulin therapy has practical limitations and intensification of insulin therapy poses problems (weight gain, nocturnal hypoglycaemia). Several alternative therapeutic approaches have been explored to restore insulin sensitivity, either through a direct effect on the GH/IGF-1 axis, or through drugs with a direct insulin sensitivity effect, but all these approaches remain to be confirmed and the safety and acceptability of these treatments to be established on a long-term basis.
Diabetes Metab 2001 Sep
PMID:Metabolic impact of puberty on the course of type 1 diabetes. 1178 32

Resistance to insulin-like growth factor I (IGF-1)-induced cardiac contractile response has been reported in diabetes. To evaluate the role of prediabetic insulin resistance to cardiac IGF-1 resistance, whole body insulin resistance was generated with dietary sucrose and contractile function was evaluated in ventricular myocytes. Mechanical properties were evaluated using an IonOptix system and intracellular Ca(2+) transients were measured as changes in fura-2 fluorescence intensity (Delta FFI). After 8 weeks of feeding, sucrose rats displayed euglycemia, hepatomeglay and normal heart size, and glucose intolerance, confirming the presence of insulin resistance. Myocytes from sucrose-fed rats displayed decreased peak shortening (PS), reduced resting FFI, increased intracellular Ca(2+) clearing, associated with normal duration of shortening and relengthening compared to myocytes from starch-fed rats. IGF-1 (10(-10)-10(-6) M) caused a similar concentration-dependent decrease in PS in both groups. Only the highest concentration of IGF-1 elicited an inhibition on Delta FFI in sucrose myocytes. In addition, the IGF-1-induced response was abolished by the IGF-1 receptor antagonist H-1356 in both groups, and by the nitric oxide synthase inhibitor L-NAME in starch but not sucrose myocytes. These results indicated prediabetic insulin resistance alters cardiac contractile function at the myocytes level, but may not be permissive to cardiac contractile resistance to IGF-1.
Diabetes Res Clin Pract 2002 Feb
PMID:Prediabetic insulin resistance is not permissive to the development of cardiac resistance to insulin-like growth factor I in ventricular myocytes. 1179 74

Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-alpha and 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GRalpha and 11beta-HSD1 expression in skeletal myoblasts from men (n = 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. Positive associations were evident between myoblast expression of GRalpha under basal conditions and levels of insulin resistance (r(2) = 0.34, P < 0.05), BMI (r(2) = 0.49, P < 0.01), percent body fat (r(2) = 0.34, P < 0.02), and blood pressure (r(2) = 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GRalpha expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11beta-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r(2) = 0.68, P < 0.001), BMI (r(2) = 0.63, P < 0.005), and blood pressure (r(2) = 0.27, P < 0.05). Regulation of GRalpha and 11beta-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GRalpha and 11beta -HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.
Diabetes 2002 Apr
PMID:Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. 1191 27


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