During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, while prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing β-cells1–3. However, the exact mechanisms by which the lactogenic hormones drive β-cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to drive β-cell proliferation. Serotonin synthetic enzyme Tph1 and serotonin production increased sharply in β-cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked β-cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Gαq-linked serotonin receptor Htr2b in maternal islets increased during pregnancy and normalized just prior to parturition, while expression of the Gαi-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked β-cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking β-cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes4.

Impaired insulin secretion and insulin resistance are a characteristic feature of Type II (non-insulin-dependent) diabetes mellitus [1,2]. In spite of extensive studies on the pathophysiology of diabetes, islet pathology and its pathogenesis remain controversial.Classical studies using histochemical methods to identify endocrine cells have reported varying results, including the severe loss of beta cells [3], modest changes with amyloid deposition [4,5] and even no change of islet beta-cell population [6]. Immunohistochemical techniques for the identification of specific populations of islet endocrine cells, showed a nearly 50 % reduction in beta-cell volume density in European Type II non-obese diabetic patients compared with non-diabetic control subjects [7]. Other studies have reported a 24 % reduction of islet beta-cell area density, a 58 % increase in A cell area density and a deposition of amyloid that correlated with the severity of islet pathology [8]. In another study of European Type II diabetic patients, a separate research group has reported Diabetologia (2002) Reduced beta-cell mass and expression of oxidative stress-related DNA damage in the islet of Japanese Type II diabetic patients Abstract Aims/hypothesis. We examined the pancreatic islet lesions in Japanese patients with Type II diabetes mellitus to determine if the damage was related to oxidative stress. Methods. Morphometric analyses were performed on immunostained sections of the tail portion of the pancreas from 14 diabetic and 15 non-diabetic patients. Amyloid deposition and oxidative stress-induced tissue damage were evaluated by Congo-red staining and immunostaining. Resistance to oxidative stress was assessed from immunostaining results for Cu, Zn-superoxide dismutase (SOD). Expression of (pro)insulin mRNA was assessed by in situ hybridisation. Results. The pancreas from diabetic patients had amyloid deposition in about 15 % of the islets, intensified reactions of 8-OHdG and HNE, as well as reduced expression of SOD. Islet volume density of beta cells and total beta-cell mass in the pancreas from diabetic patients were reduced by 22 % (p < 0.001) and 30 % (p < 0.05). Islet volume density and total mass of (pro)insulin mRNA-positive cells were similarly reduced in diabetic patients by 22 % (p < 0.001) and 39 % (p < 0.05), respectively. Islet volume density of A cells was increased by 20 % (p < 0.001) but total mass did not change. There were no changes in volume densities of islet, D and PP cells. Reduced beta-cell volume density correlated with increased positive staining of 8-OHdG. Conclusion/interpretation. Japanese Type II diabetic patients show a reduction of beta-cell mass and evidence of increased oxidative stress-related tissue damage that is correlated with the extent of the beta-cell lesions. [Diabetologia (2002) 45: 85±96]

Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end‐products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ‐specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long‐term hyperglycemia are critical for peripheral nerve damage, resulting in distal‐predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00070.x, 2010)

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Diabetic neuropathy is the commonest form of peripheral neuropathy in the developed countries of the world. In diabetic patients, the presence of peripheral neuropathy increases their risks for developing foot ulceration and subsequent necrosis that necessitates lower limb amputation. Although the precise mechanisms underlying diabetic neuropathy remain unclear, there is evidence that hyperglycemia-induced formation of advanced glycation end products (AGEs) is related to diabetic neuropathy; AGE-modified peripheral nerve myelin is susceptible to phagocytosis by macrophages and contributes to segmental demyelination; modification of major axonal cytoskeletal proteins such as tubulin, neurofilament, and actin by AGEs results in axonal atrophy/degeneration and impaired axonal transport; and glycation of extracellular matrix protein laminin leads to impaired regenerative activity in diabetic neuropathy. Recently, the receptor for AGEs (RAGE) has been found to colocalize with AGEs in diabetic peripheral nerves. This suggests that, in diabetic neuropathy, AGEs and AGE/RAGE interactions induce oxidative stress, result in upregulation of nuclear factor (NF)-kappaB and various NF-kappaB-mediated proinflammatory genes, and exaggerate neurological dysfunction, including altered pain sensation. Additionally, AGE/RAGE-induced oxidative stress further accelerates formation of glycoxidation products such as Nepsilon-(carboxymethyl)lysine and pentosidine. Although new drugs that inhibit the formation of AGEs and block the AGE-RAGE interaction are being studied, no effective treatment modalities against AGE-induced nerve injury are currently available clinically. A therapeutic strategy to prevent and ameliorate diabetic neuropathy using anti-AGE agents needs to be established. In this review, the current issues involved in the role of the glycation process and the potential treatment options for diabetic neuropathy are explored.