Diabetes
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Review Randomized Controlled Trial Multicenter Study Clinical Trial
Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy.
Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. ⋯ A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM.
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Comparative Study
Dietary cow's milk protein does not alter the frequency of diabetes in the BB rat.
One theory of the pathogenesis of IDDM proposes that exposure to cow's milk proteins triggers the disease in genetically susceptible individuals. We tested this hypothesis in the BB/Wor rat model of human IDDM. Diabetes-prone (DP) BB/Wor rats spontaneously develop IDDM. ⋯ In contrast, there was no relationship between diet and susceptibility of DR-BB/Wor rats to IDDM induction. However, the methods used to induce IDDM in DR-BB/Wor animals were found to induce antibodies against BSA. We conclude the following: 1) Dietary modification can reduce spontaneous IDDM expression in DP-BB/Wor rats, but the agent of protection is not elimination of cow's milk protein. 2) The addition of BSA or intact milk protein does not abrogate the effectiveness of a protective diet. 3) The genetic susceptibility of the DR-BB/Wor rat to autoimmune diabetes is unaffected by any of the tested diets, but a role of anti-BSA-like autoreactivity in IDDM expression cannot be excluded.
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Defective glucagon secretion during hypoglycemia is characteristic of long-standing type I diabetes. To determine whether this defect can be corrected by successful intrahepatic islet transplantation, we performed studies of hypoglycemia in four nondiabetic patients with chronic pancreatitis who had undergone total pancreatectomy and successful intrahepatic islet autotransplantation, in two type I diabetic recipients of successful intrahepatic islet allotransplantation, and in matched control subjects. We examined 1) whether intrahepatic islet autotransplantation provides glucagon secretion during prolonged periods of hypoglycemia and 2) whether intrahepatic islet allotransplantation in type I diabetic patients and consequent long-term normoglycemia reestablishes native alpha-cell responses to hypoglycemia. ⋯ In contrast, both allo- and autograft recipients had glucagon responses to intravenous arginine. These data uniquely demonstrate that: 1) intrahepatic islet transplant grafts secrete glucagon in response to arginine, but fail to secrete glucagon in response to sustained hypoglycemia; and 2) the restoration of sustained normoglycemia for over 2 years in type I diabetic patients may not reestablish glucagon responses from the native pancreas during hypoglycemia. Transplantation sites other than the liver may be required to achieve normal glucagon secretion from the transplanted islets.
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Comparative Study
The defective glucagon response from transplanted intrahepatic pancreatic islets during hypoglycemia is transplantation site-determined.
The optimal site for pancreatic islet cell transplantation is presently unclear, although the liver has been the most commonly used. However, glucagon secretion from islets that have been autotransplanted in liver has been reported to be unresponsive to hypoglycemia yet responsive to arginine. To determine whether this selective glucagon secretory defect is related to the intrahepatic site of islet implantation or to the process of transplantation per se, we studied counterregulatory responses to hypoglycemia in dogs with pancreatic islet autotransplantation in the hepatic parenchyma (the intrahepatic [IH] group, n = 9) or the peritoneal cavity (the intraperitoneal [IP] group, n = 9), following total pancreatectomy, and compared them with the responses in normal controls (n = 10). ⋯ Epinephrine responses to hypoglycemia were similar in all groups, whereas neither of the transplanted groups (IH and IP) had pancreatic polypeptide responses. There was a prompt rise in plasma glucagon after intravenous arginine in all groups. These data indicate that glucagon unresponsiveness to hypoglycemia is specific to intrahepatically transplanted islets, rendering the liver a disadvantageous site for optimal alpha-cell function.
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The kallikrein-kinin system (KKS) has been postulated to play a role in modulation of hemodynamic function in diabetes and to contribute to the hemodynamic effects of angiotensin-converting enzyme inhibition (CEI). To further explore the KKS and its interactions with the renin-angiotensin system (RAS), studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic rats. In protocol 1, control and diabetic rats were studied before and after administration of one of two dissimilar B2 kinin receptor antagonists (BK2As), or vehicle. ⋯ These studies suggest that the endogenous KKS has only a minor role in modulation of renal hemodynamics in the euvolemic diabetic rat, in the absence of KKS stimulation by CEI. However, angiotensin-converting enzyme is also kininase II, which serves to increase endogenous kinin activity. The increased kinin activity resulting from CEI treatment may participate, to a modest degree, in hemodynamic regulation of the diabetic kidney.