Type 2 diabetes is characterized by impaired insulin secretion. Some but not all studies suggest that a decrease in beta-cell mass contributes to this. We examined pancreatic tissue from 124 autopsies: 91 obese cases (BMI >27 kg/m(2); 41 with type 2 diabetes, 15 with impaired fasting glucose [IFG], and 35 nondiabetic subjects) and 33 lean cases (BMI <25 kg/m(2); 16 type 2 diabetic and 17 nondiabetic subjects). We measured relative beta-cell volume, frequency of beta-cell apoptosis and replication, and new islet formation from exocrine ducts (neogenesis). Relative beta-cell volume was increased in obese versus lean nondiabetic cases (P = 0.05) through the mechanism of increased neogenesis (P < 0.05). Obese humans with IFG and type 2 diabetes had a 40% (P < 0.05) and 63% (P < 0.01) deficit and lean cases of type 2 diabetes had a 41% deficit (P < 0.05) in relative beta-cell volume compared with nondiabetic obese and lean cases, respectively. The frequency of beta-cell replication was very low in all cases and no different among groups. Neogenesis, while increased with obesity, was comparable in obese type 2 diabetic, IFG, or nondiabetic subjects and in lean type 2 diabetic or nondiabetic subjects. However, the frequency of beta-cell apoptosis was increased 10-fold in lean and 3-fold in obese cases of type 2 diabetes compared with their respective nondiabetic control group (P < 0.05). We conclude that beta-cell mass is decreased in type 2 diabetes and that the mechanism underlying this is increased beta-cell apoptosis. Since the major defect leading to a decrease in beta-cell mass in type 2 diabetes is increased apoptosis, while new islet formation and beta-cell replication are normal, therapeutic approaches designed to arrest apoptosis could be a significant new development in the management of type 2 diabetes, because this approach might actually reverse the disease to a degree rather than just palliate glycemia.

https://diabetes.diabetesjournals.org/content/diabetes/52/1/102.full.pdf

β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

https://gut.bmj.com/content/gutjnl/66/1/6.full.pdf

Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

/pdf/from-the-triumvirate-to-the-ominous-octet-a-new-paradigm-for-4dfkm05iuh.pdf

From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

Pathogenesis of type 2 diabetes mellitus

Infection of the gastric antrum by Helicobacter pylori is characterised by a cellular inflammatory infiltrate. Whether cytokines are involved in the pathogenesis of this gastritis has been investigated by studying the effect of eradicating H pylori on the expression of genes encoding the cytokines interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in the antral mucosa. Gastric antral biopsy specimens were taken from nine patients with duodenal ulcers and cytokine transcripts were identified and quantified by northern blotting. After H pylori had been eradicated the chronic inflammatory infiltrate decreased in all the patients and the polymorphonuclear infiltrate virtually disappeared. Expression of genes also decreased. After eradication, the median TNF-alpha mRNA/rRNA fell to 48% (p = 0.02) and the median IL-8 mRNA/rRNA fell to 5% (p = 0.004) of initial values. These results support the role of increased synthesis of these cytokines in the pathogenesis of the gastritis.

https://gut.bmj.com/content/gutjnl/35/11/1567.full.pdf

Cytokine gene expression in Helicobacter pylori associated antral gastritis.

The intestinal basolateral membrane Ca(2+)-transporting adenosinetriphosphatase is the energy-dependent step in the absorption of dietary Ca2+ by the vitamin D-dependent transcellular pathway. Mult...

Human and rat intestinal plasma membrane calcium pump isoforms

https://www.gastrojournal.org/article/S0016-5085(97)00371-5/pdf

Differences in expression of homeobox transcription factors in proximal and distal human small intestine

The plasma membrane Ca(2+)-pumping adenosinetriphosphatase (PMCA) is the energy-dependent step in the active vitamin D-dependent absorption of dietary Ca2+ by the enterocyte. Studies of the various PMCA genes and splicing variants in humans and rats have indicated that the isoform known as PMCA1b is the predominant form expressed in small intestine. Using an oligonucleotide probe, we have studied the regional and cellular distribution of PMCA1 transcripts in rabbit intestinal tissues by in situ hybridization. On small intestinal RNA blots, this hybridized to species similar in size to those detected by PMCA1-specific cDNA probes; an additional larger transcript was present in rabbit than in rat or human. In situ hybridization signals were principally in the enterocyte population of the mucosa and were maximal in differentiating enterocytes on the lower part of the villus, a pattern similar to that previously demonstrated for other nutrient transporters. Reflecting the capacity of the different small intestinal segments to transport Ca2+, much higher levels of transcript were detected by both methods proximally (in duodenum) than distally (in jejunum and ileum) and were also higher in cecum and ascending colon mucosa than in descending colon. We conclude that as enterocytes differentiate in regions that absorb Ca2+, they express high levels of mRNA for PMCA1. These results confirm the importance of transcriptional regulation of this gene for active Ca2+ absorption.

Cellular and regional expression of transcripts of the plasma membrane calcium pump PMCA1 in rabbit intestine.

https://www.gastrojournal.org/article/S0016-5085(97)00281-3/pdf

The effect of gastrin-releasing peptide on gastrin and somatostatin messenger RNAs in humans infected with Helicobacter pylori

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